FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Tipre, DN Lu, JQ Fujita, M Ichise, M Vines, D Innis, RB AF Tipre, DN Lu, JQ Fujita, M Ichise, M Vines, D Innis, RB TI Radiation dosimetry estimates for the PET serotonin transporter probe C-11-DASB determined from whole-body imaging in non-human primates SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE C-11-DASB; serotonin transporter; dosimetry; whole-body biodistribution; PET; positron emission tomography ID DEPRESSION; DISORDER AB The radiotracer 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile labelled in the N-methyl position (C-11-DASB) is a selective radioligand for the in vivo quantification of serotonin transporters (SERTs) using positron emission tomography (PET). The current study quantified the distribution of activity in two rhesus monkeys after the injection of approximately 333 MBq (9 mCi) C-11-DASB. Whole-body images were acquired at 22 time points for a total of 120 min following injection of the radioligand. Source organs were identified at each time point from both tomographic images (using multiple regions of interest on each tomograph for each organ) and a single planar image (using a single region of interest for each organ). The peak activities in planar images in the five identified source organs (expressed as per cent injected dose (ID)) were lungs (24% ID at 1.5 min), kidneys (6.5% ID at 4 min), liver (8% ID at 3 min), brain (4% ID at 5 min) and spleen (0.42% ID at 3 min). Mono-exponential fitting of activity overlying the bladder suggested that approximately 14% of activity was excreted via the urine. The radiation burden to the body was calculated from residence times of these source organs and then scaled to corresponding human values. The calculated effective dose from tomographic and planar images was 6.0 and 6.4 muGy(.)MBq(-1) (22.3 and 23.7 mrad(.)mCi(-1)), respectively. The planar analysis was much easier to perform, and generally yielded slightly higher (i.e., more conservative) estimates of radiation burden than the tomographic analysis. The estimated radiation burden of C-11-DASB is relatively modest and would allow multiple scans per research subject per year. ((C) 2004 Lippincott Williams Wilkins). C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Tipre, DN (reprint author), NIMH, Mol Imaging Branch, Bldg 1,Rm B3-10,1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. EM TipreD@intra.nimh.nih.gov NR 12 TC 19 Z9 19 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0143-3636 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD JAN PY 2004 VL 25 IS 1 BP 81 EP 86 DI 10.1097/01.mnm.0000109363.12233.a5 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 814GF UT WOS:000220962500011 PM 15061269 ER PT J AU Zhang, Y Dufau, ML AF Zhang, Y Dufau, ML TI Gene silencing by nuclear orphan receptors SO NUCLEAR RECEPTOR COREGULATORS SE VITAMINS AND HORMONES-ADVANCES IN RESEARCH AND APPLICATIONS LA English DT Review ID ADRENAL HYPOPLASIA CONGENITA; PROMOTER-TRANSCRIPTION FACTOR; RETINOIC ACID RECEPTOR; LUTEINIZING-HORMONE RECEPTOR; LIGAND-BINDING DOMAIN; MULLERIAN-INHIBITING SUBSTANCE; SMALL-HETERODIMER-PARTNER; COUP-TF-II; ACTIVATED ESTROGEN-RECEPTORS; NEGATIVE FEEDBACK-REGULATION AB Nuclear orphan receptors represent a large and diverse subgroup in the nuclear receptor superfamily. Although putative ligands for these orphan members remain to be identified, some of these receptors possess intrinsic activating, inhibitory, or dual regulatory functions in development, differentiation, homeostasis, and reproduction. In particular, gene-silencing events elicited by chicken ovalbumin upstream promoter-transcription factors (COUP-TFs); dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1); germ cell nuclear factor (GCNF); short heterodimer partner (SHP); and testicular receptors 2 and 4 (TR2 and TR4) are among the best characterized. These orphan receptors are critical in controlling basal activities or hormonal responsiveness of numerous target genes. They employ multiple and distinct mechanisms to mediate target gene repression. Complex cross-talk exists between these orphan receptors at their cognate DNA binding elements and an array of steroid/nonsteroid hormone receptors, other transcriptional activators, coactivators and corepressors, histone modification enzyme complexes, and components of basal transcriptional components. Therefore, perturbation induced by these orphan receptors at multiple levels, including DNA binding activities, receptor homo- or hetero-dimerization, recruitment of cofactor proteins, communication with general transcriptional machinery, and changes at histone acetylation status and chromatin structures, may contribute to silencing of target gene expression in a specific promoter or cell-type context. Moreover, the findings derived from gene-targeting studies have demonstrated the significance of these orphan receptors' function in physiologic settings. Thus, COUP-TFs, DAX-1, GCNF, SHP, and TR2 and 4 are known to be required for multiple physiologic and biologic functions, including neurogenesis and development of the heart and vascular system steroidogenesis and sex determination, gametogenesis and embryonic development, and cholesterol/lipid homeostasis. (C) 2004 Elsevier Inc. C1 NIH, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), NIH, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. NR 224 TC 33 Z9 34 U1 1 U2 6 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0083-6729 J9 VITAM HORM PY 2004 VL 68 BP 1 EP 48 PG 48 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA BAO82 UT WOS:000223083600001 PM 15193450 ER PT B AU Cho-Chung, YS AF Cho-Chung, YS BE Gewirtz, AM TI Antisense protein kinase A-RI alpha restores normal signal transduction signatures to inhibit tumor growth SO NUCLEIC ACID THERAPEUTICS IN CANCER SE CANCER DRUG DISCOVERY AND DEVELOPMENT LA English DT Proceedings Paper CT Meeting on Nucleic Acid Therapeutics in Cancer CY APR, 2000 CL Bryn Mawr, PA SP Doris Duke Charitable Fdn, Univ Penn, Canc Ctr ID MAMMARY EPITHELIAL-CELLS; RII(BETA) REGULATORY SUBUNIT; SELECTIVE CAMP ANALOGS; AMP BINDING-PROTEINS; BREAST-CANCER CELLS; CYCLIC-AMP; GENE-EXPRESSION; OVARIAN-CANCER; NUCLEAR TRANSLOCATION; MULTIDRUG-RESISTANCE C1 NCI, Cellular Biochem Sect, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Bethesda, MD 20892 USA. NR 75 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 1-58829-258-4 J9 CANC DRUG DISC DEV JI Canc. Drug. Disc. Dev. PY 2004 BP 199 EP 212 PG 14 WC Biotechnology & Applied Microbiology; Oncology SC Biotechnology & Applied Microbiology; Oncology GA BAB49 UT WOS:000221470600015 ER PT J AU Frith, MC Hansen, U Spouge, JL Weng, ZP AF Frith, MC Hansen, U Spouge, JL Weng, ZP TI Finding functional sequence elements by multiple local alignment SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA REGULATORY MOTIFS; FACTOR-BINDING SITES; RESPONSE ELEMENTS; GENOME; IDENTIFICATION; CONSERVATION; INFORMATION; STATISTICS; DROSOPHILA; ALGORITHM AB Algorithms that detect and align locally similar regions of biological sequences have the potential to discover a wide variety of functional motifs. Two theoretical contributions to this classic but unsolved problem are presented here: a method to determine the width of the aligned motif automatically; and a technique for calculating the statistical significance of alignments, i.e. an assessment of whether the alignments are stronger than those that would be expected to occur by chance among random, unrelated sequences. Upon exploring variants of the standard Gibbs sampling technique to optimize the alignment, we discovered that simulated annealing approaches perform more efficiently. Finally, we conduct failure tests by applying the algorithm to increasingly difficult test cases, and analyze the manner of and reasons for eventual failure. Detection of transcription factor-binding motifs is limited by the motifs' intrinsic subtlety rather than by inadequacy of the alignment optimization procedure. C1 Boston Univ, Bioinformat Program, Boston, MA 02215 USA. Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. Boston Univ, Dept Biol, Boston, MA 02215 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Spouge, JL (reprint author), Boston Univ, Bioinformat Program, 44 Cummington St, Boston, MA 02215 USA. EM spouge@ncbi.nlm.nih.gov; zhiping@bu.edu OI Frith, Martin/0000-0003-0998-2859 FU NCI NIH HHS [R01 CA081157, R01 CA081157-05, R01-CA81157]; NIGMS NIH HHS [P20 GM066401, 1P20GM066401-01] NR 44 TC 106 Z9 114 U1 0 U2 5 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 JAN PY 2004 VL 32 IS 1 BP 189 EP 200 DI 10.1093/nar/gkh169 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774NE UT WOS:000188988700035 PM 14704356 ER PT J AU Graziewicz, MA Sayer, JM Jerina, DM Copeland, WC AF Graziewicz, MA Sayer, JM Jerina, DM Copeland, WC TI Nucleotide incorporation by human DNA polymerase gamma opposite benzo[a]pyrene and benzo[c]phenanthrene diol epoxide adducts of deoxyguanosine and deoxyadenosine SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RAT-LIVER MITOCHONDRIA; MUTATIONAL CONSEQUENCES; INSERTION FIDELITY; SEQUENCE CONTEXT; ESCHERICHIA-COLI; PRIMER-EXTENSION; NUCLEAR-DNA; IN-VITRO; BENZOPYRENE; BENZO(A)PYRENE AB Mitochondria are major cellular targets of benzo[a]pyrene (BaP), a known carcinogen that also inhibits mitochondrial proliferation. Here, we report for the first time the effect of site-specific N-2-deoxyguanosine (dG) and N-6-deoxyadenosine (dA) adducts derived from BaP 7,8-diol 9,10-epoxide (BaP DE) and dA adducts from benzo[c]phenanthrene 3,4-diol 1,2-epoxide (BcPh DE) on DNA replication by exonuclease-deficient human mitochondrial DNA polymerase (pol gamma) with and without the p55 processivity subunit. The catalytic subunit alone primarily misincorporated dAMP and dGMP opposite the BaP DE-dG adducts, and incorporated the correct dTMP as well as the incorrect dAMP opposite the DE-dA adducts derived from both BaP and BcPh. In the presence of p55 the polymerase incorporated all four nucleotides and catalyzed limited translesion synthesis past BaP DE-dG adducts but not past BaP or BcPh DE-dA adducts. Thus, all these adducts cause erroneous purine incorporation and significant blockage of further primer elongation. Purine misincorporation by pol gamma opposite the BaP DE-dG adducts resembles that observed with the Y family pol eta. Blockage of translesion synthesis by these DE adducts is consistent with known BaP inhibition of mitochondrial (mt)DNA synthesis and suggests that continued exposure to BaP reduces mtDNA copy number, increasing the opportunity for repopulation with pre-existing mutant mtDNA and a resultant risk of mitochondrial genetic diseases. C1 NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov NR 50 TC 39 Z9 39 U1 0 U2 8 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 JAN PY 2004 VL 32 IS 1 BP 397 EP 405 DI 10.1093/nar/gkh213 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774NE UT WOS:000188988700057 PM 14729924 ER PT J AU Jeong, HS Backlund, PS Chen, HC Karavanov, AA Crouch, RJ AF Jeong, HS Backlund, PS Chen, HC Karavanov, AA Crouch, RJ TI RNase H2 of Saccharomyces cerevisiae is a complex of three proteins SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RIBONUCLEASE-H; DNA-REPLICATION; SUBSTRATE-SPECIFICITY; CRITHIDIA-FASCICULATA; ESCHERICHIA-COLI; YEAST; HII; TYPE-2; GENES; IDENTIFICATION AB The composition of RNase H2 has been a long-standing problem. Whereas bacterial and archaeal RNases H2 are active as single polypeptides, the Saccharomyces cerevisiae homolog, Rnh2Ap, when expressed in Escherichia coli, fails to produce an active RNase H2. By affinity chromatography purification and identification of polypeptides associated with a tagged S.cerevisiae Rnh2Ap, we obtained a complex of three proteins (Rnh2Ap, Ydr279p and Ylr154p) that together are necessary and sufficient for RNase H2 activity. Deletion of the gene encoding any one of the proteins or mutations in the catalytic site in Rnh2A led to loss of RNase H2 activity. Even when S.cerevisiae RNase H2 is catalytically compromised, it still exhibits a preference for cleavage of the phosphodiester bond on the 5' side of a ribonucleotide-deoxyribonucleotide sequence in substrates mimicking RNA-primed Okazaki fragments or a single ribonucleotide embedded in a duplex DNA. Interestingly, Ydr279p and Ylr154p have homologous proteins only in closely related species. The multisubunit nature of S.cerevisiae RNase H2 may be important both for structural purposes and to provide a means of interacting with other proteins involved in DNA replication/repair and transcription. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Ciphergen Biosyst Inc, Fremont, CA 94555 USA. RP Crouch, RJ (reprint author), NICHHD, Mol Genet Lab, NIH, Bldg 6B,Room 2B-231, Bethesda, MD 20892 USA. EM robert_crouch@nih.gov NR 36 TC 47 Z9 52 U1 0 U2 2 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 JAN PY 2004 VL 32 IS 2 BP 407 EP 414 DI 10.1093/nar/gkh209 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774NH UT WOS:000188989000010 PM 14734815 ER PT J AU Shchyolkina, AK Kaluzhny, DN Borisova, OF Hawkins, ME Jernigan, RL Jovin, TM Arndt-Jovin, DJ Zhurkin, VB AF Shchyolkina, AK Kaluzhny, DN Borisova, OF Hawkins, ME Jernigan, RL Jovin, TM Arndt-Jovin, DJ Zhurkin, VB TI Formation of an intramolecular triple-stranded DNA structure monitored by fluorescence of 2-aminopurine or 6-methylisoxanthopterin SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PTERIDINE NUCLEOSIDE ANALOGS; GENETIC-RECOMBINATION; ETHIDIUM-BROMIDE; BASE STACKING; ABASIC SITES; ACTIVE-SITE; PARALLEL; COMPLEX; CONFORMATION; SEQUENCE AB The parallel (recombination) 'R-triplex' can accommodate any nucleotide sequence with the two identical DNA strands in parallel orientation. We have studied oligonucleotides able to fold back into such a recombination-like structure. We show that the fluorescent base analogs 2-aminopurine (2AP) and 6-methylisoxanthopterin (6MI) can be used as structural probes for monitoring the integrity of the triple-stranded conformation and for deriving the thermodynamic characteristics of these structures. A single adenine or guanine base in the third strand of the triplex-forming and the control oligonucleotides, as well as in the double-stranded (ds) and single-stranded (ss) reference molecules, was substituted with 2AP or 6MI. The 2AP*(T.A) and 6MI*(C.G) triplets were monitored by their fluorescence emission and the thermal denaturation curves were analyzed with a quasi-two-state model. The fluorescence of 2AP introduced into an oligonucleotide sequence unable to form a triplex served as a negative control. We observed a remarkable similarity between the thermodynamic parameters derived from melting of the secondary structures monitored through absorption of all bases at 260 nm or from fluorescence of the single base analog. The similarity suggests that fluorescence of the 2AP and 6MI base analogs may be used to monitor the structural disposition of the third strand. We consider the data in the light of alternative 'branch migration' and 'strand exchange' structures and discuss why these are less likely than the R-type triplex. C1 Max Planck Inst Biophys Chem, Dept Mol Biol, D-37070 Gottingen, Germany. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. NCI, NIH, Bethesda, MD 20892 USA. RP Arndt-Jovin, DJ (reprint author), Max Planck Inst Biophys Chem, Dept Mol Biol, D-37070 Gottingen, Germany. EM djovin@gwdg.de RI Jernigan, Robert/A-5421-2012; Kaluzhny, Dmitry/G-7256-2014 NR 37 TC 24 Z9 24 U1 0 U2 8 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 JAN PY 2004 VL 32 IS 2 BP 432 EP 440 DI 10.1093/nar/gkh158 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774NH UT WOS:000188989000013 PM 14739235 ER PT J AU Ling, Y Sankpal, UT Robertson, AK McNally, JG Karpova, T Robertson, KD AF Ling, Y Sankpal, UT Robertson, AK McNally, JG Karpova, T Robertson, KD TI Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAMMALIAN DEVELOPMENT; P53 ACTIVITY; C-JUN; METHYLATION; FAMILY; GENE; CHROMATIN; PIAS1; EXPRESSION; RECEPTOR AB The de novo DNA methyltransferase Dnmt3a is one of three mammalian DNA methyltransferases that has been shown to play crucial roles in embryonic development, genomic imprinting and transcriptional silencing. Despite its importance, very little is known about how the enzymatic activity and transcriptional repression functions of Dnmt3a are regulated. Here we show that Dnmt3a interacts with multiple components of the sumoylation machinery, namely the E2 sumo conjugating enzyme Ubc9 and the E3 sumo ligases PIAS1 and PIASxalpha, all of which are involved in conjugating the small ubiquitin-like modifier polypeptide, SUMO-1, to its target proteins. Dnmt3a is modified by SUMO-1 in vivo and in vitro and the region of Dnmt3a responsible for interaction maps to the N-terminal regulatory domain. Functionally, sumoylation of Dnmt3a disrupts its ability to interact with histone deacetylases (HDAC1/2), but not with another interaction partner, Dnmt3b. Conditions that enhance the sumoylation of Dnmt3a in vivo abolish its capacity to repress transcription. These studies reveal a new level of regulation governing Dnmt3a whereby a post-translational modification can dramatically regulate its interaction with specific protein partners and alter its ability to repress transcription. C1 NCI, Fluorescence Imaging Grp, LRBGE, NIH, Bethesda, MD 20892 USA. NCI, Epigenet Gene Regulat & Canc Sect, LRBGE, NIH, Bethesda, MD 20892 USA. RP Robertson, KD (reprint author), NCI, Fluorescence Imaging Grp, LRBGE, NIH, Bldg 41,41 Lib Dr, Bethesda, MD 20892 USA. EM robertk@mail.nih.gov NR 52 TC 89 Z9 95 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2004 VL 32 IS 2 BP 598 EP 610 DI 10.1093/nar/gkh195 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774NH UT WOS:000188989000031 PM 14752048 ER PT J AU Sismour, AM Lutz, S Park, JH Lutz, MJ Boyer, PL Hughes, SH Benner, SA AF Sismour, AM Lutz, S Park, JH Lutz, MJ Boyer, PL Hughes, SH Benner, SA TI PCR amplification of DNA containing non-standard base pairs by variants of reverse transcriptase from Human Immunodeficiency Virus-1 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID POLYMERASE-I; ESCHERICHIA-COLI; GENETIC ALPHABET; ENZYMATIC INCORPORATION; RESISTANCE; REPLICATION; RECOGNITION; XANTHOSINE; SEQUENCE; CRYSTAL AB As the next step towards generating a synthetic biology from artificial genetic information systems, we have examined variants of HIV reverse transcriptase (RT) for their ability to synthesize duplex DNA incorporating the non-standard base pair between 2,4-diaminopyrimidine (pyDAD), a pyrimidine presenting a hydrogen bond 'donor-acceptor-donor' pattern to the complementary base, and xanthine (puADA), a purine presenting a hydrogen bond 'acceptor-donor-acceptor' pattern. This base pair fits the Watson-Crick geometry, but is joined by a pattern of hydrogen bond donor and acceptor groups different from those joining the GC and AT pairs. A variant of HIV-RT where Tyr 188 is replaced by Leu, has emerged from experiments where HIV was challenged to grow in the presence of drugs targeted against the RT, such as L-697639, TIBO and nevirapine. These drugs bind at a site near, but not in, the active site. This variant accepts the pyDAD-puADA base pair significantly better than wild type HIV-RT, and we used this as a starting point. A second mutation, E478Q, was introduced into the Y188L variant, in the event that the residual nuclease activity observed is due to the RT, and not a contaminant. The doubly mutated RT incorporated the non-standard pair with sufficient fidelity that the variant could be used to amplify oligonucleotides containing pyDAD and puADA through several rounds of a polymerase chain reaction (PCR) without losing the non-standard base pair. This is the first time where DNA containing non-standard base pairs with alternative hydrogen bonding patterns has been amplified by a full PCR. This work also illustrates a research strategy that combines in clinico pre-evolution of proteins followed by rational design to obtain an enzyme that meets a particular technological specification. C1 Univ Florida, Dept Chem, Gainesville, FL 32611 USA. Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32611 USA. Emory Univ, Dept Chem, Atlanta, GA 30322 USA. Hanbat Natl Univ, Dept Chem Technol, Taejon 305719, South Korea. Novartis Pharma, CH-4002 Basel, Switzerland. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Benner, SA (reprint author), Univ Florida, Dept Chem, Gainesville, FL 32611 USA. EM benner@chem.ufl.edu RI Lutz, Stefan /H-7853-2013 FU NCI NIH HHS [CA-09229, T32 CA009229]; NIGMS NIH HHS [GM 54048, R01 GM054048, R01 GM054048-08S1] NR 42 TC 49 Z9 51 U1 1 U2 14 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 JAN PY 2004 VL 32 IS 2 BP 728 EP 735 DI 10.1093/nar/gkh241 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774NH UT WOS:000188989000044 PM 14757837 ER PT J AU Horton, JR Ratner, G Banavali, NK Huang, N Choi, Y Maier, MA Marquez, VE MacKerell, AD Cheng, XD AF Horton, JR Ratner, G Banavali, NK Huang, N Choi, Y Maier, MA Marquez, VE MacKerell, AD Cheng, XD TI Caught in the act: visualization of an intermediate in the DNA base-flipping pathway induced by Hhal methyltransferase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EMPIRICAL FORCE-FIELD; TARGET BASE; C-H; (CYTOSINE C5)-METHYLTRANSFERASE; NUCLEIC-ACIDS; HYDROGEN-BOND; DYNAMICS; OLIGONUCLEOTIDES; SIMULATIONS; MISMATCHES AB Rotation of a DNA or RNA nucleotide out of the double helix and into a protein pocket ('base flipping') is a mechanistic feature common to some DNA/RNA-binding proteins. Here, we report the structure of HhaI methyltransferase in complex with DNA containing a south-constrained abasic carbocyclic sugar at the target site in the presence of the methyl donor byproduct AdoHcy. Unexpectedly, the locked south pseudosugar appears to be trapped in the middle of the flipping pathway via the DNA major groove, held in place primarily through Van der Waals contacts with a set of invariant amino acids. Molecular dynamics simulations indicate that the structural stabilization observed with the south-constrained pseudosugar will not occur with a north-constrained pseudosugar, which explains its lowered binding affinity. Moreover, comparison of structural transitions of the sugar and phosphodiester backbone observed during computational studies of base flipping in the M.HhaI-DNA-AdoHcy ternary complex indicate that the south-con strained pseudosugar induces a conformation on the phosphodiester backbone that corresponds to that of a discrete intermediate of the base-flipping pathway. As previous crystal structures of M.HhaI ternary complex with DNA displayed the flipped sugar moiety in the antipodal north conformation, we suggest that conversion of the sugar pucker from south to north beyond the middle of the pathway is an essential part of the mechanism through which flipping must proceed to reach its final destination. We also discuss the possibility of the south-constrained pseudosugar mimicking a transition state in the phosphodiester and sugar moieties that occurs during DNA base flipping in the presence of M.HhaI. C1 Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Grad Program Biochem Cell & Dev Biol, Atlanta, GA 30322 USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. ISIS Pharmaceut Inc, Carlsbad, CA 92008 USA. RP Cheng, XD (reprint author), Emory Univ, Sch Med, Dept Biochem, 1510 Clifton Rd, Atlanta, GA 30322 USA. EM xcheng@emory.edu RI Horton, John/F-2375-2010; Choi, Yongseok/F-8375-2012; OI Choi, Yongseok/0000-0002-3622-3439; Banavali, Nilesh/0000-0003-2206-7049; MacKerell, Alex/0000-0001-8287-6804 FU NIGMS NIH HHS [GM49245, GM51501, R01 GM049245, R01 GM051501, R29 GM051501] NR 30 TC 39 Z9 40 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PY 2004 VL 32 IS 13 BP 3877 EP 3886 DI 10.1093/nar/gkh701 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 853TE UT WOS:000223851000011 PM 15273274 ER PT J AU von Kobbe, C Harrigan, JA Schreiber, V Stiegler, P Piotrowski, J Dawut, L Bohr, VA AF von Kobbe, C Harrigan, JA Schreiber, V Stiegler, P Piotrowski, J Dawut, L Bohr, VA TI Poly(ADP-ribose) polymerase 1 regulates both the exonuclease and helicase activities of the Werner syndrome protein SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MOLECULAR NICK-SENSOR; DNA-LIGASE-III; FUNCTIONAL INTERACTION; IN-VITRO; RECQ HELICASES; WRN PROTEIN; DAMAGE; COMPLEX; KINASE; XRCC1 AB Werner syndrome (WS) is a genetic premature aging disorder in which patients appear much older than their chronological age. The gene mutated in WS encodes a nuclear protein (WRN) which possesses 3'-5' exonuclease and ATPase-dependent 3'-5' helicase activities. The genomic instability associated with WS cells and the biochemical characteristics of WRN suggest that WRN plays a role in DNA metabolic pathways such as transcription, replication, recombination and repair. Recently we have identified poly(ADP-ribose) polymerase-1 (PARP-1) as a new WRN interacting protein. In this paper, we further mapped the interacting domains. We found that PARP-1 bound to the N-terminus of WRN and to the C-terminus containing the RecQ-conserved (ROC) domain. WRN bound to the N-terminus of PARP-1 containing DNA binding and BRCA1 C-terminal (BRCT) domains. We show that unmodified PARP-1 inhibited both WRN exonuclease and helicase activities, and to our knowledge is the only known WRN protein partner that inactivates both of the WRN's catalytic activities suggesting a biologically significant regulation. Moreover, this dual inhibition seems to be specific for PARP-1, as PARP-2 did not affect WRN helicase activity and only slightly inhibited WRN exonuclease activity. The differential effect of PARP-1 and PARP-2 on WRN catalytic activity was not due to differences in affinity for WRN or the DNA substrate. Finally, we demonstrate that the inhibition of WRN by PARP-1 was influenced by the poly(ADP-ribosyl)ation state of PARP-1. The biological relevance of the specific modulation of WRN catalytic activities by PARP-1 are discussed in the context of pathways in which these proteins may function together, namely in the repair of DNA strand breaks. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Strasbourg 1, Ecole Super Biotechnol Strasbourg, CNRS, UPR 9003, F-67412 Illkirch Graffenstaden, France. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Schreiber, Valerie/M-5007-2016 OI Schreiber, Valerie/0000-0003-0507-639X NR 47 TC 68 Z9 70 U1 0 U2 4 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. PY 2004 VL 32 IS 13 BP 4003 EP 4014 DI 10.1093/nar/gkh721 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 853TE UT WOS:000223851000025 PM 15292449 ER PT J AU McCulloch, SD Kokoska, RJ Chilkova, O Welch, CM Johansson, E Burgers, PMJ Kunkel, TA AF McCulloch, SD Kokoska, RJ Chilkova, O Welch, CM Johansson, E Burgers, PMJ Kunkel, TA TI Enzymatic switching for efficient and accurate translesion DNA replication SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SYN THYMINE DIMER; POLYMERASE-ETA; SACCHAROMYCES-CEREVISIAE; ERROR-PRONE; CIS-SYN; XERODERMA-PIGMENTOSUM; LESION-BYPASS; CRYSTAL-STRUCTURE; REV1 PROTEIN; YEAST AB When cyclobutane pyrimidine dimers stall DNA replication by DNA polymerase (Pol) delta or epsilon, a switch occurs to allow translesion synthesis by DNA polymerase eta, followed by another switch that allows normal replication to resume. In the present study, we investigate these switches using Saccharomyces cerevisiae Pol delta, Pol epsilon and Pol eta and a series of matched and mismatched primer templates that mimic each incorporation needed to completely bypass a cis-syn thymine-thymine (TT) dimer. We report a complementary pattern of substrate use indicating that enzymatic switching involving localized translesion synthesis by Pol eta and mismatch excision and polymerization by a major replicative polymerase can account for the efficient and accurate dimer bypass known to suppress sunlight-induced mutagenesis and skin cancer. C1 NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU NIGMS NIH HHS [GM58534, R01 GM058534, R01 GM032431] NR 45 TC 61 Z9 64 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PY 2004 VL 32 IS 15 BP 4665 EP 4675 DI 10.1093/nar/gkh777 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 855BE UT WOS:000223947100024 PM 15333698 ER PT J AU Miller, JT Khvorova, A Scaringe, SA Le Grice, SFJ AF Miller, JT Khvorova, A Scaringe, SA Le Grice, SFJ TI Synthetic tRNA(Lys,3) as the replication primer for the HIV-1(HXB2) and HIV-1(Mal) genomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BINDING-SITE COMPLEMENTARY; TRANSFER-RNA SYNTHETASE; STRAND DNA-SYNTHESIS; TYPE-1 REVERSE TRANSCRIPTION; NUCLEOCAPSID PROTEIN; SECONDARY STRUCTURE; EFFICIENT INITIATION; PRIMER/TEMPLATE COMPLEX; MODIFIED NUCLEOTIDES AB In order to determine the contribution of modified bases on the efficiency with which tRNA(Lys,3) is used in vitro as the HIV-1 replication primer, the properties of synthetic derivatives prepared by three independent methods were compared to the natural, i.e. fully modified, tRNA. When prepared directly by in vitro run-off transcription, we show here that the predominant tRNA species is 77 nt, representing a non-templated addition of a single nucleotide. As a consequence, this aberrant tRNA inefficiently primes (-) strand strong stop DNA synthesis from the primer binding site (PBS) on the HIV-1 viral RNA genome to which it must hybridize. In contrast, correctly sized tRNA(Lys,3) can be prepared by (i) total chemical synthesis and ligation of 'half' tRNAs, (ii) transcription of a cassette whose DNA template contained strategically placed 2'-O-Methyl-containing ribonucleotides and (iii) processing from a larger precursor by means of targeted cleavage with Escherichia coli RNase H. When each of these 76 nt tRNAs was supplemented into a (-) strand strong stop DNA synthesis reaction utilizing the HXB2 strain of HIV-1, the amount of product obtained was comparable to that from the fully modified counterpart. Parallel assays monitoring early events in (-) strand strong stop DNA synthesis using either the HXB2 or Mal strain of HIV-1 RNA as the template indicated little difference in the pattern or total product amount when primed with either natural or synthetic tRNA(Lys,3). In addition, nuclease mapping of PBS-bound tRNA suggests inter-molecular base pairing between bases of the tRNA anticodon domain and the U-rich U5-IR loop of the viral 5' leader region is less stable on the HIV-1(HXB2) genome than the HIV-1(Mal) isolate. C1 NCI, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. Dharmacon Inc, Lafayette, CO 80026 USA. RP Le Grice, SFJ (reprint author), NCI, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM slegrice@ncifcrf.gov NR 56 TC 7 Z9 8 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. PY 2004 VL 32 IS 15 BP 4687 EP 4695 DI 10.1093/nar/gkh813 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 855BE UT WOS:000223947100026 PM 15342789 ER PT J AU Zhao, H Dean, A AF Zhao, H Dean, A TI An insulator blocks spreading of histone acetylation and interferes with RNA polymerase II transfer between an enhancer and gene SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BETA-GLOBIN LOCUS; CREB-BINDING PROTEIN; TRANSCRIPTION FACTOR GATA-1; CONTROL REGION; CHROMATIN-STRUCTURE; HEMATOPOIETIC TRANSCRIPTION; ERYTHROID-DIFFERENTIATION; INTERGENIC TRANSCRIPTION; REGULATORY INTERACTIONS; PROMOTER INTERACTIONS AB We studied the mechanism by which an insulator interrupts enhancer signaling to a gene using stably replicated chromatin templates containing the human beta-globin locus control region HS2 enhancer and a target globin gene. The chicken beta-globin 5' HS4 (cHS4) insulator acted as a positional enhancer blocker, inhibiting promoter remodeling and transcription activation only when placed between the enhancer and gene. Enhancer blocking by cHS4 reduced histone hyperacetylation across a zone extending from the enhancer to the gene and inhibited recruitment of CBP and p300 to HS2. Enhancer blocking also led to accumulation of RNA polymerase II at HS2 and within cHS4, accompanied by its diminution at the gene promoter. The enhancer blocking effects were completely attributable to the CTCF binding site in cHS4. These findings provide experimental evidence for the involvement of spreading in establishment of a broad zone of histone modification by an enhancer, as well as for blocking by an insulator of the transfer of RNA polymerase II from an enhancer to a promoter. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov NR 61 TC 58 Z9 62 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. PY 2004 VL 32 IS 16 BP 4903 EP 4914 DI 10.1093/nar/gkh832 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 858QT UT WOS:000224207500020 PM 15371553 ER PT J AU Huck, L Scherrer, A Terzi, L Johnson, AE Bernstein, HD Cusack, S Weichenrieder, O Strub, K AF Huck, L Scherrer, A Terzi, L Johnson, AE Bernstein, HD Cusack, S Weichenrieder, O Strub, K TI Conserved tertiary base pairing ensures proper RNA folding and efficient assembly of the signal recognition particle Alu domain SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SRP-RNA; SECONDARY STRUCTURE; ELONGATION ARREST; 7SL RNA; SEQUENCE RECOGNITION; SRP9/14 SUBUNIT; MAMMALIAN-CELLS; PROTEIN; BINDING; NUCLEOLUS AB Proper folding of the RNA is an essential step in the assembly of functional ribonucleoprotein complexes. We examined the role of conserved base pairs formed between two distant loops in the Alu portion of the mammalian signal recognition particle RNA (SRP RNA) in SRP assembly and functions. Mutations disrupting base pairing interfere with folding of the Alu portion of the SRP RNA as monitored by probing the RNA structure and the binding of the protein SRP9/14. Complementary mutations rescue the defect establishing a role of the tertiary loop-loop interaction in RNA folding. The same mutations in the Alu domain have no major effect on binding of proteins to the S domain suggesting that the S domain can fold independently. Once assembled into a complete SRP, even particles that contain mutant RNA are active in arresting nascent chain elongation and translocation into microsomes, and, therefore, tertiary base pairing does not appear to be essential for these activities. Our results suggest a model in which the loop-loop interaction and binding of the protein SRP9/14 play an important role in the early steps of SRP RNA folding and assembly. C1 Univ Geneva, Dept Biol Cellulaire, CH-1211 Geneva 4, Switzerland. Texas A&M Univ, Dept Med Biochem & Genet, Syst Hlth Sci Ctr, College Stn, TX 77843 USA. NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. European Mol Biol Lab, Grenoble Outstn, F-38042 Grenoble 9, France. RP Strub, K (reprint author), Netherlands Canc Inst, Dept Mol Carcinogenesis H2, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM Strub@cellbio.unige.ch RI Johnson, Arthur/G-3457-2012; OI Weichenrieder, Oliver/0000-0001-5818-6248; Cusack, Stephen/0000-0002-9324-0796 FU NIGMS NIH HHS [R01 GM026494, R01GM26494] NR 44 TC 13 Z9 14 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. PY 2004 VL 32 IS 16 BP 4915 EP 4924 DI 10.1093/nar/gkh837 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 858QT UT WOS:000224207500021 PM 15383645 ER PT J AU Huang, JQ Fan, T Yan, QS Zhu, HM Fox, S Issaq, HJ Best, L Gangi, L Munroe, D Muegge, K AF Huang, JQ Fan, T Yan, QS Zhu, HM Fox, S Issaq, HJ Best, L Gangi, L Munroe, D Muegge, K TI Lsh, an epigenetic guardian of repetitive elements SO NUCLEIC ACIDS RESEARCH LA English DT Article ID H3 LYSINE-9 METHYLATION; DNA METHYLATION; PERICENTRIC HETEROCHROMATIN; CYTOSINE METHYLATION; HISTONE MODIFICATION; CHROMATIN DYNAMICS; FAMILY-MEMBER; SNF2 FAMILY; GENOME; GENE AB The genome is burdened with repetitive sequences that are generally embedded in silenced chromatin. We have previously demonstrated that Lsh (lymphoid-specific helicase) is crucial for the control of heterochromatin at pericentromeric regions consisting of satellite repeats. In this study, we searched for additional genomic targets of Lsh by examining the effects of Lsh deletion on repeat regions and single copy gene sequences. We found that the absence of Lsh resulted in an increased association of acetylated histones with repeat sequences and transcriptional reactivation of their silenced state. In contrast, selected single copy genes displayed no change in histone acetylation levels, and their transcriptional rate was indistinguishable compared to Lsh-deficient cells and wild-type controls. Microarray analysis of total RNA derived from brain and liver tissues revealed that <0.4% of the 15 247 examined loci were abnormally expressed in Lsh-/-embryos and almost two-thirds of these deregulated sequences contained repeats, mainly retroviral LTR (long terminal repeat) elements. Chromatin immunoprecipitation analysis demonstrated a direct interaction of Lsh with repetitive sites in the genome. These data suggest that the repetitive sites are direct targets of Lsh action and that Lsh plays an important role as 'epigenetic guardian' of the genome to protect against deregulation of parasitic retroviral elements. C1 NCI, LMI, SAIC, Basic Res Program, Frederick, MD 21701 USA. NCI, Lab Mol Technol, SAIC, Frederick, MD 21701 USA. NCI, Lab Proteom & Analyt Technol, SAIC, Frederick, MD 21701 USA. RP Muegge, K (reprint author), NCI, LMI, SAIC, Basic Res Program, Bldg 469,Room 243, Frederick, MD 21701 USA. EM muegge@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 45 TC 69 Z9 70 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PY 2004 VL 32 IS 17 BP 5019 EP 5028 DI 10.1093/nar/gkh821 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860PL UT WOS:000224355400012 PM 15448183 ER PT J AU Babenko, VN Krylov, DM AF Babenko, VN Krylov, DM TI Comparative analysis of complete genomes reveals gene loss, acquisition and acceleration of evolutionary rates in Metazoa, suggests a prevalence of evolution via gene acquisition and indicates that the evolutionary rates in animals tend to be conserved SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROTEIN FAMILIES; DIVERGENCE; DATABASE; CLASSIFICATION; DUPLICATION; EUKARYOTES; LIKELIHOOD; ORIGIN AB In this study we systematically examined the differences between the proteomes of Metazoa and other eukaryotes. Metazoans (Homo sapiens, Ceanorhabditis elegans and Drosophila melanogaster) were compared with a plant (Arabidopsis thaliana), fungi (Saccharomyces cerevisiae and Schizosaccaromyces pombe) and Encephalitozoan cuniculi. We identified 159 gene families that were probably lost in the Metazoan branch and 1263 orthologous families that were specific to Metazoa and were likely to have originated in their last common ancestor (LCA). We analyzed the evolutionary rates of pan-eukaryotic protein families and identified those with higher rates in animals. The acceleration was shown to occur in: (i) the LCA of Metazoa or (ii) independently in the Metazoan phyla. A high proportion of the accelerated Metazoan protein families was found to participate in translation and ribosome biogenesis, particularly mitochondrial. By functional analysis we show that no metabolic pathway in animals evolved faster than in other organisms. We conclude that evolution in the LCA of Metazoa was extensive and proceeded largely by gene duplication and/or invention rather than by modification of extant proteins. Finally, we show that the rate of evolution of a gene family in animals has a clear, but not absolute, tendency to be conserved. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Krylov, DM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM krylov@ncbi.nlm.nih.gov RI Babenko, Vladimir/K-5609-2014 NR 31 TC 11 Z9 11 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. PY 2004 VL 32 IS 17 BP 5029 EP 5035 DI 10.1093/nar/gkh833 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860PL UT WOS:000224355400013 PM 15448184 ER PT J AU Antony, S Arimondo, PB Sun, JS Pommier, Y AF Antony, S Arimondo, PB Sun, JS Pommier, Y TI Position- and orientation-specific enhancement of topoisomerase I cleavage complexes by triplex DNA structures SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HELIX-FORMING OLIGONUCLEOTIDES; DIOL EPOXIDE ADDUCTS; VACCINIA TOPOISOMERASE; CRYSTAL-STRUCTURES; NUCLEIC-ACIDS; ACTIVE-SITE; CAMPTOTHECIN; MECHANISM; SEQUENCE; 8-OXOGUANINE AB Topoisomerase I (Top1) activities are sensitive to various endogenous base modifications, and anticancer drugs including the natural alkaloid camptothecin. Here, we show that triple helix-forming oligonucleotides (TFOs) can enhance Top1-mediated DNA cleavage by affecting either or both the nicking and the closing activities of Top1 depending on the position and the orientation of the triplex DNA structure relative to the Top1 site. TFO binding 1 bp downstream from the Top1 site enhances cleavage by inhibiting religation and to a lesser extent DNA nicking. In contrast, TFO binding 4 bp downstream from the Top1 site enhances DNA nicking especially when the 3' end of the TFO is proximal to the Top1 site. However, when the orientation of the triplex is inverted, with its 5' terminus 4 bp downstream from the Top1 site, religation is also inhibited. These position- and orientation-dependent effects of triplex structures on the Top1-mediated DNA cleavage and religation are discussed in the context of molecular modeling and effects of TFO on DNA twist and mobility at the duplex/triplex junction. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. CNRS MNHN, UMR 5153, USM Museum Natl Hist Nat 0503, INSERM,U565, F-75231 Paris 05, France. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 53 TC 11 Z9 11 U1 0 U2 6 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. PY 2004 VL 32 IS 17 BP 5163 EP 5173 DI 10.1093/nar/gkh847 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860PL UT WOS:000224355400027 PM 15469908 ER PT J AU Iyer, LM Makarova, KS Koonin, EV Aravind, L AF Iyer, LM Makarova, KS Koonin, EV Aravind, L TI Comparative genomics of the FtsK-HerA superfamily of pumping ATPases: implications for the origins of chromosome segregation, cell division and viral capsid packaging SO NUCLEIC ACIDS RESEARCH LA English DT Review ID MULTIPLE SEQUENCE ALIGNMENT; ESSENTIAL VIRULENCE PROTEIN; SITE-SPECIFIC RECOMBINATION; AGROBACTERIUM-TUMEFACIENS; CRYSTAL-STRUCTURE; BACTERIAL CONJUGATION; BINDING DOMAIN; EVOLUTIONARY HISTORY; THERMOPHILIC ARCHAEA; ESCHERICHIA-COLI AB Recently, it has been shown that a predicted P-loop ATPase (the HerA or MlaA protein), which is highly conserved in archaea and also present in many bacteria but absent in eukaryotes, has a bidirectional helicase activity and forms hexameric rings similar to those described for the TrwB ATPase. In this study, the FtsK-HerA superfamily of P-loop ATPases, in which the HerA clade comprises one of the major branches, is analyzed in detail. We show that, in addition to the FtsK and HerA clades, this superfamily includes several families of characterized or predicted ATPases which are predominantly involved in extrusion of DNA and peptides through membrane pores. The DNA-packaging ATPases of various bacteriophages and eukaryotic double-stranded DNA viruses also belong to the FtsK-HerA superfamily. The FtsK protein is the essential bacterial ATPase that is responsible for the correct segregation of daughter chromosomes during cell division. The structural and evolutionary relationship between HerA and FtsK and the nearly perfect complementarity of their phyletic distributions suggest that HerA similarly mediates DNA pumping into the progeny cells during archaeal cell division. It appears likely that the HerA and FtsK families diverged concomitantly with the archaeal-bacterial division and that the last universal common ancestor of modern life forms had an ancestral DNA-pumping ATPase that gave rise to these families. Furthermore, the relationship of these cellular proteins with the packaging ATPases of diverse DNA viruses suggests that a common DNA pumping mechanism might be operational in both cellular and viral genome segregation. The herA gene forms a highly conserved operon with the gene for the NurA nuclease and, in many archaea, also with the orthologs of eukaryotic double-strand break repair proteins MRE11 and Rad50. HerA is predicted to function in a complex with these proteins in DNA pumping and repair of double-stranded breaks introduced during this process and, possibly, also during DNA replication. Extensive comparative analysis of the 'genomic context' combined with in-depth sequence analysis led to the prediction of numerous previously unnoticed nucleases of the NurA superfamily, including a specific version that is likely to be the endonuclease component of a novel restriction-modification system. This analysis also led to the identification of previously uncharacterized nucleases, such as a novel predicted nuclease of the Sir2-type Rossmann fold, and phosphatases of the HAD superfamily that are likely to function as partners of the FtsK-HerA superfamily ATPases. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov NR 108 TC 173 Z9 174 U1 0 U2 5 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. PY 2004 VL 32 IS 17 BP 5260 EP 5279 DI 10.1093/nar/gkh828 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 860PL UT WOS:000224355400038 PM 15466593 ER PT J AU He, YJ Neumann, RD Panyutin, IG AF He, YJ Neumann, RD Panyutin, IG TI Intramolecular quadruplex conformation of human telomeric DNA assessed with I-125-radioprobing SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRIPLEX-FORMING OLIGONUCLEOTIDE; STRAND BREAKS; SYNTHETIC OLIGODEOXYNUCLEOTIDE; CRYSTAL-STRUCTURE; I-125 DECAY; SEQUENCE; HAIRPIN; NA+; K+; RECOGNITION AB A repeated non-coding DNA sequence d(TTAGGG)(n) is present in the telomeric ends of all human chromosomes. These repeats can adopt multiple inter and intramolecular non-B-DNA conformations that may play an important role in biological processes. Two intramolecular structures of the telomeric oligonucleotide dAGGG(TTAGGG)(3), antiparallel and parallel, have been solved by NMR and X-ray crystallography. In both structures, the telomeric sequence adopts an intramolecular quadruplex structure that is stabilized by G-4 quartets, but the ways in which the sequence folds into the quadruplex are different. The folds of the human telomeric DNA were described as an anti-parallel basket-type and a parallel propeller-type. We applied I-125-radioprobing to determine the conformation of the telomeric quadruplex in solution, in the presence of either Na+ or K+ ions. The probability of DNA breaks caused by decay of I-125 is inversely related to the distance between the radionuclide and the sugar unit of the DNA backbone; hence, the conformation of the DNA backbone can be deduced from the distribution of breaks. The probability of breaks measured in the presence of Na+ and K+ were compared with the distances in basket-type and propeller-type quadruplexes obtained from the NMR and crystal structures. Our radioprobing data demonstrate that the antiparallel conformation was present in solution in the presence of both K+ and Na+. The preferable conformation in the Na+-containing solution was the basket-type antiparallel quadruplex whereas the presence of K+ favored the chair-type antiparallel quadruplex. Thus, we believe that the two antiparallel and the parallel conformations may coexist in solution, and that their relative proportion is determined by the type and concentration of ions. C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C401, Bethesda, MD 20892 USA. EM igorp@helix.nih.gov NR 44 TC 101 Z9 104 U1 2 U2 6 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. PY 2004 VL 32 IS 18 BP 5359 EP 5367 DI 10.1093/nar/gkh875 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 865LI UT WOS:000224704200009 PM 15475390 ER PT J AU Galperin, MY Koonin, EV AF Galperin, MY Koonin, EV TI 'Conserved hypothetical' proteins: prioritization of targets for experimental study SO NUCLEIC ACIDS RESEARCH LA English DT Review ID YEAST SACCHAROMYCES-CEREVISIAE; COMPARATIVE GENOME ANALYSIS; ESCHERICHIA-COLI ENCODES; RIBOSOME-LESS PLASTIDS; FE-S CLUSTER; ESSENTIAL GENES; TRANSFER-RNA; NAD KINASE; HAEMOPHILUS-INFLUENZAE; STRUCTURAL GENOMICS AB Comparative genomics shows that a substantial fraction of the genes in sequenced genomes encodes 'conserved hypothetical' proteins, i.e. those that are found in organisms from several phylogenetic lineages but have not been functionally characterized. Here, we briefly discuss recent progress in functional characterization of prokaryotic 'conserved hypothetical' proteins and the possible criteria for prioritizing targets for experimental study. Based on these criteria, the chief one being wide phyletic spread, we offer two 'top 10' lists of highly attractive targets. The first list consists of proteins for which biochemical activity could be predicted with reasonable confidence but the biological function was predicted only in general terms, if at all ('known unknowns'). The second list includes proteins for which there is no prediction of biochemical activity, even if, for some, general biological clues exist ('unknown unknowns'). The experimental characterization of these and other 'conserved hypothetical' proteins is expected to reveal new, crucial aspects of microbial biology and could also lead to better functional prediction for medically relevant human homologs. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS [Z99 LM999999] NR 153 TC 200 Z9 211 U1 1 U2 12 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. PY 2004 VL 32 IS 18 BP 5452 EP 5463 DI 10.1093/nar/gkh885 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 865LI UT WOS:000224704200018 PM 15479782 ER PT J AU Hashiguchi, K Stuart, JA de Souza-Pinto, NC Bohr, VA AF Hashiguchi, K Stuart, JA de Souza-Pinto, NC Bohr, VA TI The C-terminal alpha O helix of human Ogg1 is essential for 8-oxoguanine DNA glycosylase activity: the mitochondrial beta-Ogg1 lacks this domain and does not have glycosylase activity SO NUCLEIC ACIDS RESEARCH LA English DT Article ID OXIDATIVE DAMAGE; BASE-EXCISION; INTRACELLULAR-LOCALIZATION; SACCHAROMYCES-CEREVISIAE; BIOCHEMICAL EXPLORATION; SECONDARY STRUCTURE; STRUCTURAL BASIS; REPAIR PATHWAYS; CLONING; CELLS AB The human Ogg1 glycosylase is responsible for repairing 8-oxo-7,8-dihydroguanine (8-oxoG) in both nuclear and mitochondrial DNA. Two distinct Ogg1 isoforms are present; alpha-Ogg1, which mainly localizes to the nucleus and beta-Ogg1, which localizes only to mitochondria. We recently showed that mitochondria from rho(0) cells, which lack mitochondrial DNA, have similar 8-oxoG DNA glycosylase activity to that of wild-type cells. Here, we show that beta-Ogg1 protein levels are similar to80% reduced in rho(0) cells, suggesting beta-Ogg1 is not responsible for 8-oxoG incision in mitochondria. Thus, we characterized the biochemical properties of recombinant beta-Ogg1. Surprisingly, recombinant beta-Ogg1 did not show any significant 8-oxoG DNA glycosylase activity in vitro. Since beta-Ogg1 lacks the C-terminal alphaO helix present in alpha-Ogg1, we generated mutant proteins with various amino acid substitutions in this domain. Of the seven amino acid positions substituted (317-323), we identified Val-317 as a novel critical residue for 8-oxoG binding and incision. Our results suggest that the alphaO helix is absolutely necessary for 8-oxoG DNA glycosylase activity, and thus its absence may explain why beta-Ogg1 does not catalyze 8-oxoG incision in vitro. Western blot analysis revealed the presence of significant amounts of alpha-Ogg1 in human mitochondria. Together with previous localization studies in vivo, this suggests that alpha-Ogg1 protein may provide the 8-oxoG DNA glycosylase activity for the repair of these lesions in human mitochondrial DNA. beta-Ogg1 may play a novel role in human mitochondria. C1 NIA, Lab Mol Gerontol, IRP, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, IRP, NIH, Box 1,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X NR 47 TC 61 Z9 61 U1 0 U2 4 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. PY 2004 VL 32 IS 18 BP 5596 EP 5608 DI 10.1093/nar/gkh863 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 865LI UT WOS:000224704200032 PM 15494448 ER PT J AU Georgakilas, AG Bennett, PV Wilson, DM Sutherland, BM AF Georgakilas, AG Bennett, PV Wilson, DM Sutherland, BM TI Processing of bistranded abasic DNA clusters in gamma-irradiated human hematopoietic cells SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE-EXCISION-REPAIR; DOUBLE-STRAND BREAKS; APURINIC APYRIMIDINIC SITES; AVERAGE LENGTH ANALYSIS; ESCHERICHIA-COLI; IONIZING-RADIATION; MAMMALIAN-CELLS; MAJOR HUMAN; DEOXYRIBONUCLEIC-ACID; GEL-ELECTROPHORESIS AB Clustered DNA damages-two or more lesions on opposing strands and within one or two helical turns-are formed in cells by ionizing radiation or radiomimetic antitumor drugs. They are hypothesized to be difficult to repair, and thus are critical biological damages. Since individual abasic sites can be cytotoxic or mutagenic, abasic DNA clusters are likely to have significant cellular impact. Using a novel approach for distinguishing abasic clusters that are very closely spaced (putrescine cleavage) or less closely spaced (Nfo protein cleavage), we measured induction and processing of abasic clusters in 28SC human monocytes that were exposed to ionizing radiation. gamma-rays induced similar to1 double-strand break: 1.3 putrescine-detected abasic clusters: 0.8 Nfo-detected abasic clusters. After irradiation, the 28SC cells rejoined double-strand breaks efficiently within 24 h. In contrast, in these cells, the levels of abasic clusters decreased very slowly over 14 days to background levels. In vitro repair experiments that used 28SC cell extracts further support the idea of slow processing of specific, closely spaced abasic clusters. Although some clusters were removed by active cellular repair, a substantial number was apparently decreased by 'splitting' during DNA replication and subsequent cell division. The existence of abasic clusters in 28SC monocytes, several days after irradiation suggests that they constitute persistent damages that could lead to mutation or cell killing. C1 Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. E Carolina Univ, Dept Biol, Greenville, NC 27858 USA. NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Sutherland, BM (reprint author), Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. EM bms@bnl.gov FU NCI NIH HHS [R01 CA 86897, R01 CA086897] NR 48 TC 91 Z9 93 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PY 2004 VL 32 IS 18 BP 5609 EP 5620 DI 10.1093/nar/gkh871 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 865LI UT WOS:000224704200033 PM 15494449 ER PT J AU Antony, S Theruvathu, JA Brooks, PJ Lesher, DT Redinbo, M Pommier, Y AF Antony, S Theruvathu, JA Brooks, PJ Lesher, DT Redinbo, M Pommier, Y TI Enhancement of camptothecin-induced topoisomerase I cleavage complexes by the acetaldehyde adduct N-2-ethyl-2 '-deoxyguanosine SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DIOL EPOXIDE ADDUCTS; WHITE BLOOD-CELLS; DNA-ADDUCTS; MINOR-GROOVE; MECHANISM; ALCOHOL; DERIVATIVES; THREONINE; INDUCTION; SEQUENCE AB The activity of DNA topoisomerase I (Top1), an enzyme that regulates DNA topology, is impacted by DNA structure alterations and by the anticancer alkaloid camptothecin (CPT). Here, we evaluated the effect of the acetaldehyde-derived DNA adduct, N-2-ethyl-2'-deoxyguanosine (N-2-ethyl-dG), on human Top1 nicking and closing activities. Using purified recombinant Top1, we show that Top1 nicking-closing activity remains unaffected in N-2-ethyl-dG adducted oligonucleotides. However, the N-2-ethyl-dG adduct enhanced CPT-induced Top1-DNA cleavage complexes depending on the relative position of the N-2-ethyl-dG adduct with respect to the Top1 cleavage site. The Top1-mediated DNA religation (closing) was selectively inhibited when the N-2-ethyl-dG adduct was present immediately 3' from the Top1 site (position +1). In addition, when the N-2-ethyl-dG adduct was located at the -5 position, CPT enhanced cleavage at an alternate Top1 cleavage site immediately adjacent to the adduct, which was then at position +1 relative to this new alternate Top1 site. Modeling studies suggest that the ethyl group on the N-2-ethyl-dG adduct located at the 5' end of a Top1 site (position +1) sterically blocks the dissociation of CPT from the Top1-DNA complex, thereby inhibiting further the religation (closing) reaction. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 30 TC 10 Z9 11 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. PY 2004 VL 32 IS 18 BP 5685 EP 5692 DI 10.1093/nar/gkh902 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 865LI UT WOS:000224704200040 PM 15498925 ER PT J AU Akagi, K Suzuki, T Stephens, RM Jenkins, NA Copeland, NG AF Akagi, K Suzuki, T Stephens, RM Jenkins, NA Copeland, NG TI RTCGD: retroviral tagged cancer gene database SO NUCLEIC ACIDS RESEARCH LA English DT Article ID POLYMERASE-CHAIN-REACTION; INSERTIONAL MUTAGENESIS; GENOME BROWSER; MOUSE GENOME; SEQUENCE; IDENTIFICATION; PATHWAYS; UCSC AB Retroviral insertional mutagenesis in mouse hematopoietic tumors provides a potent cancer gene discovery tool in the post-genome-sequence era. To manage multiple high-throughput insertional mutagenesis screening projects, we developed the Retroviral Tagged Cancer Gene Database (RTCGD; http://RTCGD.ncifcrf.gov). A sequence analysis pipeline determines the genomic position of each retroviral integration site cloned from a mouse tumor, the distance between it and the nearest candidate disease gene(s) and its orientation with respect to the candidate gene(s). The pipeline also identifies genomic regions that are targets of retroviral integration in more than one tumor (common integration sites, CISs) and are thus likely to encode a disease gene. Users can search the database using a specified gene symbol, chromosome number or tumor model to identify both CIS genes and unique viral integration sites or compare the integration sites cloned by different laboratories using different models. As a default setting, users first review the CIS Lists and then Clone Lists. CIS Lists describe CISs and their candidate disease genes along with links to other public databases and clone lists. Clone Lists describe the viral integration site clones along with the tumor model and tumor type from which they were cloned, candidate disease gene(s), genomic position and orientation of the integrated provirus with respect to the candidate gene(s). It also provides a pictorial view of the genomic location of each integration site relative to neighboring genes and markers. Researchers can identify integrations of interest and compare their results with those for multiple tumor models and tumor types using RTCGD. C1 NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. ABCC Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Copeland, NG (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. EM Copeland@ncifcrf.gov NR 21 TC 235 Z9 238 U1 0 U2 2 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 JAN 1 PY 2004 VL 32 SI SI BP D523 EP D527 DI 10.1093/nar/gkh013 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000125 PM 14681473 ER PT J AU Benson, DA Karsch-Mizrachi, I Lipman, DJ Ostell, J Wheeler, DL AF Benson, DA Karsch-Mizrachi, I Lipman, DJ Ostell, J Wheeler, DL TI GenBank: update SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DATABASE AB GenBank (R) is a comprehensive database that contains publicly available DNA sequences for more than 140 000 named organisms, obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects. Most submissions are made using the Bankit (web) or Sequin program and accession numbers are assigned by GenBank staff upon receipt. Daily data exchange with the EMBL Data Library in the UK and the DNA Data Bank of Japan helps ensure worldwide coverage. GenBank is accessible through NCBI's retrieval system, Entrez, which integrates data from the major DNA and protein sequence databases along with taxonomy, genome mapping, protein structure and domain information, and the biomedical journal literature via PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. To access GenBank and its related retrieval and analysis services, go to the NCBI home page at: hftp://www.ncbi.nim.nih.gov. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Wheeler, DL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM wheeler@ncbi.nlm.nih.gov NR 12 TC 278 Z9 292 U1 0 U2 8 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 JAN 1 PY 2004 VL 32 SI SI BP D23 EP D26 DI 10.1093/nar/gkh045 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000002 PM 14681350 ER PT J AU Bodenreider, O AF Bodenreider, O TI The Unified Medical Language System (UMLS): integrating biomedical terminology SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The Unified Medical Language System (http://umlsks.nlm.nih.gov) is a repository of biomedical vocabularies developed by the US National Library of Medicine. The UMLS integrates over 2 million names for some 900 000 concepts from more than 60 families of biomedical vocabularies, as well as 12 million relations among these concepts. Vocabularies integrated in the UMLS Metathesaurus include the NCBI taxonomy, Gene Ontology, the Medical Subject Headings (MeSH), OMIM and the Digital Anatomist Symbolic Knowledge Base. UMLS concepts are not only inter-related, but may also be linked to external resources such as GenBank. In addition to data, the UMLS includes tools for customizing the Metathesaurus (MetamorphoSys), for generating lexical variants of concept names (Ivg) and for extracting UMLS concepts from text (MetaMap). The UMLS knowledge sources are updated quarterly. All vocabularies are available at no fee for research purposes within an institution, but UMLS users are required to sign a license agreement. The UMLS knowledge sources are distributed on CD-ROM and by FTP. C1 NIH, Lister Hill Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20894 USA. RP Bodenreider, O (reprint author), NIH, Lister Hill Ctr Biomed Commun, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM olivier@nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 10 TC 601 Z9 611 U1 5 U2 33 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 JAN 1 PY 2004 VL 32 SI SI BP D267 EP D270 DI 10.1093/nar/gkh061 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000061 PM 14681409 ER PT J AU Galperin, MY AF Galperin, MY TI The molecular biology database collection: 2004 update SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The Molecular Biology Database Collection is a public resource listing key databases of value to the biologist, including those featured in this issue of Nucleic Acids Research, and other high-quality databases. All databases included in this Collection are freely available to the public. This listing aims to serve as a convenient starting point for searching the web for reliable information on various aspects of molecular biology, biochemistry and genetics. This year's update includes 548 databases, 162 more than the previous one. The databases are organized in a hierarchical classification that should simplify finding the right database for each given task. Each database in the list comes with a recently updated brief description. The database list and the database descriptions can be accessed online at the Nucleic Acids Research web site hftp://nar. oupjournals.org/. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS [Z99 LM999999] NR 8 TC 33 Z9 34 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 JAN 1 PY 2004 VL 32 SI SI BP D3 EP D22 DI 10.1093/nar/gkh143 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000001 PM 14681349 ER PT J AU Goh, SH Lee, YT Bouffard, GG Miller, JL AF Goh, SH Lee, YT Bouffard, GG Miller, JL TI Hembase: browser and genome portal for hematology and erythroid biology SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RESOURCES; DATABASE; TOOL AB Hembase (http://hembase.niddk.nih.gov) is an integrated browser and genome portal designed for web-based examination of the human erythroid transcriptome. To date, Hembase contains 15 752 entries from erythroblast Expressed Sequenced Tags (ESTs) and 380 referenced genes relevant for erythropoiesis. The database is organized to provide a cytogenetic band position, a unique name as well as a concise annotation for each entry. Search queries may be performed by name, keyword or cytogenetic location. Search results are linked to primary sequence data and three major human genome browsers for access to information considered current at the time of each search. Hembase provides interested scientists and clinical hematologists with a genome-based approach toward the study of erythroid biology. C1 NHGRI, NIH, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. EM jm7f@nih.gov NR 9 TC 13 Z9 14 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 JAN 1 PY 2004 VL 32 SI SI BP D572 EP D574 DI 10.1093/nar/gkh129 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000135 PM 14681483 ER PT J AU Kreppel, L Fey, P Gaudet, P Just, E Kibbe, WA Chisholm, RL Kimmel, AR AF Kreppel, L Fey, P Gaudet, P Just, E Kibbe, WA Chisholm, RL Kimmel, AR TI dictyBase: a new Dictyostelium discoideum genome database SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROTEIN DATA-BANK AB Dictyostelium discoideum is a powerful and genetically tractable model system used for the study of numerous cellular molecular mechanisms including chemotaxis, phagocytosis and signal transduction. The past 2 years have seen a significant expansion in the scope and accessibility of online resources for Dictyostelium. Recent advances have focused on the development of a new comprehensive online resource called dictyBase (http://dictybase.org). This database not only provides access to genomic data including functional annotation of genes, gene products and chromosomal mapping, but also to extensive biological information such as mutant phenotypes and corresponding reference material. In conjunction with additional sites (http://genome. imb-jena.de/dictyostelium/, http://dictyensembl. bioch.bcm.tmc.edu and http://www.sanger.ac.uk/ Projects/D-discoideum/) from the genome sequencing and assembly centers, these improvements have expanded the scope of the Dictyostelium databases making them accessible and useful to any researcher interested in comparative and functional genomics in metazoan organisms. C1 NIDDKD, Lab CEllular & Dev Biol 50 3351, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Ctr Med Genet, Chicago, IL 60611 USA. RP Kimmel, AR (reprint author), NIDDKD, Lab CEllular & Dev Biol 50 3351, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov RI Chisholm, Rex/B-3418-2009; Fey, Petra/O-5977-2015; Kibbe, Warren/B-2106-2010 OI Chisholm, Rex/0000-0002-5638-3990; Fey, Petra/0000-0002-4532-2703; Kibbe, Warren/0000-0001-5622-7659 FU NIGMS NIH HHS [GM064426, R01 GM064426] NR 9 TC 46 Z9 46 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 1 PY 2004 VL 32 SI SI BP D332 EP D333 DI 10.1093/nar/gkh138 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000079 PM 14681427 ER PT J AU Packer, BR Yeager, M Staats, B Welch, R Crenshaw, A Kiley, M Eckert, A Beerman, M Miller, E Bergen, A Rothman, N Strausberg, R Chanock, SJ AF Packer, BR Yeager, M Staats, B Welch, R Crenshaw, A Kiley, M Eckert, A Beerman, M Miller, E Bergen, A Rothman, N Strausberg, R Chanock, SJ TI SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The SNP500Cancer Database provides sequence and genotype assay information for candidate single nucleotide polymorphisms (SNPs) useful in mapping complex diseases, such as cancer. The database is an integral component of the NCI's Cancer Genome Anatomy Project. SNP500Cancer provides bi-directional sequencing information on a set of control DNA samples derived from anonymized subjects (102 Coriell samples representing four self-described ethnic groups: African/African-American, Caucasian, Hispanic and Pacific Rim). All SNPs are chosen from public databases and reports, and the choice of genes includes a bias towards non-synonymous and promoter SNPs in genes that have been implicated in one or more cancers. The web site is searchable by gene, chromosome, gene ontology pathway and by known dbSNP ID. As of July 2003, the database contains over 3400 SNPs, 2490 of which have been sequenced in the SNP500Cancer population. For each analyzed SNP, gene location and over 200 bp of surrounding annotated sequence (including nearby SNPs) are provided, with frequency information in total and per subpopulation, and calculation of Hardy-Weinberg Equilibrium (HWE) for each subpopulation. Sequence validated SNPs with minor allele frequency >5% are entered into a high-throughput pipeline for genotyping analysis to determine concordance for the same 102 samples. The website provides the conditions for validated genotyping assays. SNP500Cancer provides an invaluable resource for investigators to select SNPs for analysis, design genotyping assays using validated sequence data, choose selected assays already validated on one or more genotyping platforms, and select reference standards for genotyping assays. The SNP500Cancer Database is freely accessible via the web page at http://snp500cancer.nci.nih.gov/. C1 NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21701 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Off Canc Genet, Bethesda, MD 20892 USA. NCI, Sect Genom Variat, Pediat Oncol Branch, NIH, Gaithersburg, MD USA. RP Packer, BR (reprint author), NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21701 USA. EM packerb@mail.nih.gov OI Bergen, Andrew/0000-0002-1237-7644 NR 6 TC 129 Z9 133 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 1 PY 2004 VL 32 SI SI BP D528 EP D532 DI 10.1093/nar/gkh005 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000126 PM 14681474 ER PT J AU Wheeler, DL Church, DM Edgar, R Federhen, S Helmberg, W Madden, TL Pontius, JU Schuler, GD Schriml, LM Sequeira, E Suzek, TO Tatusova, TA Wagner, L AF Wheeler, DL Church, DM Edgar, R Federhen, S Helmberg, W Madden, TL Pontius, JU Schuler, GD Schriml, LM Sequeira, E Suzek, TO Tatusova, TA Wagner, L TI Database resources of the National Center for Biotechnology Information: update SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENE-EXPRESSION; PSI-BLAST; PROTEIN; SEQUENCE; ENTREZ; SEARCH; TOOL; HOMOLOGY AB In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources for the data in GenBank and other biological data made available through NCBI's website. NCBI resources include Entrez, PubMed, PubMed Central, LocusLink, the NCBI Taxonomy Browser, BLAST, BLAST Link (BLink), Electronic PCR, OrfFinder, Spidey, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, Cancer Chromosome Aberration Project (CCAP), Entrez Genomes and related tools, the Map Viewer, Model Maker, Evidence Viewer, Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, SARS Coronavirus Resource, SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheritance in Man (OMIM), the Molecular Modeling Database (MMDB), the Conserved Domain Database (CDD) and the Conserved Domain Architecture Retrieval Tool (CDART). Augmenting many of the web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at: http://www.ncbi.nim.nih.gov. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Wheeler, DL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM wheeler@ncbi.nlm.nih.gov RI Suzek, Tugba/B-6943-2015 NR 28 TC 193 Z9 201 U1 0 U2 6 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 JAN 1 PY 2004 VL 32 SI SI BP D35 EP D40 DI 10.1093/nar/gkh073 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 763HM UT WOS:000188079000005 PM 14681353 ER PT J AU Faix, J Kreppel, L Shaulsky, G Schleicher, M Kimmel, AR AF Faix, J Kreppel, L Shaulsky, G Schleicher, M Kimmel, AR TI A rapid and efficient method to generate multiple gene disruptions in Dictyostelium discoideum using a single selectable marker and the Cre-loxP system SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENOME; SITE; INTEGRATION; CELLS; IDENTIFICATION; RECOMBINATION; MORPHOGENESIS; EXPRESSION; CRE/LOX; DNA AB Dictyostelium discoideum has proven an exceptionally powerful system for studying numerous aspects of cellular and developmental functions. The relatively small (similar to34 Mb) chromosomal genome of Dictyostelium and high efficiency of targeted gene disruption have enabled researchers to characterize many specific gene functions. However, the number of selectable markers in Dictyostelium is restricted, as is the ability to perform effective genetic crosses between strains. Thus, it has been difficult to create multiple mutations within an individual cell to study epistatic relationships among genes or potential redundancies between various pathways. We now describe a robust system for the production of multiple gene mutations in Dictyostelium by recycling a single selectable marker, Blasticidin S resistance, using the Cre-loxP system. We confirm the effectiveness of the system by generating a single cell carrying four separate gene disruptions. Furthermore, the cells remain sensitive to transformation for additional targeted or random mutagenesis requiring Blasticidin selection and for functional expression studies of mutated or tagged proteins using other selectable markers. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Munich, A Butenandt Inst Zellbiol, D-80336 Munich, Germany. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Kimmel, AR (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov NR 22 TC 129 Z9 131 U1 2 U2 14 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. PY 2004 VL 32 IS 19 AR e143 DI 10.1093/nar/gnh136 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873DI UT WOS:000225259100002 PM 15507682 ER PT J AU Kuo, J Inman, J Brownstein, M Usdin, TB AF Kuo, J Inman, J Brownstein, M Usdin, TB TI Evaluation of vector-primed cDNA library production from microgram quantities of total RNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FULL-LENGTH CDNA; HIGH-EFFICIENCY CLONING; CONSTRUCTION; VASOPRESSIN; COLLECTION; CELLS AB cDNA sequences are important for defining the coding region of genes, and full-length cDNA clones have proven to be useful for investigation of the function of gene products. We produced cDNA libraries containing 3.5-5 x 10(5) primary transformants, starting with 5 mug of total RNA prepared from mouse pituitary, adrenal, thymus, and pineal tissue, using a vector-primed cDNA synthesis method. Of similar to1000 clones sequenced, similar to20% contained the full open reading frames (ORFs) of known transcripts, based on the presence of the initiating methionine residue codon. The libraries were complex, with 94, 91, 83 and 55% of the clones from the thymus, adrenal, pineal and pituitary libraries, respectively, represented only once. Twenty-five full-length clones, not yet represented in the Mammalian Gene Collection, were identified. Thus, we have produced useful cDNA libraries for the isolation of full-length cDNA clones that are not yet available in the public domain, and demonstrated the utility of a simple method for making high-quality libraries from small amounts of starting material. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Genet Lab, Bldg 35,Room 1B-215,35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov RI Brownstein, Michael/B-8609-2009 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 18 TC 1 Z9 1 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. PY 2004 VL 32 IS 22 AR e183 DI 10.1093/nar/gnh181 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 887ME UT WOS:000226309400009 PM 15601994 ER PT J AU Rattray, AJ AF Rattray, AJ TI A method for cloning and sequencing long palindromic DNA junctions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; SACCHAROMYCES-CEREVISIAE; INVERTED REPEATS; GENE AMPLIFICATION; MRE11 COMPLEX; GERM-LINE; YEAST; RECOMBINATION; MEIOSIS; REPAIR AB DNA sequences containing long adjacent inverted repeats (palindromes) are inherently unstable and are associated with many types of chromosomal rearrangements. The instability associated with palindromic sequences also creates difficulties in their molecular analysis: long palindromes (>250 bp/arm) are highly unstable in Escherichia coli, and cannot be directly PCR amplified or sequenced due to their propensity to form intra-strand hairpins. Here, we show that DNA molecules containing long palindromes (>900 bp/arm) can be transformed and stably maintained in Saccharomyces cerevisiae cells lacking a functional SAE2 gene. Treatment of the palindrome-containing DNA with sodium bisulfite at high temperature results in deamination of cytosine, converting it to uracil and thus reducing the propensity to form intra-strand hairpins. The bisulfite-treated DNA can then be PCR amplified, cloned and sequenced, allowing determination of the nucleotide sequence of the junctions. Our data demonstrates that long palindromes with either no spacer (perfect) or a 2 bp spacer can be stably maintained, recovered and sequenced from sae2Delta yeast cells. Since DNA sequences from mammalian cells can be gap repaired by their co-transformation into yeast cells with an appropriate vector, the methods described in this manuscript should provide some of the necessary tools to isolate and characterize palindromic junctions from mammalian cells. C1 NCI, Frederick Canc Res & Dev Ctr, GRCBL, Frederick, MD 21702 USA. RP Rattray, AJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, GRCBL, POB B,Bldg 539 Room 151, Frederick, MD 21702 USA. EM rattray@ncifcrf.gov RI Rattray, Alison/A-4847-2008 NR 43 TC 15 Z9 15 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PY 2004 VL 32 IS 19 AR e155 DI 10.1093/nar/gnh143 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873DI UT WOS:000225259100014 PM 15534362 ER PT J AU Xiang, CC Mezey, E Chen, M Key, S Ma, L Brownstein, MJ AF Xiang, CC Mezey, E Chen, M Key, S Ma, L Brownstein, MJ TI Using DSP, a reversible cross-linker, to fix tissue sections for immunostaining, microdissection and expression profiling SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LASER CAPTURE MICRODISSECTION; MESSENGER RIBONUCLEIC-ACIDS; GENE-EXPRESSION; MAGNOCELLULAR NEURONS; MICROARRAY ANALYSIS; SUPRAOPTIC NUCLEUS; RNA; AMPLIFICATION; FIXATION; SAMPLES AB Mammalian organs are typically comprised of several cell populations. Some (e.g. brain) are very heterogeneous, and this cellular complexity makes it difficult, if not impossible, to interpret expression profiles obtained with microarrays. Instruments, such as those manufactured by Leica or Arcturus, that permit laser capture microdissection of specific cells or cell groups from tissues were developed to solve this problem. To take full advantage of these instruments, however, one must be able to recognize cell populations of interest and, after they are harvested, to extract intact, unmodified RNA from them. Here we describe a novel, fast and simple method to fix and immunostain tissue sections that permits this to be done. C1 NIMH, Genet Lab, NHGRI, NIH, Bethesda, MD 20892 USA. NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Brownstein, MJ (reprint author), NIMH, Genet Lab, NHGRI, NIH, Bldg 36,Room 3D06,36 Convent Dr, Bethesda, MD 20892 USA. EM brownstm@mail.nih.gov NR 20 TC 23 Z9 24 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PY 2004 VL 32 IS 22 AR e185 DI 10.1093/nar/gnh185 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 887ME UT WOS:000226309400011 PM 15604454 ER PT J AU Lewis, MS Reily, MM AF Lewis, MS Reily, MM TI Estimation of weights for various methods of the fitting of equilibrium data from the analytical ultracentrifuge SO NUMERICAL COMPUTER METHODS, PT E SE METHODS IN ENZYMOLOGY LA English DT Review C1 Off Res Serv, Div Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Lewis, MS (reprint author), Off Res Serv, Div Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. NR 6 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2004 VL 384 BP 232 EP 242 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BAC02 UT WOS:000221514100014 PM 15081690 ER PT J AU Permana, PA Del Parigi, A Tataranni, PA AF Permana, PA Del Parigi, A Tataranni, PA TI Microarray gene expression profiling in obesity and insulin resistance SO NUTRITION LA English DT Article ID AUTOSOMAL GENOMIC SCAN; WHITE ADIPOSE-TISSUE; EARLY-ONSET OBESITY; BODY-MASS INDEX; PIMA-INDIANS; SKELETAL-MUSCLE; DIABETES-MELLITUS; ENERGY-METABOLISM; MEXICAN-AMERICANS; LEPTIN DEFICIENCY C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ USA. RP Permana, PA (reprint author), Carl T Hayden Vet Affairs Med Ctr, ERS-161,650 E Indian Sch Rd, Phoenix, AZ 85012 USA. EM paska.permana@med.va.gov NR 70 TC 16 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 0899-9007 J9 NUTRITION JI Nutrition PD JAN PY 2004 VL 20 IS 1 BP 134 EP 138 DI 10.1016/j.nut.2003.09.023 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 763KD UT WOS:000188083300024 PM 14698028 ER PT J AU Luijten, M Thomsen, AR van den Berg, JAH Wester, PW Verhoef, A Nagelkerke, NJD Adlercreutz, H van Kranen, HJ Piersma, AH Sorensen, IK Rao, GN van Kreijl, CF AF Luijten, M Thomsen, AR van den Berg, JAH Wester, PW Verhoef, A Nagelkerke, NJD Adlercreutz, H van Kranen, HJ Piersma, AH Sorensen, IK Rao, GN van Kreijl, CF TI Effects of soy-derived isoflavones and a high-fat diet on spontaneous mammary rimor development in Tg.NK (MMTV/c-neu) mice SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID BREAST-CANCER RISK; TIME-RESOLVED FLUOROIMMUNOASSAY; ESTROGEN-RECEPTOR-BETA; SPRAGUE-DAWLEY RATS; TRANSGENIC MICE; PLASMA ENTEROLACTONE; GENISTEIN; CARCINOGENESIS; TUMORIGENESIS; ONCOGENE AB Phytoestrogens such as isoflavonoids and lignans have been postulated as breast cancer protective constituents in soy and whole-grain cereals. We investigated the ability of isoflavones (IFs) and flaxseed to modulate spontaneous mammary tumor development in female heterozygous Tg.NK (MMTV/c-neu) mice. Two different exposure protocols were applied, either from 4 wk of age onward (postweaning) or during gestation and lactation (perinatal). In the postweaning exposure study, mice were fed IFs or flaxseed in a high-fat diet. In addition, flaxseed in a low-fat diet was tested. Postweaning exposure to IFs and flaxseed tended to accelerate the onset of mammary adenocarcinoma development, although tumor burden at necropsy was not changed significantly. Perinatal IF exposure resulted in enhanced mammary gland differentiation, but palpable mammary tumor onset was not affected. However, tumor burden at necropsy in the perinatal exposure study was significantly increased in the medium- and high-IF dose groups. Comparison of both exposure scenarios revealed a strongly accelerated onset of tumor growth after perinatal high-fat diet exposure compared with the low-fat diet. This study shows that breast cancer-modulating effects of phytoestrogens are dependent both on the background diet and on the timing of exposure in the life cycle. C1 Natl Inst Publ Hlth & Environm, Lab Toxicol Pathol & Genet, NL-3720 BA Bilthoven, Netherlands. Natl Inst Publ Hlth & Environm, Ctr Informat Technol & Methodol, NL-3720 BA Bilthoven, Netherlands. Danish Inst Food & Vet Res, Dept Toxicol & Risk Assessment, DK-2860 Soborg, Denmark. Univ Helsinki, Inst Prevent Med Nutr & Canc, Folkhalsan Res Ctr, Helsinki, Finland. Univ Helsinki, Div Clin Chem, Helsinki, Finland. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Luijten, M (reprint author), Natl Inst Publ Hlth & Environm, Lab Toxicol Pathol & Genet, POB 1, NL-3720 BA Bilthoven, Netherlands. EM mirjam.luijten@rivm.nl NR 48 TC 25 Z9 25 U1 1 U2 1 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PY 2004 VL 50 IS 1 BP 46 EP 54 DI 10.1207/s15327914nc5001_7 PG 9 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 877OV UT WOS:000225580800007 PM 15572297 ER PT J AU de Boer, JG Yang, HY Holcroft, J Skov, K AF de Boer, JG Yang, HY Holcroft, J Skov, K TI Chemoprotection against N-nitrosomethylbenzylamine-induced mutation in the rat esophagus SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID DIETARY ELLAGIC ACID; DIALLYL SULFIDE; TRANSGENIC MICE; BIG BLUE(R); GREEN TEA; METABOLIC-ACTIVATION; LUNG TUMORIGENESIS; CANCER; INHIBITION; LIVER AB Prevention of esophageal cancer may be possible through dietary modification or supplementation. In this study we have investigated the mutation preventive properties of ellagic acid, green tea, and diallyl sulfide (DAS) against the mutagenicity of the nitrosamine N-nitrosomethylbenzylamine (NMBA) in the esophagus of the rat. In addition, the effect of the consumption of ethanol on the mutagenicity of NMBA was examined. NMBA is specific in inducing tumors in the rat esophagus and has been used in many studies investigating the mechanism and the prevention of this cancer. We found that the type of mutations induced by two 2-mg/kg subcutaneous injections of NMBA in the lacI gene of "Big Blue" rats is consistent with that found previously for nitrosamines in other systems and consists of G: C-->A: T transitions. We report that the addition of ellagic acid to the feed, replacing drinking water with green tea, and gavage with DAS significantly reduced the mutagenicity of NMBA. In contrast, the addition of 5% ethanol to the drinking water increased the mutagenicity of NMBA. This is consistent with findings that these compounds modulate NMBA-induced carcinogenesis in the rat. C1 Univ Victoria, Ctr Biomed Res, Victoria, BC V8W 3N5, Canada. NCI, Lab Populat Genet, CCR, NIH, Bethesda, MD 20892 USA. Univ Ottawa, Ottawa, ON K1H 8M5, Canada. British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. RP de Boer, JG (reprint author), Univ Victoria, Ctr Biomed Res, POB 3020 STN CSC, Victoria, BC V8W 3N5, Canada. EM jdboer@uvic.ca NR 53 TC 16 Z9 18 U1 0 U2 0 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PY 2004 VL 50 IS 2 BP 168 EP 173 DI 10.1207/s15327914nc5002_6 PG 6 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 889PK UT WOS:000226454700006 PM 15623463 ER PT J AU Joseph, MA Moysich, KB Freudenheim, JL Shields, PG Bowman, ED Zhang, YS Marshall, JR Ambrosone, CB AF Joseph, MA Moysich, KB Freudenheim, JL Shields, PG Bowman, ED Zhang, YS Marshall, JR Ambrosone, CB TI Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID POSTMENOPAUSAL BREAST-CANCER; LUNG-CANCER; DIETARY ISOTHIOCYANATES; ALLYL ISOTHIOCYANATE; CYTOCHROME P4501A1; FRUIT CONSUMPTION; PHASE-2 ENZYMES; THETA GSTT1; GENOTYPE; ACCUMULATION AB Cruciferous vegetables contain anticarcinogenic isothiocyanates (ITCs), particularly the potent sulforaphane, which may decrease risk of prostate cancer through induction of phase II enzymes, including glutathione S-transferases (GSTs). We evaluated this hypothesis in a population-based, case-control study of prostate cancer including 428 men with incident prostate cancer and 537 community controls. An in-person interview included an extensive food-frequency questionnaire. Genotyping for deletions in GSTM1 and GSTT1 was performed in a subset of men who provided blood. Intakes of cruciferous vegetables and of broccoli, the greatest source of sulforaphane, were associated with decreased prostate cancer risk at all levels above the lowest consumers [adjusted 4th quartile odds ratio (OR) = 0.58; 95% confidence interval (CI) = 0.38, 0.89, and 0.72 (95% CI = 0.49, 1.06)], respectively In relation to genotypes, there was a nonsignificant increase in risk with the GSTT I null genotype (OR = 1.51; 95% CI = 0.98, 2.31) but no effects of GSTM1 genotype. However men with GSTM1-present genotype and high broccoli intake had the greatest reduction in risk (OR = 0.49; 95% CI = 0.27, 0.89). Our findings provide evidence that two or more servings per month of cruciferous vegetables may reduce risk of prostate cancer, especially among men with GSTM1-present alleles, and are consistent with a role of dietary ITCs as chemopreventive agents against prostate cancer C1 Roswell Pk Canc Inst, Dept Epidemiol, Div Canc Prevent & Populat Sci, Buffalo, NY 14263 USA. Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14263 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Roswell Pk Canc Inst, Dept Epidemiol, Div Canc Prevent & Populat Sci, Elm & Carlton St, Buffalo, NY 14263 USA. EM Christine.Ambrosone@roswellpark.org RI Shields, Peter/I-1644-2012 FU NCI NIH HHS [CA81137, CA96789] NR 39 TC 117 Z9 125 U1 1 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PY 2004 VL 50 IS 2 BP 206 EP 213 DI 10.1207/s15327914nc5002_11 PG 8 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 889PK UT WOS:000226454700011 PM 15623468 ER PT J AU Radimer, KL Ballard-Barbash, R Miller, JS Fay, MP Schatzkin, A Troiano, R Kreger, BE Splansky, GL AF Radimer, KL Ballard-Barbash, R Miller, JS Fay, MP Schatzkin, A Troiano, R Kreger, BE Splansky, GL TI Weight change and the risk of late-onset breast cancer in the original Framingham cohort SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID BODY-SIZE; PHYSICAL-ACTIVITY; UNITED-STATES; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; DIFFERENT PERIODS; GAIN; LIFE; OBESITY; HEALTH AB Objective: Adult weight gain has been associated with a twofold risk of postmenopausal breast cancer Data are limited regarding whether weight gain at specific periods of marked changes in estrogen- and insulin-related hormones have different risk associations. This study assesses the relation of adult weight change overall and at specific, hormonally relevant times with diagnosis of a first breast cancer after age 55 (late onset). Methods: Framingham study data were used to assess premenopausal (25-44 yr), perimenopausal (45-55 yr), postmenopausal (after 55 yr), and adult lifetime (from 25 yr) weight change in relation to late-onset breast cancer in 2,873 women followed for up to 48 yr with 206 late-onset breast cancers. Results: Adult lifetime weight gain was associated with an increased risk of late-onset breast cancer (P trend = 0.046). Weight gain during specific time periods was not associated with breast cancer Data suggested a possible decreased risk of breast cancer with weight loss from ages 25 to 44 and 45 to 55 yr (relative risk = 0.4 [0.2-1.2] and 0.5 [0.3-0.9], respectively). Conclusion: These data confirm prior reports of an association between adult lifetime weight gain and increased risk of late-onset breast cancer and support current recommendations to avoid adult weight gain. C1 Ctr Dis Control & Prevent, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Informat Management Syst, Silver Spring, MD 20904 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Boston Univ, Med Ctr, Framingham Heart Dis Epidemiol Study, Boston, MA 02118 USA. RP Radimer, KL (reprint author), Ctr Dis Control & Prevent, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4221, Hyattsville, MD 20782 USA. EM kir5@cdc.gov RI Fay, Michael/A-2974-2008; OI Troiano, Richard/0000-0002-6807-989X; Fay, Michael P./0000-0002-8643-9625 NR 51 TC 27 Z9 27 U1 1 U2 4 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PY 2004 VL 49 IS 1 BP 7 EP 13 DI 10.1207/s15327914nc4901_2 PG 7 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 856VH UT WOS:000224072800002 PM 15456630 ER PT J AU Slattery, ML Ballard-Barbash, R Potter, JD Ma, KN Caan, BJ Anderson, K Samowitz, W AF Slattery, ML Ballard-Barbash, R Potter, JD Ma, KN Caan, BJ Anderson, K Samowitz, W TI Sex-specific differences in colon cancer associated with p53 mutations SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID GROWTH-FACTOR-I; HORMONE-BINDING GLOBULIN; BODY-MASS INDEX; INSULIN-RESISTANCE; COLORECTAL-CANCER; BREAST-CANCER; POSTMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES; PHYSICAL-ACTIVITY; MENSTRUAL-CYCLE AB Introduction: Sex-specific differences in observed incidence rates, tumor subsite, and diet and lifestyle associations with colon cancer have been observed. We evaluate sex-specific associations with p53 mutations in colon cancer to add to understanding of these differences. Data from a large population-based incident case-control study of colon cancer were used to evaluate age and gender associations with p53 mutations. To obtain a better understanding of gender-specific associations, we evaluated the role of estrogen as a mediator of risk. For these analyses, women were classified as estrogen positive or negative, based on menopausal status and use of hormone replacement therapy (HRT). Results: There was a significant interaction between age and sex and risk of an acquired p53 mutation compared with p53 Wt. Among men, there was an increase in p53 mutations with age, whereas among women the opposite was observed. Associations with parity, oral contraceptive use, and total ovulatory months were not associated with p53 mutations. However, recent use of HRT reduced risk of all tumors, as did being estrogen positive. Women who were estrogen positive (either premenopausal or recent users of HRT) were at a significantly increased risk of an acquired p53 mutation if they consumed a diet with a high sugar index (odds ratio = 2.94; 95% confidence interval = 1.47-5.89); similar increases in risk of p53 mutations were not observed for men or women who were estrogen negative. Conclusions: Although sex-specific associations were detected for acquired p53 mutations, they do not indicate a unique role of estrogens in the mutation of p53. These data are consistent with a role for estrogen in altering susceptibility to diet and lifestyle factors possibly via an insulin-related mechanism. C1 Univ Utah, Dept Family & Prevent Med, Hlth Res Ctr, Salt Lake City, UT 84108 USA. NCI, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Kaiser Permanente Med Care Program, Oakland, CA 94612 USA. Univ Minnesota, Minneapolis, MN 55454 USA. Univ Utah, Dept Surg Pathol, Salt Lake City, UT 84108 USA. RP Slattery, ML (reprint author), Univ Utah, Dept Family & Prevent Med, Hlth Res Ctr, 375 Chipeta Way,Suite A, Salt Lake City, UT 84108 USA. EM mslatter@hrc.utah.edu OI Potter, John/0000-0001-5439-1500 FU NCI NIH HHS [R01 CA048998, CA48998, CA61757, N01-PC-67000, R01 CA048998-10, R01 CA061757, R01 CA061757-09] NR 42 TC 6 Z9 6 U1 0 U2 0 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PY 2004 VL 49 IS 1 BP 41 EP 48 DI 10.1207/s15327914nc4901_6 PG 8 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 856VH UT WOS:000224072800006 PM 15456634 ER PT J AU Lissowska, J Gail, MH Pee, D Groves, FD Sobin, LH Nasierowska-Guttmejer, A Sygnowska, E Zatonski, W Blot, WJ Chow, WH AF Lissowska, J Gail, MH Pee, D Groves, FD Sobin, LH Nasierowska-Guttmejer, A Sygnowska, E Zatonski, W Blot, WJ Chow, WH TI Diet and stomach cancer risk in Warsaw, Poland SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID GASTRIC-CANCER; NUTRIENT INTAKE; DIFFUSE TYPES; ESOPHAGUS; EPIDEMIOLOGY; CAROTENOIDS; CARDIA; SPAIN; CARCINOGENESIS; ADENOCARCINOMA AB Some of the world's highest rates of stomach cancer are found in Poland. Reasons for the increased incidence are not known, but high intake of sausages and other preserved foods and low intake of fresh fruits and vegetables may be involved. A case-control study comprising residents newly diagnosed with stomach cancer during 1994-96 and controls randomly selected from the general population was conducted in Warsaw, Poland. Standardized interviews were conducted to ascertain usual consumption of 118 common foods and beverages and other exposures. Using data from direct interviews with 274 cases and 463 controls, odds ratios of stomach cancer were calculated as estimates of risks associated with dietary factors, adjusting for age, sex, education, smoking, and caloric intake. Risk of stomach cancer was inversely related to intake of total fruits and dark green-yellow vegetables and to indices of vitamins C and E and alpha- and beta-carotenes. However, risk was not significantly increased among those with high intake of pickled/salted vegetables and sausages. Risks were positively associated with increased intake of breads/cereals/rice/pasta and other refined grains, as well as a high carbohydrate index. Our findings add to the evidence of a protective effect of fruits and certain vegetables on stomach cancer risk, but do not indicate that high intake of sausage and other preserved foods typical in the Polish diet has contributed to the country's elevated stomach cancer incidence. Our data also suggest that high carbohydrate consumption may influence risk, but further confirmation is needed. C1 Ctr Canc, Div Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. Inst Oncol, Div Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Serv Inc, Rockville, MD USA. Armed Forces Inst Pathol, Div Gastrointestinal Pathol, Washington, DC 20306 USA. Ctr Canc, Div Histopathol, PL-02781 Warsaw, Poland. M Sklodowska Curie Inst Oncol, Div Histopathol, PL-02781 Warsaw, Poland. S Cardinal Wyszynski Inst Cardiol, Div Cardiovasc Dis Epidemiol & Prevent, Warsaw, Poland. Int Epidemiol Inst, Rockville, MD USA. RP Lissowska, J (reprint author), Ctr Canc, Div Canc Epidemiol & Prevent, W Roentgena 5, PL-02781 Warsaw, Poland. EM lissowsj@coi.waw.pl OI Lissowska, Jolanta/0000-0003-2695-5799 FU NCI NIH HHS [N02-CP-71103, N02-CP-40501, N01-CP-05626] NR 63 TC 55 Z9 59 U1 0 U2 7 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PY 2004 VL 48 IS 2 BP 149 EP 159 DI 10.1207/s15327914nc4802_4 PG 11 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 842SS UT WOS:000223025100004 PM 15231449 ER PT J AU Fischer, L Mahoney, C Jeffcoat, AR Koch, MA Thomas, BF Valentine, JL Stinchcombe, T Boan, J Crowell, JA Zeisel, SH AF Fischer, L Mahoney, C Jeffcoat, AR Koch, MA Thomas, BF Valentine, JL Stinchcombe, T Boan, J Crowell, JA Zeisel, SH TI Clinical characteristics and pharmacokinetics of purified soy isoflavones: Multiple-dose administration to men with prostate neoplasia SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID GENISTEIN INDUCES APOPTOSIS; BREAST-CANCER CELLS; GENE-EXPRESSION; ANTIGEN; PHYTOESTROGENS; EXCRETION; GROWTH; CONSUMPTION; INHIBITION; DAIDZEIN AB A phase I clinical trial was conducted to determine the safety, pharmacokinetic parameters, and efficacy of orally administered isoflavones (genistein and daidzein, potential cancer chemotherapeutic agents) over a 3-mo period in men with prostate neoplasia. Twenty men, ages 40 and above, with stage B, C, or D adenocarcinoma of the prostate were treated with a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein)for 84 days. The delivered dose of isoflavones was more than 10-fold higher than that typically taken by prostate cancer patients. In men with prostate cancer, relatively minor side effects of chronic isoflavone treatment were observed including some estrogenic effects (breast changes, increased frequency of hot flashes). Serum dehydroepiandrosterone was decreased by 31.7% (P = 0.0004) at the end of treatment. Except for those subjects whose prostate-specific antigen (PSA) values were below 0.4 ng/ml, subjects had a history of increasing PSA levels prior to the trial. This increase continued during the trial both while on soy isoflavones and after treatment was discontinued. On average the rate of rise accelerated after soy isoflavones were discontinued, but that difference did not attain statistical significance. Genistein and daidzein were rapidly cleared from plasma and excreted in urine. Pharmacokinetic data for chronic dose administration were similar to single-dose administration for the isoflavones investigated except that we observed slightly longer circulation time for daidzein. C1 Univ N Carolina, Sch Publ Hlth, Sch Med, Dept Nutr, Chapel Hill, NC 27599 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Duke Univ, Dept Med, Durham, NC 27710 USA. NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, Rockville, MD 20852 USA. RP Zeisel, SH (reprint author), Univ N Carolina, Sch Publ Hlth, Sch Med, Dept Nutr, CB 7461,McGavran Greenberg Bldg, Chapel Hill, NC 27599 USA. EM steven_zeisel@unc.edu OI Thomas, Brian/0000-0002-0097-4804 FU NCI NIH HHS [CA16086, N01-CN-65117]; NCRR NIH HHS [RR00046]; NIDDK NIH HHS [DK56350]; NIEHS NIH HHS [ES10126] NR 35 TC 55 Z9 57 U1 0 U2 4 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PY 2004 VL 48 IS 2 BP 160 EP 170 DI 10.1207/s15327914nc4802_5 PG 11 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 842SS UT WOS:000223025100005 PM 15231450 ER PT J AU Hakkarainen, R Partonen, T Haukka, J Virtamo, J Albanes, D Lonnqvist, J AF Hakkarainen, Reeta Partonen, Timo Haukka, Jari Virtamo, Jarmo Albanes, Demetrius Loennqvist, Jouko TI Food and nutrient intake in relation to mental wellbeing SO NUTRITION JOURNAL LA English DT Article AB Background: We studied food consumption and nutrient intake in subjects with depressed mood, anxiety and insomnia as indices of compromised mental wellbeing. Methods: The study population consisted of 29,133 male smokers aged 50 to 69 years who entered the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in 1985-1988. This was a placebo-controlled trial to test whether supplementation with alpha-tocopherol or beta-carotene prevents lung cancer. At baseline 27,111 men completed a diet history questionnaire from which food and alcohol consumption and nutrient intake were calculated. The questionnaire on background and medical history included three symptoms on mental wellbeing, anxiety, depression and insomnia experienced in the past four months. Results: Energy intake was higher in men who reported anxiety or depressed mood, and those reporting any such symptoms consumed more alcohol. Subjects reporting anxiety or depressed mood had higher intake of omega-3 fatty acids and omega-6 fatty acids. Conclusions: Our findings conflict with the previous reports of beneficial effects of omega-3 fatty acids on mood. C1 [Hakkarainen, Reeta; Partonen, Timo; Haukka, Jari; Loennqvist, Jouko] Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. [Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. [Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hakkarainen, R (reprint author), Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. EM reeta.hakkarainen@ktl.fi; timo.partonen@ktl.fi; jari.haukka@stakes.fi; jarmo.virtamo@ktl.fi; daa@nih.gov; jouko.lonnqvist@ktl.fi RI Albanes, Demetrius/B-9749-2015; Haukka, Jari/G-1484-2014; OI Haukka, Jari/0000-0003-1450-6208; Partonen, Timo/0000-0003-1951-2455 FU Public Health Service contracts [N01-CN-45165, N01-RC-45035]; National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA FX The authors thank Ms Satu Mannisto, Ph.D., from the Department of Epidemiology and Health Promotion, National Public Health Institute, Finland for her expertise, help and support. The ATBC Study was supported by Public Health Service contracts (N01-CN-45165 and N01-RC-45035) with the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA. NR 26 TC 27 Z9 29 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PY 2004 VL 3 AR 14 DI 10.1186/1475-2891-3-14 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA V40MD UT WOS:000209481800014 PM 15363099 ER PT J AU Mahabir, S Baer, DJ Johnson, LL Dorgan, JF Campbell, W Brown, E Hartman, TJ Clevidence, B Albanes, D Judd, JT Taylor, PR AF Mahabir, Somdat Baer, David J. Johnson, Laura L. Dorgan, Joanne F. Campbell, William Brown, Ellen Hartman, Terryl J. Clevidence, Beverly Albanes, Demetrius Judd, Joseph T. Taylor, Philip R. TI The effects of moderate alcohol supplementation on estrone sulfate and DHEAS in postmenopausal women in a controlled feeding study SO NUTRITION JOURNAL LA English DT Article AB Background: We have demonstrated that moderate alcohol consumption (15 g/d, 30 g/d) for 8 weeks resulted in significantly increased levels of serum estrone sulfate and DHEAS in 51 postmenopausal women in a randomized, placebo-controlled trial. We now report on the relationships between serum estrone sulfate and dehydroepiandrosterone sulfate (DHEAS) levels after 4 weeks of moderate alcohol supplementation, and compare the results to the 8 weeks data to elucidate time-to-effect differences. Methods: Postmenopausal women (n = 51) consumed 0 (placebo), 15 (1 drink), and 30 (2 drinks) g alcohol (ethanol)/day for 8 weeks as part of a controlled diet in a randomized crossover design. Blood samples were drawn at baseline, at 4 weeks and at 8 weeks. Changes in estrone sulfate and DHEAS levels from placebo to 15 g and 30 g alcohol per day were estimated using linear mixed models. Results and Discussion: At week 4, compared to the placebo, estrone sulfate increased an average 6.9% (P = 0.24) when the women consumed 15 g of alcohol per day, and 22.2% (P = 0.0006) when they consumed 30 g alcohol per day. DHEAS concentrations also increased significantly by an average of 8.0% (P < 0.0001) on 15 g of alcohol per day and 9.2% (P < 0.0001) when 30 g alcohol was consumed per day. Trend tests across doses for both estrone sulfate (P = 0.0006) and DHEAS (P < 0.0001) were significant. We found no significant differences between the absolute levels of serum estrone sulfate at week 4 versus week 8 (P = 0.32) across all doses. However, absolute DHEAS levels increased from week 4 to week 8 (P < 0.0001) at all three dose levels. Conclusions: These data indicate that the hormonal effects due to moderate alcohol consumption are seen early, within 4 weeks of initiation of ingestion. C1 [Mahabir, Somdat; Johnson, Laura L.; Taylor, Philip R.] NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Dorgan, Joanne F.] Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. [Campbell, William; Brown, Ellen; Clevidence, Beverly; Judd, Joseph T.] ARS, Human Nutr Res Ctr, USDA, Beltsville, MD USA. [Hartman, Terryl J.] Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Mahabir, S (reprint author), NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM mahabirs@mail.nih.gov; baer@bhnrc.arsusda.gov; johnslau@mail.nih.gov; JF_Dorgan@fccc.edu; campbell@bhnrc.arsusda.gov; ellbrown@jhsph.edu; tjha@psu.edu; bev@bhnrc.arsusda.gov; albanesd@mail.nih.gov; judd@bhnrc.arsusda.gov; ptaylor@mail.nih.gov RI Albanes, Demetrius/B-9749-2015 FU [Y1-SC-8012] FX The present work was funded in part by interagency agreement Y1-SC-8012 NR 15 TC 19 Z9 19 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PY 2004 VL 3 AR 11 DI 10.1186/1475-2891-3-11 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA V40MD UT WOS:000209481800011 PM 15353002 ER PT J AU Dombrowski, MP Schatz, M Wise, R Momirova, V Landon, M Mabie, W Newman, RB McNellis, D Hauth, JC Lindheimer, M Caritis, SN Leveno, KJ Meis, P Miodovnik, M Wapner, RJ Paul, RH Varner, MW O'Sullivan, MJ Thurnau, GR Conway, DL AF Dombrowski, MP Schatz, M Wise, R Momirova, V Landon, M Mabie, W Newman, RB McNellis, D Hauth, JC Lindheimer, M Caritis, SN Leveno, KJ Meis, P Miodovnik, M Wapner, RJ Paul, RH Varner, MW O'Sullivan, MJ Thurnau, GR Conway, DL TI Asthma during pregnancy SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 20th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 31-FEB 05, 2000 CL MIAMI BEACH, FL SP Soc Maternal Fetal Med ID PERINATAL OUTCOMES; WOMEN; LABOR; POPULATION; MORBIDITY; SEVERITY; DELIVERY; RISK AB OBJECTIVE: To determine neonatal and maternal outcomes stratified by asthma severity during pregnancy by using the 1993 National Asthma Education Program Working Group on Asthma and Pregnancy definitions of asthma severity. The primary hypothesis was that moderate or severe asthmatics would have an increased incidence of delivery at <32 weeks of gestation compared with nonasthmatic controls. METHODS: This was a multicenter, prospective, observational cohort study conducted over 4 years at 16 university hospital centers. Asthma severity was defined according to the National Asthma Education Program Working Group on Asthma and Pregnancy classification and modified to include medication requirements. This study had 80% power to detect a 2- to 3-fold increase in delivery less than 32 weeks of gestation among the cohort with the moderate or severe asthma compared with controls. Secondary outcome measures included obstetrical and neonatal outcomes. RESULTS: The final analysis included 881 nonasthmatic controls, 873 with mild asthma, 814 with moderate, and 52 with severe asthma. There were no significant differences in the rates of preterm delivery less than 32 weeks (moderate or severe 3.0%, mild 3.4%, controls 3.3%; P = .873) or less than 37 weeks of gestation. There were no significant differences for neonatal outcomes except discharge diagnosis of neonatal sepsis among the mild group compared with controls, adjusted odds ratio 2.9, 95% confidence interval 1.2, 6.8. There were no significant differences for maternal complications except for an increase in overall cesarean delivery rate among the moderate-or-severe group compared with controls (adjusted odds ratio 1.4, 95% confidence interval 1.1, 1.8). CONCLUSION: Asthma was not associated with a significant increase in preterm delivery or other adverse perinatal outcomes other than a discharge diagnosis of neonatal sepsis. Cesarean delivery rate was increased among the cohort with moderate or severe asthma. (Obstet Gynecol 2004;103:5-12. (C) 2004 by The American College of Obstetricians and Gynecologists). C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Kaiser Permanente, San Diego, CA USA. Johns Hopkins Univ, Baltimore, MD USA. George Washington Univ, Biostat Ctr, Washington, DC USA. Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH USA. Univ Tennessee, Memphis, TN USA. Med Coll S Carolina, Charleston, SC USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Chicago, Chicago, IL 60637 USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA USA. UT SW Med Ctr, Dallas, TX USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Cincinnati, Cincinnati, OH USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Univ So Calif, Los Angeles, CA USA. Miami Univ, Miami, FL USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. RP Dombrowski, MP (reprint author), St Johns Hosp, Dept Obstet & Gynecol, 22151 Moross Rd,Suite 313, Detroit, MI 48236 USA. EM Mitchell.Dombrowski@stjohn.org RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Wise, Robert/0000-0002-8353-2349; Varner, Michael/0000-0001-9455-3973 FU NICHD NIH HHS [HD27860, HD21410, HD21414, HD21434, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD36801] NR 26 TC 110 Z9 112 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2004 VL 103 IS 1 BP 5 EP 12 DI 10.1097/01.AOG.0000103994.75162.16 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875IJ UT WOS:000225413400003 PM 14704237 ER PT J AU Dunson, DB Baird, DD Colombo, B AF Dunson, DB Baird, DD Colombo, B TI Increased infertility with age in men and women SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID IN-VITRO FERTILIZATION; CUMULATIVE PREGNANCY CURVES; MENSTRUAL-CYCLE; FECUNDABILITY; STERILITY; BIRTH; FERTILITY; OVULATION; PROBABILITY; POPULATION AB OBJECTIVE: To estimate the effects of aging on the percentage of outwardly healthy couples who are sterile (completely unable to conceive without assisted reproduction) or infertile (unable to conceive within a year of unprotected intercourse) METHODS: A prospective fecundability study was conducted in a sample of 782 couples recruited from 7 European centers for natural family planning. Women aged 18-40 years were eligible. Daily intercourse records were used to adjust for timing and frequency of intercourse when estimating the per-menstrual-cycle probability of conception. The number of menstrual cycles required to conceive a clinical pregnancy and the probability of sterility and infertility were derived from the estimated fecundability distributions for men and women of different ages. RESULTS: Sterility was estimated at about 1%; this percent did not change with age. ne percentage infertility was estimated at 8% for women aged 19-26 years, 13-14% for women aged 27-34 years and 18% for women aged 35-39 years. Starting in the late 30s, male age was an important factor, with the percentage failing to conceive within 12 cycles increasing from an estimated 18-28% between ages 35 and 40 years. The estimated percentage of infertile couples that would be able to conceive after an additional 12 cycles of trying varied from 43-63% depending on age. CONCLUSION: Increased infertility in older couples is attributable primarily to declines in fertility rates rather than to absolute sterility. Many infertile couples will conceive if they try for an additional year. (C) 2004 byTbc American College of Obstetricians and Gynecologists. C1 Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Padua, Dept Stat, I-35100 Padua, Italy. RP Dunson, DB (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM dunson1@niehs.nih.gov OI Baird, Donna/0000-0002-5544-2653 NR 37 TC 148 Z9 157 U1 1 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2004 VL 103 IS 1 BP 51 EP 56 DI 10.1097/01.AOG.0000100153.24061.45 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875IJ UT WOS:000225413400010 PM 14704244 ER PT J AU Seidman, MM Glazer, PM AF Seidman, MM Glazer, PM TI Setting standards in gene repair SO OLIGONUCLEOTIDES LA English DT Editorial Material C1 NIA, NIH, Baltimore, MD 21224 USA. Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. RP Seidman, MM (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM SeidmanM@grc.nia.nih.gov; peter.glazer@yale.edu NR 2 TC 4 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1545-4576 J9 OLIGONUCLEOTIDES JI Oligonucleotides PY 2004 VL 14 IS 2 BP 79 EP 79 DI 10.1089/1545457041526263 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 842AO UT WOS:000222974900001 PM 15294071 ER PT J AU Chen, HX AF Chen, HX TI Expanding the clinical development of bevacizumab SO ONCOLOGIST LA English DT Article; Proceedings Paper CT 2nd Annual Solid Tumor Investigators Meeting CY SEP 26-29, 2002 CL Scottsdale, AZ DE vascular endothelial growth factor; clinical trial; cancer; monoclonal antibody; bevacizumab ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; HUMAN PANCREATIC-CANCER; OVARIAN-CANCER; FACTOR EXPRESSION; PROSTATE-CANCER; MONOCLONAL-ANTIBODY; MYELODYSPLASTIC SYNDROMES; INTERFERON ALPHA-2A; RANDOMIZED-TRIAL AB Bevacizutnab (Avastin(TM); Genentech, Inc.; South San Francisco, CA) is a recombinant, humanized monoclonal antibody to vascular endothelial growth factor, a key regulator of tumor angiogenesis. Bevacizumab demonstrated potent antitumor activity in preclinical models and has also shown biologic activity and clinical benefit in clinical studies. Notably, a randomized, placebo-controlled phase II trial in renal cell carcinoma demonstrated a significantly longer time to tumor progression with bevacizumab monotherapy. Furthermore, in a phase III trial for untreated advanced colorectal cancer, the addition of bevacizumab to chemotherapy led to significantly longer overall survival and progression-free survival times than chemotherapy alone. The clinical development of bevacizurnab has been expanded to include confirmatory phase III trials and exploratory phase II trials in a variety of solid tumors and hematologic malignancies. Treatment regimens being examined include bevacizumab alone and in combination with conventional chemotherapy, radiation, immune therapy, and biologically targeted agents. C1 NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Chen, HX (reprint author), NCI, Canc Therapy Evaluat Program, 6130 Execut Blvd,EPN 7131, Bethesda, MD 20892 USA. EM chenh@ctep.nci.nih.gov NR 78 TC 28 Z9 30 U1 0 U2 4 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2004 VL 9 SU 1 BP 27 EP 35 DI 10.1634/theoncologist.9-suppl_1-27 PG 9 WC Oncology SC Oncology GA 831QK UT WOS:000222209600005 PM 15178813 ER PT J AU Warren, KE AF Warren, KE TI NMR spectroscopy and pediatric brain tumors SO ONCOLOGIST LA English DT Article DE brain; imaging; tumor; spectroscopy; pediatric; metabolic activity ID MAGNETIC-RESONANCE-SPECTROSCOPY; PROTON MR SPECTROSCOPY; IN-VIVO; MALIGNANT GLIOMAS; METABOLITE; CHILDREN; ASTROCYTOMAS; RESECTION AB Proton nuclear magnetic resonance spectroscopy (H-1-NMRS) is a noninvasive in vivo technique that utilizes conventional MR imaging hardware to obtain biochemical information from a discrete volume of tissue after suppression of the water signal. MR spectroscopy coupled with conventional MR imaging allows correlation of structural changes with biochemical processes in tissues by measuring specific metabolites present in brain tissue. NMRS is commonly used in the evaluation of patients with brain tumors. This article reviews the basic principles of spectroscopy and its use in evaluating pediatric patients with brain tumors. C1 NCI, Neuro Oncol Branch, Bethesda, MD 20892 USA. RP Warren, KE (reprint author), NCI, Neuro Oncol Branch, Bloch Bldg 82,Room 224,9030 Old Georgetown Rd, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov NR 49 TC 21 Z9 22 U1 0 U2 0 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2004 VL 9 IS 3 BP 312 EP 318 DI 10.1634/theoncologist.9-3-312 PG 7 WC Oncology SC Oncology GA 828KP UT WOS:000221972500010 PM 15169986 ER PT J AU Grover, A Alexander, HR AF Grover, A Alexander, HR TI The past decade of experience with isolated hepatic perfusion SO ONCOLOGIST LA English DT Article DE liver metastases; primary hepatic neoplasms; colorectal cancer; ocular melanoma; isolation perfusion; regional chemotherapy; hyperthermia ID TUMOR-NECROSIS-FACTOR; METASTATIC COLORECTAL-CANCER; ISOLATED LIVER PERFUSION; ISOLATED HYPERTHERMIC LIVER; PROSPECTIVE RANDOMIZED TRIAL; UVEAL MELANOMA; MITOMYCIN-C; INTRAARTERIAL FLOXURIDINE; 1ST-LINE TREATMENT; PLUS FLUOROURACIL AB Metastatic or primary unresectable cancers confined to the liver are the sole or life-limiting component of disease for many patients with colorectal cancer, ocular melanoma, neuroendocrine tumors, or primary colangioor hepatocellular carcinomas. Regional treatment strategies including infusional chemotherapy and local ablative therapy are under investigation, but have limitations with respect to the clinical conditions under which they can be employed. Isolated hepatic perfusion (IHP) was first clinically applied over 40 years ago, but because of its technical complexity, the attendant potential morbidity, and the lack of documented efficacy, it has not enjoyed consistent or widespread evaluation. In light of the antitumor activity with isolated limb perfusion with tumor necrosis factor (TNF) and melphalan in patients with unresectable extremity sarcoma or in transit melanoma, this regimen has been administered via IHP at several centers worldwide for patients with unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers from multiple histologies confined to the liver. Patient selection is important to ensure good results with minimal morbidity and mortality. Work to define the appropriate clinical groups is ongoing at many clinical centers. C1 NCI, Surg Metabol Sect, Surg Branch,Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Metabol Sect, Surg Branch,Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 2B07, Bethesda, MD 20892 USA. EM Richard_Alexander@nih.gov NR 64 TC 32 Z9 33 U1 0 U2 0 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PY 2004 VL 9 IS 6 BP 653 EP 664 DI 10.1634/theoncologist.9-6-653 PG 12 WC Oncology SC Oncology GA 873XG UT WOS:000225314200006 PM 15561809 ER PT J AU Tsuda, H Bandera, CA Birrer, MJ Hashiguchi, Y Berkowitz, RS Mok, SC AF Tsuda, H Bandera, CA Birrer, MJ Hashiguchi, Y Berkowitz, RS Mok, SC TI Cyclin E amplification and overexpression in clear cell adenocarcinoma of the ovary SO ONCOLOGY LA English DT Article DE cyclin E; ovarian cancer; gene amplification; clear cell; biomarker ID GENE AMPLIFICATION; PROTEIN ACCUMULATION; RNA OVEREXPRESSION; POOR-PROGNOSIS; BREAST-CANCER; P53 MUTATION; E EXPRESSION; CARCINOMA; D1; P27(KIP1) AB Objective: The purpose of this study is to compare DNA, mRNA and protein levels of the cyclin E between clear cell (CC) and serous (SC) ovarian carcinomas, and evaluate the relationship between cyclin E and p53 status. Method: We examined the DNA, mRNA and protein levels of cyclin E and the protein level of p53 in 44 CCs and 39 SCs using microdissected tissues. Results: Relative cyclin E mRNA expression was significantly higher in CC (3.62, 95% CI, 2.24-4.99) than in SC (1.75, 95% CI, 1.05-2.45; p=0.0098). The percentage of positive nuclear staining of cyclin E was significantly higher in CC (48.3, 95% CI, 40.4-56.1) than SC (25.3, 95% CI, 17.4-33.3; p=0.0001). The mRNA and protein expression of cyclin E was significantly correlated (r=0.66, p<0.0001). However, the correlation between relative DNA copy number and relative mRNA expression was not significant (r=-0.063; p=0.66). Percentage of positive nuclear staining of cyclin E was significantly higher in p53 positive cases (51.8, 95% CI, 40.0-63.5) than p53 negative cases (36.2, 95% CI, 28.2-44.2; p=0.028). Conclusions: Cyclin E expression is significantly higher in CC than in SC. Cyclin E expression is significantly related with p53 positivity. Copyright (C) 2004 S. Karger AG, Basel. C1 Harvard Univ, Brigham & Womens Hosp, Lab Gynecol Oncol,Sch Med, Dept Obstet & Gynecol,Div Gynecol Oncol, Boston, MA 02115 USA. Osaka City Gen Hosp, Dept Obstet & Gynecol, Osaka, Japan. NCI, Biomarkers & Prevent Res Branch, Rockville, MD USA. RP Mok, SC (reprint author), Harvard Univ, Brigham & Womens Hosp, Lab Gynecol Oncol,Sch Med, Dept Obstet & Gynecol,Div Gynecol Oncol, BLI-447,221 Longwood Ave, Boston, MA 02115 USA. EM scmok@rics.bwh.harvard.edu FU NCI NIH HHS [CA86381, R33CA103595, P50CA165009] NR 32 TC 21 Z9 21 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0030-2414 J9 ONCOLOGY-BASEL JI Oncology PY 2004 VL 67 IS 3-4 BP 291 EP 299 DI 10.1159/000081332 PG 9 WC Oncology SC Oncology GA 873DG UT WOS:000225258900016 PM 15557791 ER PT J AU Davis, T Schoenfeldt, M AF Davis, T Schoenfeldt, M TI Clinical trials - Referral resource SO ONCOLOGY-NEW YORK LA English DT Article ID MYELOID-LEUKEMIA C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. RP Davis, T (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 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 JAN PY 2004 VL 18 IS 1 BP 62 EP + PG 3 WC Oncology SC Oncology GA 052CZ UT WOS:000238210000008 PM 14768407 ER PT J AU Xie, H Hou, LF Shields, PG Winn, DM Gridley, G Bravo-Otero, E Diehl, SR Bowman, ED Brown, LM Hayes, RB AF Xie, H Hou, LF Shields, PG Winn, DM Gridley, G Bravo-Otero, E Diehl, SR Bowman, ED Brown, LM Hayes, RB TI Metabolic polymoryphisms, smoking, and oral cancer in Puerto Rico SO ONCOLOGY RESEARCH LA English DT Article DE polymorphism; enzymes; smoking; carcinoma ID GLUTATHIONE-S-TRANSFERASE; SQUAMOUS-CELL CARCINOMA; TOBACCO-RELATED CANCERS; GENETIC-POLYMORPHISM; PHARYNGEAL CANCERS; NECK-CANCER; LUNG-CANCER; RISK; SUSCEPTIBILITY; GSTM1 AB Genetic polymorphisms resulting in variation in metabolism of tobacco carcinogens may influence oral cancer risk. In a population-based case-control study in Puerto Rico, genotypes of CYP1A1, GSTM1, and GSTT1 were determined by a PCR-based method for 132 oral cancer patients and 143 control subjects. Genotype-associated risks were estimated by logistic regression. The null variant of GSTM1 was associated with a marginally significant decrease in oral cancer risk [odds ratio (OR) = 0.6, 95% confidence interval (CI) = 0.3-1.0, and P for trend = 0.09]. Risks increased with increasing cigarette use among subjects with the GSTM1-present genotype (P for trend <0.0001), rising to OR = 9.5, 95% Cl = 3.0-30, among the heaviest cigarette users. In contrast, among subjects with the GSTM1-null genotype, risks did not clearly increase with increasing cigarette use (P for trend <0.61; OR = 1.8, 95% Cl = 0.6-5.2 among the heaviest tobacco users). The GSTT1-null variant (OR = 1.0, 95% Cl = 0.5-1.9) and CYP1A1(462Val) variant (OR = 0.9, 95% CI = 0.5-1.7) were not associated with the risk. Risks rose with increasing cigarette use in a similar manner for subjects with or without the CYP1A1(462Val) variant (P for interaction = 0.3) and for subjects with or without the GSTT1-null genotype (P for interaction = 0.4). In conclusion, cigarette use significantly increased the risk of oral cancer in this population. The GSTM1-present genotype was associated with higher tobacco-associated risk for oral cancer among heavy smokers than the null genotype. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. Univ Puerto Rico, Sch Dent, San Juan, PR 00936 USA. UMDNJ, New Jersey Dent Sch, Ctr Pharmacogenom & Complex Dis Res, Newark, NJ 07101 USA. RP Hayes, RB (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Rm 8114,6120 Execut Blvd, Bethesda, MD 20892 USA. EM hayesr@mail.nih.gov RI Shields, Peter/I-1644-2012 NR 37 TC 24 Z9 25 U1 1 U2 2 PU COGNIZANT COMMUNICATION CORP PI ELMSFORD PA 3 HARTSDALE ROAD, ELMSFORD, NY 10523-3701 USA SN 0965-0407 J9 ONCOL RES JI Oncol. Res. PY 2004 VL 14 IS 6 BP 315 EP 320 PG 6 WC Oncology SC Oncology GA 827JL UT WOS:000221895500006 PM 15206494 ER PT S AU Vogel, A Hassan, M Hattery, D Demos, S Russo, A Tao, Y Gandjbakhche, A AF Vogel, A Hassan, M Hattery, D Demos, S Russo, A Tao, Y Gandjbakhche, A BE Alfano, RR Katz, A TI Multimodality imaging techniques to assess collagen breakdown in mouse model after radiation SO OPTICAL BIOPSY V SE PROCEEDINGS OF THE SOCIETY OF PHOTO-OPTICAL INSTRUMENTATION ENGINEERS (SPIE) LA English DT Proceedings Paper CT Conference on Optical Biopsy V CY JAN 27-28, 2004 CL San Jose, CA SP SPIE C1 NIH, Bethesda, MD 20892 USA. RP Vogel, A (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-5234-3 J9 P SOC PHOTO-OPT INS PY 2004 VL 5326 BP 130 EP 130 PG 1 WC Engineering, Biomedical; Optics; Spectroscopy SC Engineering; Optics; Spectroscopy GA BAS05 UT WOS:000223341600022 ER PT S AU Hattery, D Hassan, M Vogel, A Demos, S Yarchoan, R Gandjbakhche, A AF Hattery, D Hassan, M Vogel, A Demos, S Yarchoan, R Gandjbakhche, A BE Alfano, RR Katz, A TI Two-layer model-based spectroscopic analysis of multispectral NIR images of embedded tumors SO OPTICAL BIOPSY V SE PROCEEDINGS OF THE SOCIETY OF PHOTO-OPTICAL INSTRUMENTATION ENGINEERS (SPIE) LA English DT Proceedings Paper CT Conference on Optical Biopsy V CY JAN 27-28, 2004 CL San Jose, CA SP SPIE C1 NIH, Bethesda, MD 20892 USA. RP Hattery, D (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-5234-3 J9 P SOC PHOTO-OPT INS PY 2004 VL 5326 BP 131 EP 131 PG 1 WC Engineering, Biomedical; Optics; Spectroscopy SC Engineering; Optics; Spectroscopy GA BAS05 UT WOS:000223341600023 ER PT S AU Simonsen, L Reichert, TA Blackwelder, WC Miller, MA AF Simonsen, L Reichert, TA Blackwelder, WC Miller, MA BE Kawaoka, Y TI Benefits of influenza vaccination on influenza-related mortality among elderly in the US: an unexpected finding SO OPTIONS FOR THE CONTROL OF INFLUENZA V SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 5th International Conference on Options for the Control of Influenza CY OCT 07-11, 2003 CL Okinawa, JAPAN SP Pharmaceut Manufacturers Assoc Tokyo, Pharmaceut Assoc Osaka, Wyeth Vaccine, MedImmune, Fujirebio, Nagoya City Univ, Takara Bio, Rikaken, Japan Bio Sci Lab, Japanese Soc Control Influenza, Japanese Fdn Promot Int Med Res Corp, Japanese Soc Virol, Japanese Soc Clin Virol, NPO Biomed Sci Assoc, WHO, Minist Hlth, Labor & Welfare Japan DE influenza; mortality; mathematical models; influenza vaccination AB Although elderly influenza vaccination coverage increased from similar to 15% to similar to 65% during 1980-1999 in the US, estimates of influenza-related mortality also increased during this period. We examined these apparently conflicting findings by adjusting mortality estimates for aging within the elderly and the incidence of influenza A (H3N2) virus circulation. Using national mortality statistics for 1968 through 1999, we generated age-specific monthly rates for pneumonia and influenza (P&I) and all-cause mortality for persons greater than or equal to65 years of age. We estimated influenza-related mortality as the winter excess in mortality over a Serfling model baseline. After adjusting for age and considering only A (H3N2)-dominated seasons, we found that excess mortality declined sharply among younger elderly (65-74 years) during 1968-1980, but remained level after 1980. Among the most elderly (85+ years), excess mortality rates were essentially unchanged over the entire study period. In conclusion, the increase in elderly influenza vaccination coverage in the US after 1980 was not accompanied by a decline in influenza-related mortality. We hypothesize that disparity in vaccination rates among frail elderly, combined with reduced responsiveness to vaccination with age, may account for these findings. (C) 2004 Elsevier B.V. All rights reserved. C1 NIAID, NIH, Bethesda, MD 20892 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Simonsen, L (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 11 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51639-5 J9 INT CONGR SER PY 2004 VL 1263 BP 163 EP 167 DI 10.1016/j.ics.2004.02.038 PG 5 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BAU81 UT WOS:000223655000035 ER PT S AU Cauchemez, S Carrat, F Viboud, C Valleron, AJ Boelle, PY AF Cauchemez, S Carrat, F Viboud, C Valleron, AJ Boelle, PY BE Kawaoka, Y TI Quantifying the role of children in influenza spread: an analysis of household follow-up SO OPTIONS FOR THE CONTROL OF INFLUENZA V SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 5th International Conference on Options for the Control of Influenza CY OCT 07-11, 2003 CL Okinawa, JAPAN SP Pharmaceut Manufacturers Assoc Tokyo, Pharmaceut Assoc Osaka, Wyeth Vaccine, MedImmune, Fujirebio, Nagoya City Univ, Takara Bio, Rikaken, Japan Bio Sci Lab, Japanese Soc Control Influenza, Japanese Fdn Promot Int Med Res Corp, Japanese Soc Virol, Japanese Soc Clin Virol, NPO Biomed Sci Assoc, WHO, Minist Hlth, Labor & Welfare Japan DE influenza; infectious disease; household; MCMC ID TRANSMISSION; CONTACTS AB Quantifying the role of children in influenza spread is needed to propose efficient strategies to control influenza epidemics. We developed a statistical model to estimate all parameters required in this evaluation. It was applied to a data set consisting of the follow-up of influenza symptoms in 1124 subjects from 334 households during 15 days. For each clinical case, the data were augmented with the unobserved dates of the start and the end of the infectious period. The posterior distribution of the parameters was obtained using Markov Chain Monte Carlo sampling. We estimated that children were more likely to transmit than adults (posterior probability: 98%), but that the average infectious period was similar in children (3.4 days, 95% confidence interval CI [1.8,5.2]) and adults (3.8 days, CI [2.9,4.7]). The posterior probability that children had a larger community risk was 77% and the posterior probability that they were more susceptible than adults was 75%. From simulation, we found that considering a child immune in a household led to a decrease of the probability of infection for adults twice as large as when considering an adult immune, and had the same effect on children as when considering two adults immune. (C) 2004 Elsevier B.V. All rights reserved. C1 INSERM, U444, F-75571 Paris 12, France. Assistance Publ Hop, Paris, France. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Cauchemez, S (reprint author), INSERM, U444, 27 Rue Chaligny, F-75571 Paris 12, France. NR 5 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51639-5 J9 INT CONGR SER PY 2004 VL 1263 BP 288 EP 290 DI 10.1016/j.ics.2004.02.065 PG 3 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BAU81 UT WOS:000223655000063 ER PT S AU Viboud, C Boelle, PY Cauchemez, S Lavenu, A Valleron, AJ Flahault, A Carrat, F AF Viboud, C Boelle, PY Cauchemez, S Lavenu, A Valleron, AJ Flahault, A Carrat, F BE Kawaoka, Y TI Risk factors of influenza transmission in households SO OPTIONS FOR THE CONTROL OF INFLUENZA V SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 5th International Conference on Options for the Control of Influenza CY OCT 07-11, 2003 CL Okinawa, JAPAN SP Pharmaceut Manufacturers Assoc Tokyo, Pharmaceut Assoc Osaka, Wyeth Vaccine, MedImmune, Fujirebio, Nagoya City Univ, Takara Bio, Rikaken, Japan Bio Sci Lab, Japanese Soc Control Influenza, Japanese Fdn Promot Int Med Res Corp, Japanese Soc Virol, Japanese Soc Clin Virol, NPO Biomed Sci Assoc, WHO, Minist Hlth, Labor & Welfare Japan DE influenza/epidemiology; transmission; household studies; child; risk factor ID INFECTIONS; CONTACTS; ILLNESS; FAMILY AB We quantify here the risk factors of influenza transmission in households from a prospective study conducted in the 1999-2000 winter season in France. Two hundred seventy-nine households were enrolled in the study, where a member-the index case-visited his/her general practitioner for influenza-like illness and tested positive for influenza A/H3N2. A standardized daily questionnaire allowed for identification of secondary cases of clinical influenza among the 543 contacts followed up for 15 days. Overall, 131 secondary cases occurred among the 543 household contacts (24.1%). There was an increased risk of clinical influenza in preschool contacts as compared with older contacts. There was also an increased risk in contacts exposed to preschool index cases and school-age index cases as compared with those exposed to adult index cases. No other factor was associated with transmission of the disease. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Paris 06, INSERM, Epidemiol & Informat Sci, U444,CHU St Antoine, F-75571 Paris 12, France. RP Viboud, C (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. NR 10 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51639-5 J9 INT CONGR SER PY 2004 VL 1263 BP 291 EP 294 DI 10.1016/j.ics.2004.01.013 PG 4 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BAU81 UT WOS:000223655000064 ER PT S AU Simonsen, L Reichert, TA Miller, MA AF Simonsen, L Reichert, TA Miller, MA BE Kawaoka, Y TI The virtues of antigenic sin: consequences of pandemic recycling on influenza-associated mortality SO OPTIONS FOR THE CONTROL OF INFLUENZA V SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 5th International Conference on Options for the Control of Influenza CY OCT 07-11, 2003 CL Okinawa, JAPAN SP Pharmaceut Manufacturers Assoc Tokyo, Pharmaceut Assoc Osaka, Wyeth Vaccine, MedImmune, Fujirebio, Nagoya City Univ, Takara Bio, Rikaken, Japan Bio Sci Lab, Japanese Soc Control Influenza, Japanese Fdn Promot Int Med Res Corp, Japanese Soc Virol, Japanese Soc Clin Virol, NPO Biomed Sci Assoc, WHO, Minist Hlth, Labor & Welfare Japan DE pandemic influenza; mortality; models; sero-archaeology AB The 1969 influenza A(H3N2) "Hong Kong" pandemic in the United States was characterized by recycling of the H3 antigen, which reemerged after 77 years of absence. Sero-archaeological studies conducted on blood samples, collected in early 1968, demonstrated that the majority of the very elderly had H3 antibodies prior to the time they were exposed to the 1968 A(H3N2) pandemic virus. These antibodies were remnants of exposure to H3N2 viruses circulating before 1891. Others have hypothesized that these pre-existing antibodies should have conveyed a protective effect during the 1968 A(H3N2) pandemic, but this has never been demonstrated. In this study, we used national pneumonia and influenza (P&I) mortality data to demonstrate that the elderly age cohort over the age of 77 was, in fact, protected from influenza-related mortality during the 1968 pandemic. We found that the risk of influenza-related mortality among the elderly aged 75-79 and older, measured as excess P&I mortality, did not increase during the pandemic relative to surrounding severe non-pandemic influenza seasons. These findings have an implication for pandemic planning and the prioritization of high-risk groups for vaccination in the scenario of vaccine shortage. (C) 2004 Elsevier B.V. All rights reserved. C1 NIAID, Off Global Affairs, NIH, Bethesda, MD 20892 USA. Entropy Res Inst, Fogarty Int Ctr, NIH, Bethesda, MD USA. RP Simonsen, L (reprint author), NIAID, Off Global Affairs, NIH, 6610 Rockledge Dr,Rm 2033, Bethesda, MD 20892 USA. NR 5 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51639-5 J9 INT CONGR SER PY 2004 VL 1263 BP 791 EP 794 DI 10.1016/j.ics.2004.01.029 PG 4 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BAU81 UT WOS:000223655000179 ER PT S AU Matsuoka, Y Subbarao, K Chen, HL Warnes, C Altholtz, M Jadhao, S Swayne, D Cox, N AF Matsuoka, Y Subbarao, K Chen, HL Warnes, C Altholtz, M Jadhao, S Swayne, D Cox, N BE Kawaoka, Y TI Development and evaluation of candidate influenza a vaccines for pandemic preparedness SO OPTIONS FOR THE CONTROL OF INFLUENZA V SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 5th International Conference on Options for the Control of Influenza CY OCT 07-11, 2003 CL Okinawa, JAPAN SP Pharmaceut Manufacturers Assoc Tokyo, Pharmaceut Assoc Osaka, Wyeth Vaccine, MedImmune, Fujirebio, Nagoya City Univ, Takara Bio, Rikaken, Japan Bio Sci Lab, Japanese Soc Control Influenza, Japanese Fdn Promot Int Med Res Corp, Japanese Soc Virol, Japanese Soc Clin Virol, NPO Biomed Sci Assoc, WHO, Minist Hlth, Labor & Welfare Japan DE influenza A; pandemic vaccine; reassortment AB Pandemic vaccine seed viruses for H5N1, H5N2 and H9N2 subtypes were prepared and evaluated. Formalin-inactivated reassortant vaccines using A/Puerto Rico/8/34 (PR8) as a donor of internal genes with surface glycoprotein genes, hemagglutinin (HA) and neuraminidase (NA), of H5N2 and H9N2 subtypes, were generated by conventional reassortment. A reassortant virus for the highly pathogenic H5N1 subtype was prepared using reverse genetics with a genetically modified HA gene. All candidate vaccines were immunogenic in mice and ferrets, and mice immunized with inactivated vaccines were completely protected against challenge infection with wild-type parent viruses. All viruses were non-pathogenic for chickens in the standard USDA pathotyping test. (C) 2004 Published by Elsevier B.V. C1 Ctr Dis Control & Prevent, Influenza Branch, Atlanta, GA 30333 USA. NIH, Lab Infect Dis, Bethesda, MD USA. Harbin Vet Res Inst, Harbin, Peoples R China. USDA, SE Poultry Res Lab, Athens, GA USA. RP Matsuoka, Y (reprint author), Ctr Dis Control & Prevent, Influenza Branch, 1600 Clifton Rd NE,MS-G16, Atlanta, GA 30333 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51639-5 J9 INT CONGR SER PY 2004 VL 1263 BP 813 EP 817 DI 10.1016/j.ics.2004.01.045 PG 5 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA BAU81 UT WOS:000223655000184 ER PT J AU Zhao, JL Mao, J Luo, R Li, FR Pokharel, GP Ellwein, LB AF Zhao, JL Mao, J Luo, R Li, FR Pokharel, GP Ellwein, LB TI Accuracy of noncycloplegic autorefraction in school-age children in China SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE astigmatism; autorefraction; children's vision; cycloplegia; refractive error ID HAND-HELD AUTOREFRACTOR; REFRACTIVE ERROR; SINGAPOREAN CHILDREN; MYOPIA; POPULATION; PROGRESSION; ASTIGMATISM AB Purpose. To evaluate the accuracy of noncycloplegic autorefraction in a representative sample of school-age children in China. Methods. Refractive error was measured with an autorefractor, both before and after cycloplegia induced with cyclopentolate, in a population-based sample of 4973 children between the ages of 7 and 18 years. Spherical equivalent refractive error and astigmatism as represented by Jackson crossed-cylinders (J(0) and J(45)) were the main outcome measures. Results. Noncycloplegic measurements of equivalent spheres were consistently more negative or less positive than those after cycloplegia, with mean +/- SD differences of -1.23 +/- 0.97 D. The differences were particularly large for hyperopic eyes (mean difference of -2.98 +/- 1.65 D for hyperopia of at least +2.00 D) while becoming progressively smaller for emmetropic eyes, and smaller yet for myopic eyes (mean difference of -0.41 +/- 0.46 D for myopia of -2.00 D or more). Increasing age was associated with increased, but clinically insignificant, differences. Little difference was found between noncycloplegic and cycloplegic measurements of astigmatism: mean J(0) and J(45) differences were -0.08 +/- 0.13 D and -0.01 +/- 0.09 D, respectively. Conclusions. Noncycloplegic autorefraction was found to be highly inaccurate in school-age children and, thus, not suitable for studies of refractive error or for prescription of glasses in this population. C1 NEI, NIH, Bethesda, MD 20892 USA. WHO, CH-1211 Geneva, Switzerland. Beijing Union Med Coll Hosp, Dept Ophthalmol, Beijing, Peoples R China. Chinese Acad Med Sci, Eye Res Ctr, Beijing 100037, Peoples R China. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM ellweinl@nei.nih.gov FU NEI NIH HHS [N01-EY-2103] NR 25 TC 47 Z9 52 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD JAN PY 2004 VL 81 IS 1 BP 49 EP 55 DI 10.1097/00006324-200401000-00010 PG 7 WC Ophthalmology SC Ophthalmology GA 768XK UT WOS:000188596000009 PM 14747761 ER PT J AU Akintoye, SO Otis, LL Atkinson, JC Brahim, J Kushner, H Robey, PG Collins, MT AF Akintoye, SO Otis, LL Atkinson, JC Brahim, J Kushner, H Robey, PG Collins, MT TI Analyses of variable panoramic radiographic characteristics of maxillo-mandibular fibrous dysplasia in McCune-Albright syndrome SO ORAL DISEASES LA English DT Article DE fibrous dysplasia; radiograph; maxilla; mandible; McCune-Albright syndrome ID CEMENTO-OSSIFYING FIBROMAS; DISTINGUISHING FEATURES; FIBROOSSEOUS LESIONS; BONE; JAWS; ENDOCRINOPATHIES; HYPERTHYROIDISM; DYSFUNCTION; MUTATIONS; SPECTRUM AB OBJECTIVE: Fibrous dysplasia (FD) is a rare skeletal disease caused by activating GNAS1 gene mutations often found in association with the McCune-Albright syndrome (MAS). Multiple bones may be affected in FD, including maxilla and mandible. Patients with MAS have different endocrinopathies that can further influence bone metabolism. The purposes of this cross-sectional study are to characterize FD panoramic radiographic patterns, and to evaluate the effects of age, endocrinopathies and renal phosphate wasting on radiographic characteristics of maxillo-mandibular FD in MAS. SUBJECTS AND METHODS: Fifty-one consecutive MAS patients were screened and panoramic radiographs of 43 patients with craniofacial FD were evaluated and analyzed for FD involvement. Clinical chemistries were evaluated for associations between radiographic patterns and age, endocrinopathies or renal phosphate wasting using Fisher's Exact Test. RESULTS: Four types of radiographic changes were observed: ground glass (granular/condensed trabeculae), radiolucent (lytic), mixed radiolucent/radio-opaque (mixed density) or radio-opaque (sclerotic). Masking or displacement of the maxillary sinus (range: 77.8-86.4%) and mandibular canal (range: 55.6-75.0%) were prevalent in FD sites. Sixty-three percent of the MAS patients had multiple dysregulated endocrine/metabolic functions, the most common were hyperthyroidism, precocious puberty and renal phosphate wasting. There were no statistically significant associations between radiographic patterns and age, endocrinopathies or renal phosphate wasting. CONCLUSIONS: Maxillo-mandibular FD images in panoramic radiographs fall within a spectrum of four different patterns. Patients with facial asymmetry and any of these radiographic patterns should be promptly referred for further radiographic tests and endocrine evaluation if MAS is suspected. C1 Univ Penn, Sch Dent Med, Dept Oral Med, Robert Schattner Ctr, Philadelphia, PA 19104 USA. Natl Inst Dent & Craniofacila Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. Univ Maryland, Sch Dent, Dept Oral Med & Diagnost Sci, Baltimore, MD 21201 USA. Biomed Comp Inst, Philadelphia, PA USA. RP Akintoye, SO (reprint author), Univ Penn, Sch Dent Med, Dept Oral Med, Robert Schattner Ctr, Room 212,240 S 40th St, Philadelphia, PA 19104 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 38 TC 8 Z9 10 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1354-523X J9 ORAL DIS JI Oral Dis. PD JAN PY 2004 VL 10 IS 1 BP 36 EP 43 DI 10.1046/j.1354-523X.2003.00971.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 756EH UT WOS:000187452500008 PM 14996293 ER PT S AU Fleeton, M Contractor, N Leon, F He, JP Wetzel, D Dermody, T Iwasaki, A Kelsall, B AF Fleeton, M Contractor, N Leon, F He, JP Wetzel, D Dermody, T Iwasaki, A Kelsall, B BE Weiner, HL Mayer, L Strober, W TI Involvement of dendritic cell subsets in the induction of oral tolerance and immunity SO ORAL TOLERANCE: NEW INSIGHTS AND PROSPECTS FOR CLINICAL APPLICATION SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Oral Tolerance CY OCT 23-26, 2003 CL New York, NY SP New York Acad Sci DE dendritic cell; tolerance; cytokines; reovirus ID T-CELLS; REOVIRUS INFECTION; EPITHELIAL-CELLS; PEYERS-PATCHES; NEONATAL MICE; IN-VIVO; MUCOSAL; RESPONSES; ANTIGEN; CD8-ALPHA(+) AB Dendritic cells (DCs) play a central role in the generation of immune responses in the intestine. I)Cs induce differentiation and tolerance of T cells, and may have a direct role in B cell switching to IgA. Four distinct. subsets of CD11c(+) DCs are present in murine Peyer's patches, which represent primary sites for the induction of mucosal T and B cell responses. Studies suggest that CD11b+ DCs or plasmacytoid DCs may be specialized for the induction of regulatory T cells, and CD8 alpha(+) DCs for the induction of clonal deletion in response to soluble oral antigen, while all DC subsets (including CD8 alpha(-)/CD11b(-) DCs) may be involved in responses to pathogens. We are currently using reovirus type-1 Lang (T1L) to explore the role of DC populations in mucosal immunity in vivo, as oral administration of live T1L to mice induces strong mucosal and systemic antiviral immune responses, whereas oral administration of inactivated T1L results in tolerance to viral proteins. We found that primary infection with T1L occurs in epithelial cells of the PP follicle-associated epithelium, but that CD8a-/CD11b- DCs in the subepithelial dome region (SED) are loaded with T1L antigens in the absence of active DC infection. At least a portion of this antigen is associated with cell fragments from apoptotic epithelial cells, demonstrating that SED DCs cross-present antigens from apoptotic epithelial cells. In vitro, in contrast to exposure to several TLR-ligands or anti-CD40, exposure to T1L does not activate DCs to mature or to produce cytokines, despite clear loading of the DCs with viral antigens. These data suggest that T1L is taken up by a "silent" receptor on DCs, and that the induction of immunity to T1L is dependent on signals from non-DCs following active viral infection that induce DC maturation. Thus, the decision between tolerance and immunity to inactive and live virus, respectively, likely depends on whether there is active infection of epithelial cells by T1L, which results in the elaboration of molecules, such as cytokines, that induce DC maturation. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. RP Kelsall, B (reprint author), Lab Mol Immunol, Mucosal Immunobiol Sect, 10-11 N228,10 Ctr Dr, Bethesda, MD 20892 USA. EM Kelsall@nih.gov NR 26 TC 26 Z9 27 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-508-7 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1029 BP 60 EP 65 DI 10.1196/annals.1309.008 PG 6 WC Immunology; Multidisciplinary Sciences SC Immunology; Science & Technology - Other Topics GA BBT79 UT WOS:000227728600008 PM 15681744 ER PT S AU Strober, W Fuss, I Boirivant, M Kitani, A AF Strober, W Fuss, I Boirivant, M Kitani, A BE Weiner, HL Mayer, L Strober, W TI Insights into the mechanism of oral tolerance derived from the study of models of mucosal inflammation SO ORAL TOLERANCE: NEW INSIGHTS AND PROSPECTS FOR CLINICAL APPLICATION SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Oral Tolerance CY OCT 23-26, 2003 CL New York, NY SP New York Acad Sci DE regulatory T cells; cell-transfer colitis; TGF-beta; TNBS-colitis; IL-10 ID REGULATORY T-CELLS; TGF-BETA; DENDRITIC CELLS; EXPERIMENTAL COLITIS; MURINE COLITIS; IN-VIVO; MICE; IL-10; DIFFERENTIATION; INDUCTION AB Murine models of mucosal inflammation are frequently due to the inability of the mouse to mount a regulatory T cell response. To the extent that such responses arise from oral tolerance mechanisms, these models provide a unique way of studying oral tolerance. In this paper we focus on the regulatory cells generated in two of the most well-studied of such models, the cell-transfer model and the TNBS-colitis model. Our analysis leads to the view that regulatory cells generated by the oral tolerance seen in mucosal inflammation are, at least in part, cells that recognize self-antigens or antigens in the mucosal microflora whose effector function relies on the expression of TGF-beta. C1 NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. Ist Super Sanita, Dept Infect Parasit & Immune Mediated Dis, Immune Mediated Dis Sect, Rome, Italy. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov; wstrober@niaid.nih.gov RI BOIRIVANT, MONICA/B-9977-2016 NR 39 TC 12 Z9 12 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-508-7 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1029 BP 115 EP 131 DI 10.1196/annals.1309.029 PG 17 WC Immunology; Multidisciplinary Sciences SC Immunology; Science & Technology - Other Topics GA BBT79 UT WOS:000227728600015 PM 15681751 ER PT S AU Kaser, A Nieuwenhuis, EES Strober, W Mayer, L Fuss, I Colgan, S Blumberg, RS AF Kaser, A Nieuwenhuis, EES Strober, W Mayer, L Fuss, I Colgan, S Blumberg, RS BE Weiner, HL Mayer, L Strober, W TI Natural killer T cells in mucosal homeostasis SO ORAL TOLERANCE: NEW INSIGHTS AND PROSPECTS FOR CLINICAL APPLICATION SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Oral Tolerance CY OCT 23-26, 2003 CL New York, NY SP New York Acad Sci DE mucosal homeostasis; inflammatory bowel disease; CD1; CD1d; natural killer T (NKT) cells; epithelial cells; antigen-presenting cells ID INTESTINAL EPITHELIAL-CELLS; INFLAMMATORY-BOWEL-DISEASE; I-LIKE MOLECULE; NKT CELLS; PSEUDOMONAS-AERUGINOSA; TISSUE DISTRIBUTION; ULCERATIVE-COLITIS; OXAZOLONE COLITIS; CRYSTAL-STRUCTURE; DENDRITIC CELLS AB The mucosal-associated lymphoid tissues (MALT), including the gut-associated lymphoid tissues, are a tightly regulated environment. In fact, it might be stated that on the basis of studies from animal models of inflammatory bowel disease (IBD), the major means of peripheral regulation of immune responses in the intestine is not necessarily from processes such as deletion or anergy, but more likely from the controls imposed upon responses due to the activities of a variety of regulatory subsets of cells. One type of regulatory cellular subset that has recently gained attention is the subset of T cells that are associated with CD1d-restricted responses. Recently, CD1d-restricted T cells have been increasingly appreciated to play a significant role in mucosal tissues of the intestine and lung, for example. Insights from these studies have clearly elevated these cells to particular importance in the regulation of a variety of infectious and inflammatory conditions, such as those associated with idiopathic IBD. In this review, we focus on recent observations on the characteristics of CD1d-restricted pathways in mucosal compartments, after a brief introduction into the biology of CD1d and CD1d-restricted T cells. C1 Harvard Univ, Brigham & Womens Hosp, Div Gastroenterol, Sch Med, Boston, MA 02115 USA. Erasmus Med Ctr, Rotterdam, Netherlands. NIH, Bethesda, MD 20892 USA. Mt Sinai Sch Med, New York, NY 10029 USA. RP Blumberg, RS (reprint author), Harvard Univ, Brigham & Womens Hosp, Div Gastroenterol, Sch Med, 75 St Francis St, Boston, MA 02115 USA. EM rblumberg@partners.org NR 62 TC 9 Z9 10 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-508-7 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1029 BP 154 EP 168 DI 10.1196/annals.1309.032 PG 15 WC Immunology; Multidisciplinary Sciences SC Immunology; Science & Technology - Other Topics GA BBT79 UT WOS:000227728600018 PM 15681754 ER PT S AU Nagler-Anderson, C Strober, W AF Nagler-Anderson, C Strober, W BE Weiner, HL Mayer, L Strober, W TI Mechanisms of oral tolerance: Regulatory T cells - Summary of Part III SO ORAL TOLERANCE: NEW INSIGHTS AND PROSPECTS FOR CLINICAL APPLICATION SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Oral Tolerance CY OCT 23-26, 2003 CL New York, NY SP New York Acad Sci C1 Massachusetts Gen Hosp E, Mucosal Immun Lab, Boston, MA 02129 USA. NIH, Bethesda, MD 20892 USA. RP Nagler-Anderson, C (reprint author), Massachusetts Gen Hosp E, Mucosal Immun Lab, Bldg 114,16th Mail Stop 114-3503, Boston, MA 02129 USA. EM cnagleranderson@partners.org NR 0 TC 1 Z9 1 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-508-7 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1029 BP 169 EP 171 DI 10.1196/annals.1309.026 PG 3 WC Immunology; Multidisciplinary Sciences SC Immunology; Science & Technology - Other Topics GA BBT79 UT WOS:000227728600019 ER PT S AU Nussenblatt, R AF Nussenblatt, R BE Weiner, HL Mayer, L Strober, W TI Orally and nasally induced tolerance studies in ocular inflammatory disease - Guidance for future interventions SO ORAL TOLERANCE: NEW INSIGHTS AND PROSPECTS FOR CLINICAL APPLICATION SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Oral Tolerance CY OCT 23-26, 2003 CL New York, NY SP New York Acad Sci DE uveitis; oral tolerance; nasal tolerance; corneal engraftment ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; RETINAL S-ANTIGEN; UVEITIS-PATIENTS; INDUCTION; PEPTIDE; AUTOANTIGEN; RATS AB The induction of both oral and nasal tolerance has been used in both experimental models of ocular disease and clinically. Initial work centered around the abrogation of experimental autoimmune uveitis using either one or two whole uveitogenic antigens. Other models of ocular disease have included a corneal transplant model, demonstrating that feeding splenocytes from the donor strain of rats enhanced corneal engraftment. Fragments of pertinent antigens have been shown to alter the expression of experimental uveitis and possibly human disease. A randomized, masked study in uveitis provided valuable information for future studies, demonstrating that single antigen feeding provided far better protection than the feeding of multiple antigens. This review will deal with animal and human studies in the treatment of ocular inflammatory disease with the goal of extracting from past experience how to construct a future study in humans. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, R (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10S219,10 Ctr Dr, Bethesda, MD 20892 USA. EM DrBob@nei.nih.gov NR 18 TC 5 Z9 5 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-508-7 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1029 BP 278 EP 285 DI 10.1196/annals.1309.058 PG 8 WC Immunology; Multidisciplinary Sciences SC Immunology; Science & Technology - Other Topics GA BBT79 UT WOS:000227728600029 PM 15681765 ER PT S AU Strober, W AF Strober, W BE Weiner, HL Mayer, L Strober, W TI Oral tolerance: Animal disease models and human trials - Summary of Part V SO ORAL TOLERANCE: NEW INSIGHTS AND PROSPECTS FOR CLINICAL APPLICATION SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Oral Tolerance CY OCT 23-26, 2003 CL New York, NY SP New York Acad Sci C1 NIAID, Host Def Lab, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Host Def Lab, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov; wstrober@niaid.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-508-7 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1029 BP 310 EP 312 DI 10.1196/annals.1309.078 PG 3 WC Immunology; Multidisciplinary Sciences SC Immunology; Science & Technology - Other Topics GA BBT79 UT WOS:000227728600032 ER PT J AU Pearce, LV Petukhov, PA Szabo, T Kedei, N Bizik, F Kozikowski, AP Blumberg, PM AF Pearce, LV Petukhov, PA Szabo, T Kedei, N Bizik, F Kozikowski, AP Blumberg, PM TI Evodiamine functions as an agonist for the vanilloid receptor TRPV1 SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID COMPETITIVE ANTAGONIST; THIOUREA DERIVATIVES; POSSIBLE INVOLVEMENT; RUTAECARPA; CAPSAICIN; FRUITS; BINDING AB Evodiamine, a quinozole alkaloid constituent of Evodia rutaecarpa, has been reported previously to induce several responses comparable to capsaicin in animal systems. Here, we characterize evodiamine as an agonist for rat TRPV1 expressed heterologously in CHO cells. Evodiamine bound to rat TRPV1 with a K-i of 5.95+/-0.87 muM, as measured by inhibition of [H-3] RTX binding (capsaicin, K-i=1.8+/-0.3 muM). Evodiamine was a full agonist for induction of Ca-45(2+) uptake, with an EC50 of 856+/-43 nM (capsaicin, EC50=45+/-4 nM) and was competitively antagonized by capsazepine, as revealed by a Schild plot. The pattern of cellular response, as determined by calcium imaging, was similar to that with capsaicin and yielded an EC50 of 1.03+/-0.21 muM. Molecular modeling suggested a consistent pattern of overlap between evodiamine and TRPV1 agonists. We conclude that evodiamine represents a novel class of agonists for rat TRPV1, albeit 3-19-fold less potent than capsaicin, and thus represents a new potential class of lead molecules for drug development. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bldg 37,Room 4048,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov NR 13 TC 34 Z9 37 U1 1 U2 2 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PY 2004 VL 2 IS 16 BP 2281 EP 2286 DI 10.1039/b404506h PG 6 WC Chemistry, Organic SC Chemistry GA 845FC UT WOS:000223221600006 PM 15305207 ER PT J AU Talanova, GG Talanov, VS Hwang, HS Park, C Surowiec, K Bartsch, RA AF Talanova, GG Talanov, VS Hwang, HS Park, C Surowiec, K Bartsch, RA TI Rigid versus flexible: how important is ligand "preorganization" for metal ion recognition by lower rim-functionalized calix[4]arenes? SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID CONFORMATIONAL ISOMERS; SOLVENT-EXTRACTION; COMPLEXATION; CATIONS; SELECTIVITY; ALKALI; CALIX<4>ARENES; DESIGN; CAVITY; ARENE AB For an assessment of the outcomes from use of an appropriately "preorganized" calixarene-based ionophore versus its conformationally mobile prototype, solvent extraction propensities of flexible calix[4] arene di-[N-(X-sulfonyl) carboxamides] for alkali, alkaline earth metal cations, Pb2+, Ag+ and Hg2+ are compared with those for seven new rigid analogs fixed in the cone, partial cone and 1,3-alternate conformations. For each of the metal ions, the preferred calix[4] arene conformation was determined from the NMR spectra for the metal salt of the flexible ligand. Except for Ag+, flexible calix[4] arene di-[N-(X-sulfonyl) carboxamides] were found to provide greater metal ion extraction efficiency and better selectivity than the corresponding "preorganized" ionophores. C1 Howard Univ, Dept Chem, Washington, DC 20059 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Texas Tech Univ, Dept Chem & Biochem, Lubbock, TX 79409 USA. RP Talanova, GG (reprint author), Howard Univ, Dept Chem, 525 Coll St NW, Washington, DC 20059 USA. EM gtalanova@howard.edu; richard.bartsch@ttu.edu NR 28 TC 18 Z9 19 U1 0 U2 3 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PY 2004 VL 2 IS 18 BP 2585 EP 2592 DI 10.1039/b407812h PG 8 WC Chemistry, Organic SC Chemistry GA 851IU UT WOS:000223679600008 PM 15351822 ER PT J AU Svarovsky, SA Taraban, MB Barchi, JJ AF Svarovsky, SA Taraban, MB Barchi, JJ TI Facile photochemical synthesis of mixed siloxyacetal glycosides as potential pH-sensitized prodrugs for selective treatment of solid tumors SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID ALPHA-SILYL KETONES; INTRACELLULAR PH; ACYL SILANES; MECHANISTIC PHOTOCHEMISTRY; STEREOSELECTIVE SYNTHESIS; ACYLSILANES; CHEMISTRY; CANCER; THERAPY; SILOXYCARBENES AB Photochemical reactions of a variety of acylsilanes with peracetylated free glycosides in anhydrous benzene at ambient temperature yielded novel, highly acid-sensitive siloxyacetal glycosides in 75-90% yields with complete retention of configuration at the anomeric center. Subsequent deacetylation of triisopropylsiloxy- and tert-butyldimethylsiloxy derivatives with sodium methoxide in methanol afforded deprotected siloxyacetal glycosides in nearly quantitative yields. Acid hydrolysis of trimethylsilyl siloxyacetals proceeded with a half-life of 17.5 minutes at pH 6.2 which is vastly superior to the decomposition rate of conventional acetals under similar conditions. The structure of one of the novel siloxyacetals was confirmed by X-ray crystallography. In vitro biological studies showed that glucose-derived siloxyacetals may serve as potential pH-activated prodrugs for selective treatment of solid tumors. C1 NCI, Med Chem Lab, Frederick, MD 21702 USA. Russian Acad Sci, Inst Chem Kinet & Combust, Siberian Div, Novosibirsk 630090, Russia. RP Svarovsky, SA (reprint author), NCI, Med Chem Lab, 376 Boyles St, Frederick, MD 21702 USA. EM ssvarovs@ncifcrf.gov RI Barchi Jr., Joseph/N-3784-2014 NR 57 TC 8 Z9 8 U1 1 U2 4 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PY 2004 VL 2 IS 21 BP 3155 EP 3161 DI 10.1039/b405786d PG 7 WC Chemistry, Organic SC Chemistry GA 865LA UT WOS:000224703400018 PM 15505722 ER PT J AU Lester, GE AF Lester, GE TI The osteoarthritis initative: A report from the national institutes of health SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT 9th World Congress of the Osteoarthritis-Research-Society-International CY DEC 02-05, 2004 CL Chicago, IL SP Osteoarthritis Res Soc Int C1 NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PY 2004 VL 12 SU B BP S3 EP S4 PG 2 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 879HY UT WOS:000225708200009 ER PT J AU Ling, SM Dredge, E Conwit, RA Metter, EJ AF Ling, SM Dredge, E Conwit, RA Metter, EJ TI Electromyographic characteristics associated with radiographic osteoarthritis of the knee SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT 9th World Congress of the Osteoarthritis-Research-Society-International CY DEC 02-05, 2004 CL Chicago, IL SP Osteoarthritis Res Soc Int C1 NIA, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PY 2004 VL 12 SU B BP S17 EP S18 PG 2 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 879HY UT WOS:000225708200042 ER PT J AU Matsumoto, K Kamiya, K Atsumi, F Shimizu, K Yamada, Y Kimata, K Watanabe, H AF Matsumoto, K Kamiya, K Atsumi, F Shimizu, K Yamada, Y Kimata, K Watanabe, H TI Proteoglycan aggregate of versican/PG-M in cartilage SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT 9th World Congress of the Osteoarthritis-Research-Society-International CY DEC 02-05, 2004 CL Chicago, IL SP Osteoarthritis Res Soc Int C1 Aichi Med Univ, Inst Mol Sci Med, Nagakute, Aichi 48011, Japan. Matsunami Gen Hosp, Dept Orthopaed Surg, Gifu, Japan. Gifu Univ, Sch Med, Dept Orthopaed Surg, Gifu 500, Japan. Natl Inst Dental & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PY 2004 VL 12 SU B BP S104 EP S104 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 879HY UT WOS:000225708200255 ER PT J AU Nevitt, MC Felson, DT Lester, GE AF Nevitt, MC Felson, DT Lester, GE TI Design and rationale of the Osteoarhtritis Initiative SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT 9th World Congress of the Osteoarthritis-Research-Society-International CY DEC 02-05, 2004 CL Chicago, IL SP Osteoarthritis Res Soc Int C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Boston Univ, Boston, MA 02215 USA. NIAMSD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PY 2004 VL 12 SU B BP S4 EP S4 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 879HY UT WOS:000225708200010 ER PT J AU Wildy, KS Kwoh, CK Newman, AB Boudreau, RM Peterfy, CP Carbone, LC Harris, TB Nevitt, MC AF Wildy, KS Kwoh, CK Newman, AB Boudreau, RM Peterfy, CP Carbone, LC Harris, TB Nevitt, MC TI Osteoarthritis MRI features associated with discordant knee pain in an elderly population SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT 9th World Congress of the Osteoarthritis-Research-Society-International CY DEC 02-05, 2004 CL Chicago, IL SP Osteoarthritis Res Soc Int C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Synarc Inc, San Francisco, CA USA. Univ Tennessee, Memphis, TN USA. NIA, Bethesda, MD 20892 USA. UCSF, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PY 2004 VL 12 SU B BP S18 EP S19 PG 2 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 879HY UT WOS:000225708200044 ER PT J AU Zhang, Z Fan, J Becker, KG Graff, RD Lee, GM Francomano, CA AF Zhang, Z Fan, J Becker, KG Graff, RD Lee, GM Francomano, CA TI Gene expression profiles of isolated human chondrons and chondrocytes - A comparative cDNA microarray study SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT 9th World Congress of the Osteoarthritis-Research-Society-International CY DEC 02-05, 2004 CL Chicago, IL SP Osteoarthritis Res Soc Int C1 NIA, IRP, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Univ N Carolina, Thurston Arthritis Canc Ctr, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PY 2004 VL 12 SU B BP S41 EP S41 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 879HY UT WOS:000225708200095 ER PT J AU Paloski, WH Black, TO Metter, EJ AF Paloski, WH Black, TO Metter, EJ TI Postflight balance control recovery in an elderly astronaut: A case report SO OTOLOGY & NEUROTOLOGY LA English DT Article DE balance; posturography; elderly; plasticity; astronaut; space flight; adaptation ID SPATIAL ORIENTATION; POSTURAL CONTROL; OLDER ADULTS; POSTUROGRAPHY; AGE AB Objective: To examine the sensorimotor adaptive response of a 77-year-old man exposed to the gravito-inertial challenges of orbital space flight. Study Design: Prospective case study with retrospective comparisons. Setting: NASA Neurosciences Laboratory (Johnson Space Center) and Baseline Data Collection Facility (Kennedy Space Center). Primary Participant: One 77-year-old mate shuttle astronaut. Intervention: Insertion into low Earth orbit was used to remove 2 : gravitational stimuli and thereby trigger sensorimotor adaptation to the microgravity environment. Graviceptor stimulation was reintroduced at landing, and sensorimotor readaptation to the terrestrial environment was tracked to completion. Main Outcome Measures: Computerized dynamic posturography tests were administered before and after orbital flight to determine the magnitude and time course of recovery. Results: The elderly astronaut exhibited balance control performance decrements on landing day; however, there were no significant differences between his performance and that of younger astronauts tested on the same shuttle mission or on previous shuttle missions of similar duration. Conclusions: These results demonstrate that the physiological changes attributed to aging do not necessarily impair adaptive sensorimotor control processes. C1 NASA, Lyndon B Johnson Space Ctr, Neurosci Lab, Houston, TX 77058 USA. Legacy Clin Res & Technol Ctr, Portland, OR USA. NIA, Clin Invest Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Paloski, WH (reprint author), NASA, Lyndon B Johnson Space Ctr, Neurosci Lab, Mail Code SK, Houston, TX 77058 USA. EM wpaloski@ems.jsc.nasa.gov FU NIA NIH HHS [1ZO1AG00014-41]; PHS HHS [00205] NR 19 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD JAN PY 2004 VL 25 IS 1 BP 53 EP 56 DI 10.1097/00129492-200401000-00011 PG 4 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 780JZ UT WOS:000189378700013 PM 14724493 ER PT J AU Joseph, EK Chen, XJ Khasar, SG Levine, JD AF Joseph, EK Chen, XJ Khasar, SG Levine, JD TI Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat SO PAIN LA English DT Article DE acquired immune deficiency syndrome; highly active anti-retroviral therapy; mitochondrial toxicity; nucleoside reverse transcriptase inhibitors; painful peripheral neuropathy; primary afferent nociceptor ID PROTEIN-KINASE-C; STREPTOZOTOCIN-DIABETIC RAT; ROOT GANGLION NEURONS; IMMUNODEFICIENCY-VIRUS-INFECTION; TOXIC NEUROPATHY; SENSORY NEURONS; RISK-FACTORS; 2',3'-DIDEOXYCYTIDINE DDC; ANTIRETROVIRAL THERAPY; ELECTRICAL-STIMULATION AB To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2,3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. Since suramin, an anti-parasitic and anti-cancer drug, which shares with the anti-retroviral nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular calcium, and a sensory neuropathy in humans, also produced mechanical hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular calcium. Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy. (C) 2003 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 Univ Calif San Francisco, NIH Pain Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, Div Neurosci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Program Biomed Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. RP Joseph, EK (reprint author), Univ Calif San Francisco, NIH Pain Ctr, Box 0440,Room C522,521 Parnassus Ave, San Francisco, CA 94143 USA. EM aley@itsa.ucsf.edu FU NINDS NIH HHS [NS42546] NR 69 TC 81 Z9 88 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JAN PY 2004 VL 107 IS 1-2 BP 147 EP 158 DI 10.1016/j.pain.2003.10.010 PG 12 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 766XR UT WOS:000188409500021 PM 14715401 ER PT J AU Yabroff, KR Mandelblatt, JS Ingham, J AF Yabroff, KR Mandelblatt, JS Ingham, J TI The quality of medical care at the end-of-life in the USA: existing barriers and examples of process and outcome measures SO PALLIATIVE MEDICINE LA English DT Review DE barriers; cancer; end-of-life; palliative care; quality of care ID PHYSICIAN-ASSISTED SUICIDE; TERMINALLY-ILL PATIENTS; BEREAVED FAMILY MEMBERS; PALLIATIVE-CARE; BREAST-CANCER; ADVANCE DIRECTIVES; UNITED-STATES; HEALTH-CARE; HOSPITALIZED-PATIENTS; TREATMENT PREFERENCES AB Context: Cancer is a leading cause of morbidity and mortality in the USA and despite many recent advances in detection and treatment, over half a million cancer patients in this country will die from their disease each year. Objective: Using cancer as a prototype, we provide a conceptual framework to identify and review barriers to optimal end-of-life care and propose examples of linked process and outcome measures that could be used to evaluate whether standards of optimal end-of-life care are being achieved. Methods: We propose a conceptual model of end-of-life care and use this model to review the published literature to identify the key goals of optimal end-of-life care and summarize existing barriers to optimal end-of-life care. We then provide examples of process and outcome measures linked to the goals of optimal end-of-life care and domains within the conceptual framework. Results: Within all components of care at the end-of-life - societal attitudes, health care system(s), providers, and patients and their families - there are significant barriers to the quality of care. Some of the most critical barriers to optimal care at the end-of-life in the USA are limited availability, and coverage of, co-ordinated service delivery; poor provider communication and diagnostic skills; limited opportunities for training in palliative care; patient fears and attitudes towards the sick role, and a lack of, or inadequate health insurance. Proposed patient, provider, and system level measures of the quality of care were guided by goals of optimal end-of-life care, and focus on communication about prognosis and risks and benefits of treatment, development of clear and informed treatment goals, delivery of services consistent with treatment goals, and promotion of quality of life. Conclusions: At present, there are substantial societal, health care system, provider, and patient barriers to obtaining optimal cancer care at the end-of-life. Ongoing discussions about appropriate measures of the quality of end-of-life care are gaining momentum, however. The proposed process and outcome measures for assessing optimal end-of-life care use cancer as a prototype, but are broadly applicable to other patient populations with life-threatening disease. C1 Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Dept Human Oncol,Canc Control Program, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Med, Div Hematol & Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Palliat Care Program, Washington, DC 20007 USA. RP Yabroff, KR (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4005, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU AHRQ HHS [HS 08395]; NINR NIH HHS [NR 05225] NR 209 TC 64 Z9 65 U1 5 U2 13 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 0269-2163 J9 PALLIATIVE MED JI Palliat. Med. PY 2004 VL 18 IS 3 BP 202 EP 216 DI 10.1191/0269216304pm880oa PG 15 WC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medicine, General & Internal SC Health Care Sciences & Services; Public, Environmental & Occupational Health; General & Internal Medicine GA 826DW UT WOS:000221810500005 PM 15198133 ER PT J AU Valenzuela, JG AF Valenzuela, JG TI Exploring tick saliva: from biochemistry to 'sialomes' and functional genomics SO PARASITOLOGY LA English DT Article DE functional genomics; high-throughput approaches; molecular biology; pharmacology; tick saliva ID LONE STAR TICK; ORNITHODOROS-SAVIGNYI ACARI; AMBLYOMMA-AMERICANUM L.; PLATELET-AGGREGATION INHIBITOR; FACTOR XA INHIBITOR; IXODES-SCAPULARIS; DERMACENTOR-ANDERSONI; BOOPHILUS-MICROPLUS; BLOOD-COAGULATION; GLAND EXTRACT AB Tick saliva, a fluid once believed to be only relevant for lubrication of mouthparts and water balance, is now well known to be a cocktail of potent anti-haemostatic, anti-inflammatory and immunomodulatory molecules that helps these arthropods obtain a blood meal from their vertebrate hosts. The repertoire of pharmacologically active components in this cocktail is impressive as well as the number of targets they specifically affect. These salivary components change the physiology of the host at the bite site and, consequently, some pathogens transmitted by ticks take advantage of this change and become more infective. Tick salivary proteins have therefore become an attractive target to control tick-borne diseases. Recent advances in molecular biology, protein chemistry and computational biology are accelerating the isolation, sequencing and analysis of a large number of transcripts and proteins from the saliva of different ticks. Many of these newly isolated genes code for proteins with homologies to known proteins allowing identification or prediction of their function. However, most of these genes code for proteins with unknown functions therefore opening the road to functional genomic approaches to identify their biological activities and roles in blood feeding and hence, vaccine development to control tick-borne diseases. C1 NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Valenzuela, JG (reprint author), NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, 4 Ctr Dr,4-B2-35, Bethesda, MD 20892 USA. EM jvilenzuela@niaid.nih.gov NR 92 TC 66 Z9 66 U1 0 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 EI 1469-8161 J9 PARASITOLOGY JI Parasitology PY 2004 VL 129 SU S BP S83 EP S94 DI 10.1017/S0031182004005189 PG 12 WC Parasitology SC Parasitology GA 940HP UT WOS:000230134600006 PM 15938506 ER PT S AU Brown, KE AF Brown, KE BE Robertson, JS TI Variants of B19 SO PDA/EMEA EUROPEAN VIRUS SAFETY FORUM SE DEVELOPMENTS IN BIOLOGICALS LA English DT Proceedings Paper CT PDA/EMEA European Virus Safety Forum 2003 CY SEP 29-OCT 01, 2003 CL Paul-Ehrlich Inst, Langen, GERMANY SP PDA, European Agcy Evaluat Med Prod HO Paul-Ehrlich Inst ID HUMAN PARVOVIRUS B19; SIMIAN PARVOVIRUS; CYNOMOLGUS MONKEYS; APLASTIC-ANEMIA; IDENTIFICATION; INFECTION AB The human parvovirus B19 (B19), the only known human pathogenic parvovirus, was discovered in 1975. Like other parvoviruses it is a small (22-24 nm diameter) non-enveloped icosahedral virus, with a single-stranded genome. As part of its life history it replicates to high titre in the bone marrow, and in acute infection high titres of infectious virus are present in the peripheral blood. Parvovirus B19 is therefore not an uncommon 'contaminant' of blood and blood products [1]. In addition the lack of lipid membrane envelope renders parvoviruses insensitive to solvent detergents, and the small genome confers relative resistance to heat and gamma irradiation. Many medical reviews have been written on the molecular biology, clinical features, approaches to diagnosis and management, and these should be consulted for more information [2]. This review will give an overview of the biology of parvovirus B19 infection, and the more recently described variants of parvovirus B19. C1 NIH, Bethesda, MD 20892 USA. RP Brown, KE (reprint author), NIH, Bldg 10 Room 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. EM brownk@nhlbi.nih.gov NR 15 TC 7 Z9 11 U1 0 U2 1 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 1424-6074 BN 3-8055-7873-3 J9 DEV BIOLOGICALS JI Dev. Biols PY 2004 VL 118 BP 71 EP 77 PG 7 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy; Virology SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy; Virology GA BDW88 UT WOS:000235894400009 PM 15645675 ER PT J AU Perez-Atayde, AR Kearney, DI Bricker, JT Colan, SD Easley, KA Kaplan, S Lai, WW Lipshultz, SE Moodie, DS Sopko, G Starc, TJ AF Perez-Atayde, AR Kearney, DI Bricker, JT Colan, SD Easley, KA Kaplan, S Lai, WW Lipshultz, SE Moodie, DS Sopko, G Starc, TJ CA P2C2 HIV Study Grp TI Cardiac, aortic, and pulmonary arteriopathy in HIV-infected children: The prospective (PCHIV)-C-2-H-2 multicenter study SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; POSITIVE PATIENTS; COMPLICATIONS; DISEASE AB Arteriopathy in human immunodeficiency virus (HIV)infected patients is being increasingly recognized, especially in children. However, few studies have histologically evaluated the coronary arteries in HIV-infected children, and none have systematically assessed the aorta and pulmonary arteries. The coronary arteries, thoracic aorta, and the main and branch pulmonary arteries from the postmortem hearts of 14 HIV-infected children were systematically reviewed for vasculopathic lesions and compared with 14 age-matched controls. Findings from the HIV-infected children were compared with clinical, laboratory, and other postmortem findings. Coronary arteriopathy, seen in seven (50%) of the HIV-infected children, was primarily calcific, and it was associated with decreased CD3 and CD4 peripheral blood counts. Large vessel arteriopathy, seen in 9 (64%) of the 14 HIV-infected children, was primarily centered on the vasa vasorum and consisted mainly of medial hypertrophy and chronic inflammation. Large vessel lesions were associated with increased left ventricular mass z-scores (P = 0.02), and 78% of patients with large vessel arteriopathy had postmortem cardiomegaly. Coronary and large vessel arteriopathies are common in pediatric HIV-infection and have different clinicopathologic features suggesting different pathogenesis. C1 Harvard Univ, Sch Med, Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. Texas Childrens Hosp, Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Texas Childrens Hosp, Baylor Coll Med, Dept Cardiol, Houston, TX 77030 USA. Cleveland Clin Fdn, Dept Biostat, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Epidemiol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Div Pediat & Adolescent Med, Cleveland, OH 44195 USA. Univ Calif Los Angeles, Med Ctr, Div Pediat Cardiol, Dept Pediat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. CUNY Mt Sinai Sch Med, Div Pediat Cardiol, Dept Pediat, New York, NY 10029 USA. NHLBI, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Presbyterian Hosp, Div Pediat Cardiol, Dept Pediat, New York, NY 10032 USA. RP Perez-Atayde, AR (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Dept Pathol, 300 Longwood Ave, Boston, MA 02115 USA. EM antonio.perezatayde@tch.harvard.edu RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU NCRR NIH HHS [RR-00188, RR-00043, RR-00071, RR-00533, RR-00645, RR-00865]; NHLBI NIH HHS [N01 HR096037, N01-HR-96038, N01-HR-96039, N01-HR-96040, N01-HR-96041, N01-HR-96042, N01-HR-96043] NR 20 TC 9 Z9 9 U1 0 U2 0 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 JAN-FEB PY 2004 VL 7 IS 1 BP 61 EP 70 DI 10.1007/s10024-003-1001-9 PG 10 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 814LD UT WOS:000220975300010 PM 15255036 ER PT J AU Imoisili, MA Bonwit, AM Bulas, DI AF Imoisili, MA Bonwit, AM Bulas, DI TI Toothpick puncture injuries of the foot in children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE toothpick; osteomyelitis; puncture wound ID WOODEN FOREIGN-BODIES; EIKENELLA-CORRODENS OSTEOMYELITIS; COMPUTED-TOMOGRAPHY; TISSUE; ULTRASONOGRAPHY; LOCALIZATION; BODY AB We reviewed the medical records of five children seen between January 1997 and September 2003 for toothpick puncture injuries of the foot. Failure to visualize retained toothpicks by plain radiographs delayed early removal. Patients subsequently developed recurrent foot cellulitis, complicated by foot osteomyelitis in three cases. Ultrasound, computed tomography or magnetic resonance imaging detected the toothpicks. These imaging tools should be considered for initial evaluation of these patients. C1 Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Radiol, Washington, DC 20010 USA. Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. RP Imoisili, MA (reprint author), Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. EM imoisilim@cder.fda.gov NR 21 TC 8 Z9 8 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 JAN PY 2004 VL 23 IS 1 BP 80 EP 82 DI 10.1097/00006454-200401000-00026 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 768VB UT WOS:000188554800019 PM 14743056 ER PT J AU Johnson, TR Graham, BS AF Johnson, TR Graham, BS TI Contribution of respiratory syncytial virus G antigenicity to vaccine-enhanced illness and the implications for severe disease during primary respiratory syncytial virus infection SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT International Congress on Respiratory Viruses CY 2003 CL CHANTILLY, VIRGINIA DE respiratory syncytial virus; eosinophil; pathogenesis.; CD4 T cells; type 2 cytokines ID REPLICATION IN-VITRO; MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; CONTROL PULMONARY INFLAMMATION; ANGIOTENSIN-CONVERTING ENZYME; MARROW TRANSPLANT RECIPIENTS; FORMALIN-INACTIVATED VIRUS; ATTACHMENT G GLYCOPROTEIN; REACTIVE AIRWAY DISEASE; HELPER TYPE-2 CYTOKINES; LYMPHOCYTE-T RESPONSES AB Background. Immunization of BALB/c mice with vaccinia virus expressing the G glycoprotein (vvG) of respiratory syncytial virus (RSV) or with formalin-inactivated alum-precipitated RSV (FI-RSV) predisposes for severe illness, type 2 cytokine production and pulmonary eosinophilia after challenge with live RSV. This similar disease profile has led to the proposal that the presence of the G glycoprotein in the FI-RSV preparation was the immunologic basis for the vaccine-associated enhancement of disease observed in the failed clinical trials of the 1960s. However, processes of disease pathogenesis observed in FI-RSV- and vvG-immunized mice suggest that FI-RSV and vvG immunizations induce immune responses of different compositions and requirements that converge to produce similar disease outcomes upon live virus challenge. Methods. The potential role of RSV G present in FI-RSV preparations in increasing postimmunization disease severity was explored in mice. Results. The absence of RSV G or its immunodominant epitope during FI-RSV immunization does not reduce disease severity after RSV challenge. Furthermore although depletion of Vbeta14(+) T cells during RSV challenge modulates disease in G-primed mice, minimal impact on disease in FI-RSV-immunized mice is observed. Conclusion. FI-RSV vaccine-enhanced illness is not attributable to RSV G. Furthermore formulation of a safe and effective RSV vaccine must ensure RSV antigen production, processing and presentation via the endogenous pathways. Thus gene delivery by vector, by DNA or by live attenuated virus are attractive vaccine approaches. C1 NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, Bethesda, MD USA. RP Johnson, TR (reprint author), NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, Bethesda, MD USA. NR 132 TC 23 Z9 23 U1 0 U2 2 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 JAN PY 2004 VL 23 IS 1 SU S BP S46 EP S56 DI 10.1097/01.inf.0000108192.94692.d2 PG 11 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 770LF UT WOS:000188731700012 PM 14730270 ER PT J AU Johnson, MD Mitchell, AR Troup, EC Bhowmick, DA Wait, SD Aulino, J Zhuang, ZP Weil, RJ AF Johnson, MD Mitchell, AR Troup, EC Bhowmick, DA Wait, SD Aulino, J Zhuang, ZP Weil, RJ TI Congenital cystic hemangioblastomas of the cerebral hemisphere in a neonate without alteration in the VHL gene SO PEDIATRIC NEUROSURGERY LA English DT Article DE cyst; hemangioblastoma; neonate; tumor suppressor gene; von Hippel-Lindau disease ID HIPPEL-LINDAU-DISEASE; TUMOR-SUPPRESSOR GENE; SUPRATENTORIAL HEMANGIOBLASTOMA; MUTATIONS; CHILDHOOD; GERMLINE AB A 4-week-old child presented with lethargy, emesis, decreased spontaneous movements, and a bulging fontanelle. Neuroimaging demonstrated a large, hemispheric, multicystic lesion with multiple enhancing nodules, which, on pathological examination, proved to be multiple, distinct hemangioblastomas. Careful molecular analysis failed to reveal alterations of the VHL gene. This represents an uncommon presentation for these tumors and suggests that genes other than VHL may be important in the genesis of these tumors. Copyright (C) 2004 S. Karger AG, Basel. C1 NINDS, SNB, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Radiol, Nashville, TN 37212 USA. Med Ctr Cent Geogria, Dept Pathol, Macon, GA USA. Georgia Neurosurg Inst, Macon, GA USA. RP Weil, RJ (reprint author), NINDS, SNB, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM weilr@ninds.nih.gov NR 25 TC 8 Z9 8 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1016-2291 J9 PEDIATR NEUROSURG JI Pediatr. Neurosurg. PY 2004 VL 40 IS 3 BP 124 EP 127 DI 10.1159/000079854 PG 4 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA 869XK UT WOS:000225017700005 PM 15367802 ER PT J AU Coffey, MJ Wilfond, B Ross, LF AF Coffey, MJ Wilfond, B Ross, LF TI Ethical assessment of clinical asthma trials including children subjects SO PEDIATRICS LA English DT Article DE asthma; clinical trials; placebo-controlled trials; children; ethics ID BUDESONIDE INHALATION SUSPENSION; DRY POWDER INHALER; QUALITY-OF-LIFE; PLACEBO-CONTROLLED TRIAL; LONG-TERM SAFETY; LEUKOTRIENE RECEPTOR ANTAGONIST; FLUTICASONE PROPIONATE POWDER; RANDOMIZED CONTROLLED TRIAL; MODERATE PERSISTENT ASTHMA; STEROID-DEPENDENT ASTHMA AB Background. The inclusion of children with asthma in clinical asthma trials is increasing, including their participation in placebo-controlled trials (PCTs). The objectives of this study are to assess whether children with asthma have been harmed by their participation in PCTs. Methods. Seventy clinical asthma trials involving children published between January 1998 and December 2001 that involved distinct US research populations were identified. Studies were reviewed to determine whether all subjects with more than mild asthma received daily antiinflammatory medication as recommended by national guidelines. Sixty-two clinical asthma trials included data about subject withdrawal and were analyzed for the frequency of asthma exacerbations. Results. Forty-five studies were designed as PCTs and did not require that all subjects with more than mild asthma receive antiinflammatory medications. Of 24 953 subjects, 4653 (19%) for whom data are available withdrew from research, and 1247 subjects (9.4%) withdrew from PCTs due to asthma exacerbations compared with 358 subjects (3.1%) in other trials. In PCTs, subjects withdrew more frequently from the placebo arms than the active-treatment arms and did so more frequently because of an asthma exacerbation (667 or 15% vs 580 or 6.5%). Fifty-two studies enrolled both children and adults, although only 1 performed subset analysis of the children. Conclusions. Subjects enrolled in PCTs of asthma have been exposed to unnecessary risks and harms. Clinical asthma trials involving children and adults do not benefit children as a class because they rarely provide subset analysis of children subjects. C1 Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. Univ Chicago, MacLean Ctr Clin Med Eth, Chicago, IL 60637 USA. NHGRI, Bioeth Res Sect, Med Genet Branch, Bethesda, MD 20892 USA. Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Genet Sect, Bethesda, MD USA. RP Ross, LF (reprint author), Univ Chicago, Dept Pediat, 5841 S Maryland Ave,MC 6082, Chicago, IL 60637 USA. EM lross@uchicago.edu FU NLM NIH HHS [1 G13 LM07472-01] NR 95 TC 13 Z9 14 U1 2 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JAN PY 2004 VL 113 IS 1 BP 87 EP 94 DI 10.1542/peds.113.1.87 PG 8 WC Pediatrics SC Pediatrics GA 762XX UT WOS:000188010600029 PM 14702454 ER PT J AU Yu, SM Huang, ZHJ Singh, GK AF Yu, SM Huang, ZHJ Singh, GK TI Health status and health services utilization among US Chinese, Asian Indian, Filipino, and other Asian/Pacific Islander children SO PEDIATRICS LA English DT Article DE child; Asian American children; immigrants; health status; health services access and utilization ID CAUSE-SPECIFIC MORTALITY; UNITED-STATES; IMMIGRANT CHILDREN; BORN CHILDREN; NATIVE-BORN; ACCESS; CARE; DIFFERENTIALS; AMERICAN; INSURANCE AB Objective. This study examines the health status and health services access and utilization characteristics of US Chinese, Asian Indian, Filipino, other Asian/Pacific Islander (API), and non-Hispanic white children by using nationally representative data. Methods. We analyzed the aggregated data file from the National Health Interview Survey from 1997 to 2000 including 334 Chinese, 287 Asian Indian, 292 Filipino, 696 "other API," and 29 016 non-Hispanic white children <18 years old. Bivariate and multivariate analyses were conducted to examine the relationship between Asian ethnicities and dependent variables including components of health status, health services access, and utilization. Results. Logistic regression reveals that all Asian American children were less likely to miss school because of illness or injury or have learning disabilities compared with non-Hispanic whites. Other APIs were less likely to be taking prescription medication for at least 3 months, and Asian Indian children were half as likely to have chronic conditions. Chinese, Filipino, and other API children were more likely to be without contact with a health professional within the past 12 months. Citizenship/ nativity status, maternal education attainment, and poverty status were all significant independent risk factors for health care access and utilization. Conclusions. Asian ethnicities and being foreign-born are generally associated with more favorable health status measures such as school absence, learning disability, use of prescription medications, and chronic conditions. However, these attributes are negatively associated with health care access and utilization, suggesting the need for outreach to Asian immigrant populations to educate them on accessing the US health care system. C1 Maternal & Child Hlth Bur, Off Data & Informat Management, Rockville, MD 20857 USA. NCI, NIH, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Yu, SM (reprint author), Maternal & Child Hlth Bur, Off Data & Informat Management, 5600 Fishers Ln,18A-55, Rockville, MD 20857 USA. EM syu@hrsa.gov NR 41 TC 56 Z9 59 U1 1 U2 7 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 JAN PY 2004 VL 113 IS 1 BP 101 EP 107 DI 10.1542/peds.113.1.101 PG 7 WC Pediatrics SC Pediatrics GA 762XX UT WOS:000188010600031 PM 14702456 ER PT J AU Alexander, D AF Alexander, D TI A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin SO PEDIATRICS LA English DT Editorial Material ID MESOPORPHYRIN C1 NICHHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Alexander, D (reprint author), NICHHD, NIH, Dept Hlth & Human Serv, 31 Ctr Dr,Room 2A03,MSC 2425, Bethesda, MD 20892 USA. EM da43w@nih.gov NR 4 TC 4 Z9 5 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 JAN PY 2004 VL 113 IS 1 BP 135 EP 135 DI 10.1542/peds.113.1.135 PG 1 WC Pediatrics SC Pediatrics GA 762XX UT WOS:000188010600040 PM 14702465 ER PT B AU Teruya, K Mazur, S Appella, E AF Teruya, Kenta Mazur, Sharlyn Appella, Ettore BE Chorev, M Sawyer, TK TI Multiple condensations of peptide thioesters prepared by the "safety-catch" resin approach: Synthesis of p53 (303-393) SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA ID TUMOR-SUPPRESSOR P53; POLYPEPTIDE-SYNTHESIS; SUPERCOILED DNA; TERMINAL DOMAIN; BINDING; SEGMENT C1 NCI, NIH, Bethesda, MD 20892 USA. RP Teruya, K (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 127 EP 128 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100056 ER PT B AU Krajewski, K Long, YQ Marchand, C Pommier, Y Roller, PP AF Krajewski, Krzysztof Long, Ya-Qiu Marchand, Christophe Pommier, Yves Roller, Peter P. BE Chorev, M Sawyer, TK TI Synthesis and biological activity of dimeric HIV-1 integrase inhibitory peptides SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA ID PROTEIN; CELLS C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Krajewski, K (reprint author), NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RI Marchand, Christophe/D-8559-2016 NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 329 EP 330 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100136 ER PT B AU Bryant, SD Salvadori, S Guerrini, R Balboni, G Jinsmaa, Y Lazarus, LH AF Bryant, Sharon D. Salvadori, Severo Guerrini, Remo Balboni, Gianfranco Jinsmaa, Yunden Lazarus, Lawrence H. BE Chorev, M Sawyer, TK TI Molecular modeling of opioidmimetics containing the Dmt-Tic-Bid pharmacophores and docking with the delta-opioid receptor SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA C1 NIEHS, Peptide Neurochem Sect, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC 27709 USA. RP Bryant, SD (reprint author), NIEHS, Peptide Neurochem Sect, Lab Computat Biol & Risk Assessment, POB 12233, Res Triangle Pk, NC 27709 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 453 EP 454 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100189 ER PT B AU Roller, PP Li, P Zhang, MC Zhang, XD Long, YQ Peach, ML Nicklaus, M Liu, HP Yang, DJ AF Roller, Peter P. Li, Peng Zhang, Manchao Zhang, Xiaodong Long, Ya-Qiu Peach, Megan L. Nicklaus, Marc Liu, Hongpeng Yang, Dajun BE Chorev, M Sawyer, TK TI Peptidomimetic design of cyclic Grb2-SH2 domain antagonists not relying on pTyr or its mimics SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA ID NONPHOSPHORYLATED INHIBITOR; BINDING; LIGANDS C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Roller, PP (reprint author), NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 501 EP 503 PG 3 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100211 ER PT B AU Shi, ZD Wei, CQ Wang, X Lee, K Liu, H Zhang, M Vasselli, J Roberts, LR Worthy, KM Fivash, MJ Fisher, RJ Bottaro, DP Linehan, WM Yang, D Burke, TR AF Shi, Z. -D. Wei, C. -Q. Wang, X. Lee, K. Liu, H. Zhang, M. Vasselli, J. Roberts, L. R. Worthy, K. M. Fivash, M. J. Fisher, R. J. Bottaro, D. P. Linehan, W. M. Yang, D. Burke, T. R., Jr. BE Chorev, M Sawyer, TK TI Macrocyclization in the design of tetrapeptide mimetics that display potent inhibition of Grb2 SH2 domain binding in whole cell systems SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA ID LIGANDS C1 NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. RP Shi, ZD (reprint author), NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. RI Burke, Terrence/N-2601-2014 NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 515 EP 517 PG 3 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100217 ER PT B AU Li, P Peach, ML Zhang, MC Liu, HP Yang, DJ Nicklaus, M Roller, PP AF Li, Peng Peach, Megan L. Zhang, Manchao Liu, Hongpeng Yang, Dajun Nicklaus, Marc Roller, Peter P. BE Chorev, M Sawyer, TK TI Potent Grb2-SH2 domain antagonists discovered by extensive SAR studies SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA ID SH2; SRC C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Li, P (reprint author), NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 518 EP 519 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100218 ER PT B AU Yamaguchi, H Houtman, JCD Samelson, LE Appella, E AF Yamaguchi, Hiroshi Houtman, Jon C. D. Samelson, Lawrence E. Appella, Ettore BE Chorev, M Sawyer, TK TI Synthesis and application of large phosphopeptides from the linker for activation of T cells (LAT) protein SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA ID ANTIGEN RECEPTOR; SIGNAL-TRANSDUCTION; ADAPTER PROTEINS C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yamaguchi, H (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 534 EP 535 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100223 ER PT B AU Lee, K Kang, SU Gao, Y Yao, ZJ Phan, J Wu, L Liang, J Waugh, DS Zhang, ZY Burke, TR AF Lee, Kyeong Kang, Sang Uk Gao, Yang Yao, Zhu-Jun Phan, Jason Wu, Li Liang, Jiao Waugh, David S. Zhang, Zhong-Yin Burke, Terrence R., Jr. BE Chorev, M Sawyer, TK TI Tripeptide inhibitors of Yersinia protein-tyrosine phosphatase as potential leads for therapeutic development against plague SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA C1 NCI, Med Chem Lab, NIH, CCR, Frederick, MD 21702 USA. RP Kang, SU (reprint author), NCI, Med Chem Lab, NIH, CCR, Frederick, MD 21702 USA. RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 544 EP 545 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100228 ER PT B AU Jinsmaa, Y Okada, Y Tsuda, Y Sasaki, Y Ambo, A Bryant, SA Lazarus, LH AF Jinsmaa, Yunden Okada, Yoshio Tsuda, Yuko Sasaki, Yusuke Ambo, Akihio Bryant, Sharon A. Lazarus, Lawrence H. BE Chorev, M Sawyer, TK TI Potent antinociceptive activity by a novel opioid, 3-(3'-dmt-aminopropyl)-6-(4'-dmt-aminobutyl)-5-methyl-2(1H)-pyrazinone SO Peptide Revolution: Genomics, Proteomics & Therapeutics LA English DT Proceedings Paper CT 18th American Peptide Symposium CY JUL 19-23, 2003 CL BOSTON, MA ID RECEPTOR-BINDING ACTIVITY; PYRAZINONE RING; PEPTIDES; MIMETICS; DMT C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Jinsmaa, Y (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA BN 0-9715560-1-6 PY 2004 BP 669 EP 670 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BEQ46 UT WOS:000238911100281 ER PT J AU Ungerleider, LG Heekeren, H Marrett, S Bandettini, PA AF Ungerleider, LG Heekeren, H Marrett, S Bandettini, PA TI Perceptual decision-making in human prefrontal cortex SO PERCEPTION LA English DT Meeting Abstract C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM ungerlei@intra.nimh.nih.gov RI Heekeren, Hauke/B-7739-2008 OI Heekeren, Hauke/0000-0001-7912-6826 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PION LTD PI LONDON PA 207 BRONDESBURY PARK, LONDON NW2 5JN, ENGLAND SN 0301-0066 J9 PERCEPTION JI Perception PY 2004 VL 33 SU S BP 23 EP 23 PG 1 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA 858NN UT WOS:000224198700071 ER PT J AU Cooper, GS Longnecker, MP Peters, RK AF Cooper, GS Longnecker, MP Peters, RK TI Ovarian cancer risk and use of phenolphthalein-containing laxatives SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE ovarian cancer; phenolphthalein; laxative AB Purpose Experimental studies in rodents demonstrated the carcinogenic potential of phenolphthalein, the active ingredient in some laxatives, administered at doses similar to the dose that could be used by humans. Ovarian cancer was one of the cancers observed in these studies. We examined the association between epithelial ovarian cancer and use of phenolphthalein-containing laxatives in a population-based case-control study. Methods The study includes 356 epithelial ovarian cancer cases (256 invasive, 100 borderline) and 424 controls. Cases were identified through a population-based registry in Los Angeles County in 1992-1998, and controls were matched to cases by age, race/ethnicity and neighborhood. Data on laxative use (specific brands, frequency of use, usual dose) were obtained by structured in-person interview. Results Compared to women who never used a laxative, ever use of a phenolphthalein-containing laxative was not associated with an increased risk of invasive ovarian cancer (odds ratio (OR) 1.1, 95% confidence interval (CI) 0.75, 1.5) or of borderline ovarian cancer (OR 0.75, 95%CI 0.37, 1.5). Total days used, mean number of pills per day and cumulative dose were also unrelated to risk. Conclusions This study provides some assurance that phenolphthalein-containing laxatives do not increase the risk of ovarian cancer in humans. These findings are of particular importance to those countries in which phenolphthalein is still used in over-the-counter medications. Published in 2003 John Wiley Sons, Ltd. C1 NIEHS, Epidemiol Branch A3 05, Res Triangle Pk, NC 27709 USA. USC, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. RP Cooper, GS (reprint author), NIEHS, Epidemiol Branch A3 05, POB 12233, Res Triangle Pk, NC 27709 USA. EM cooper1@niehs.nih.gov OI Longnecker, Matthew/0000-0001-6073-5322 FU NCI NIH HHS [CA 61132, CA 14089, N01-PC-67010, CA 17054] NR 16 TC 6 Z9 7 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2004 VL 13 IS 1 BP 35 EP 39 DI 10.1002/pds.824 PG 5 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 768GW UT WOS:000188536100005 PM 14971121 ER PT J AU Nelson, DR Zeldin, DC Hoffman, SMG Maltais, LJ Wain, HM Nebert, DW AF Nelson, DR Zeldin, DC Hoffman, SMG Maltais, LJ Wain, HM Nebert, DW TI Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants SO PHARMACOGENETICS LA English DT Article DE cytochrome P450; nomenclature; pseudogenes; mouse; human ID ARACHIDONIC-ACID; FUNCTIONAL-CHARACTERIZATION; EVOLUTION; IDENTIFICATION; P450; SUBFAMILY; CLUSTER; ORGANIZATION; SEQUENCE; CLONING AB Objectives Completion of both the mouse and human genome sequences in the private and public sectors has prompted comparison between the two species at multiple levels. This review summarizes the cytochrome P450 (CYP) gene superfamily. For the first time, we have the ability to compare complete sets of CYP genes from two mammals. Use of the mouse as a model mammal, and as a surrogate for human biology, assumes reasonable similarity between the two. It is therefore of interest to catalog the genetic similarities and differences, and to clarify the limits of extrapolation from mouse to human. Methods Data-mining methods have been used to find all the mouse and human CYP sequences; this includes 102 putatively functional genes and 88 pseudogenes in the mouse, and 57 putatively functional genes and 58 pseudogenes in the human. Comparison is made between all these genes, especially the seven main CYP gene clusters. Results and conclusions The seven CYP clusters are greatly expanded in the mouse with 72 functional genes versus only 27 in the human, while many pseudogenes are present; presumably this phenomenon will be seen in many other gene superfamily clusters. Complete identification of all pseudogene sequences is likely to be clinically important, because some of these highly similar exons can interfere with PCR-based genotyping assays. A naming procedure for each of four categories of CYP pseudogenes is proposed, and we encourage various gene nomenclature committees to consider seriously the adoption and application of this pseudogene nomenclature system. (C) 2004 Lippincott Williams Wilkins. C1 Univ Tennessee, Dept Mol Sci, Memphis, TN 38163 USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Miami Univ, Dept Zool, Oxford, OH 45056 USA. Jackson Lab, MGNC, Bar Harbor, ME 04609 USA. UCL, Dept Biol, HUGO Gene Nomenclature Comm, London NW1 2HE, England. Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. Univ Cincinnati, Med Ctr, Ctr Environm Genet, Cincinnati, OH 45267 USA. RP Nelson, DR (reprint author), Univ Tennessee, Dept Mol Sci, Memphis, TN 38163 USA. EM dnelson@utmem.edu OI Nelson, David/0000-0003-0583-5421 FU NIEHS NIH HHS [P30 ES06096] NR 52 TC 479 Z9 508 U1 7 U2 35 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD JAN PY 2004 VL 14 IS 1 BP 1 EP 18 DI 10.1097/01.fpc.0000054151.92680.31 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 779HG UT WOS:000189288800001 PM 15128046 ER PT J AU Klotsman, M Weinberg, CR Davis, K Binnie, CG Hartmann, KE AF Klotsman, M Weinberg, CR Davis, K Binnie, CG Hartmann, KE TI A case-based evaluation of SRD5A1, SRD5A2, AR, and ADRA1A as candidate genes for severity of BPH SO PHARMACOGENOMICS JOURNAL LA English DT Article DE BPH; prostate; testosterone 5-alpha-reductase; adrenergic alpha-antagonists ID BENIGN PROSTATIC HYPERPLASIA; ANDROGEN RECEPTOR GENE; 5-ALPHA-REDUCTASE TYPE-II; STEROID 5-ALPHA-REDUCTASE; CAG REPEAT; CANCER RISK; POLYMORPHISM; ASSOCIATION; EXPRESSION; MEN AB In men with a clinical diagnosis of benign prostatic hyperplasia (BPH), polytomous logistic regression analysis was conducted to evaluate associations between two silent polymorphisms in SRD5A1 ( codon positions 30 and 116), two polymorphisms in SRD5A2 (Val89Leu substitution and C to T transition in intron 1), a trinucleotide (CAG)(n) repeat in androgen receptor (AR), and an Arg492Cys substitution in ADRA1A and clinical parameters that characterize severity of BPH. Candidate gene selection was based on two mechanistic pathways targeted by pharmacotherapy for BPH: (1) androgen metabolic loci contributing to prostate growth ( static obstruction); and ( 2) factors affecting smooth muscle tone (dynamic obstruction). Polymorphisms in SRD5A2 were not associated with severity of BPH; however, SRD5A1 polymorphisms were associated with severity of BPH. The process(es) in which these silent single-nucleotide polymorphisms (SNPs) influence BPH phenotypes is unknown and additional studies will be needed to assess whether these SNPs have direct functional consequences. The characterization of additional molecular factors that contribute to static and dynamic obstruction may help predict response to pharmacotherapy and serve to identify novel drug targets for the clinical management of BPH. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. GlaxoSmithKline, Genet Res, Res Triangle Pk, NC USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. GlaxoSmithKline, World Wide Epidemiol, Res Triangle Pk, NC USA. GlaxoSmithKline, Discovery Genet, Res Triangle Pk, NC USA. RP Klotsman, M (reprint author), POB 13398,5 Moore Dr, Res Triangle Pk, NC 27709 USA. EM michael.x.klotsman@gsk.com NR 48 TC 9 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PY 2004 VL 4 IS 4 BP 251 EP 259 DI 10.1038/sj.tpj.6500248 PG 9 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 839IO UT WOS:000222777500007 PM 15136785 ER PT J AU Kanai, H Sawa, A Chen, RW Leeds, P Chuang, DM AF Kanai, H Sawa, A Chen, RW Leeds, P Chuang, DM TI Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons SO PHARMACOGENOMICS JOURNAL LA English DT Article DE valproate; excitotoxiciy; cerebellar granule cells; neuroprotection; GAPDH; histone deacetylase ID CEREBELLAR GRANULE NEURONS; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; STRESS-PROTEINS; MOOD STABILIZER; MOUSE MODEL; CELL-DEATH; EXPRESSION; GLUTAMATE; INDUCTION; PATHWAY AB Valproic acid (VPA), used to treat bipolar mood disorder and seizures, also inhibits histone deacetylase (HDAC). Here, we found that VPA and other HDAC inhibitors, butyrate and trichostatin A, robustly protected mature cerebellar granule cell cultures from excitotoxicity induced by SYM 2081 ((2S, 4R)-4-methylglutamate), an inhibitor of excitatory amino-acid transporters and an agonist of low-affinity kainate receptors. These neuroprotective effects required protracted treatment and were correlated with enhanced acetylated histone levels, indicating HDAC inhibition. SYM-induced excitotoxicity was blocked by MK-801 ((5R, 10S)-(+)-5- methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate), supporting that the toxicity was largely N-methyl-D-aspartate receptor dependent. SYM excitotoxicity had apoptotic characteristics and was prevented by a caspase inhibitor. SYM-induced apoptosis was associated with a rapid and robust nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a housekeeping gene previously shown to be proapoptotic. VPA pretreatment suppressed SYM 2081-induced GAPDH nuclear accumulation, concurrent with its neuroprotective effects. Chromatin immunoprecipitation (ChIP) revealed that GAPDH is copresent with acetylated histone H3, including Lys9-acetylated histone, and that VPA treatment caused a time-dependent decrease in the levels of nuclear GAPDH with a concomitant increase in acetylated histones in the ChIP complex. Our results strongly suggest that VPA protects neurons from excitotoxicity through inhibition of HDAC activity and that this protective effect may involve suppression of excitotoxicity-induced accumulation of GAPDH protein in the nucleus. C1 NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bldg 10,Rm 4C-206,10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov NR 41 TC 76 Z9 81 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PY 2004 VL 4 IS 5 BP 336 EP 344 DI 10.1038/sj.tpj.6500269 PG 9 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 865HI UT WOS:000224692900007 PM 15289798 ER PT J AU Fricker, G Miller, DS AF Fricker, G Miller, DS TI Modulation of drug transporters at the blood-brain barrier SO PHARMACOLOGY LA English DT Article DE ABC proteins; active transport; blood brain barrier; membrane carrier proteins; Mrp; P-glycoprotein; immunoliposomes; nanoparticles; drug targeting; Oat; Oatp ID MULTIDRUG-RESISTANCE PROTEIN; MICROVESSEL ENDOTHELIAL-CELLS; P-GLYCOPROTEIN; IN-VITRO; EFFLUX TRANSPORT; CAPILLARY ENDOTHELIUM; INCREASED SENSITIVITY; PARKINSONS-DISEASE; POLYPEPTIDE 2; GENE LEADS AB A major challenge in the management of diseases of the central nervous system is the limited penetration of drugs into the brain. The structures responsible are the capillaries of the brain, whose endothelial cells form the so-called blood-brain barrier. Understanding the cellular and molecular structure as well as integrated function of this barrier is a prerequisite for successful drug delivery to the brain. Here we briefly review current knowledge about the active transport proteins (ABC and organic anion transporters) which function at the blood-brain barrier. We describe novel approaches to (1) modulate carrier protein function, and (2) circumvent the transporter-based carrier by targeted site-specific drug delivery systems, such as immunoliposome and nanoparticulate systems. Copyright (C) 2004 S. Karger AG, Basel. C1 Univ Heidelberg, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Fricker, G (reprint author), Univ Heidelberg, Inst Pharm & Mol Biotechnol, Neuenheimer Feld 366, D-69120 Heidelberg, Germany. EM gert.fricker@uni-hd.de NR 61 TC 65 Z9 67 U1 2 U2 10 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0031-7012 J9 PHARMACOLOGY JI Pharmacology PY 2004 VL 70 IS 4 BP 169 EP 176 DI 10.1159/000075545 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 800KQ UT WOS:000220027600001 PM 15001817 ER PT J AU Eisenhofer, G Lenders, JWM Pacak, K AF Eisenhofer, G Lenders, JWM Pacak, K TI Biochemical diagnosis of pheochromocytoma SO PHEOCHROMOCYTOMA SE FRONTIERS OF HORMONE RESEARCH LA English DT Review ID CLONIDINE-SUPPRESSION TEST; MULTIPLE ENDOCRINE NEOPLASIA; URINARY CATECHOLAMINE METABOLITES; LIQUID-CHROMATOGRAPHY; ELECTROCHEMICAL DETECTION; PLASMA-CATECHOLAMINES; MALIGNANT PHEOCHROMOCYTOMA; CREATININE EXCRETION; 3-METHOXY-4-HYDROXYMANDELIC ACID; HYPERTENSIVE PATIENTS C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Univ Nijmegen St Radboud Hosp, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands. NICHHD, Pediat & Reprod Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Eisenhofer, G (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,10 Ctr Dr,MSC 1620,Room 6N252, Bethesda, MD 20892 USA. RI Lenders, J.W.M./L-4487-2015 NR 113 TC 27 Z9 30 U1 0 U2 2 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 0301-3073 J9 FRONT HORM RES JI Front.Horm.Res. PY 2004 VL 31 BP 76 EP 106 PG 31 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA BX95G UT WOS:000186920600005 PM 14674306 ER PT J AU Pacak, K Eisenhofer, G Ilias, I AF Pacak, K Eisenhofer, G Ilias, I TI Diagnostic imaging of pheochromocytoma SO PHEOCHROMOCYTOMA SE FRONTIERS OF HORMONE RESEARCH LA English DT Review ID I-131 METAIODOBENZYLGUANIDINE SCINTIGRAPHY; NEURAL CREST TUMORS; MALIGNANT PHEOCHROMOCYTOMA; MIBG SCINTIGRAPHY; I-123 METAIODOBENZYLGUANIDINE; EXTRAADRENAL PHEOCHROMOCYTOMA; RECEPTOR SCINTIGRAPHY; MAGNETIC-RESONANCE; EVOLVING CONCEPTS; ADRENAL-GLAND C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42,MSC-1583, Bethesda, MD 20892 USA. NR 55 TC 7 Z9 7 U1 0 U2 1 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 0301-3073 J9 FRONT HORM RES JI Front.Horm.Res. PY 2004 VL 31 BP 107 EP 120 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA BX95G UT WOS:000186920600006 PM 14674307 ER PT J AU Nemukhin, AV Grigorenko, BL Topol, IA Burt, SK AF Nemukhin, AV Grigorenko, BL Topol, IA Burt, SK TI QM/MM modeling of the glutathione-hydroxymethyl radical reaction in watery SO PHYSICAL CHEMISTRY CHEMICAL PHYSICS LA English DT Article ID FRAGMENT POTENTIAL METHOD; NUCLEOPHILIC AROMATIC-SUBSTITUTION; AB-INITIO; CLAISEN REARRANGEMENT; CHORISMATE MUTASE; ATOM ABSTRACTION; H ABSTRACTION; SOLVATION; CLUSTERS; ENERGIES AB The reactions of hydroxymethyl radical (CH2OH)-C-circle with glutathione tripeptide GSH and with methylthiol CH3SH in water are modeled by using the effective fragment potential (EFP) based quantum mechanical molecular mechanical (QM/MM) methods. In the case of glutathione, the reactive part of the cysteine residue of the tripeptide and the hydroxymethyl moiety are included to the quantum part. The remaining part of GSH assigned to the MM subsystem is represented by flexible chains of small effective fragments. The energy profiles for the condensed phase reactions have been constructed by using the transition state structure of the gas-phase reference reaction of hydroxymethyl radical (CH2OH)-C-circle with methylthiol CH3SH. Optimization of geometry parameters of the systems, including coordinates of environmental particles, leads to the structures at the top of the barrier, as well as for reagent interaction complexes and product interaction complexes. The energy difference between the top of the barrier and the reagent interaction complex is considered as a measure of activation energy, which allows us to treat all systems at the uniform level. According to simulation results, the activation barrier for the aqueous reaction of hydroxymethyl radical with methylthiol should be slightly higher, and for the aqueous reaction of hydroxymethyl radical with glutathione in the lowest energy conformation should be slightly lower than that of the reference gas-phase reaction. A conclusion about higher activation barrier for aqueous reaction (CH2OH)-C-circle+CH3SH in comparison to the gas-phase process, obtained here within the supermolecular approach, is consistent with the literature results of solvation models. It is shown that conformations of peptide chain of glutathione may modify the gas-phase reaction energy pro. le of the reacting species to a larger extent than the influence of water molecules. The role of the peptide chain seems to be to provide either beneficial or unfavorable arrangement of the reagents in the interaction complex. C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Nemukhin, AV (reprint author), Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. EM anem@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015 NR 45 TC 8 Z9 8 U1 0 U2 3 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1463-9076 J9 PHYS CHEM CHEM PHYS JI Phys. Chem. Chem. Phys. PY 2004 VL 6 IS 5 BP 1031 EP 1038 DI 10.1039/b311293d PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 778JL UT WOS:000189236000027 ER PT J AU Dagdug, L Berezhkovskii, AM Weiss, GH AF Dagdug, L Berezhkovskii, AM Weiss, GH TI Kinetics of ligand equilibration between tubular and vesicular parts of the endosome SO PHYSICAL REVIEW E LA English DT Article ID ENDOCYTOSIS; CHANNEL AB The kinetics of ligand equilibration between the tubular and vesicular parts of the endosome are studied for ligands diffusing in the vesicle and in a narrow cylindrical tubule attached to it. The key quantity in our analysis is the fraction of ligands in the vesicle at time t, P(ves)(t). We derive an expression for the Laplace transform of P(ves)(t) as a function of the vesicle volume and the length and radius of the tubule as well as the ligand diffusion coefficients in the vesicle and in the tubule. This transform is used to find the average equilibration time as a function of the system parameters. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Dagdug, L (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. NR 17 TC 3 Z9 3 U1 1 U2 1 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD JAN PY 2004 VL 69 IS 1 AR 012902 DI 10.1103/PhysRevE.69.012902 PN 1 PG 4 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 773WC UT WOS:000188946500062 PM 14995658 ER PT J AU Croarkin, E Danoff, J Barnes, C AF Croarkin, E Danoff, J Barnes, C TI Evidence-based rating of upper-extremity motor function tests used for people following a stroke SO PHYSICAL THERAPY LA English DT Article DE evidence-based rating; motor function tests; stroke; upper extremity ID FUGL-MEYER ASSESSMENT; INTERRATER RELIABILITY; ASSESSMENT SCALE; ARM FUNCTION; VALIDITY; RECOVERY; PERFORMANCE; IMPAIRMENT; VALIDATION; HAND AB Introduction. Tests of upper-extremity motor function used for people following a stroke have been described, but reliability and validity (psychometric properties) of measurements obtained with these tests have not been consistently established. This investigation was performed: (1) to review literature relative to upper-extremity motor function testing during rehabilitation following a stroke, (2) to develop selection criteria for identifying these tests in the literature, and (3) to rate the tests relative to their psychometric properties. Method. Literature searches were done using 2 databases. Reports of 4 psychometric properties were sought: interrater reliability, test-retest reliability, convergent validity or concurrent validity, and predictive validity. Results. Nine tests met the inclusion criteria of having psychometric properties reported in the literature. No test had evidence for all 4 psychometric properties. Only the Nine-Hole Peg Test was supported by 3 out of 4 properties. Most tests had 2 properties Supported. Concurrent validity or convergent validity was most frequently described; test-retest reliability was least frequently described. Conclusions. More complete psychometric support is needed for upper-extremity motor function tests applied following a stroke. The absence of psychometric support, however, does not mean that a test has no value. Clinicians are cautioned not to generalize psychometric evidence. [Croarkin E, Danoff J, Barnes C. Evidence-based rating of upper-extremity motor function tests used for people following a stroke]. C1 Phys Therapy Sect, NIH, Bethesda, MD 20892 USA. George Washington Univ, Ctr Med, Dept Exercise Sci, Washington, DC 20052 USA. NIH, Phys Therapy Sect, Bethesda, MD 20892 USA. RP Croarkin, E (reprint author), Phys Therapy Sect, NIH, Bldg 10,Room 6S-235,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ecroarkin@cc.nih.gov NR 32 TC 47 Z9 48 U1 0 U2 0 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD JAN PY 2004 VL 84 IS 1 BP 62 EP 74 PG 13 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 805XW UT WOS:000220400000006 PM 14992677 ER PT J AU Nedvidkova, J Dostalova, I Bartak, V Papezova, H Pacak, K AF Nedvidkova, J Dostalova, I Bartak, V Papezova, H Pacak, K TI Increased subcutaneous abdominal tissue norepinephrine levels in patients with anorexia nervosa: an in vivo microdialysis study SO PHYSIOLOGICAL RESEARCH LA English DT Article; Proceedings Paper CT Meeting of the Czech-and-Slovak-Physiological-Societies CY 2003 CL Plzen, CZECH REPUBLIC SP Czech Physiol Soc, Slovak Physiol Soc DE anorexia nervosa; catecholamines; adipose tissue; microdialysis; maprotiline ID ADIPOSE-TISSUE; DOPAMINE TRANSPORTER; METABOLISM; LIPOLYSIS; ENDOCRINE; EXERCISE; PLASMA AB The present study was designed to measure interstitial levels of norepinephrine-regulating lipolysis (NE) in subcutaneous abdominal adipose tissue of anorexia nervosa (AN) patients and control subjects under basal conditions and after the local administration of an inhibitor of NE re-uptake, maprotiline. In vivo microdialysis technique was used to assess subcutaneous adipose NE levels in five women with AN (body mass index 14.62+/-0.47 kg/m(2)) and six age-matched controls (22.1+/-0.52 kg/m(2)). NE was assayed using high performance liquid chromatography with electrochemical detection after batch alumina extraction. Measured basal adipose tissue NE levels reflecting its interstitial levels were significantly increased in AN patients compared to the controls (106.0+/-20.9 vs. 40.0+/-5.0 pg/ml). The local maprotiline administration resulted in a significant increase in adipose tissue NE levels (AN patients: 440.0+/-28.6 vs. 202.0+/-33.0 pg/ml in the controls) in both groups. Markedly increased subcutaneous abdominal adipose tissue NE levels in AN patients compared to control subjects reflect increased sympathetic nervous system activity but not altered membrane noradrenergic transporter system in anorexia nervosa patients. C1 Inst Endocrinol, Prague 11694 1, Czech Republic. Charles Univ, Dept Psychiat, Fac Med 1, Prague, Czech Republic. NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD USA. RP Nedvidkova, J (reprint author), Inst Endocrinol, Narodni 8, Prague 11694 1, Czech Republic. EM jara.nedvidkova@tiscali.cz NR 18 TC 13 Z9 13 U1 0 U2 0 PU ACAD SCIENCES CZECH REPUBLIC, INST PHYSIOLOGY PI PRAGUE 4 PA VIDENSKA 1083, PRAGUE 4 142 20, CZECH REPUBLIC SN 0862-8408 J9 PHYSIOL RES JI Physiol. Res. PY 2004 VL 53 IS 4 BP 409 EP 413 PG 5 WC Physiology SC Physiology GA 847WZ UT WOS:000223430000008 PM 15312000 ER PT J AU Suzman, R AF Suzman, Richard TI Research on population aging at NIA: Retrospect and prospect SO POPULATION AND DEVELOPMENT REVIEW LA English DT Article C1 NIA, NIH, Bethesda, MD 20892 USA. RP Suzman, R (reprint author), NIA, NIH, Bethesda, MD 20892 USA. NR 35 TC 4 Z9 5 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0098-7921 J9 POPUL DEV REV JI Popul. Dev. Rev. PY 2004 VL 30 SU S BP 239 EP 264 PG 26 WC Demography; Sociology SC Demography; Sociology GA V42VV UT WOS:000202895900011 ER PT J AU Yu, H Ito, Y AF Yu, H Ito, Y TI Preparative separation of proteins using centrifugal precipitation chromatography based on solubility in ammonium sulfate solution SO PREPARATIVE BIOCHEMISTRY & BIOTECHNOLOGY LA English DT Article DE centrifugal precipitation chromatography; protein separation and purification; ammonium sulfate gradient precipitation; preparative separation; dialysis tubing; convoluted tubing ID FRACTIONATION AB A preparative modification of the centrifugal precipitation chromatography (CPC) is described. The sample-loading capacity is improved in the present system by the use of convoluted tubing containing dialysis tubing instead of a dialysis membrane placed between a pair of disks equipped with mirror-imaged spiral grooves as in the original design. The system uses, basically, the same principle of as the original CPC, in that a concentration gradient of precipitant is generated under a centrifugal force field. The protein sample injected into the CPC column is exposed to an increasing concentration of the precipitant where it precipitates at various portions of the column according to its solubility. The gradient isthen gradually lowered so that the sample undergoes dissolution and precipitation many times within the column; the proteins finally elute from the column according to their solubilities. A basic study was performed using this machine to separate human albumin and 3-globulin using ammonium sulfate (AS) as precipitant. Preliminary results indicate that this method can separate 500 mg of protein. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Rm 3334,South Dr MSC 8014, Bethesda, MD 20892 USA. EM itoy@nhlbi.nith.gov NR 7 TC 11 Z9 11 U1 3 U2 10 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1082-6068 J9 PREP BIOCHEM BIOTECH JI Prep. Biochem. Biotechnol. PY 2004 VL 34 IS 1 BP 1 EP 12 DI 10.1081/PB-120027109 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 801EK UT WOS:000220079000001 PM 15046293 ER PT J AU Goff, DC Mitchell, P Finnegan, J Pandey, D Bittner, V Feldman, H Meischke, H Goldberg, RJ Luepker, RV Raczynski, JM Cooper, L Mann, C REACT Study Grp AF Goff, DC Mitchell, P Finnegan, J Pandey, D Bittner, V Feldman, H Meischke, H Goldberg, RJ Luepker, RV Raczynski, JM Cooper, L Mann, C REACT Study Grp TI Knowledge of heart attack symptoms in 20 US communities. Results from the rapid early action for coronary treatment community trial SO PREVENTIVE MEDICINE LA English DT Article DE myocardial infarction; delay; community trial; symptoms; knowledge ID ACUTE MYOCARDIAL-INFARCTION; UNITED-STATES; REACT TRIAL; DELAY; POPULATION; HEALTH; INTERVENTION; PREVALENCE; EMERGENCY; SEEKING AB Background. Effective treatment for patients with acute myocardial infarction is limited by patient delay in seeking care. Inadequate knowledge of heart attack symptoms may prolong delay. An intervention designed to reduce delay was tested in the Rapid Early Action for Coronary Treatment (REACT) Community Trial. In this report, the impact on knowledge of heart attack symptoms is presented. Methods. Twenty communities were randomized to intervention or comparison status in a matched-pair design. Intervention strategies included community organization, public education, professional education, and patient education. The main outcome measures were based on information regarding knowledge of symptoms collected in a series of four random-digit-dialed telephone surveys. Results. Knowledge of REACT-targeted symptoms increased in intervention communities. No change was observed in comparison communities. The net effect was an increase of 0.44 REACT-targeted symptoms per individual (P < 0.001). The intervention effect was greater in ethnic minorities, persons with lower household incomes, and those with family or spouse history of heart attack (P < 0.05). Conclusions. The REACT intervention was modestly successful in increasing the general public's knowledge of the complex constellation of heart attack symptoms. The intervention program was somewhat more effective in reaching disadvantaged subgroups, including ethnic minorities and persons with lower income. Despite these successes, the post-intervention level of knowledge was suboptimal. (C) 2003 American Health Foundation and Elsevier Inc. All rights reserved. C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. New England Res Inst, Watertown, MA 02472 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55455 USA. Rush Univ, Chicago, IL 60612 USA. Univ Alabama, Sch Med, Birmingham, AL 35294 USA. Univ Washington, Seattle, WA 98195 USA. Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. NHLBI, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Portland, OR 97239 USA. RP Goff, DC (reprint author), Wake Forest Univ, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. OI Bittner, Vera/0000-0001-9456-850X FU NHLBI NIH HHS [HL-53141, HL-53135, HL-53149, HL-53155, HL-53142, HL-53211] NR 27 TC 32 Z9 32 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 0091-7435 J9 PREV MED JI Prev. Med. PD JAN PY 2004 VL 38 IS 1 BP 85 EP 93 DI 10.1016/j.ypmed.2003.09.037 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 758UC UT WOS:000187667700011 PM 14672645 ER PT B AU Marx, SJ AF Marx, SJ GP MEDIMOND TI Genetics of hyperparathyroidism SO PROCEEDINGS OF THE 12TH INTERNATIONAL CONGRESS OF ENDOCRINOLOGY LA English DT Proceedings Paper CT 12th International Congress of Endocrinology CY AUG 31-SEP 04, 2004 CL Lisbon, PORTUGAL ID FAMILIAL ISOLATED HYPERPARATHYROIDISM; JAW TUMOR SYNDROME; PARATHYROID CARCINOMA; GERMLINE MUTATION; HRPT2; PARAFIBROMIN AB Primary hyperparathyroidism (HPT) almost always arises from mutation in one or more gene(s) in the parathyroid chief cell. Conversely, some other hormone hypersecretion states, such as thyrotoxicosis, usually arise outside of the hormone secreting cell. Most parathyroid tumors are sporadic, and most of the somatically mutated genes that contribute to common variety parathyroid adenoma(s) are not known. Hereditary categories represent only about 5% of all HPT cases. Hereditary aspects have promoted identification of the genes for five of the six categories of hereditary HPT (1). C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Marx, SJ (reprint author), NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND PUBLISHING CO PI BOLOGNA PA VIA RUBBIANI 6/2, 40124 BOLOGNA, ITALY BN 88-7587-071-3 PY 2004 BP 247 EP 255 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA BBR36 UT WOS:000227355300038 ER PT B AU Stratakis, CA AF Stratakis, CA GP MEDIMOND TI Genetics of adrenocortical tumors SO PROCEEDINGS OF THE 12TH INTERNATIONAL CONGRESS OF ENDOCRINOLOGY LA English DT Proceedings Paper CT 12th International Congress of Endocrinology CY AUG 31-SEP 04, 2004 CL Lisbon, PORTUGAL ID SPOTTY SKIN PIGMENTATION; DEPENDENT PROTEIN-KINASE; ALPHA REGULATORY SUBUNIT; GASTRIC STROMAL SARCOMA; CARNEY COMPLEX; INHIBIN ALPHA; PRKAR1A GENE; I-ALPHA; ENDOCRINE OVERACTIVITY; APC GENE AB Adrenocortical hyperplasia is a polyclonal process but ACTs are mostly monoclonal lesions [1-3], indicating that genetic changes at specific loci in the genome are needed for adrenal tumorigenesis. These include the genes coding for TP53, KIP2/p57, insulin-like growth factor type-II (IGF2), angiotensin-II, endothelin-1, diminuto/Dwarf-1, adrenomedullin, urotensin II, novH and cAMP-early repressor. Perhaps the best characterized gene so far is p53 (TP53). However, p53 expression does not always correlate with prognosis and it is rarely seen in monoclonal but highly differentiated tumors, indicating that mutations in this gene are a late event in the process of sporadic ACT formation [1,2,4]. In the present review, we will attempt to present a model of tumorigenesis for the adrenal cortex that stems from new data, collected over the last 10 years by molecular genomic, positional cloning and animal model approaches. C1 NICHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. NR 48 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND PUBLISHING CO PI BOLOGNA PA VIA RUBBIANI 6/2, 40124 BOLOGNA, ITALY BN 88-7587-071-3 PY 2004 BP 405 EP 411 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA BBR36 UT WOS:000227355300061 ER PT S AU Nolte, G Holroyd, T Carver, F Coppola, R Hallett, M AF Nolte, G Holroyd, T Carver, F Coppola, R Hallett, M GP ieee TI Localizing brain interactions from rhythmic EEG/MEG data SO PROCEEDINGS OF THE 26TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-7 SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 26th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY SEP 01-05, 2004 CL San Francisco, CA SP IEEE Engn Med & Biol Soc, Whitaker Fdn, Cyberonics, NIH, NIBIB, NIDOCD, NINDS DE cross-spectrum; MEG; connectivity; volume conduction; alpha-rhythm; dipole model ID EEG AB The interpretation of MEG/EEG data in terms of brain connectivity is largely obscured by artefacts of volume conduction, i.e. by the fact that a single source is observable in many channels. Here, we analyze a measure which is insensitive to spurious connectivity arising from volume conducted "self-interaction". For rhythmic data such a measure can be given by the imaginary part of the cross-spectrum between EEG/MEG channels. For the derivation we essentially exploit that a signal is not time-lagged to itself. To localize the sources of this observed interaction we fit a model cross-spectrum consisting of N interacting dipoles to the sample cross-spectrum. The relation to the maximum likelihood estimator will be discussed in detail. The method is illustrated for MEG data of human alpha rhythm in eyes closed condition. The eigenvalues of the imaginary cross-spectrum clearly indicate the presence of at least 4 necessarily interacting sources. Fits of 2 to,6 dipoles in a realistic volume conductor all resulted in locations scattered in the mesial part of the occipital lobe. C1 NIH, Bethesda, MD 20892 USA. RP Nolte, G (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 0-7803-8439-3 J9 P ANN INT IEEE EMBS PY 2004 VL 26 BP 998 EP 1001 PN 1-7 PG 4 WC Computer Science, Interdisciplinary Applications; Engineering, Multidisciplinary; Engineering, Biomedical; Medicine, Research & Experimental; Neurosciences; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Research & Experimental Medicine; Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA BBG76 UT WOS:000225461800256 ER PT S AU Hassan, M Hattery, D Vogel, A Chernomordik, V Demos, S Aleman, K Little, R Yarchoan, R AF Hassan, M Hattery, D Vogel, A Chernomordik, V Demos, S Aleman, K Little, R Yarchoan, R GP ieee TI Noninvasive Infrared Imaging for quantitative assessment of tumor vasculature and response to therapy SO PROCEEDINGS OF THE 26TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-7 SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 26th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY SEP 01-05, 2004 CL San Francisco, CA SP IEEE Engn Med & Biol Soc, Whitaker Fdn, Cyberonics, NIH, NIBIB, NIDOCD, NINDS DE nfrared imaging; angiogenesis; kaposi's sarcoma; anti-KS therapy ID ENDOTHELIAL GROWTH-FACTOR; KAPOSIS-SARCOMA AB In this study we are investigating three infrared imaging techniques, thermography, multispectral imaging and Laser Doppler imaging (LDI) to assess parameters of vascularity in lesions of Kaposi's sarcoma (KS) and response to therapy. Thermography, multispectral imaging and LDI were recorded over the lesion and compare to normal skin either adjacent to the lesion or on the contralateral side. The KS lesions generally had increased temperature, blood volume (as measured by multispectral imaging) and blood flux (as measured by LDI) as compare to normal skin. After the treatment with experimental anti-KS drug, temperature, blood volume and blood flow of the lesion were significantly reduced from the baseline. These techniques hold promise to assess physiological parameter in KS lesion and their changes with therapy. C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Hassan, M (reprint author), NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 0-7803-8439-3 J9 P ANN INT IEEE EMBS PY 2004 VL 26 BP 1200 EP 1202 PN 1-7 PG 3 WC Computer Science, Interdisciplinary Applications; Engineering, Multidisciplinary; Engineering, Biomedical; Medicine, Research & Experimental; Neurosciences; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Research & Experimental Medicine; Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA BBG76 UT WOS:000225461800309 ER PT S AU Martino, RL AF Martino, RL GP ieee TI The importance of multidisciplinary teams in a large biomedical research program SO PROCEEDINGS OF THE 26TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-7 SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 26th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY SEP 01-05, 2004 CL San Francisco, CA SP IEEE Engn Med & Biol Soc, Whitaker Fdn, Cyberonics, NIH, NIBIB, NIDOCD, NINDS DE biomedical imaging; biomedical instrumentation; collaborative research; multidisciplinary teams; telemedicine AB The formation of multidisciplinary teams is vital to modern biomedical research. These teams are important contributors to the advancement of scientific discovery as well as the translation of those discoveries into useful clinical practice. The issues involved in providing scientific and technical expertise in computational science and engineering to support a large biomedical research program are presented. The activities of the Division of Computational Bioscience (DCB) of the Center for Information Technology (CIT) at the National Institutes of Health (NIH) are highlighted. Professionals in this organization apply the concepts and technologies of computer science, engineering, physical science and mathematics to biomedical applications, making available this expertise to the NIH Intramural Research Program (IRP). The areas of application include imaging, informatics, instrumentation, telemedicine, structural biology and mathematical analysis. Examples where collaborative research and development teams containing DCB professionals have worked to produce significant results are presented. These examples are a chromosome microdissection instrument, a telemedicine system for radiation oncology, and a medical image archive. C1 US Dept HHS, NIH, Bethesda, MD USA. RP US Dept HHS, NIH, Bethesda, MD USA. NR 9 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 0-7803-8439-3 J9 P ANN INT IEEE EMBS PY 2004 VL 26 BP 5188 EP 5191 PN 1-7 PG 4 WC Computer Science, Interdisciplinary Applications; Engineering, Multidisciplinary; Engineering, Biomedical; Medicine, Research & Experimental; Neurosciences; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Research & Experimental Medicine; Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA BBG76 UT WOS:000225461801370 ER PT S AU Ershow, AG Hill, JO Baldwin, JT AF Ershow, AG Hill, JO Baldwin, JT GP ieee TI Novel engineering approaches to obesity, overweight, and energy balance: Public health needs and research opportunities SO PROCEEDINGS OF THE 26TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-7 SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 26th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY SEP 01-05, 2004 CL San Francisco, CA SP IEEE Engn Med & Biol Soc, Whitaker Fdn, Cyberonics, NIH, NIBIB, NIDOCD, NINDS DE obesity; energy balance; engineering; devices; overweight; sensors ID DOUBLY LABELED WATER; MATERNAL OBESITY; PREVALENCE; DEFECTS AB The obesity epidemic is one of the most rapidly evolving public health problems of our day. At present, 2/3 of American adults and 1/6 of American children and adolescents are considered either overweight or obese. Public health concern about obesity is high and reflects documented increased risk of cardiovascular disease, type 2 diabetes, many forms of cancer, gallbladder disease, and osteoarthritis, and increased mortality from these ailments, especially among the most obese. Innovative engineering technologies are needed to address a large range of problems in energy balance, intake, and expenditure that are associated with the obesity epidemic. Excess adipose tissue, representing fat storage, ultimately derives from an imbalance between energy intake and energy expenditure. Novel sensors, devices, imaging technologies, nanotechnology, biomaterials, and other approaches need to be developed and evaluated through multidisciplinary collaborations between engineers, physical scientists, and scientists with expertise in obesity and nutrition. The goal is to encourage research to develop useful technologies and tools to facilitate research and eventually to support therapeutic advances and behavioral change. Furthermore, the possibility of re-engineering the "built environment" to encourage higher levels of physical activity has been suggested as another promising and important approach to which engineers can contribute (see http://www.obesityresearch.nih.gov). C1 NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Ershow, AG (reprint author), NHLBI, Div Heart & Vasc Dis, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 0-7803-8439-3 J9 P ANN INT IEEE EMBS PY 2004 VL 26 BP 5212 EP 5214 PN 1-7 PG 3 WC Computer Science, Interdisciplinary Applications; Engineering, Multidisciplinary; Engineering, Biomedical; Medicine, Research & Experimental; Neurosciences; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Research & Experimental Medicine; Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA BBG76 UT WOS:000225461801380 ER PT B AU Mao, S Thoma, GR AF Mao, S Thoma, GR BE Villaneuva, JJ TI Bayesian learning of 2D document layout models for preservation metadata extraction SO Proceedings of the Fourth IASTED International Conference on Visualization, Imaging, and Image Processing LA English DT Proceedings Paper CT 4th IASTED International Conference on Visualization, Imaging, and Image Processing CY SEP 06-08, 2004 CL Marbella, SPAIN SP Int Assoc Sci & Technol Dev, World Modelling Simulat Forum DE 2D document layout models; preservation metadata extraction; Bayesian learning AB Digital preservation addresses the storage, maintainance, accessibility, and technical integrity of digital materials over the long term. Preservation metadata is the information required to perforin these tasks. Given the volume of these journals and high labor cost of manual metadata entry, automated metadata extraction is necessary. Document layout analysis is a process of partitioning document images into hierarchically structured and labeled homogeneous physical regions. Descriptive metadata such as bibliographic information can then be extracted from these segmented and labeled regions using OCR. While numerous algorithms have been proposed for document layout analysis. most of them require manually specified rules or models. In this paper, we first define the hierarchical 2D layout model of document pages as a set of attributed hidden semi-Markov Models (HSMM). Each attributed HSMM represents the projection profile of the character bounding boxes in a physical region on either the X or Y axis. We then describe a Bayesian-based method to learn 2D layout models from the unstructured and labeled physical regions in a set of training pages. We compare the zoning and labeling performance of the learned HSMM-based model, a learned baseline model, and two rule-based systems on 69 test pages and show that the HSMM-based model has the best overall performance, and comparable or better performance for individual fields. C1 US Natl Lib Med, Bethesda, MD 20894 USA. RP Mao, S (reprint author), US Natl Lib Med, Bethesda, MD 20894 USA. NR 12 TC 4 Z9 4 U1 0 U2 1 PU ACTA PRESS PI CALGARY PA B6, STE 101, 2509 DIEPPE AVE SW, CALGARY, ALBERTA T3E 7J9, CANADA BN 0-88986-454-3 PY 2004 BP 329 EP 334 PG 6 WC Computer Science, Artificial Intelligence; Computer Science, Software Engineering; Imaging Science & Photographic Technology SC Computer Science; Imaging Science & Photographic Technology GA BCC31 UT WOS:000228556600057 ER PT B AU Kuznetsov, VA Pickalov, VV Knott, GD Kanapin, AA AF Kuznetsov, V. A. Pickalov, V. V. Knott, G. D. Kanapin, A. A. GP RASSB TI Analysis of proteome compexity based on counting domain-to-protein links SO Proceedings of the Fourth International Conference on Bioinformatics of Genome Regulation and Structure, Vol 1 LA English DT Proceedings Paper CT 4th International Conference on Bioinformatics of Genome Regulation and Structure (BGRS 2004) CY JUL 25-30, 2004 CL Novosibirsk, RUSSIA SP Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Lab Theoret Genet DE proteome complexity; evolution; domain-to-protein links; skew distributions ID EVOLUTION AB We define the list of domains to proteins, together with the numbers of their occurrences (links to proteins) found in the proteome of an organism to be the domain-to-protein linkage profile (DPLP) of the proteome. We estimated the DPLP for the 156 fully-sequenced genome organisms represented in the InterPro database. This work, presents several quantitative measures of the complexity of a proteome based on the DPLP. For each of the 156 studied organisms, we found two large subsets of domains: the domains which occur two or more times in at least one protein, and the domains which are not duplicated within any protein of the proteome. The latter set of domains well reflects the increasing trend of biological complexity due to evolution. The statistical distributions of the number of domain-to-protein links in the proteome and the estimates of the differences between the DPLPs for pairs of organisms are used as measures of relative biological complexity of the organisms. In particular, we show quantitatively the greater complexity of the human proteome, relative to that of a mouse or a rat. These differences are only partially reflected in the number of protein-coding genes estimated for these species by the sequencing genome projects. C1 NIH, CIT, Bethesda, MD 20892 USA. RP Kuznetsov, VA (reprint author), NIH, CIT, Bethesda, MD 20892 USA. RI Pickalov, Valery/K-3848-2012; Kanapin, Alexander/E-7632-2013; Pickalov, Valery/B-7262-2008 OI Pickalov, Valery/0000-0001-9362-6966; Pickalov, Valery/0000-0001-9362-6966 NR 5 TC 0 Z9 0 U1 0 U2 1 PU RUSSIAN ACAD SCI SIBERIAN BRANCH PI NOVOSIBIRSK PA NOVOSKIBRISK 90, MORSKOI, PROSP 2, 630090 NOVOSIBIRSK, RUSSIA PY 2004 BP 293 EP 297 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Computer Science GA BFJ66 UT WOS:000242399100074 ER PT B AU Kuznetsov, VA AF Kuznetsov, V. A. GP RASSB TI Validation of random birth-death model of evolution of proteome complexity SO Proceedings of the Fourth International Conference on Bioinformatics of Genome Regulation and Structure, Vol 1 LA English DT Proceedings Paper CT 4th International Conference on Bioinformatics of Genome Regulation and Structure (BGRS 2004) CY JUL 25-30, 2004 CL Novosibirsk, RUSSIA SP Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Lab Theoret Genet DE proteome complexity; evolution; domain-to-protein links; skew distributions AB We have shown that counting the domain-to-protein links observed in the protein and protein domain/motifs data sets and analysis of statistical distributions of these counts lead to common probabilistic model of evolution of proteome complexity of the archael, bacterial and eukaryotic organisms (Kuznetsov et al., 2002; Kuznetsov, 2003a, b). In this work, using InterPro data sets, we test several basic assumptions and predictions of our model. C1 NIH, CIT, Bethesda, MD 20892 USA. RP Kuznetsov, VA (reprint author), NIH, CIT, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU RUSSIAN ACAD SCI SIBERIAN BRANCH PI NOVOSIBIRSK PA NOVOSKIBRISK 90, MORSKOI, PROSP 2, 630090 NOVOSIBIRSK, RUSSIA PY 2004 BP 298 EP 302 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Computer Science GA BFJ66 UT WOS:000242399100075 ER PT B AU Babenko, VN Sverdlov, A Rogozin, IB Koonin, EV AF Babenko, V. N. Sverdlov, A. Rogozin, I. B. Koonin, E., V GP RASSB TI Evolution of gene structure in eukaryotic genomes SO Proceedings of the Fourth International Conference on Bioinformatics of Genome Regulation and Structure, Vol 2 LA English DT Proceedings Paper CT 4th International Conference on Bioinformatics of Genome Regulation and Structure (BGRS 2004) CY JUL 25-30, 2004 CL Novosibirsk, RUSSIA SP Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Lab Theoret Genet DE spliceosomal intron; evolutionary conservation; reverse transcription; homologous recombination ID INTRON POSITIONS AB Motivation: In spite of numerous computational studies, origins, and mechanisms of evolution of eukaryotic spliceosomal introns remain mysterious. We approached these problems from a comparative-genomic standpoint i.e., by comparing homologous gene structures in 7 eukaryotic lineages representing three kingdoms and using the parsimony principle to reconstruct evolutionary scenarios. This allowed us to identify previously unnoticed features of splice-site sequences and gene organization. Results: In an attempt to gain insight into the dynamics of intron evolution in eukaryotic protein-coding genes, the distributions of old introns, which are conserved between distant phylogenetic lineages, and new, lineage-specific introns along the gene length were examined. A significant excess of old introns,in 5'-regions of genes was-detected. New introns, when analyzed in bulk, showed a nearly flat distribution from the 5'- to the 3'-end. However, analysis,of new intron distributions in individual genomes revealed notable lineage-specific features. While in intron-poor genomes, particularly yeast Schizosaccharomyces pombe, the 5'-portions of genes contain a significantly greater number of new introns than the 3'-portions, the intron-rich genomes of humans and Arabidopsis show the opposite trend. These observations seem to be compatible with the view that introns are both lost and inserted in 3'-terminal portions of genes more often than in 5'-portions. Over-representation of 3'-terminal sequences among cDNAs that mediate intron loss appears to be the most likely explanation for the apparent preferential loss of introns in the distal parts of genes. Preferential insertion of introns in the 3'-portions suggests that introns might be inserted via. a reverse-transcription-mediated pathway similar to that implicated in intron loss. C1 NCBI, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Babenko, VN (reprint author), NCBI, Natl Lib Med, NIH, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. RI Babenko, Vladimir/K-5609-2014 NR 7 TC 0 Z9 0 U1 0 U2 1 PU RUSSIAN ACAD SCI SIBERIAN BRANCH PI NOVOSIBIRSK PA NOVOSKIBRISK 90, MORSKOI, PROSP 2, 630090 NOVOSIBIRSK, RUSSIA PY 2004 BP 173 EP 176 PG 4 WC Biochemical Research Methods; Biology; Computer Science, Interdisciplinary Applications; Evolutionary Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Computer Science; Evolutionary Biology GA BFJ68 UT WOS:000242400300041 ER PT B AU Yoshinaga, K AF Yoshinaga, K BE Makino, T Sugi, T TI Interface between the endocrine and immune systems in establishment and maintenance of pregnancy SO PROCEEDINGS OF THE IX INTERNATIONAL CONGRESS OF REPRODUCTIVE IMMUNOLOGY - ISIR LA English DT Proceedings Paper CT 9th International Congress of Reproductive Immunology CY OCT 11-15, 2004 CL Hakone, JAPAN ID PROGESTERONE; UTERUS; PERMEABILITY; PROLACTIN; RAT AB To understand how pregnancy is established and maintained, both endocrine and immune aspects must be studied in parallel. Advances in biomedical sciences have led us to explore how hormones, growth factors, cytokines and various other factors act through signal transduction pathways and how these molecules regulate gene expression. While certain molecules play roles in the endocrine system, others do in the immune system. More importantly, certain molecules are involved in both systems. By investigating these molecules from both aspects, we may find that they constitute a portion of the interface between the endocrine and immune systems. It is assumed that the endocrine conditions create the maternal environment, protecting the conceptus, and the maternal immune system directs the mother to reject foreign body (conceptus). Identification and characterization of the interface between these two systems should serve as a basis to improve our understanding of the establishment of pregnancy. C1 NICHD, Reprod Sci Branch, Populat Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. RP Yoshinaga, K (reprint author), NICHD, Reprod Sci Branch, Populat Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND PUBLISHING CO PI BOLOGNA PA VIA RUBBIANI 6/2, 40124 BOLOGNA, ITALY BN 88-7587-093-4 PY 2004 BP 53 EP 58 PG 6 WC Immunology; Obstetrics & Gynecology; Reproductive Biology SC Immunology; Obstetrics & Gynecology; Reproductive Biology GA BBG14 UT WOS:000225379400010 ER PT B AU Gail, M Chatterjee, N AF Gail, M Chatterjee, N BE Lin, DY Heagerty, PJ TI Some biases that may affect kin-cohort studies for estimating the risks from identified disease genes SO PROCEEDINGS OF THE SECOND SEATTLE SYMPOSIUM IN BIOSTATISTICS: ANALYSIS OF CORRELATED DATA SE LECTURE NOTES IN STATISTICS LA English DT Proceedings Paper CT 2nd Seattle Symposium in Biostatistics - Analysis of Correlated Data CY NOV 20-21, 2000 CL Seattle, WA SP Pfizer, Univ Washington, Sch Public Hlth & Commun Med, Div Public Hlth Sci, Fred Hutchinson Canc Res Ctr DE gene penetrance; absolute risk; genotyped proband design; Mendelian disease; autosomal dominant ID AUTOSOMAL-DOMINANT MUTATION; ESTIMATING PENETRANCE; DESIGNS; BRCA1 AB The kin-cohort design can be used to estimate the absolute risk of disease (penetrance) associated with an identified mutation. In the kin-cohort design a volunteer (proband) is genotyped and provides information on the disease histories (phenotypes) of his or her first degree relatives. We review some of the strengths and weaknesses of this design before focusing on two types of bias. One bias can arise if the joint distribution of phenotypes of family members, conditional on their genotypes, is mis-specified. In particular, the assumption of conditional independence of phenotypes given genotypes can lead to overestimates of penetrance. If probands are sampled completely at random, a composite likelihood approach can be used that is robust to residual familial correlations, given genotypes. If the sample is enriched in probands with disease, however, one is forced into making some assumptions on the joint distribution of the phenotypes, given genotypes. For phenotypes characterized by age at disease onset, biases can result if no allowance is made for an influence of genotype on competing causes of mortality or on mortality rates following disease onset. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Gail, M (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NR 11 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 0-387-20862-3 J9 LECT NOTES STAT PY 2004 VL 179 BP 175 EP 187 PG 13 WC Statistics & Probability SC Mathematics GA BBP54 UT WOS:000226892800010 ER PT S AU Spinetti, I Toni, C Presciuttini, S Domenici, R AF Spinetti, I Toni, C Presciuttini, S Domenici, R BE Doutremepuich, C Morling, N TI Localization of DNA on a dishcloth used as a strangulation tool allowed perpetrator identification within a family SO PROGRESS IN FORENSIC GENETICS 10 SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 20th International Congress of the International-Society-for-Forensic-Genetics CY SEP 09-13, 2003 CL Arcachon, FRANCE SP Int Soc Forens Genet DE strangulation; DNA pattern; STR ID TRACES AB A case report of a domestic murder is presented. The victim was strangled with a kitchen cloth; the suspect, victim's ex-husband, who still frequented the house, admitted of having used that cloth, though to dry his hands only. The pattern of DNA amplified from the cloth, belonging to both victim and suspect, allowed suspect's version to be rejected. (C) 2003 Published by Elsevier B.V. C1 Univ Pisa, Sch Med, Unit Legal Med, I-56100 Pisa, Italy. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Presciuttini, S (reprint author), UO Med Legale, Scuola Med, Via Roma 55, I-56126 Pisa, Italy. NR 3 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51505-4 J9 INT CONGR SER PY 2004 VL 1261 BP 497 EP 498 DI 10.1016/S0531-5131(03)01642-X PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Legal SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Legal Medicine GA BAU90 UT WOS:000223657000165 ER PT S AU Presciuttini, S Toni, C Marroni, F Spinetti, I Bailey-Wilson, JE Domenici, R AF Presciuttini, S Toni, C Marroni, F Spinetti, I Bailey-Wilson, JE Domenici, R BE Doutremepuich, C Morling, N TI The number of STR markers necessary to resolve relationships in deficiency paternity cases SO PROGRESS IN FORENSIC GENETICS 10 SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 20th International Congress of the International-Society-for-Forensic-Genetics CY SEP 09-13, 2003 CL Arcachon, FRANCE SP Int Soc Forens Genet DE STR; familial relationships; DNA markers; deficiency paternity AB The inference about the biological relationship between pairs of individuals using genetic markers plays a central role in many areas of human genetics. We investigated the number of markers (M) that are necessary to assign a given proportion of pairs (50%, 60%, 70%, 80%, 90%, 95%, and 99%) to their correct relationship at three predefined probability levels (99%, 99.9%, and 99.99%) against several alternative hypotheses. The following relationships were considered: (1) full sibs (FS), (2) second degree (2D, including half-sibs, grandparent-grandchild and avuncular pairs), (3) first cousins (FC), (4) unrelated individuals (UR). (C) 2003 Published by Elsevier B.V. C1 Univ Pisa, Sch Med, Unit Legal Med, I-56100 Pisa, Italy. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Presciuttini, S (reprint author), Ctr Retrovirus, Ctr Stat Genet, SS Abetone & Brennero 2, I-56127 Pisa, Italy. OI Marroni, Fabio/0000-0002-1556-5907 NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51505-4 J9 INT CONGR SER PY 2004 VL 1261 BP 541 EP 543 DI 10.1016/S0531-5131(03)01664-9 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Legal SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Legal Medicine GA BAU90 UT WOS:000223657000180 ER PT J AU Nixon, JB Kim, KS Lamb, PW Bottone, FG Eling, TE AF Nixon, JB Kim, KS Lamb, PW Bottone, FG Eling, TE TI 15-lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE 15-lipoxygenase-1; colorectal cancer; microarray; lipid metabolites; 13-HODE ID MUTANT P53 EXPRESSION; GENE-EXPRESSION; METALLOTHIONEIN EXPRESSION; COLON-CANCER; MATRIX METALLOPROTEINASE-1; CELL-DIFFERENTIATION; SIGNALING PATHWAY; PATIENT SURVIVAL; PPAR-GAMMA; CARCINOMA AB The localization of 15-lipoxygenase-1 (15-LO-1) in human colorectal carcinoma and normal adjacent tissue was examined using immunohistochemistry. In normal tissues, 15-LO-1 was strongly localized in the mucosal epithelium. Conversely, in tumor tissues, staining for 15-LO-1 was dispersed throughout the tissue, weak in neoplastic epithelium, and strong in stromal inflammatory cells. The addition of 50 muM 13(S)-hydroxyeicosatetraenoic acid (HODE), resulted in decreased cell proliferation after 72 h, but lower concentrations (5 or 10 muM) had no effect compared to vehicle treated Caco-2 cells. In addition, 13(S)-HODE had no effect on apoptosis or differentiation of the Caco-2 cells. Microarray analyses of RNA from Caco-2 cells treated with 50 muM 13(S)-HODE revealed changes in 17 genes. HCT-116 colorectal cells were stably transfected with 15-LO-1. In athymic nude mice, transplantable tumors derived from 15-LO-1 HCT-116 cells were smaller than tumors derived from vector HCT-116 cells. These data demonstrate that 13(S)-HODE induces changes in gene expression and has anti-tumorigenic effects. Published by Elsevier Ltd. C1 NIEHS, Eicosanoid Biochem Sect, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, Eicosanoid Biochem Sect, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 35 TC 52 Z9 54 U1 2 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD JAN PY 2004 VL 70 IS 1 BP 7 EP 15 DI 10.1016/j.plefa.2003.07.001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 757MY UT WOS:000187567100002 PM 14643174 ER PT J AU Chae, SS Proia, RL Hla, T AF Chae, SS Proia, RL Hla, T TI Constitutive expression of the SlP(1) receptor in adult tissues SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE sphingosine-1-phosphate; EDG-1; gene expression ID SPHINGOSINE 1-PHOSPHATE RECEPTORS; ENDOTHELIAL GROWTH-FACTOR; PROTEIN-COUPLED RECEPTOR; SPHINGOSINE-1-PHOSPHATE; EDG-1; CELLS; ACTIVATION; PHOSPHORYLATION; RHO AB S1P(1) (also known as EDG-1) is a G-protein coupled receptor for the bioactive lipid, sphingosine-1-phosphate (S1P). Activation of S1P(1) receptor in endothelial cells induces diverse cellular effects, including cell proliferation, survival, migration and morphogenesis. Recent in vivo studies showed that the S1P(1) receptor is required in vascular maturation during development. While a number of studies reported a functional role of S1P(1) in vascular system and the presence of S1P(1) transcripts in various mouse organs, tissue distribution of S1P(1) has not been fully defined. In this study, we determined the expression pattern of S1P(1) by beta-galactosidase reporter gene expression, which is knocked into the S1P(1) focus. We show that S1P(1) is widely expressed in various cell types of adult mouse tissues, suggesting a regulatory role of this receptor in numerous physiological processes in both vascular and non-vascular tissues. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Connecticut, Ctr Hlth, Dept Cell Biol, Ctr Vasc Biol, Farmington, CT 06030 USA. NIDDK, Genet Dis & Dev Branch, NIH, Bethesda, MD USA. RP Hla, T (reprint author), Univ Connecticut, Ctr Hlth, Dept Cell Biol, Ctr Vasc Biol, Farmington, CT 06030 USA. EM hla@nso2.uchc.edu RI Proia, Richard/A-7908-2012; Hla, Timothy/G-5873-2012 OI Hla, Timothy/0000-0001-8355-4065 FU NHLBI NIH HHS [HL67330, HL70694] NR 26 TC 66 Z9 66 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-6980 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD JAN PY 2004 VL 73 IS 1-2 BP 141 EP 150 DI 10.1016/j.prostaglandins.2004.01.006 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 818JF UT WOS:000221240700013 PM 15165038 ER PT J AU Ahaghotu, C Baffoe-Bonnie, A Kittles, R Pettaway, C Powell, I Royal, C Wang, H Vijayakumar, S Bennett, J Hoke, G Mason, T Bailey-Wilson, J Boykin, W Berg, K Carpten, J Weinrich, S Trent, J Dunston, G Collins, F AF Ahaghotu, C Baffoe-Bonnie, A Kittles, R Pettaway, C Powell, I Royal, C Wang, H Vijayakumar, S Bennett, J Hoke, G Mason, T Bailey-Wilson, J Boykin, W Berg, K Carpten, J Weinrich, S Trent, J Dunston, G Collins, F TI Clinical characteristics of African-American men with hereditary prostate cancer: the AAHPC study SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE hereditary prostate cancer; African Americans ID RADICAL PROSTATECTOMY; PATHOLOGICAL FEATURES; SUSCEPTIBILITY LOCUS; SURVIVAL; INHERITANCE; POPULATION; FAMILIES; LINKAGE AB Introduction: The African-American Hereditary Prostate Cancer (AAHPC) Study was designed to recruit African-American families fulfilling very stringent criteria of four or more members diagnosed with prostate cancer at a combined age at diagnosis of 65 years or less. This report describes the clinical characteristics of a sample of affected AAHPC family members. Methods: In all, 92 African-American families were recruited into the study between 1998 and 2002. Complete clinical data including age and PSA at diagnosis, number of affected per family, stage, grade, and primary treatment were available on 154 affected males. Nonparametric Wilcoxon two-sample tests and Fisher's exact test (two-tailed), were performed to compare families with 4-6 and >6 affected males with respect to clinical characteristics. Results: The mean number of affected men per family was 5.5, with a mean age at diagnosis of 61.0 (+/- 8.4) years. Age at diagnosis, PSA and Gleason score did not show significant differences between the two groups of families. Based on the Gleason score, 77.2% of affected males had favorable histology. Significantly, there were marked differences between the two groups in the frequency of node-positive disease (P = 0.01) and distant metastases (P = 0.0001). Radical prostatectomy was the preferred primary therapy for 66.2% of all affected men followed by 20.8% who chose radiation therapy. Conclusions: Our findings suggest that affected males who carry the highest load of genetic factors are at the highest risk for early dissemination of disease, thus efforts at early diagnosis and aggressive therapeutic approaches may be warranted in these families. Since the primary therapy choices in our study favored definitive treatment (87.0%) when compared to the 1983 and 1995 SEER data in which 28 and 64% received definitive treatment, respectively, it appears that affected African-American men in multiplex families may be demonstrating the reported psycho-social impact of family history on screening practices and treatment decisions for prostate cancer. C1 Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Howard Univ, Div Urol, Washington, DC 20059 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Howard Univ, Dept Microbiol, Washington, DC 20059 USA. MD Anderson Med Ctr, Houston, TX USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Howard Univ, Dept Pediat, Washington, DC 20059 USA. Univ Illinois, Chicago, IL USA. Midtown Urol, Atlanta, GA USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Michael Reese Hosp & Med Ctr, Chicago, IL 60616 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Translat Gen Res Inst, Genet Basis Human Dis Res Div, Phoenix, AZ USA. Univ S Carolina, Columbia, SC 29208 USA. RP Ahaghotu, C (reprint author), Howard Univ Hosp, Div Urol, 2041 Georgia Ave Suite 4C02, Washington, DC 20060 USA. EM cahaghotu@howard.edu FU NCI NIH HHS [CA-06927]; NHGRI NIH HHS [HG-75418]; NIEHS NIH HHS [N01-ES-75418] NR 30 TC 18 Z9 19 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PY 2004 VL 7 IS 2 BP 165 EP 169 DI 10.1038/sj.pcan.4500719 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 837TM UT WOS:000222663200014 PM 15175665 ER PT S AU Trott, JF Hovey, RC Koduri, S Vonderhaar, BK AF Trott, JF Hovey, RC Koduri, S Vonderhaar, BK BE Pickering, LK Morrow, AL RuizPalacios, GM Schanler, RJ TI Multiple new isoforms of the human prolactin receptor gene SO PROTECTING INFANTS THROUGH HUMAN MILK: ADVANCING THE SCIENTIFIC EVIDENCE SE ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT 11th International Conference of the International-Society-for-Research-in-Human-Milk-and-Lactation CY OCT 04-08, 2002 CL Mexico City, MEXICO SP Int Soc Res Human Milk & Lactat ID BREAST-CANCER CELLS; PROMOTER UTILIZATION; EXPRESSION; CLONING; FORMS; MICE; LONG C1 NCI, Mol & Cellular Endocrinol Sect, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Trott, JF (reprint author), NCI, Mol & Cellular Endocrinol Sect, Mammary Biol & Tumorigenesis Lab, Room 5B47,10 Ctr Dr, Bethesda, MD 20892 USA. EM trottj@mac.com; rhovey@zoo.uvm.edu NR 16 TC 11 Z9 12 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0065-2598 BN 0-306-48588-5 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2004 VL 554 BP 495 EP 499 PG 5 WC Medicine, Research & Experimental; Nutrition & Dietetics; Obstetrics & Gynecology; Pediatrics SC Research & Experimental Medicine; Nutrition & Dietetics; Obstetrics & Gynecology; Pediatrics GA BAU75 UT WOS:000223641000068 PM 15384631 ER PT S AU Venti, A Giordano, T Eder, P Bush, AI Lahiri, DK Greig, NH Rogers, JT AF Venti, A Giordano, T Eder, P Bush, AI Lahiri, DK Greig, NH Rogers, JT BE Lahiri, DK TI The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5 '-untranslated region SO PROTECTIVE STRATEGIES FOR NEURODEGENERATIVE DISEASES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 7th International Conference on Protective Strategies for Neurodegenerative Diseases CY AUG 14-18, 2004 CL Univ British Columbia, Vancouver, CANADA SP NIH, Vancouver BioMed Hlth Res Fdn HO Univ British Columbia DE amyloid precursor protein (APP); Alzheimer's disease; iron-responsive elements ID AMYLOID PRECURSOR PROTEIN; METAL-ION TRANSPORTER; ALZHEIMERS-DISEASE; REGULATES TRANSLATION; J774 MACROPHAGES; BINDING; INTERLEUKIN-1; EXPRESSION; DISCOVERY; TAU AB The Alzheimer's amyloid precursor protein (APP) is the metallo-protein that is cleaved to generate the pathogenic A beta peptide. We showed that iron closely regulated the expression of APP by 5'-untransiated region (5'-UTR) sequences in APP mRNA. Iron modulated APP holoprotein expression by a pathway similar to iron control of the translation of the ferritin-L and -H mRNAs by iron-responsive elements in their 5'-UTRs. APP gene transcription is also responsive to copper deficit where the Menkes protein depleted fibroblasts of copper to suppress transcription of APP through metal regulatory and copper regulatory sequences upstream of the APP 5' cap site. APP is a copper-zinc metalloprotein and chelation of Fe3+ by desferrioxamine and Cu2+ by clioquinol appeared to provide effective therapy for the treatment of AD in limited patient studies. We have introduced an RNA-based screen for small APP 5'-UTR binding molecules to identify leads that limit APP translation (but not APLP-1 and APLP-2) and amyloid A beta peptide production. A library of 1200 drugs was screened to identify lead drugs that limited APP 5'-UTR-directed translation of a reporter gene. The efficacy of these leads was confirmed for specificity in a cell-based secondary assay to measure the steady-state levels of APP holoprotein relative to APLP-1/APLP-2 by Western blotting. Several chelators were identified among the APP 5'-UTR directed leads consistent with the presence of an IRE stem-loop in front of the start codon of the APP transcript. The APP 5'-UTR-directed drugs-desferrioxamine (Fe3+ chelator), tetrathiomolybdate (Cu2+ chelator), and dimercaptopropanol (Pb2+ and Hg2+ chelator)-each suppressed APP holoprotein expression (and lowered A beta peptide secretion). The novel anticholinesterase phenserine also provided "proof of concept" for our strategy to target the APP 5'-UTR sequence to identify "anti-amyloid" drugs. We further defined the interaction between iron chelation and phenserine action to control APP 5'-UTR-directed translation in neuroblastoma (MY) transfectants. Phenserine was most efficient to block translation under conditions of intracellular iron chelation with desferrioxamine suggesting that this anticholinesterase operated through an iron (metal)-dependent pathway at the APP 5'-UTR site. C1 Massachusetts Gen Hosp E, Genet & Aging Res Unit, Dept Psychiat, HMS Neurosci, Charlestown, MA 02129 USA. Louisiana State Univ, Dept Mol Biol & Biochem, Shreveport, LA 71130 USA. Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. NIA, Baltimore, MD 21224 USA. RP Rogers, JT (reprint author), Massachusetts Gen Hosp E, Genet & Aging Res Unit, Dept Psychiat, HMS Neurosci, Charlestown, MA 02129 USA. EM jrogers@partners.org RI Bush, Ashley/A-1186-2007 OI Bush, Ashley/0000-0001-8259-9069 FU NIA NIH HHS [AG18884, AG21081, AG18379] NR 38 TC 36 Z9 38 U1 0 U2 4 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-529-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1035 BP 34 EP 48 DI 10.1196/annals.1332.003 PG 15 WC Multidisciplinary Sciences; Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Science & Technology - Other Topics; Neurosciences & Neurology; Pharmacology & Pharmacy GA BBW48 UT WOS:000228130300003 PM 15681799 ER PT S AU Lahiri, DK Chen, DM Lahiri, P Rogers, JT Greig, NH Bondy, S AF Lahiri, DK Chen, DM Lahiri, P Rogers, JT Greig, NH Bondy, S BE Lahiri, DK TI Melatonin, metals, and gene expression - Implications in aging and neurodegenerative disorders SO PROTECTIVE STRATEGIES FOR NEURODEGENERATIVE DISEASES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 7th International Conference on Protective Strategies for Neurodegenerative Diseases CY AUG 14-18, 2004 CL Univ British Columbia, Vancouver, CANADA SP NIH, Vancouver BioMed Hlth Res Fdn HO Univ British Columbia DE aging; amyloid; brain; diet; melatonin; mRNA; metals; mouse; synaptic protein ID AGE-RELATED-CHANGES; AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; NEUROBLASTOMA-CELLS; OXIDATIVE DAMAGE; CEREBRAL-CORTEX; PINEAL-GLAND; RAT-BRAIN; CALORIC RESTRICTION; DIETARY MELATONIN AB Melatonin is a hormone secreted by the pineal gland, mostly in the dark period of the light/dark cycle, with corresponding fluctuations reflected in the plasma melatonin levels. This hormone plays a critical role in the regulation of various neural and endocrine processes that are synchronized with daily change in photoperiod. Abnormal melatonin levels are associated with metabolic disturbances and other disorders. Melatonin potentially plays an important role in aging, prolongation of life span, and health in the aged individual. It may exert a beneficial action on neurodegenerative conditions in those with debilitating diseases. It interacts with metals and, in some cases, neutralizes their toxic effects. Levels of melatonin decrease with aging in mice. Its dietary supplementation has recently been shown to result in a significant rise in levels of endogenous melatonin in serum as well as all other tissue samples tested. The effects of dietary melatonin have been studied in the brain of mice with regard to nitric oxide synthase, synaptic proteins, and amyloid beta peptides (A beta), which are involved in amyloid deposition and plaque formation in Alzheimer's disease (AD). Melatonin supplementation has no significant effect on cerebral cortical levels of nitric oxide synthase or synaptic proteins, such as synaptophysin and SNAP-25. Notably, however, elevated brain melatonin levels resulted in a significant reduction in levels of toxic cortical A beta of both 40- and 42-amino-acid forms. Taken together, these results suggest that dietary melatonin supplementation may slow the neurodegenerative changes associated with brain aging and that the depletion of melatonin in the brain of aging mice may, in part, account for this adverse change. C1 Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. Banaras Hindu Univ, Womens Coll, Dept Chem, Varanasi 221005, Uttar Pradesh, India. Harvard Univ, Sch Med, Boston, MA 02115 USA. NIA, NIH, Baltimore, MD 21224 USA. Univ Calif Irvine, Dept Community & Environm Med, Irvine, CA 92717 USA. RP Lahiri, DK (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, 791 Union Dr, Indianapolis, IN 46202 USA. EM dlahiri@iupui.edu; dlahiri@iupui.edu FU NIA NIH HHS [AG 16794, AG 18379, AG 18884]; NIEHS NIH HHS [ES 7992] NR 57 TC 13 Z9 15 U1 1 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-529-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1035 BP 216 EP 230 DI 10.1196/annals.1332.014 PG 15 WC Multidisciplinary Sciences; Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Science & Technology - Other Topics; Neurosciences & Neurology; Pharmacology & Pharmacy GA BBW48 UT WOS:000228130300014 PM 15681810 ER PT S AU Greig, NH Mattson, MP Perry, T Chan, SL Giordano, T Sambamurti, K Rogers, JT Ovadia, H Lahiri, DK AF Greig, NH Mattson, MP Perry, T Chan, SL Giordano, T Sambamurti, K Rogers, JT Ovadia, H Lahiri, DK BE Lahiri, DK TI New therapeutic strategies and drug candidates for neurodegenerative diseases p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists SO PROTECTIVE STRATEGIES FOR NEURODEGENERATIVE DISEASES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 7th International Conference on Protective Strategies for Neurodegenerative Diseases CY AUG 14-18, 2004 CL Univ British Columbia, Vancouver, CANADA SP NIH, Vancouver BioMed Hlth Res Fdn HO Univ British Columbia DE TNF-alpha; p53; GLP-1 receptor (GLP-1R) ID GLUCAGON-LIKE PEPTIDE-1; NECROSIS-FACTOR-ALPHA; CENTRAL-NERVOUS-SYSTEM; AMYLOID-BETA-PEPTIDE; PROGRAMMED CELL-DEATH; PROTEIN MESSENGER-RNA; UA-RICH SEQUENCES; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; PRECURSOR PROTEIN AB Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate-limiting steps within the pathological cascade. Such targets include TNF-alpha, p53, and GLP-1 receptor. The cytokine TNF-alpha is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, A beta, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzo-thiazole and -oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults. C1 NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr,Intramural Res Program,NIH, Baltimore, MD 21224 USA. Louisiana State Univ, Dept Mol Biol & Biochem, Shreveport, LA 71130 USA. Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Genet & Aging Unit, Charlestown, MA 02129 USA. Hadassah Hebrew Univ Hosp, Agnes Ginges Ctr Human Neurogenet, Dept Neurol, Jerusalem, Israel. Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr,Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM greign@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS NR 119 TC 67 Z9 71 U1 1 U2 8 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-529-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1035 BP 290 EP 315 DI 10.1196/annals.1332.018 PG 26 WC Multidisciplinary Sciences; Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Science & Technology - Other Topics; Neurosciences & Neurology; Pharmacology & Pharmacy GA BBW48 UT WOS:000228130300018 PM 15681814 ER PT J AU Urieto, JO Liu, TF Black, JH Cohen, KA Hall, PD Willingham, MC Pennell, LK Hogge, DE Kreitman, RJ Frankel, AE AF Urieto, JO Liu, TF Black, JH Cohen, KA Hall, PD Willingham, MC Pennell, LK Hogge, DE Kreitman, RJ Frankel, AE TI Expression and purification of the recombinant diphtheria fusion toxin DT(388)IL3 for phase I clinical trials SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE diphtheria toxin; interleukin-3; monkeys ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; INTERLEUKIN-3 RECEPTOR; STEM-CELLS; PROTEIN; RESISTANCE; SURVIVAL; MICE; PROLIFERATION; CYTOTOXICITY AB A genetically engineered fusion toxin targeted to acute myeloid leukemia (AML) blasts was designed with the first 388 amino acid residues of diphtheria toxin with an H-M linker fused to human interleukin-3. The cDNA was subcloned in the pRK bacterial expression plasmid and used to transform BLR (DE3) Escherichia coli. A single transformed colony was grown in Superbroth with ampicillin; bacteria were centrifuged at an OD650 of 1.3; master cell bank aliquots of bacteria in 30% glycerol/Superbroth were frozen and stored at -80 degreesC. Master cell bank bacteria were diluted 1500-fold into Superbroth and recombinant protein was induced with 1 mM IPTG at an OD650 of 0.6. After two additional hours of fermentation, inclusion bodies were isolated, washed, and denatured in guanidine hydrochloride and dithioerythritol. Recombinant protein was refolded by diluted 100-fold in cold buffer with arginine and oxidized glutathione. After dialysis, purified protein was obtained after anion-exchange, size exclusion on FPLC, and polymyxin B affinity chromatography. The final material was filter sterilized, aseptically vialed, and stored at -80 degreesC. seventy-five 3-L bacterial culture preparations were made and pooled for the AT-1 batch (568 mL) and twenty-four 3-L bacterial culture preparations were made and pooled for the AT-2 batch (169 mL). The final product was characterized by Coomassie Plus protein assay, Coomassie-stained SDS-PAGE, limulus amebocyte lysate endotoxin assay, human AML TF/H-ras cell cytotoxicity assay, sterility, tandem mass spectroscopy, IL3 receptor binding affinity, ADP ribosylation activity, inhibition of normal human CFU-GM, disulfide bond analysis, immunoblots, peptide mapping, stability, HPLC TSK3000, N-terminal sequencing, E coli DNA contamination, C57BL/6 mouse toxicity, cynomolgus monkey toxicity, and immunohistochemistry. Yields were 25.7 +/- 5.6 mg/L bacterial culture of denatured fusion toxin. After refolding and chromatography, final yields were 20 +/- 11% or 5 mg/L. Vialed product was sterile. Batches were in 0.25 M sodium chloride/5 rnM Tris, pH 8, and had protein concentrations of 1.8-1.9 mg/mL. Purity by SDS-PAGE was 99 +/- 1%. Aggregates by HPLC were < 1%. Potency revealed a 48 h IC50 of 6-8 pM on TF/H-ras cells. Endotoxin levels were 1 eu/mg. The remaining chemical and biologic assays confirmed the purity, composition, and functional activities of the molecule. The LD10 in mice was 250 mug/kg/day every other day for six doses. The MTD in monkeys was 60 mug/kg/day every other day for six doses. Drug did not react with tested frozen human tissue sections by immunohistochemistry. There was no evidence of loss of solubility, proteolysis aggregation, or loss of potency over 6 months at -80 and -20 degreesC. Further, the drug was stable at 4 and 25 degreesC in the plastic syringe and administration tubing for 24 h and at 37 degreesC in human serum for 24 h. The synthesis of this protein drug should be useful for production for clinical phase I/II clinical trials and may be suitable for other diphtheria fusion toxins indicated for clinical development. (C) 2003 Elsevier Inc. All rights reserved. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Med Univ S Carolina, Dept Pharm, Charleston, SC 29425 USA. Univ S Alabama, Sch Med, Canc Res Inst, Mobile, AL 36688 USA. British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Frankel, AE (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. FU NCI NIH HHS [R21CA90550, R01CA76178, R01CA090263]; NCRR NIH HHS [T32RR007009] NR 29 TC 28 Z9 36 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD JAN PY 2004 VL 33 IS 1 BP 123 EP 133 DI 10.1016/j.pep.2003.09.003 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 757XV UT WOS:000187587500015 PM 14680969 ER PT J AU Blonder, J Conrads, TP Yu, LR Terunuma, A Janini, GM Issaq, HJ Vogel, JC Veenstra, TD AF Blonder, J Conrads, TP Yu, LR Terunuma, A Janini, GM Issaq, HJ Vogel, JC Veenstra, TD TI A detergent- and cyanogen bromide-free method for integral membrane proteomics: Application to Halobacterium purple membranes and the human epidermal membrane proteome SO PROTEOMICS LA English DT Article DE epidermal tissue; integral membrane proteins; liquid chromatography; sample preparation; tandem mass spectrometry ID IONIZATION MASS-SPECTROMETRY; SPECIES NRC-1; PROTEINS; BACTERIORHODOPSIN; LOCALIZATION; RHODOPSIN; LEVEL AB A simple and rapid method for characterizing hydrophobic integral membrane proteins and its utility for membrane proteomics using microcapillary liquid chromatography, coupled on-line with tandem mass spectrometry (muLC-MS/MS) is described. The present technique does not rely on the use of detergents, strong organic acids or cyanogen bromide-mediated proteolysis. A buffered solution of 60% methanol was used to extract, solubilize, and tryptically digest proteins within a preparation of Halobacterium (H.) halobium purple membranes. Analysis of the digested purple membrane proteins by muLC-MS/MS resulted in the identification of all the predicted tryptic peptides of bacteriorhodopsin, including those that are known to be post-translationally modified. In addition, 40 proteins from the purple membrane preparation were also identified of, which 80% are predicted to contain between 1 and 16 transmembrane domains. To evaluate the general applicability of the method, the same extraction, solubilization, and digestion conditions were applied to a plasma membrane fraction prepared from human epidermal sheets. A total of 117 proteins was identified in a single muLC-MS/MS analysis, of which 55% are known to be integral or associated with the plasma membrane. Due to its simplicity, efficiency, and absence of MS interfering compounds, this technique can be used for the characterization of other integral membrane proteins and may be concomitantly applied for the analysis of membrane protein complexes or large-scale proteomic studies of different membrane samples. C1 NCI, Biomed Proteom Program, SAIC Frederick Inc, Lab Proteom & Analyt Technol,Mass Spectrometry Ct, Frederick, MD 21702 USA. NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP Veenstra, TD (reprint author), NCI, Biomed Proteom Program, SAIC Frederick Inc, Lab Proteom & Analyt Technol,Mass Spectrometry Ct, Frederick, MD 21702 USA. EM veenstra@ncitcrf.gov FU PHS HHS [N01-C0-12400] NR 28 TC 111 Z9 122 U1 3 U2 12 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD JAN PY 2004 VL 4 IS 1 BP 31 EP 45 DI 10.1002/pmic.200300543 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768VQ UT WOS:000188591100006 PM 14730670 ER PT J AU Sechi, S AF Sechi, S TI Mass spectrometric approaches to quantitative proteomics SO PROTEOMICS IN NEPHROLOGY SE CONTRIBUTIONS TO NEPHROLOGY LA English DT Article ID COMPLEX PROTEIN MIXTURES; CODED AFFINITY TAGS; RECEPTOR SIGNALING PATHWAYS; SEQUENCE DATABASES; ELECTROSPRAY-IONIZATION; POSTTRANSLATIONAL MODIFICATIONS; IDENTIFICATION TECHNOLOGY; TYROSINE PHOSPHORYLATION; PHOSPHOPROTEOME ANALYSIS; LIQUID-CHROMATOGRAPHY C1 NIDDKD, DHHS, Div Diabet Endocrinol & Met Dis, NIH, Bethesda, MD 20892 USA. RP Sechi, S (reprint author), NIDDKD, DHHS, Div Diabet Endocrinol & Met Dis, NIH, 6707 Democracy Blvd,Rm 611, Bethesda, MD 20892 USA. NR 103 TC 9 Z9 9 U1 0 U2 0 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 0302-5144 J9 CONTRIB NEPHROL JI Contrib.Nephrol. PY 2004 VL 141 BP 59 EP 78 PG 20 WC Urology & Nephrology SC Urology & Nephrology GA BY13L UT WOS:000187846000005 PM 14650225 ER PT J AU Petricoin, EF Liotta, LA AF Petricoin, EF Liotta, LA TI Clinical proteomics: Application at the bedside SO PROTEOMICS IN NEPHROLOGY SE CONTRIBUTIONS TO NEPHROLOGY LA English DT Article ID ARTIFICIAL NEURAL-NETWORKS; OVARIAN-CANCER; MASS-SPECTROMETRY; BIOMARKER; CLASSIFICATION; IDENTIFICATION; PREDICTION; DISCOVERY; PROSTATE; DISEASE C1 US FDA, Ctr Biol Evaluat & Res, Off Director, FDA NCI Clin Proteom Program, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Pathol Lab, FDA NCI Clin Proteom Program, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Director, FDA NCI Clin Proteom Program, Bldg 29A 2D12,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 33 TC 10 Z9 12 U1 0 U2 0 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 0302-5144 J9 CONTRIB NEPHROL JI Contrib.Nephrol. PY 2004 VL 141 BP 93 EP 103 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA BY13L UT WOS:000187846000007 PM 14650227 ER PT J AU Low, NCP Merikangas, JR Merikangas, KR AF Low, NCP Merikangas, JR Merikangas, KR TI A review of migraine and mood disorders SO PSYCHIATRIC ANNALS LA English DT Review ID PSYCHIATRIC-DISORDERS; BIPOLAR DISORDER; MAJOR DEPRESSION; CO-MORBIDITY; GENERAL-POPULATION; HEADACHE SYNDROMES; PHYSICAL ILLNESS; SUICIDE ATTEMPTS; PANIC DISORDER; YOUNG-ADULTS C1 NIMH, Sect Dev Genet Epidemiol, Mood & Anxiety Disorders Program, Intramural Res Program,NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. George Washington Univ, Sch Med, Washington, DC 20052 USA. RP Low, NCP (reprint author), NIMH, Sect Dev Genet Epidemiol, Mood & Anxiety Disorders Program, Intramural Res Program,NIH,Dept Hlth & Human Serv, Bldg 15K,Rm 208,MSC 2670,15 North Dr, Bethesda, MD 20892 USA. NR 56 TC 1 Z9 2 U1 1 U2 3 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JAN PY 2004 VL 34 IS 1 BP 33 EP 40 PG 8 WC Psychiatry SC Psychiatry GA 780AZ UT WOS:000189349900006 ER PT J AU Hamilton, BL Handley, EA AF Hamilton, BL Handley, EA TI Results of a baseline survey of NCI staff attitudes and behaviors towards consumer advocate involvement SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JAN PY 2004 VL 13 IS 1 SU S BP S25 EP S25 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 767DM UT WOS:000188425000044 ER PT J AU Hutson, SP Bakos, AD Arora, NK Keating, NL Guadagnoli, E AF Hutson, SP Bakos, AD Arora, NK Keating, NL Guadagnoli, E TI Understanding cancer treatment decision-making: Preferences from patients and physicians SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JAN PY 2004 VL 13 IS 1 SU S BP S8 EP S9 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 767DM UT WOS:000188425000015 ER PT J AU Kreps, GL AF Kreps, GL TI The role of communication in cancer pain and symptom management SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JAN PY 2004 VL 13 IS 1 SU S BP S35 EP S35 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 767DM UT WOS:000188425000065 ER PT J AU Reeve, BB AF Reeve, BB TI Applying item response theory modeling for improving cancer outcomes measurement SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JAN PY 2004 VL 13 IS 1 SU S BP S69 EP S69 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 767DM UT WOS:000188425000140 ER PT J AU Rubert, M Walsh, S Estrada, G AF Rubert, M Walsh, S Estrada, G TI Tele-care for family caregivers of cancer patients SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JAN PY 2004 VL 13 IS 1 SU S BP S6 EP S7 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 767DM UT WOS:000188425000011 ER PT J AU Rutten, LJF Arora, NK Bakos, AD Rowland, J Aziz, N AF Rutten, LJF Arora, NK Bakos, AD Rowland, J Aziz, N TI Cancer patients' information needs and information sources: A systematic review of the literature SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JAN PY 2004 VL 13 IS 1 SU S BP S34 EP S34 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 767DM UT WOS:000188425000063 ER PT J AU Rutten, LJF Arora, NK Gustafson, DH Hawkins, RP Pingree, S AF Rutten, LJF Arora, NK Gustafson, DH Hawkins, RP Pingree, S TI Informational, emotional, and decision-making support for women with breast cancer: What sources do women find helpful during the first year following diagnosis? SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JAN PY 2004 VL 13 IS 1 SU S BP S14 EP S15 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 767DM UT WOS:000188425000027 ER PT J AU Katz, JL Higgins, ST AF Katz, JL Higgins, ST TI What is represented by vertical shifts in self-administration dose-response curves? Reply SO PSYCHOPHARMACOLOGY LA English DT Letter ID COCAINE C1 NIDA, Psychobiol Sect, Addict Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Vermont, Dept Psychiat, Burlington, VT 05401 USA. Univ Vermont, Dept Psychol, Burlington, VT 05401 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Addict Res Ctr, NIH, POB 5180, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov NR 12 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2004 VL 171 IS 3 BP 360 EP 361 DI 10.1007/s00213-003-1605-9 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 765TK UT WOS:000188299500016 ER PT J AU Cuthbert, BN AF Cuthbert, BN TI An overview of NIH grant mechanisms SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S17 EP S18 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200059 ER PT J AU Dvir, SR Lissek, S Baas, JMP Grillon, C AF Dvir, SR Lissek, S Baas, JMP Grillon, C TI Trait anxiety and retention of aversive conditioning SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res DE fear-conditioning; trait anxiety; fear-potentiated startle C1 NIMH, Bethesda, MD 20892 USA. Univ Utrecht, NL-3508 TC Utrecht, Netherlands. RI Lissek, Shmuel/B-6577-2008 NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S80 EP S80 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200307 ER PT J AU Fabiani, M Brumback, C Gordon, BA Pearson, MA Lee, Y Kramer, AF McAuley, E Gratton, G AF Fabiani, M Brumback, C Gordon, BA Pearson, MA Lee, Y Kramer, AF McAuley, E Gratton, G TI Effects of cardiopulmonary fitness on neurovascular coupling in visual cortex in younger and older adults SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res C1 Univ Illinois, Chicago, IL 60680 USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S19 EP S19 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200066 ER PT J AU Kozak, MJ AF Kozak, MJ TI NIH review of grant applications SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S18 EP S18 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200061 ER PT J AU Lissek, S Orme, KS Grillon, C AF Lissek, S Orme, KS Grillon, C TI Effects of emotional regulation on startle potentiation to the threat of electric shocks SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res DE emotional regulation; fear-potentiated startle; threat of shock C1 NIMH, Bethesda, MD 20892 USA. RI Lissek, Shmuel/B-6577-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S79 EP S79 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200306 ER PT J AU Lissek, S Baas, JMP Pine, DS Orme, KS Dvir, SR Nugent, MS Rosenberger, E Rawson, E Grillon, C AF Lissek, S Baas, JMP Pine, DS Orme, KS Dvir, SR Nugent, MS Rosenberger, E Rawson, E Grillon, C TI Airpuff startle probes: An efficacious and less aversive alternative to white-noise SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res DE fear-potentiated startle; startle methodology; EMG C1 NIMH, Bethesda, MD 20892 USA. Univ Utrecht, NL-3508 TC Utrecht, Netherlands. RI Lissek, Shmuel/B-6577-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S79 EP S79 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200305 ER PT J AU Lissek, S Baas, JMP Pine, DS Orme, KS Dvir, SR Rosenberger, E Grillon, C AF Lissek, S Baas, JMP Pine, DS Orme, KS Dvir, SR Rosenberger, E Grillon, C TI Sensation seeking and the aversive motivational system SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res C1 NIMH, Bethesda, MD 20892 USA. Univ Utrecht, NL-3508 TC Utrecht, Netherlands. RI Lissek, Shmuel/B-6577-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S24 EP S24 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200084 ER PT J AU Merritt, MM Sollers, JJ Evans, MK Zonderman, AB Abernethy, DR Thayer, JF AF Merritt, MM Sollers, JJ Evans, MK Zonderman, AB Abernethy, DR Thayer, JF TI Endothelial nitric oxide synthase genotypes and total peripheral resistance at recovery from perception of affect among African Americans: Gender differences SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res DE eNOS; cardiovascular reactivity; African-Americans C1 NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S94 EP S94 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200363 ER PT J AU Ruiz-Padial, E Vila, J Thayer, JF AF Ruiz-Padial, E Vila, J Thayer, JF TI The effect of conscious and nonconscious presentation of emotion pictures on emotion modulated startle and phasic heart rate SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res DE emotion; startle; heart rate C1 Univ Jaen, Jaen, Spain. Univ Granada, E-18071 Granada, Spain. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S67 EP S67 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200255 ER PT J AU Schaefer, M Flor, H Heinze, HJ Rotte, M AF Schaefer, M Flor, H Heinze, HJ Rotte, M TI Feeling an alien limb involves the primary somatosensory cortex: A MEG study SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res DE sensory illusion; sensory cortex; body image C1 NINDS, Bethesda, MD 20892 USA. Univ Heidelberg, D-6900 Heidelberg, Germany. Univ Magdeburg, D-39106 Magdeburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S51 EP S51 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200191 ER PT J AU Thayer, JF Ruiz-Padial, E AF Thayer, JF Ruiz-Padial, E TI Neurovisceral integration and emotion regulation: What the heart is saying about the brain and why we should listen SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 44th Annual Meeting of the Society-for-Psychophysiological-Research CY OCT 20-24, 2004 CL Santa Fe, NM SP Soc Pychophysiol Res C1 NIA, Bethesda, MD 20892 USA. Univ Jaen, Jaen, Spain. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PY 2004 VL 41 SU 1 BP S23 EP S23 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RL UT WOS:000223558200079 ER PT J AU Merritt, MM Bennett, GG Williams, RB Sollers, JJ Thayer, JF AF Merritt, MM Bennett, GG Williams, RB Sollers, JJ Thayer, JF TI Low educational attainment, John Henryism, and cardiovascular reactivity to and recovery from personally relevant stress SO PSYCHOSOMATIC MEDICINE LA English DT Article ID BLOOD-PRESSURE DIFFERENCES; JOHN-HENRYISM; SOCIOECONOMIC-STATUS; AFRICAN-AMERICANS; YOUNG MEN; PITT COUNTY; JOB STRAIN; BLACK-MEN; HYPERTENSION; HOSTILITY AB Objective: The John Henryism hypothesis proposes that a high level of John Henryism (JH: high-effort coping with psychosocial demands) is predictive of hypertension at low but not high socioeconomic status (SES). The objectives of the present study were to determine whether high JH and low SES (education, income, job status, and job strain) were associated with increased cardiovascular responses to laboratory social stressors. Methods: Subjects were 58 normotensive, healthy black men age 23 to 47 years. The procedure included the completion of psychosocial questionnaires and participation in a psychophysiological reactivity protocol. The reactivity protocol involved the following experimental tasks and associated recovery periods: an active speech task and an anger recall task. Measures of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and rate pressure product (RPP) were obtained continuously using a Finapres beat-to-beat blood pressure monitor throughout the reactivity protocol. Results: At high JH, low (compared with high) education level was linked with higher DBP during anger recall and final recovery, higher SBP during final recovery, and higher HR and RPP during speech preparation and final recovery (p < .05). Among subjects with low education, high (vs. low) JH was associated with higher SBP, HR, and RPP during final recovery (P < .05). Conclusions: John Henryism may increase the risk of cardiovascular disease among people with low education by increased cardiovascular reactivity and prolonged recovery to stress. C1 Duke Univ, Ctr Med, Behav Med Res Ctr, Durham, NC USA. NIA, Gerontol Res Ctr, Baltimore, MD USA. RP Merritt, MM (reprint author), Duke Univ, Ctr Med, Behav Med Res Ctr, Durham, NC USA. EM merrittma@grc.nia.nih.gov FU NIMH NIH HHS [5T32 MH19109] NR 54 TC 43 Z9 43 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD JAN-FEB PY 2004 VL 66 IS 1 BP 49 EP 55 DI 10.1097/01.PSY.0000107909.74904.3D PG 7 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 768VL UT WOS:000188555700008 PM 14747637 ER PT J AU Hall, M Vasko, R Buysse, D Ombao, H Chen, QX Cashmere, JD Kupfer, D Thayer, JF AF Hall, M Vasko, R Buysse, D Ombao, H Chen, QX Cashmere, JD Kupfer, D Thayer, JF TI Acute stress affects heart rate variability during sleep SO PSYCHOSOMATIC MEDICINE LA English DT Article ID SYMPATHETIC-NERVE ACTIVITY; POWER SPECTRAL-ANALYSIS; MATCHED NORMAL SLEEPERS; THREE-MILE-ISLAND; OLDER-ADULTS; LATE-LIFE; INSOMNIA; DEPRESSION; IMMUNE; DISTURBANCE AB Objective: Although stress can elicit profound and lasting effects on sleep, the pathways whereby stress affects sleep are not well understood. In this study, we used autoregressive spectral analysis of the electrocardiogram (EKG) interbeat interval sequence to characterize stress-related changes in heart rate variability during sleep in 59 healthy men and women. Methods: Participants (N = 59) were randomly assigned to a control or stress condition, in which a standard speech task paradigm was used to elicit acute stress in the immediate presleep period. EKG was collected throughout the night. The high frequency component (0.15-0.4 Hz Eq) was used to index parasympathetic modulation, and the ratio of low to high frequency power (0.04-0.15 Hz Eq/0.15-0.4 Hz Eq) of heart rate variability was used to index sympathovagal balance. Results: Acute psychophysiological stress was associated with decreased levels of parasympathetic modulation during nonrapid eye movement (NREM) and rapid eye movement sleep and increased levels of sympathovagal balance during NREM sleep. Parasympathetic modulation increased across successive NREM cycles in the control group; these increases were blunted in the stress group and remained essentially unchanged across successive NREM periods. Higher levels of sympathovagal balance during NREM sleep were associated with poorer sleep maintenance and lower delta activity. Conclusions: Changes in heart rate variability associated with acute stress may represent one pathway to disturbed sleep. Stress-related changes in heart rate variability during sleep may also be important in association with chronic stressors, which are associated with significant morbidity and increased risk for mortality. C1 Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Univ Illinois, Dept Stat, Chapel Hill, NC USA. Univ Illinois, Beckman Inst, Chapel Hill, NC USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. NIA, Baltimore, MD 21224 USA. RP Hall, M (reprint author), Western Psychiat Inst & Clin, 3811 O Hara St,E-1101, Pittsburgh, PA 15213 USA. EM hallmh@msx.upmc.edu RI Hall, Martica/D-2809-2012 OI Hall, Martica/0000-0003-0642-2098 FU NCRR NIH HHS [RR00056]; NIMH NIH HHS [MH30915, MH01554, MH24652, MH52247] NR 57 TC 130 Z9 133 U1 4 U2 37 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD JAN-FEB PY 2004 VL 66 IS 1 BP 56 EP 62 DI 10.1097/01.PSY.0000106884.58744.09 PG 7 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 768VL UT WOS:000188555700009 PM 14747638 ER PT S AU Toyama, H Ichise, M Liow, JS Modell, KJ Vines, DC Zoghbi, S Esaki, T Cook, M Seidel, J Katada, K Sokoloff, L Green, MV Innis, RB AF Toyama, H Ichise, M Liow, JS Modell, KJ Vines, DC Zoghbi, S Esaki, T Cook, M Seidel, J Katada, K Sokoloff, L Green, MV Innis, RB BE Iida, H Shah, NJ Hayashi, T Watabe, H TI [F-18]FDG mouse brain PET imaging: absolute quantification of regional cerebral glucose utilization as compared with 2-[C-14]DG autoradiography SO QUANTITATION IN BIOMEDICAL IMAGING WITH PET AND MRI SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT International Workshop on Quantitation in Biomedical Imaging with PET and MRI CY JAN 26-27, 2004 CL Osaka, JAPAN DE small animal PET; mouse; (18)FDG; anesthesia; cerebral glucose metabolism ID RAT AB The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR(glc)) in mice with (18)FDG PET. To evaluate its use as a gold standard, rCMR(glc) was also measured simultaneously with the autoradiographic 2-[C-14]DG method, Serial arterial samples were drawn over 45 min to determine plasma tracer time activities and glucose concentrations. Animals were euthanized at 45 min followed first by brain PET imaging for 15 min and then by brain 2-[C-14]DG autoradiography. Average (18)FDG rCMR(glc) values in the cerebral cortex were generally lower (by 8.3%), but strongly correlated with those of 2-[C-14]DG (r(2) =0.95). The present PET imaging technique allows accurate absolute quantification of rCNIR(glc) in mice within the limits of the resolution possible with PET. (C) 2004 Elsevier B.V. All rights reserved. C1 Fujita Hlth Univ, Dept Radiol, Toyoake, Aichi 4701192, Japan. NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD USA. RP Toyama, H (reprint author), Fujita Hlth Univ, Dept Radiol, 1-98 Dengakugakubo, Toyoake, Aichi 4701192, Japan. NR 9 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-51567-4 J9 INT CONGR SER PY 2004 IS 1265 BP 255 EP 261 DI 10.1016/j.ics.2004.03.022 PG 7 WC Multidisciplinary Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Science & Technology - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA BBN26 UT WOS:000226259900035 ER PT J AU Ulanovsky, A Drozdovitch, V Bouville, A AF Ulanovsky, A Drozdovitch, V Bouville, A TI Influence of radionuclides distributed in the whole body on the thyroid dose estimates obtained from direct thyroid measurements made in Belarus after the Chernobyl accident SO RADIATION PROTECTION DOSIMETRY LA English DT Article ID POST-CHERNOBYL; CANCER; RECONSTRUCTION; SIMULATION; UKRAINE; PHANTOM; I-131 AB Thyroid dose reconstruction is most accurate when using the results of direct thyroid measurements. in which gamma radiation emitted by radionuclides present in the thyroid and in the remainder of the body is recorded by means of a radiation detector positioned against the neck. A large number of such measurements were per-formed in Belarus in May-June 1986. Owing to the short half-life of 1311 and to the intake and accumulation of caesium radioisotopes (mainly (134)Cls and Cs-137) in the body, the thyroid doses derived from thyroid measurements made after the beginning of June 1986 have so far been often considered to be unreliable. To evaluate the influence of the caesium radioisotopes to the signal recorded by an instrument performing measurement of I-131 activity in the thyroid, a Monte Carlo method was used to calculate the calibration factors of that instrument. These calculations were made for males of six reference ages: newborn, 1, 5, 10 and 15 years old, and adult. The calibration factors were combined with estimated time-dependent intake functions for 1311 and caesium radioisotopes. The fractions of the instrument indications that were due to 1311 in thyroid were thus estimated as a function of the age of the subject that was measured and of the time elapsed since the accident. Using this information when processing the thyroid measurements made in May 1986 would improve the accuracy of the thyroid dose estimates, and may make it possible to use a larger proportion of the thyroid measurements made in June 1986. C1 GSF, Natl Res Ctr, Inst Radiat Protect, D-85764 Neuherberg, Germany. SOSNY, Joint Inst Power & Nucl Res, Minsk 220109, Byelarus. Int Agcy Res Canc, F-69372 Lyon, France. NCI, DHHS, NIH, Div Canc Epidemiol & Genet,EPS 7094, Bethesda, MD 20892 USA. RP Ulanovsky, A (reprint author), GSF, Natl Res Ctr, Inst Radiat Protect, D-85764 Neuherberg, Germany. EM ulanovsky@gsf.de NR 34 TC 5 Z9 6 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PY 2004 VL 112 IS 3 BP 405 EP 418 DI 10.1093/rpd/nch410 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 886BV UT WOS:000226202400009 PM 15494363 ER PT J AU Szajek, LP Kao, CHK Kiesewetter, DO Sassaman, MB Lang, L Plascjak, P Eckelman, WC AF Szajek, LP Kao, CHK Kiesewetter, DO Sassaman, MB Lang, L Plascjak, P Eckelman, WC TI Semi-remote production of Br-76 and preparation of high specific activity radiobrominated pharmaceuticals for PET studies SO RADIOCHIMICA ACTA LA English DT Article DE bromine-76; FBAU; CRH; specific activity; PET imaging; automation ID FBAU 3',5'-DIBENZOATE; RECEPTORS; LIGAND; I-123; F-18 AB The PET radionuclide Br-76 (t(1/2) = 16.2 h) can be easily produced utilizing the nuclear reaction A S(He-3, 2n)Br-76. We use high-purity arsenic targets and isolate radioactive bromide by chromic acid oxidation followed by simple distillation of [Br-76] hydrogen bromide using a semi-remote apparatus. Use of reagents with little or no carrier bromine yields high specific activity radiobrominated pharmaceuticals prepared from the distilled [Br-76] hydrogen bromide. C1 Warren G Magnuson Clin Ctr, Positron Emiss Tomog Dept, NIH, Bethesda, MD 20892 USA. Buddhist Tzu Chi Gen Hosp, Neuro Med Sci Ctr, Hualien, Taiwan. RP Szajek, LP (reprint author), Warren G Magnuson Clin Ctr, Positron Emiss Tomog Dept, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM ls140h@mail.cc.nih.gov NR 24 TC 9 Z9 9 U1 0 U2 2 PU R OLDENBOURG VERLAG PI MUNICH PA LEKTORAT MINT, POSTFACH 80 13 60, D-81613 MUNICH, GERMANY SN 0033-8230 J9 RADIOCHIM ACTA JI Radiochim. Acta PY 2004 VL 92 IS 4-6 BP 291 EP 295 DI 10.1524/ract.92.4.291.35605 PG 5 WC Chemistry, Inorganic & Nuclear; Nuclear Science & Technology SC Chemistry; Nuclear Science & Technology GA 838ZT UT WOS:000222753800019 ER PT J AU Rhim, H Dodd, GD Chintapalli, KN Wood, BJ Dupuy, DE Hvizda, UL Sewell, PE Goldberg, SN AF Rhim, H Dodd, GD Chintapalli, KN Wood, BJ Dupuy, DE Hvizda, UL Sewell, PE Goldberg, SN TI Radiofrequency thermal ablation of abdominal tumors: Lessons learned from complications SO RADIOGRAPHICS LA English DT Article; Proceedings Paper CT Annual Meeting of the Radiological-Society-of-North-America CY NOV 25-30, 2001 CL CHICAGO, ILLINOIS SP Radiologic Soc North Amer DE abdomen, neoplasms; adrenal gland, neoplasms; kidney neoplasms; liver neoplasms; radiofrequency (RF), ablation ID HEPATOCELLULAR-CARCINOMA; LIVER METASTASES; HEPATIC-TUMORS; IMAGING FINDINGS; FOLLOW-UP; LESIONS; NEEDLE; MALIGNANCIES; CANCER; OPPORTUNITIES AB Radiofrequency (RF) thermal ablation has shown promise as a technique for treating inoperable solid tumors involving the liver, kidney, adrenal gland, and lung. However, like all other imaging-guided interventional procedures, RF ablation involves some element of risk. Varying degrees of complications can be expected, depending on factors such as the organ site and the aggressiveness of the procedure. General complications of RF ablation may be related to either imaging-guided electrode placement (eg, bleeding, infection, tumor seeding, pneumothorax) or thermal therapy (eg, nontarget thermal damage, grounding pad burns). Liver and renal-adrenal ablation may be associated with organ-specific complications. A fundamental understanding of RF ablation principles, along with adequate operator training and experience and familiarity with both thermal ablation and the broad spectrum of postablation complications, are necessary to maximize the safety and efficacy of this procedure. The standard of care for decreasing the morbidity of complications consists of prevention (including careful patient selection), early detection, and prompt, appropriate treatment. ((C))RSNA, 2004. C1 Hanyang Univ Hosp, Dept Diagnost Radiol, Seoul 133792, South Korea. Univ Texas, Hlth Sci Ctr, Dept Radiol, San Antonio, TX 78284 USA. Natl Inst Hlth Clin Ctr, Special Procedures Div, Diagnost Radiol Dept, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. Rhode Isl Hosp, Dept Diagnost Imaging, Providence, RI USA. Univ Mississippi, Med Ctr, Dept Radiol, Jackson, MS 39216 USA. Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Rhim, H (reprint author), Hanyang Univ Hosp, Dept Diagnost Radiol, 17 Haengdang Dong, Seoul 133792, South Korea. EM rhimhc@hanyang.ac.kr OI Dupuy, Damian/0000-0003-0524-5982 NR 36 TC 172 Z9 179 U1 1 U2 8 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD JAN-FEB PY 2004 VL 24 IS 1 BP 41 EP 52 DI 10.1148/rg.241025144 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 763DH UT WOS:000188058400007 PM 14730035 ER PT J AU Tal, MG Hirshberg, B Neeman, Z Bunnell, D Soleimanpour, S Bacher, J Patterson, N Chang, R Harlan, DM AF Tal, MG Hirshberg, B Neeman, Z Bunnell, D Soleimanpour, S Bacher, J Patterson, N Chang, R Harlan, DM TI Induction of diabetes in nonhuman primates by means of temporary arterial embolization and selective arterial injection of streptozotocin SO RADIOLOGY LA English DT Article; Proceedings Paper CT 88th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY DEC 01-06, 2002 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer DE animals; diabetes mellitus; experimental study; pancreas, interventional procedures; pancreas, transplantation ID INTRAHEPATIC ISLET ALLOGRAFTS; LONG-TERM SURVIVAL; CYNOMOLGUS MONKEYS; PANCREATIC-ISLETS; RHESUS-MONKEYS; HUMANIZED ANTI-CD154; PRECLINICAL MODEL; ANIMAL-MODELS; BLOOD-FLOW; TRANSPLANTATION AB PURPOSE: To develop and assess a technique for induction of C peptide-negative diabetes in adult nonhuman primates in preparation for preclinical investigation of type 1 diabetes treatments. MATERIALS AND METHODS: First, temporary embolization of the hepatic and gastric arteries was performed in 14 adult nonhuman primates (six cynomolgus, five rhesus, and three pigtail macaques). After embolization was confirmed with angiography, streptozotocin was injected at a dose of 50-70 mg/kg into the celiac artery and branches supplying the pancreas. The macaques then were given intravenous injections of arginine and glucose, and blood levels of insulin and C pepticle were measured with an enzyme-linked immunosorbent assay to determine whether diabetes had been induced. RESULTS: All but one of the macaques developed persistent long-term C peptidenegative diabetes after the streptozotocin injection. One macaque did not develop diabetes after the initial injection and was given a second dose of streoptozotocin, which did induce diabetes. None of the macaques showed any symptoms of hepatic or renal injury, and only one died (of gastric dilatation 5 days after the procedure). CONCLUSION: Streptozotocin injection after temporary embolization of the hepatic and gastric arteries is a safe and reproducible method for inducing C pepticlenegative diabetes in adult nonhuman primates in preparation for preclinical investigation of type 1 diabetes treatments. (C) RSNA, 2004. C1 Yale Univ, Sch Med, Dept Diagnost Imaging, New Haven, CT 06520 USA. NIDDKD, Transplantat & Autoimmun Branch, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. NIH, Dept Hlth & Human Serv, Surg Serv, Vet Resources Program,Off Res Serv, Bethesda, MD 20892 USA. RP Tal, MG (reprint author), Yale Univ, Sch Med, Dept Diagnost Imaging, POB 208042, New Haven, CT 06520 USA. NR 31 TC 21 Z9 22 U1 0 U2 1 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 JAN PY 2004 VL 230 IS 1 BP 163 EP 168 DI 10.1148/radiol.2301021413 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 758BR UT WOS:000187613100023 PM 14695391 ER PT J AU Tempez, A Schultz, JA Della-Negra, S Depauw, J Jacquet, D Novikov, A Lebeyec, Y Pautrat, M Caroff, M Ugarov, M Bensaoula, H Gonin, M Fuhrer, K Woods, A AF Tempez, A Schultz, JA Della-Negra, S Depauw, J Jacquet, D Novikov, A Lebeyec, Y Pautrat, M Caroff, M Ugarov, M Bensaoula, H Gonin, M Fuhrer, K Woods, A TI Orthogonal time-of-flight secondary ion mass spectrometric analysis of peptides using large gold clusters as primary ions SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID TOF-SIMS; MATRIX; YIELDS; DESORPTION; SURFACES; SLOW; BOMBARDMENT; PROJECTILES; IMPACT AB Secondary ion mass spectrometry (SIMS) for biomolecular analysis is greatly enhanced by the instrumental combination of orthogonal extraction time-of-flight mass spectrometry with massive gold cluster primary ion bombardment. Precursor peptide molecular ion yield enhancements of 1000, and signal-to-noise improvements of up to 20, were measured by comparing SIMS spectra obtained using Au+ and massive A(400)(4+) cluster primary ion bombardment of neat films of the neuropeptide fragment dynorphin 1-7. Remarkably low damage cross-sections were also measured U41 from dynorphin 1-7 and gramicidin S during prolonged bombardment with 40 keV Au-400(4+). For gramicidin S, the molecular ion yield increases slightly as a function of Au-400(4+) beam fluence up to at least 2 x 10(13) Au-400(4+)/cm(2). This is in marked contrast to the rapid decrease observed when bombarding with ions such as Au-5(+) and Au-9(+). When gramicidin S is impinged with Au-5(+), the molecular ion yield decreases by a factor of 10 after a fluence of only 8 X 10(12) ions/cm(2). Comparison of these 4 damage cross-sections implies that minimal surface damage occurs during prolonged Au-400(4+) bombardment. Several practical analytical implications are drawn from these observations. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Ionwerks Inc, Houston, TX 77030 USA. CNRS, IN2P3, Inst Phys Nucl, F-91406 Orsay, France. Univ Paris 11, Endotoxins Grp, CNRS, UMR 8619, F-91405 Orsay, France. TOFWERK AG, CH-3602 Thun, Switzerland. NIDA, IRP, Baltimore, MD 21224 USA. RP Tempez, A (reprint author), Ionwerks Inc, 2472 Bolsover St,Suite 255, Houston, TX 77030 USA. EM agnes@ionwerks.com NR 29 TC 60 Z9 61 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0951-4198 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PY 2004 VL 18 IS 4 BP 371 EP 376 DI 10.1002/rcm.1342 PG 6 WC Chemistry, Analytical; Spectroscopy SC Chemistry; Spectroscopy GA 775YR UT WOS:000189088700001 PM 14966842 ER PT J AU Mattson, MP AF Mattson, MP TI Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of Neurodegenerative disorders SO REDOX-ACTIVE METALS IN NEUROLOGICAL DISORDERS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article DE Alzheimer's disease; apoptosis; copper; Huntington's disease; iron; Parkinson's disease ID AMYOTROPHIC-LATERAL-SCLEROSIS; AMYLOID BETA-PEPTIDE; ISCHEMIC BRAIN-INJURY; PERTURBED CALCIUM HOMEOSTASIS; PROSTATE APOPTOSIS RESPONSE-4; IMPAIRS GLUTAMATE TRANSPORT; NEURONAL CA2+ HOMEOSTASIS; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; DIETARY RESTRICTION AB Membrane lipid peroxidation and oxidative modification of various membrane and associated proteins (e.g., receptors, ion transporters and channels, and signal transduction and cytoskeletal proteins) occur in a range of neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably iron and copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific neurological disorders are being elucidated. In Alzheimer's disease (AD), the amyloid beta-peptide generates reactive oxygen species and induces MAOS, resulting in disruption of cellular calcium homeostasis. In Parkinson's disease (PD), mitochondrial toxins and perturbed ubiquitin-dependent proteolysis may impair ATP production and increase oxyradical production and MAOS. The inheritance of polyglutamine-expanded huntingtin may promote neuronal degeneration in Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g., Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of iron and copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells. C1 NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Intramural Res Program, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 101 TC 100 Z9 106 U1 0 U2 4 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1012 BP 37 EP 50 DI 10.1196/annals.1306.004 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA BAB76 UT WOS:000221503700004 PM 15105254 ER PT J AU Smith, SR Cooperman, S Lavaute, T Tresser, N Ghosh, M Meyron-Holtz, E Land, W Ollivierre, H Jortner, B Switzer, R Messing, A Rouault, TA AF Smith, SR Cooperman, S Lavaute, T Tresser, N Ghosh, M Meyron-Holtz, E Land, W Ollivierre, H Jortner, B Switzer, R Messing, A Rouault, TA TI Severity of neurodegeneration correlates with compromise of iron metabolism in mice with iron regulatory protein deficiencies SO REDOX-ACTIVE METALS IN NEUROLOGICAL DISORDERS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article DE iron; neurodegeneration; IRP; substantia nigra; axonopathy; ferritin ID RAT-BRAIN; DISEASE; LOCALIZATION; DEGENERATION; ACCUMULATION AB In mammals, iron regulatory proteins 1 and 2 (IRP1 and IRP2) posttranscriptionally regulate expression of several iron metabolism proteins including ferritin and transferrin receptor. Genetically engineered mice that lack IRP2, but have the normal complement of IRP1, develop adult-onset neurodegenerative disease associated with inappropriately high expression of ferritin in degenerating neurons. Here, we report that mice that are homozygous for a targeted deletion of IRP2 and heterozygous for a targeted deletion of IRP1 (IRP1+/- IRP2-/-) develop a much more severe form of neurodegeneration, characterized by widespread axonopathy and eventually by subtle vacuolization in several areas, particularly in the substantia nigra. Axonopathy develops in white matter tracts in which marked increases in ferric iron and ferritin expression are detected. Axonal degeneration is significant and widespread before evidence for abnormalities or loss of neuronal cell bodies can be detected. Ultimately, neuronal cell bodies degenerate in the substantia nigra and some other vulnerable areas, microglia are activated, and vacuoles appear. Mice manifest gait and motor impairment at stages when axonopathy is pronounced, but neuronal cell body loss is minimal. These observations suggest that therapeutic strategies that aim to revitalize neurons by treatment with neurotrophic factors may be of value in IRP2-/- and IRP1+/- IRP2-/- mouse models of neurodegeneration. C1 NICHD, NIH, CBMB, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Virginia Tech, Lab Neurotox Studies, Blacksburg, VA USA. NeuroSci Associates, Knoxville, TN USA. Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53706 USA. Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. RP Rouault, TA (reprint author), NICHD, NIH, CBMB, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM trou@helix.nih.gov RI Meyron-Holtz, Esther/B-5991-2013 NR 23 TC 70 Z9 72 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1012 BP 65 EP 83 DI 10.1196/annals.1306.006 PG 19 WC Clinical Neurology SC Neurosciences & Neurology GA BAB76 UT WOS:000221503700006 PM 15105256 ER PT J AU Moratz, C Harrison, K Kehrl, JH AF Moratz, C Harrison, K Kehrl, JH TI Regulation of chemokine-induced lymphocyte migration by RGS proteins SO REGULATORS OF G-PROTEIN SIGNALING, PART A SE METHODS IN ENZYMOLOGY LA English DT Review ID B-LYMPHOCYTES; FAMILY-MEMBERS; ACTIVATION; RESPONSES; POLARIZATION; CHEMOTAXIS; EXPRESSION; ANTIGEN; TISSUE; ROLES AB G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by inducing the G-protein alpha (Galpha) subunit to exchange guanosine diphosphate for guanosine triphosphate. Regulators of G-protein signaling (RGS) proteins enhance the deactivation of Galpha subunits, thereby reducing the activation of downstream effectors. Several members of the RGS family are expressed in lymphocytes. Among RGS proteins with the highest levels of expression are RGS1, RGS2, RGS10, RGS13, RGS14, RGS16, and RGS19. Perhaps the most important G-protein-coupled receptors in lymphocytes potentially subject to regulation by RGS proteins are the chemokine receptors. By signaling through these receptors, chemokines help orchestrate immune cell trafficking both during the development of the immune system and during responses to exogenous or infectious agents. Thus, the level and regulation of RGS proteins in lymphocytes likely significantly impact lymphocyte migration and function. This article provides some tools for the analysis of RGS protein expression in lymphocytes and outlines a number of methods for the analysis of the effects of RGS proteins on lymphocyte migration and chemokine receptor signaling. C1 NIAID, Cell Mol Immunl Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moratz, C (reprint author), NIAID, Cell Mol Immunl Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. OI Kehrl, John/0000-0002-6526-159X NR 21 TC 32 Z9 33 U1 0 U2 3 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2004 VL 389 BP 15 EP 32 PG 18 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BAZ07 UT WOS:000224271400002 PM 15313557 ER PT J AU Jones, TLZ AF Jones, TLZ TI Role of palmitoylation in RGS protein function SO REGULATORS OF G-PROTEIN SIGNALING, PART A SE METHODS IN ENZYMOLOGY LA English DT Review ID TERMINAL CYSTEINE RESIDUES; SACCHAROMYCES-CEREVISIAE; ALPHA-SUBUNITS; LIPID RAFTS; BETA-2-ADRENERGIC RECEPTOR; CONSERVED CYSTEINE; MEMBRANE RAFTS; REGULATOR; DOMAIN; PALMITOYLTRANSFERASE AB Palmitoylation, the reversible, post-translational addition of palmitate to cysteine residues, occurs on several regulators of G-protein signaling (RGS) proteins. Palmitoylation can occur near the amino terminus, as for RGS4 and RGS16, but can also occur on a cysteine residue in the alpha4 helix of the RGS box, which is conserved in most RGS proteins. For some of the RGS proteins, palmitoylation is required to turn off G-protein signaling by accelerating GTP hydrolysis on the Galpha subunit. This article discusses the role of palmitoylation in RGS function and protocols are given for metabolic and in vitro labeling of RGS proteins with [H-3]palmitate and measurement of GTP hydrolysis in membranes. C1 NIDDKD, Div Endocrinol Diabet & Metab, NIH, Bethesda, MD 20892 USA. RP Jones, TLZ (reprint author), NIDDKD, Div Endocrinol Diabet & Metab, NIH, Bethesda, MD 20892 USA. NR 51 TC 21 Z9 21 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2004 VL 389 BP 33 EP 55 PG 23 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BAZ07 UT WOS:000224271400003 PM 15313558 ER PT J AU Ikeda, SR Jeong, SW AF Ikeda, SR Jeong, SW TI Use of RGS-insensitive G alpha subunits to study endogenous RGS protein action on G-protein modulation of N-type calcium channels in sympathetic neurons SO REGULATORS OF G-PROTEIN SIGNALING, PART A SE METHODS IN ENZYMOLOGY LA English DT Review ID VOLTAGE-DEPENDENT MODULATION; RAT HIPPOCAMPAL SYNAPSES; BETA-GAMMA-SUBUNITS; SIGNALING PROTEINS; PRESYNAPTIC INHIBITION; POINT MUTATION; CA2+ CHANNELS; REGULATORS; ACTIVATION; RECEPTORS AB Regulators of G-protein signaling (RGS) proteins are a large family of signaling proteins that control both the magnitude and temporal characteristics of heterotrimeric G-protein-mediated signaling. A current challenge is to define how endogenous RGS protein function impacts G-protein modulation of ionic channels in mammalian neurons. The experimental strategy described here utilizes distinct mutations in Galpha subunits that confer Bordetella pertussis toxin (PTX) and RGS protein insensitivity. The native signaling pathway in rat sympathetic neurons that mediates voltage-dependent modulation of N-type Ca2+ channels is ablated by PTX treatment and the signaling is reconstituted by expressing a PTX/RGS-insensitive Galpha mutant along with Gbeta and Ggamma subunits. As neurons are resistant to conventional transfection modalities, heterologous expression is accomplished by the direct microinjection of plasmids into the nucleus of the neuron. An advantage of this approach is that knowledge of the specific RGS subtypes participating in the pathway is not required. From the resulting alterations in the kinetics and pharmacology of G-protein-coupled receptor modulation of N-type Ca2+ channels, we can infer the role endogenous RGS proteins play in the signaling pathway. C1 NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. Yonsei Univ, Wonju Coll Med, Dept Physiol, Kangwon Do 220701, South Korea. RP Ikeda, SR (reprint author), NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. OI Ikeda, Stephen/0000-0002-4088-9508 NR 24 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2004 VL 389 BP 170 EP 189 PG 20 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BAZ07 UT WOS:000224271400011 PM 15313566 ER PT J AU Simonds, WF Woodard, GE Zhang, JH AF Simonds, WF Woodard, GE Zhang, JH TI Assays of nuclear localization of R7/G beta(5) complexes SO REGULATORS OF G-PROTEIN SIGNALING, PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID G-PROTEIN BETA(5); SUBCELLULAR-LOCALIZATION; RGS PROTEINS; SUBUNIT; REGULATOR; DOMAIN; BRAIN; ACCUMULATION; ACTIVATION; PATHWAYS AB Heterodimeric complexes between individual members of the R7 subfamily of regulators of G-protein signaling proteins and the Gbeta(5) isoform. of the heterotrimeric G-protein beta subunit family are strongly expressed in the cell nucleus in neurons and brain, as well as in the cytoplasm and plasma membrane. Native and recombinant Gbeta(5) and/or R7 expression have been studied in model systems like rat pheochromocytoma PC12 cells where their nuclear localization can be studied by fluorescence microscopy and/or subcellular fractionation. Nucleic acid counterstains chosen for compatibility with the fluorescent tags on secondary antibodies can facilitate the assay of R7/Gbeta(5) nuclear localization by epifluorescence or confocal laser microscopy. Subcellular fractionation allows isolation of a purified nuclear fraction that can be probed for the presence of Gbeta(5) and/or R7 subunits by immunoblots or immunoprecipitation and compared to other subcellular fractions. While the function of nuclear R7/Gbeta5 complexes is unknown, comparison with the properties of other RGS proteins that localize to the cell nucleus may suggest modes of action. Models are offered in which the reversible post-translational modification of R7/Gbeta5 complexes regulates their nuclear localization and signaling activity, whether the target of such signaling activity is in the nucleus, at the plasma membrane, or both. C1 NIH, NIDDKD, Metab Dis Branch, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIH, NIDDKD, Metab Dis Branch, Bethesda, MD 20892 USA. RI Woodard, Geoffrey/A-8608-2009 NR 35 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2004 VL 390 BP 210 EP 223 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BBF50 UT WOS:000225235700014 PM 15488180 ER PT J AU Oxford, GS Webb, CK AF Oxford, GS Webb, CK TI GoLoco motif peptides as probes of G alpha subunit specificity in coupling of G-protein-coupled receptors to ion channels SO REGULATORS OF G-PROTEIN SIGNALING, PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID BETA-GAMMA-SUBUNITS; GATED CALCIUM-CHANNELS; MUSCARINIC K+ CHANNEL; ROOT GANGLION NEURONS; CA2+ CHANNELS; SYMPATHETIC NEURONS; POTASSIUM CHANNEL; ATT-20 CELLS; MODULATION; INHIBITION AB Biochemical and structural studies of signaling proteins have revealed critical features of peptide motifs at the interaction surfaces between proteins. Such information can be used to design small peptides that can be used as functional probes of specific interactions in signaling cascades. This article describes the use of a novel domain (the GoLoco motif) found in several members of the regulators of G-protein signaling (RGS) protein family to probe the specificity of Galpha subunit involvement in the coupling of dopamine and somatostatin receptors to ion channels in the AtT20 neuroendocrine cell line. Peptides encoding the GoLoco motifs of RGS12 and AGS3 were perfused into single cells during electrical recording of agonist-induced current responses by whole cell patch clamp methods. The particular sequences chosen have been demonstrated to bind selectively to the GDP-bound form of Galpha(i), but not Galpha(o), and preclude association of Gbetagamma and Galpha(i) subunits. A functional manifestation of this property is observed in the progressive uncoupling of D2 dopamine receptors and Kir3.1/3.2 channels with repeated agonist application. Similar uncoupling is not observed with somatostatin receptors nor with D2 receptors coupling to calcium channels, suggesting Galpha subunit specificity in these signaling pathways. Motifs found in other proteins in the GPCR signaling machinery may also prove useful in assessing G-protein signaling specificity and complexity in single cells in the future. C1 Indiana Univ, Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Oxford, GS (reprint author), Indiana Univ, Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. FU NINDS NIH HHS [NS18788, NS18788-S1] NR 35 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2004 VL 390 BP 437 EP 450 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BBF50 UT WOS:000225235700027 PM 15488193 ER PT J AU Ko, MSH AF Ko, MSH TI Embryogenomics of pre-implantation mammalian development: current status SO REPRODUCTION FERTILITY AND DEVELOPMENT LA English DT Article; Proceedings Paper CT 30th Annual Conference of the International-Embryo-Transfer-Society CY JAN 10-14, 2004 CL PORTLAND, OR SP Int Embryo Transfer Soc ID SUPPRESSION SUBTRACTIVE HYBRIDIZATION; GENE-EXPRESSION PATTERNS; FULL-LENGTH CDNAS; MOUSE EMBRYOS; INITIAL ANNOTATION; SEQUENCE-ANALYSIS; CLONE SET; GENOME; MICROARRAY; LIBRARIES AB Pre-implantation development is marked by many critical molecular events, including the maternal to zygotic transition and the first differentiation of cells. Understanding such events is important, for both basic reproductive biology and practical applications, including regenerative medicine and livestock production. Scarcity of materials has hampered the progress of the field, but systematic genomics approaches are beginning to be applied to the study of pre-implantation development, resulting in unprecedented amounts of data about the pre-implantation process. The first step in embryogenomics is to collect and sequence cDNAs (expressed sequence tags (ESTs)) for genes that are expressed and function in these early embryos. Mouse work is the most advanced, with 140 111 ESTs derived from all stages of pre-implantation development currently available in the public sequence database. For other mammals, at present only approximately 1000 ESTs can be found in the public database, but efforts by several groups are generating cDNA libraries and ESTs. In the present review, the current status of the implementation of these investigative tools for mammalian pre-implantation embryos is discussed. C1 NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@grc.nia.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 58 TC 17 Z9 17 U1 2 U2 3 PU CSIRO PUBLISHING PI COLLINGWOOD PA 150 OXFORD ST, PO BOX 1139, COLLINGWOOD, VICTORIA 3066, AUSTRALIA SN 1031-3613 J9 REPROD FERT DEVELOP JI Reprod. Fertil. Dev. PY 2004 VL 16 IS 1-2 BP 79 EP 85 DI 10.1071/RD03080 PG 7 WC Developmental Biology; Reproductive Biology; Zoology SC Developmental Biology; Reproductive Biology; Zoology GA 757AP UT WOS:000187526900009 PM 14972105 ER PT J AU Rosenthal, I Sostaric, JZ Riesz, P AF Rosenthal, I Sostaric, JZ Riesz, P TI Enlightened sonochemistry SO RESEARCH ON CHEMICAL INTERMEDIATES LA English DT Review DE sonoluminescence; solute excitation; photochemistry ID INDUCED CELL-DAMAGE; GALLIUM-PORPHYRIN COMPLEX; PHOTOCHEMICAL-REACTIONS; PHOTOCATALYTIC OXIDATION; SONODYNAMIC ACTIVATION; WASTE-WATER; IN-VITRO; SONOPHOTOCATALYTIC DECOMPOSITION; PHOTOSONOCHEMICAL DEGRADATION; TIO2 PHOTOCATALYSIS AB Sonochemistry and photochemistry are initiated by high-energy transient species, which may be prone to mutual interaction. Electronic excitation of solutes by energy transfer from high energy species generated in collapsing bubbles is already supported by experimental evidence. The rates of photochemical reactions can be affected by ultrasound-induced mixing of liquids caused by microstreaming near pulsating cavitation bubbles and shockwaves due to bubble collapse. This may not only improve light absorption but also modify the pathway of reaction by increasing the contact between reagents. Finally, one may speculate about a potentially new chemistry of photoexcited solutes under the extreme conditions inside cavitation microreactors. This work reviews research on the excitation of solutes by sonoluminescence, the combined effects of ultrasound and light on liquid systems and the effect of ultrasound on photocatalytic reactions. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Agr Res Org, Volcani Ctr, Dept Food Sci, IL-50250 Bet Dagan, Israel. RP Riesz, P (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. EM rieszp@mail.nih.gov RI Sostaric, Joe/A-6033-2008 NR 85 TC 6 Z9 6 U1 3 U2 15 PU VSP BV PI ZEIST PA PO BOX 346, 3700 AH ZEIST, NETHERLANDS SN 0922-6168 J9 RES CHEM INTERMEDIAT JI Res. Chem. Intermed. PY 2004 VL 30 IS 7-8 BP 685 EP 701 DI 10.1163/1568567041856936 PG 17 WC Chemistry, Multidisciplinary SC Chemistry GA 870OL UT WOS:000225067200002 ER PT J AU Vourlekis, JS AF Vourlekis, JS TI Diagnosing cryptogenic fibrosing alveolitis SO RESPIRATION LA English DT Letter ID IDIOPATHIC PULMONARY-FIBROSIS C1 NIH, Bethesda, MD 20892 USA. RP Vourlekis, JS (reprint author), NIH, 6130 Execut Blvd,Suite 2136, Bethesda, MD 20892 USA. EM vourlekj@mail.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0025-7931 J9 RESPIRATION JI Respiration PY 2004 VL 71 IS 5 BP 546 EP 546 DI 10.1159/000080645 PG 1 WC Respiratory System SC Respiratory System GA 861HG UT WOS:000224406100021 PM 15467338 ER PT J AU Marini, AM Jiang, XY Wu, X Tian, F Zhu, DM Okagaki, P Lipsky, RH AF Marini, AM Jiang, XY Wu, X Tian, F Zhu, DM Okagaki, P Lipsky, RH TI Role of brain-derived neurotrophic factor and NF-kappa B in neuronal plasticity and survival: From genes to phenotype SO RESTORATIVE NEUROLOGY AND NEUROSCIENCE LA English DT Article ID METHYL-D-ASPARTATE; LONG-TERM-POTENTIATION; CENTRAL-NERVOUS-SYSTEM; RECEPTOR-MEDIATED NEUROPROTECTION; HIPPOCAMPAL SYNAPTIC PLASTICITY; FAMILY-BASED ASSOCIATION; RAT-BRAIN; NMDA RECEPTORS; ISCHEMIC TOLERANCE; DIETARY RESTRICTION AB Purpose: Brain-derived neurotrophic factor (BDNF) is a member of the family of neurotrophins and promotes diverse effects in neurons including development, maintenance of function, synaptic plasticity, and survival in different animal models. We present advances in our understanding of the genomics of the BDNF gene (bdnf) and its regulation by calcium-activated transcription factors, including cAMP response element binding protein (CREB) and more recently, nuclear factor kappaB; (NF-kappaB) and discuss these findings in the context of neuronal plasticity and survival. Methods: We used amplified bdnf complementary DNAs (cDNAs) and genomic DNA templates for direct sequencing and sequence variant discovery, information mining of public databases, and conventional molecular and cellular biology approaches to screen bdnf for novel regulatory elements, alternatively spliced exons, and functional sequence variants. Results: We discovered a candidate NF-kappaB site in promoter 3 of bdnf and showned that activation of N-methyl-D-aspartate (NMDA) inotropic glutamate receptors increased bdnf expression through an NF-kappaB-dependent pathway and extended the finding to show that NF-kappaB was required for NMDA neuroprotection in vitro. In addition, sequence analysis of bdnf cDNAs from different brain regions predicted at least three pre-pro-BDNF protein isoforms, two of which were previously unknown. Each isoform differs at the amino terminus and may have functional importance. Conclusions: Given the central role that BDNF plays in the developing and adult nervous system, understanding how BDNF is regulated and how it functions will enhance our knowledge of its diverse effects, which may lead to more effective treatments for neurodegenerative disorders and reveal the role of BDNF in complex phenotypes related to behavior. C1 NIAAA, Mol Genet Sect, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. RP Lipsky, RH (reprint author), NIAAA, Mol Genet Sect, Neurogenet Lab, NIH, 12420 Parklawn Dr,Suite 451, Rockville, MD 20852 USA. EM rlipsky@mail.nih.gov FU NIAAA NIH HHS [Z01-AA00325] NR 88 TC 80 Z9 91 U1 1 U2 1 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0922-6028 J9 RESTOR NEUROL NEUROS JI Restor. Neurol. Neurosci. PY 2004 VL 22 IS 2 BP 121 EP 130 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 837VV UT WOS:000222670200007 PM 15272146 ER PT J AU Celnik, PA Cohen, LG AF Celnik, PA Cohen, LG TI Modulation of motor function and cortical plasticity in health and disease SO RESTORATIVE NEUROLOGY AND NEUROSCIENCE LA English DT Review DE plasticity; motor; somatosensory; rehabilitation; TMS ID TRANSCRANIAL MAGNETIC STIMULATION; USE-DEPENDENT PLASTICITY; PERIPHERAL-NERVE STIMULATION; LONG-TERM REORGANIZATION; HUMAN VISUAL-CORTEX; SOMATOSENSORY CORTEX; INTERHEMISPHERIC INHIBITION; THEORETICAL CALCULATION; MOTORSENSORY CORTEX; BRAIN-STIMULATION AB Basic science studies demonstrated mechanisms of plasticity and metaplasticity. More recent human studies identified some of these mechanisms as operating in multiple areas of human cognition, such as learning and memory, and in functional recovery from lesions in the CNS, as in stroke. One of the goals of neurorehabilitation is the translation of these principles into rational strategies to promote recovery of function. Understanding the mechanisms and functional role of human plasticity could lead to the development of therapeutic options in situations in which there is virtually no treatment alternative, as in chronic stroke. We review some of the work performed to better understand the substrates and mechanisms underlying cortical plasticity and discuss some experimental approaches to enhance cortical plasticity and recovery of function, like cortical stimulation. C1 NIH, Human Cort Physiol Sect, NINDS, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD USA. RP NIH, Human Cort Physiol Sect, NINDS, Bldg 10,Room 5N226, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Winstein, Carolee/A-8375-2008 NR 120 TC 30 Z9 32 U1 0 U2 5 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0922-6028 EI 1878-3627 J9 RESTOR NEUROL NEUROS JI Restor. Neurol. Neurosci. PY 2004 VL 22 IS 3-5 BP 261 EP 268 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 883AU UT WOS:000225982400011 PM 15502270 ER PT J AU Zeng, XM Chen, J Liu, Y Luo, YQ Schulz, TC Robins, AJ Rao, MS Freed, WJ AF Zeng, XM Chen, J Liu, Y Luo, YQ Schulz, TC Robins, AJ Rao, MS Freed, WJ TI BGO1V: A variant human embryonic stem cell line which exhibits rapid growth after passaging and reliable dopaminergic differentiation SO RESTORATIVE NEUROLOGY AND NEUROSCIENCE LA English DT Article DE hESCs; karyotype; dopaminergic differentiation; PA6 stromal cells ID ES CELLS; NEURONS; TERATOCARCINOMA; EXPRESSION; NANOG; PLURIPOTENCY; TRISOMY-8; THERAPY; CULTURE; MODELS AB Purpose: To explore a karyotypically abnormal variant human embryonic stem cell (hESC) line, BGO1 V, as a potential model for studies of dopaminergic neuronal differentiation. Methods: The properties of BGO1V cells were compared to those of normal BG01 cells using immunocytochemistry, RT-PCR, focused microarrays and in vitro differentiation, including dopaminergic differentiation, by culturing with the stromal cell line PA6. Results: Despite the karyotypic abnormality (49, +12, +17 and XXY), undifferentiated BG01V cells expressed pluripotent ESC markers similar to BG01 cells, and retained the ability to differentiate into cell types characteristic of all three germ layers. When co-cultured with the stromal cell line PA6, BG01V cells differentiated into dopaminergic cells which exhibited properties similar to those of mature dopaminergic neurons. Conclusions: BG01V cells were easier to maintain in culture than karyotypically normal BG01 cells and can be used as an alternative pluripotent hESC type for in vitro developmental studies. C1 Natl Inst Drug Abuse, Dev & Plast Sect, Cellular Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. DHHS, NIH, Baltimore, MD USA. NIA, Neurosci Lab, Baltimore, MD USA. BresaGen Inc, Athens, GA USA. RP Zeng, XM (reprint author), Natl Inst Drug Abuse, Dev & Plast Sect, Cellular Neurobiol Branch, Intramural Res Program, 333 Cassell Dr, Baltimore, MD 21224 USA. EM xzeng@mail.nih.gov FU NIDDK NIH HHS [R24DK063689] NR 27 TC 42 Z9 42 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0922-6028 J9 RESTOR NEUROL NEUROS JI Restor. Neurol. Neurosci. PY 2004 VL 22 IS 6 BP 421 EP 428 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 920JM UT WOS:000228685200002 PM 15798361 ER PT J AU Isenberg, DA Allen, E Farewell, V Ehrenstein, MR Hanna, MG Lundberg, IE Oddis, C Pilkington, C Plotz, P Scott, D Vencovsky, J Cooper, R Rider, L Miller, F AF Isenberg, DA Allen, E Farewell, V Ehrenstein, MR Hanna, MG Lundberg, IE Oddis, C Pilkington, C Plotz, P Scott, D Vencovsky, J Cooper, R Rider, L Miller, F CA Int Myositis Clinical Studies Grp TI International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease SO RHEUMATOLOGY LA English DT Article DE myositis; disease activity assessment; damage assessment ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DERMATOMYOSITIS; POLYMYOSITIS; MORTALITY AB Objective. To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). Methods. An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. Results. The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. Conclusions. The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis. C1 UCL, Middlesex Hosp, Dept Med, Ctr Rheumatol, London W1T 4NJ, England. UCL, Dept Stat Sci, London W1T 4NJ, England. UCL, Neurol Inst, London W1T 4NJ, England. UCL, Dept Paediat & Adolescent Rheumatol, London W1T 4NJ, England. Kings Coll Hosp London, London, England. Univ Cambridge, Inst Publ Hlth, MRC, Biostat Unit, Cambridge CB2 1TN, England. Hope Hosp, Ctr Rheumat Dis, Salford M6 8HD, Lancs, England. Karolinska Inst, Karolinska Hosp, Dept Med, Rheumatol Unit, S-10401 Stockholm, Sweden. Univ Pittsburgh, Sch Med, Div Clin Immunol & Rheumatol, Pittsburgh, PA USA. NIEHS, Environm Autoimmun Grp, Off Clin Res, Bethesda, MD USA. NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD USA. Inst Rheumatol, Prague, Czech Republic. RP UCL, Middlesex Hosp, Dept Med, Ctr Rheumatol, 4th Floor,Arthur Stanley House,40-50 Tottenham St, London W1T 4NJ, England. EM d.isenberg@ucl.ac.uk RI Song, Yeong Wook/J-2765-2012; Hanna, Michael/B-1995-2009; RAVELLI, ANGELO/J-8161-2016; OI RAVELLI, ANGELO/0000-0001-9658-0385; Isenberg, David/0000-0001-9514-2455; Miller, Frederick/0000-0003-2831-9593 NR 15 TC 138 Z9 148 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD JAN PY 2004 VL 43 IS 1 BP 49 EP 54 DI 10.1093/rheumatology/keg427 PG 6 WC Rheumatology SC Rheumatology GA 756LB UT WOS:000187465600012 PM 12867580 ER PT J AU van Kouwen, MCA Oyen, WJG Nagengast, FM Jansen, JBMJ Drenth, JPH AF van Kouwen, MCA Oyen, WJG Nagengast, FM Jansen, JBMJ Drenth, JPH TI FDG-PET scanning in the diagnosis of gastrointestinal cancers SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article; Proceedings Paper CT 18th Annual Gastroenterology Symposium on Highlights of Gastroenterology CY 2003 CL NETHERLANDS DE colon cancer; diagnosis; FDG-PET oesophageal carcinoma; GIST; oncology; pancreatic cancer ID POSITRON-EMISSION-TOMOGRAPHY; RECURRENT COLORECTAL-CANCER; WHOLE-BODY PET; SQUAMOUS-CELL CARCINOMA; HUMAN PANCREATIC TUMORS; F-18 FLUORODEOXYGLUCOSE; ESOPHAGEAL CANCER; STROMAL TUMORS; DIFFERENTIAL-DIAGNOSIS; COMPUTED-TOMOGRAPHY AB This review deals with the current, well-established indications for two-(F-IS)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scanning in patients with gastrointestinal cancers-FDG-PET is a non-invasive, functional imaging technique. FDG exploits the native glucose transporter to enter the cell. Since many tumours have enhanced glucose uptake. FDG is readily, accumulated in malignant cells and can be detected by a PET camera. FDG-PET has been established as an important diagnostic tool in clinical oncology. This review deals with the current, well-established indications for FDG-PET scanning, in patients with gastrointestinal cancers. In the current practice, FDG-PET is most commonly used to stage oesophageal carcinoma, to detect and stage recurrence of colorectal carcinoma and to differentiate between benign and malignant pancreatic lesions. The benefit of FDG-PET scanning in patients with oesophagus carcinoma is best established in stage IV disease, as the diagnostic accuracy to detect metastatic disease is higher compared to the combination of computed tomography (CT) and endoscopic ultrasound (EUS). In patients with a history of colorectal carcinoma. FDG-PET scanning is particularly effective in diagnosing recurrent disease, especially in those with a rising carcinoembryonic antigen without a suspect lesion on conventional imaging. Large series have indicated that the sensitivity and specificity for detecting recurrent colorectal carcinoma are in the range of 87%-100% and 66%-100%. respectively. Equally, FDG-PET has a high sensitivity (68%-96%) and specificity (78%-100%) in detecting pancreatic carcinoma in patients with a suspicious-looking pancreatic mass on CT scan. Lastly, we focus on the use of FDG-PET as a modality for early monitoring of treatment response in patients with gastrointestinal stromal cell tumours. Without doubt, future developments will further establish the diagnostic role of the FDG-PET scan in the care of patients with gastrointestinal cancers. C1 Univ Nijmegen, Med Ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, NL-6500 AH Nijmegen, Netherlands. Univ Nijmegen, Med Ctr St Radboud, Dept Nucl Med, NL-6500 AH Nijmegen, Netherlands. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Univ Nijmegen, Med Ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, POB 9101, NL-6500 AH Nijmegen, Netherlands. EM joostphdrenth@cs.com RI Oyen, Wim/D-4178-2009; Drenth, J.P.H./H-8025-2014; Kouwen, M.C.A./L-4453-2015 OI Oyen, Wim/0000-0001-8235-7078; NR 84 TC 5 Z9 5 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0036-5521 EI 1502-7708 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PY 2004 VL 39 SU 241 BP 85 EP 92 DI 10.1080/00855920410014614 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 887JB UT WOS:000226300800015 PM 15696855 ER PT J AU Otey, E Fenton, WS AF Otey, E Fenton, WS TI Editors' introduction: Building mental illness stigma research SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material C1 NIMH, DAHBR, Stigma & Hlth Dispar Program, Bethesda, MD 20892 USA. NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. RP Otey, E (reprint author), NIMH, DAHBR, Stigma & Hlth Dispar Program, 6001 Execut Blvd,Room 6186,MSC 9625, Bethesda, MD 20892 USA. EM eotey@nih.gov NR 11 TC 7 Z9 7 U1 0 U2 1 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2004 VL 30 IS 3 BP 473 EP 475 PG 3 WC Psychiatry SC Psychiatry GA 878PO UT WOS:000225659100001 ER PT J AU Watson, AC Otey, E Westbrook, AL Gardner, AL Lamb, TA Corrigan, PW Fenton, WS AF Watson, AC Otey, E Westbrook, AL Gardner, AL Lamb, TA Corrigan, PW Fenton, WS TI Changing middle schoolers' attitudes about mental illness through education SO SCHIZOPHRENIA BULLETIN LA English DT Article DE mental illness; stigma; science education; adolescents; attitudes ID CHILDRENS ATTITUDES; PUBLIC CONCEPTIONS; ILL; STIGMA; SCHIZOPHRENIA; DANGEROUSNESS; ATTRIBUTIONS; STUDENTS; PEOPLE; LABELS AB The field test of The Science of Mental Illness curriculum supplement for middle school (grades 6-8) children provided an opportunity to assess knowledge and attitudes about mental illness in more than 1,500 middle school students throughout the United States and to evaluate the impact of an educational intervention on stigma-related attitudes. Two primary questions were examined: (1) what are the baseline knowledge and attitudes about mental illness in this sample of middle school students, and (2) does participation in a curriculum about the science of mental illness increase knowledge and improve attitudes about mental illness? Consistent with findings from other studies, results indicate that students had some understanding of mental illness as a problem of the brain with biological and psychosocial causes; however, they lacked knowledge about treatment and overall were "not sure" about many aspects of mental illness. The students did not strongly endorse negative attitudes about mental illness at baseline. The curriculum produced significant improvements in both knowledge and attitudes at posttest and was most effective in improving attitudes among those with more negative baseline attitudes. These findings suggest that a brief educational program can be an effective intervention to increase knowledge and improve attitudes about mental illness. C1 Northwestern Univ, Evanston, IL USA. NIMH, Hlth Serv, Bethesda, MD 20892 USA. NIMH, Intervent Behav Program, Bethesda, MD 20892 USA. NIMH, Sociocultural Proc & Hlth Dispar Program, Bethesda, MD 20892 USA. NIMH, Div Mental Disorders Behav Res & AIDS, Bethesda, MD 20892 USA. Ctr Res & Evaluat, Biol Sci Curriculum Study, Colorado Springs, CO USA. Univ Chicago, Tinley Pk, IL USA. RP Watson, AC (reprint author), Evanston NW Healthcare, Ctr Psychiat Rehabil, 1033 Univ Pl,Suite 450, Evanston, IL 60201 USA. EM acwatson@gmail.com FU PHS HHS [263-01-0215] NR 44 TC 71 Z9 73 U1 3 U2 15 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2004 VL 30 IS 3 BP 563 EP 572 PG 10 WC Psychiatry SC Psychiatry GA 878PO UT WOS:000225659100007 PM 15631245 ER PT J AU McNulty, JP AF McNulty, JP TI Commentary: Mental illness, society, stigma, and research SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material C1 NIMH, Schizophrenia Bulletin, Bethesda, MD 20892 USA. RP McNulty, JP (reprint author), NIMH, Schizophrenia Bulletin, 6001 Execut Blvd,Rm 8184,MSC 9663, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2004 VL 30 IS 3 BP 573 EP 575 PG 3 WC Psychiatry SC Psychiatry GA 878PO UT WOS:000225659100008 PM 15631246 ER PT J AU Pianta, RC Stuhlman, MW AF Pianta, RC Stuhlman, MW TI Teacher-child relationships and children's success in the first years of school SO SCHOOL PSYCHOLOGY REVIEW LA English DT Article ID KINDERGARTEN; PRESCHOOL; ASSOCIATIONS; TRAJECTORIES; PREDICTORS; ADJUSTMENT; OUTCOMES; SKILLS AB This work examines associations between closeness and conflict in teacher-child relationships and children's social and academic skills in first grade in a sample of 490 children. Assessments of teacher-child relationships were obtained in preschool, kindergarten, and first grade. Results demonstrate moderate correlations among teachers' ratings of conflict and slightly lower correlations among teachers' ratings of closeness across years. Hierarchical regression analyses predicted children's skills in first grade from teacher-child relationship quality. Child gender, socioeconomic status, and preschool estimates of outcomes of interest were controlled statistically. Although preschool assessments of social and academic skills were closely associated with individual skill differences at first grade, teacher-child relationship quality also was associated with changes in skill levels. Findings generally confirm that teacher-child relationships play a role in children's ability to acquire the skills necessary for success in school. C1 Univ Virginia, NICHD, Study Early Child Care, Charlottesville, VA 22903 USA. RP Pianta, RC (reprint author), Univ Virginia, NICHD, Study Early Child Care, 853 W Main St,Ste 100,Republ Pl Annex, Charlottesville, VA 22903 USA. EM rcp4p@virginia.edu OI Pianta, Robert/0000-0002-6280-8051 NR 38 TC 240 Z9 246 U1 7 U2 45 PU NATL ASSN SCHOOL PSYCHOLOGISTS PI BETHESDA PA 4340 EAST WEST HWY, STE 402, BETHESDA, MD 20814 USA SN 0279-6015 J9 SCHOOL PSYCHOL REV JI Sch. Psychol. Rev. PY 2004 VL 33 IS 3 BP 444 EP 458 PG 15 WC Psychology, Educational SC Psychology GA 863LU UT WOS:000224564100011 ER PT S AU Aberer, K Catarci, T Cudre-Mauroux, P Dillon, T Grimm, S Hacid, MS Illarramendi, A Jarrar, M Kashyap, V Mecella, M Mena, E Neuhold, EJ Ouksel, AM Risse, T Scannapieco, M Saltor, F de Santis, L Spaccapietra, S Staab, S Studer, R De Troyer, O AF Aberer, K Catarci, T Cudre-Mauroux, P Dillon, T Grimm, S Hacid, MS Illarramendi, A Jarrar, M Kashyap, V Mecella, M Mena, E Neuhold, EJ Ouksel, AM Risse, T Scannapieco, M Saltor, F de Santis, L Spaccapietra, S Staab, S Studer, R De Troyer, O BE Bouzaghoub, M Goble, C Kashyap, V Spaccapuetra, S TI Emergent semantics systems SO SEMANTICS OF A NETWORKED WORLD: SEMANTICS FOR GRID DATABASES SE Lecture Notes in Computer Science LA English DT Article; Proceedings Paper CT 1st International Conference on Semantics of a Networked World (ICSNW 2004) CY JUN 17-19, 2004 CL Paris, FRANCE SP IFIP AB With new standards like RDF or OWL paving the way for the much anticipated Semantic Web, a new breed of very large scale semantic systems is about to appear. Traditional semantic reconciliation techniques, dependent upon shared vocabularies or global ontologies, cannot be used in such open and dynamic environments. Instead, new heuristics based on emerging properties and local consensuses have to be exploited in order to foster semantic interoperability in the large. In this paper, we outline the main differences between traditional semantic reconciliation methods and these new heuristics. Also, we characterize the resulting emergent semantics systems and provide a couple of hints vis-a-vis their potential applications. C1 Swiss Fed Inst Technol, EPFL, Lausanne, Switzerland. Univ Roma La Sapienza, Rome, Italy. Univ Technol Sydney, Sydney, NSW 2007, Australia. Univ Karlsruhe, Karlsruhe, Germany. Univ Lyon 1, F-69365 Lyon, France. Free Univ Brussels, Brussels, Belgium. Natl Lib Med, Bethesda, MD 20894 USA. Univ Zaragoza, Zaragoza, Spain. Univ Illinois, Chicago, IL USA. Univ Politecn Cataluna, E-08028 Barcelona, Spain. RP Swiss Fed Inst Technol, EPFL, Lausanne, Switzerland. EM Philippe.Cudre-Mauroux@epfl.ch RI Mecella, Massimo/F-7106-2011; Aberer, Karl/G-6336-2011; ILLARRAMENDI, ARANTZA/E-3466-2016; OI ILLARRAMENDI, ARANTZA/0000-0001-9567-6326; Mecella, Massimo/0000-0002-9730-8882; Mena Nieto, Eduardo/0000-0002-7462-0080; Risse, Thomas/0000-0001-6248-1709 NR 95 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 0302-9743 BN 3-540-23609-0 J9 LECT NOTES COMPUT SC PY 2004 VL 3226 BP 14 EP 43 PG 30 WC Computer Science, Theory & Methods SC Computer Science GA BBD79 UT WOS:000225040900002 ER PT J AU Thiel, M Caldwell, C Jackson, S Sitkovsky, M AF Thiel, M Caldwell, C Jackson, S Sitkovsky, M TI Flow cytometric assessment of phagocyte functions in murine whole blood SO SHOCK LA English DT Meeting Abstract CT 6th World Congress on Trauma, Shock, Inflammation and Sepsis - Pathophysiology, Immune Consequences and Therapy CY MAR 02-06, 2004 CL Munich, GERMANY C1 NIAID, Lab Immunol & Host Def, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PY 2004 VL 21 SU 1 MA 59 BP 15 EP 15 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 810FF UT WOS:000220689500060 ER PT J AU Medvedev, AE Lentschat, A Wahl, LM Golenbock, DT Vogel, SN AF Medvedev, AE Lentschat, A Wahl, LM Golenbock, DT Vogel, SN TI Dysregulation of LPS-induced TLR4-MyD88 complex formation and IRAK-1 activation in endotoxin-tolerant cells SO SHOCK LA English DT Meeting Abstract CT 6th World Congress on Trauma, Shock, Inflammation and Sepsis - Pathophysiology, Immune Consequences and Therapy CY MAR 02-06, 2004 CL Munich, GERMANY C1 Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PY 2004 VL 21 SU 1 MA 89 BP 23 EP 23 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 810FF UT WOS:000220689500091 ER PT J AU Sternberg, EM AF Sternberg, EM TI Neuroendocrine stress response in regulation of if inflammatory responses SO SHOCK LA English DT Meeting Abstract CT 6th World Congress on Trauma, Shock, Inflammation and Sepsis - Pathophysiology, Immune Consequences and Therapy CY MAR 02-06, 2004 CL Munich, GERMANY C1 NIMH, NIH, 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 1073-2322 J9 SHOCK JI Shock PY 2004 VL 21 SU 1 MA 302 BP 76 EP 76 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 810FF UT WOS:000220689500305 ER PT J AU Wink, DA Thomas, DD Ridnour, L Mancardi, D Espey, MG AF Wink, DA Thomas, DD Ridnour, L Mancardi, D Espey, MG TI Discrete concentrations of NO activate selectively active different cellular signal transduction pathways SO SHOCK LA English DT Meeting Abstract CT 6th World Congress on Trauma, Shock, Inflammation and Sepsis - Pathophysiology, Immune Consequences and Therapy CY MAR 02-06, 2004 CL Munich, GERMANY C1 NCI, Radiat Biol Branch, Tumor Biol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PY 2004 VL 21 SU 1 MA 378 BP 95 EP 95 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 810FF UT WOS:000220689500381 ER PT J AU Chadwick, RS Shoelson, B Cai, HX AF Chadwick, RS Shoelson, B Cai, HX TI Surface Green's functions for an incompressible, transversely isotropic elastic half-space SO SIAM JOURNAL ON APPLIED MATHEMATICS LA English DT Article DE anisotropic material; asymptotic analysis; elastic material; Green's functions ID CONTACT; BODIES AB The surface displacements produced by normal and tangential point loads applied to the surface of an incompressible, transversely isotropic material are considered when anisotropy is produced by a single family of fibers oriented perpendicular to the surface normal. Three elastic constants ( two shear moduli and a fiber modulus) characterize the linear elasticity of such a material. The problems are solved analytically in two-dimensional Fourier transform space, and explicit surface displacement formulae are given for the inverses in physical space. Simple relations are given as asymptotic expansions for weak anisotropy. Computed surface displacement patterns are illustrated, and the application of the results to atomic force microscopy is discussed. C1 Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov; shoelson@helix.nih.gov; hongxuec@helix.nih.gov NR 18 TC 2 Z9 2 U1 1 U2 2 PU SIAM PUBLICATIONS PI PHILADELPHIA PA 3600 UNIV CITY SCIENCE CENTER, PHILADELPHIA, PA 19104-2688 USA SN 0036-1399 J9 SIAM J APPL MATH JI SIAM J. Appl. Math. PY 2004 VL 64 IS 4 BP 1186 EP 1197 DI 10.1137/S0036139903425338 PG 12 WC Mathematics, Applied SC Mathematics GA 831HW UT WOS:000222186500006 ER PT J AU Killgore, WD Braun, AR Belenky, G Wesensten, NJ Balkin, TJ AF Killgore, WD Braun, AR Belenky, G Wesensten, NJ Balkin, TJ TI Regional cerebral metabolic correlates of electroencephalographic activity during stage-2 and slow wave sleep: An H215OPET study SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Walter Reed Army Inst Res, Silver Spring, MD USA. NIH, Voice Speech & Language Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 050 BP 22 EP 23 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400052 ER PT J AU Malcolm, R DeVane, L Donovan, J Mojsiak, JZ Elkashef, AM Taylor, R Brady, K Myrick, H AF Malcolm, R DeVane, L Donovan, J Mojsiak, JZ Elkashef, AM Taylor, R Brady, K Myrick, H TI Modafinil as potential treatment for cocaine dependence SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Med Univ S Carolina, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. NIDA, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 112 BP 50 EP 51 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400114 ER PT J AU Bliwise, DL Ansari, FP Ancoli-Israel, S Vitiello, MV Walsh, J Foley, D AF Bliwise, DL Ansari, FP Ancoli-Israel, S Vitiello, MV Walsh, J Foley, D TI Relationship of nocturia to chronic self-reported poor sleep: Results from the 2003 NSF sleep in America poll SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Emory Univ, Atlanta, GA 30322 USA. Univ Washington, Seattle, WA 98195 USA. Univ Calif San Diego, San Diego, CA 92103 USA. NIA, Bethesda, MD 20892 USA. St Lukes Hosp, Chesterfield, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 267 BP 120 EP 120 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400269 ER PT J AU Vitiello, MV Foley, DJ Stratton, KL White, E AF Vitiello, MV Foley, DJ Stratton, KL White, E TI Prevalence of sleep complaints and insomnia in the vitamins and lifestyle (VITAL) study cohort of 77,000 older men and women SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 266 BP 120 EP 120 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400268 ER PT J AU Quan, SF Katz, R Olson, JL Bonekat, HW Enright, PL Young, T Newman, AB AF Quan, SF Katz, R Olson, JL Bonekat, HW Enright, PL Young, T Newman, AB TI Factors associated with the incidence and remission of difficulty initiating sleep in an elderly cohort-the cardiovascular health study (CHS) SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Univ Arizona, Sleep Ctr, Tucson, AZ USA. Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. Univ Wisconsin, Dept Prevent Med, Madison, WI 53706 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 268 BP 121 EP 121 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400270 ER PT J AU Vitiello, MV Foley, DJ Larsen, LH Bliwise, DL Ancoli-Israel, S Monjan, AA Walsh, JK AF Vitiello, MV Foley, DJ Larsen, LH Bliwise, DL Ancoli-Israel, S Monjan, AA Walsh, JK TI Relationship of regular napping to health and self-reported sleep quality in older adults: Results from the 2003 NSF sleep in America poll SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Univ Washington, Seattle, WA 98195 USA. NIA, Lab Epidemiol Demog & Biometry, Washington, DC USA. Emory Univ, Sch Med, Atlanta, GA USA. Univ Calif San Diego, San Diego, CA 92103 USA. VASDHS, San Diego, CA USA. NIA, Neurosci & Neuropsychol Aging Program, Washington, DC USA. St Lukes Hosp, St Johns Mercy Med Ctr, Sleep Med & Res Ctr, St Louis, MO USA. St Louis Univ, St Louis, MO 63103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 279 BP 126 EP 126 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400281 ER PT J AU Vgontzas, A Zoumakis, E Lin, H Bixler, E Vela, AB Chrousos, G AF Vgontzas, A Zoumakis, E Lin, H Bixler, E Vela, AB Chrousos, G TI Marked decrease of sleepiness in patients with sleep apnea by etanercept SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Sleep Res & Treatment Ctr, Hershey, PA 17033 USA. NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. Autonomous Univ Madrid, E-28049 Madrid, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 481 BP 215 EP 215 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400483 ER PT J AU Vgontzas, A Trakada, G Bixler, E Lin, H Zoumakis, E Chrousos, G Legro, R AF Vgontzas, A Trakada, G Bixler, E Lin, H Zoumakis, E Chrousos, G Legro, R TI Plasma IL-6 and TNF alpha levels are elevated in polycystic ovary syndrome independent of obesity and sleep disturbance SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Penn State Univ, Sleep Res & Treatment Ctr, Hershey, PA USA. Penn State Univ, Coll Med, Hershey, PA USA. NIH, Pediat & Endocrinol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 747 BP 334 EP 334 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400749 ER PT J AU Postolache, TT Benson, BE Shah, D Matthews, JR Turner, EH Guzman, A Stiller, JW Wehr, TA Rosenthal, NE Drevets, WC AF Postolache, TT Benson, BE Shah, D Matthews, JR Turner, EH Guzman, A Stiller, JW Wehr, TA Rosenthal, NE Drevets, WC TI Bright light: Lateralized effects on the regional cerebral blood flow in patients with seasonal affective disorder and healthy controls SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Univ Maryland, Sch Med, Dept Psychiat, Mood & Anxiety Program, Baltimore, MD 21201 USA. NIMH, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. NCTPAD, Inst Sports Chronobiol, Washington, DC USA. DCDMH, St Elizabeths Hosp, Psychopharmacol Consultat Serv, Washington, DC USA. RI Turner, Erick/A-4848-2008 OI Turner, Erick/0000-0002-3522-3357 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 761 BP 341 EP 341 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400763 ER PT J AU Hall, M Koru-Sengul, T Vasko, R Buysse, DJ Kupfer, DJ Omhao, H Thayer, JF AF Hall, M Koru-Sengul, T Vasko, R Buysse, DJ Kupfer, DJ Omhao, H Thayer, JF TI Stress, autonomic tone and beta power are coupled during NREM sleep SO SLEEP LA English DT Meeting Abstract CT 18th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 05-10, 2004 CL Philadelphia, PA SP Associated Profess Sleep Soc C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Univ Illinois, Champaign, IL 61820 USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2004 VL 27 SU S MA 932 BP 417 EP 417 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OX UT WOS:000223169400934 ER PT J AU Callahan, C AF Callahan, C TI Facial disfigurement and sense of self in head and neck cancer SO SOCIAL WORK IN HEALTH CARE LA English DT Article DE head and neck cancer; disfigurement; body image; coping; quality of life ID PSYCHOLOGICAL IMPACT; BODY-IMAGE; SURGERY; PSYCHOTHERAPY AB People who suffer facial disfigurement as a result of head and neck cancer experience profound psychological trauma. This article will describe the role that the face plays in an individual's sense of self and body integrity; the psychological impact on self-esteem; physiological dysfunction with or without disfigurement that pose obstacles to meaningful therapeutic Communication; implications for individual and group psychotherapy; and tasks of psychological recovery related to a transformed sense of face, body, and self. (c) 2004 by The Haworth Press, Inc. All rights reserved. C1 NIH, Ctr Clin, Dept Social Work, Bethesda, MD 20892 USA. RP Callahan, C (reprint author), NIH, Ctr Clin, Dept Social Work, Bldg 10,Room 1N252, Bethesda, MD 20892 USA. NR 36 TC 41 Z9 41 U1 1 U2 8 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0098-1389 J9 SOC WORK HEALTH CARE JI Soc. Work Health Care PY 2004 VL 40 IS 2 BP 73 EP 87 DI 10.1300/J010v40n02_05 PG 15 WC Social Work SC Social Work GA 920ZL UT WOS:000228733900005 PM 15774364 ER PT J AU McKeown, RE Weed, DL AF McKeown, RE Weed, DL TI Ethical choices in survey research SO SOZIAL-UND PRAVENTIVMEDIZIN LA English DT Article ID EPIDEMIOLOGY C1 Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. NCI, Div Canc Prevent, Rockville, MD USA. RP McKeown, RE (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. OI McKeown, Robert/0000-0002-8829-5784 NR 7 TC 0 Z9 0 U1 0 U2 0 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 0303-8408 J9 SOZ PRAVENTIV MED JI Sozial-und Pravent. PY 2004 VL 49 IS 1 BP 67 EP 68 DI 10.1007/s00038-003-3019-1 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 808GC UT WOS:000220556600016 PM 15040131 ER PT J AU Wang, GS Keifer, PA Peterkofsky, A AF Wang, GS Keifer, PA Peterkofsky, A TI Short-chain diacyl phosphatidylglycerols: which one to choose for the NMR structural determination of a membrane-associated peptide from Escherichia coli? SO SPECTROSCOPY-AN INTERNATIONAL JOURNAL LA English DT Article; Proceedings Paper CT 2nd International Conference on Biomedical Spectroscopy CY JUL 05-08, 2003 CL London, ENGLAND DE micelles; amphipathic helix; lipid chain length; CMC; NMR; Escherichia coli ID PHOSPHOTRANSFERASE SYSTEM; PROTEIN; SPECTROSCOPY; EXCHANGE; MICELLES; DOMAIN; HIV-1 AB Diacyl phosphatidylglycerols (PG) are the major anionic lipids in the Escherichia coli membrane. Short-chain dihexanoyl phosphatidylglycerol (DHPG) was previously utilized for the structural determination, by NMR spectroscopy, of the peptide corresponding to the N-terminal membrane anchor of the glucose-specific enzyme IIA (IIA(Glc)) from E. coli. This study explores the possible use of lipid micelles of dioctanoyl phosphatidylglycerol (DOPG) and didecanoyl phosphatidylglycerol (DDPG) as alternatives to DHPG. At a peptide concentration of 1 mM, the minimum peptide/lipid molar ratios required for the formation of the lipid-binding amphipathic helix are approximately 1 :40, 1:5, and 1 : 5 for DHPG, DOPG, and DDPG, respectively. Based on the lipid titration, the critical micelle concentration (CMC) of DHPG was estimated to be similar to50 MM. The H-1 spectral linewidths of the peptide bound to a variety of lipid micelles decrease in the following order: DDPG > DOPG > DHPG. The helical regions of the peptide in different anionic lipids were elucidated based on chemical shift indexes (CSI). Residues Leu2-Leu9, Leu2-Va110, and Leu2-Va110 were found to be helical in DHPG, DOPG, and DDPG, respectively, indicating that the lipid chain length had only a subtle effect on the amphipathic helix of the peptide. In light of the minimum peptide/lipid ratio and the spectral linewidth, and the CSI-derived peptide structure, DOPG is proposed as a good compromise for structural studies of this membrane-associated peptide by solution NMR spectroscopy. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, GS (reprint author), Univ Nebraska, Med Ctr, Eppley Canc Inst, 986805 Nebraska Med Ctr,Room ECI3018, Omaha, NE 68198 USA. EM gwang@unmc.edu NR 18 TC 14 Z9 14 U1 0 U2 2 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0712-4813 J9 SPECTROSC-INT J JI Spectr.-Int. J. PY 2004 VL 18 IS 2 SI SI BP 257 EP 264 PG 8 WC Biochemical Research Methods; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 827AE UT WOS:000221869800015 ER PT J AU Gadbury, GL Page, GP Edwards, J Kayo, T Prolla, TA Weindruch, R Permana, PA Mountz, JD Allison, DB AF Gadbury, GL Page, GP Edwards, J Kayo, T Prolla, TA Weindruch, R Permana, PA Mountz, JD Allison, DB TI Power and sample size estimation in high dimensional biology SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article ID GENE-EXPRESSION; MICROARRAY DATA; STATISTICAL-INFERENCE; DNA MICROARRAY; MODEL; FRAMEWORK; TESTS AB Genomic scientists often test thousands of hypotheses in a single experiment. One example is a microarray experiment that seeks to determine differential gene expression among experimental groups. Planning such experiments involves a determination of sample size that will allow meaningful interpretations. Traditional power analysis methods may not be well suited to this task when thousands of hypotheses are tested in a discovery oriented basic research. We introduce the concept of expected discovery rate (EDR) and an approach that combines parametric mixture modelling with parametric bootstrapping to estimate the sample size needed for a desired accuracy of results. While the examples included are derived from microarray studies, the methods, herein, are 'extraparadigmatic' in the approach to study design and are applicable to most high dimensional biological situations. Pilot data from three different microarray experiments are used to extrapolate EDR as well as the related false discovery rate at different sample sizes and thresholds. C1 Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. Univ Missouri, Dept Math & Stat, Rolla, MO 65401 USA. Iowa State Univ, USDA ARS, Dept Agron, Ames, IA USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI USA. Univ Wisconsin, Dept Genet & Med Genet, Madison, WI USA. Univ Wisconsin, Dept Med, Madison, WI USA. William S Middleton VA Hosp, Ctr Geriatr Res Educ & Clin, Madison, WI USA. NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. Univ Alabama, Birmingham Vet Adm Med Ctr, Birmingham, AL USA. Univ Alabama, Clin Nutr Res Ctr, Birmingham, AL 35294 USA. RP Allison, DB (reprint author), Univ Alabama, Dept Biostat, Sect Stat Genet, 1665 Univ Ave,Ryals Publ Hlth Bldg,Suite 327, Birmingham, AL 35294 USA. EM dallison@ms.soph.uab.edu OI Allison, David/0000-0003-3566-9399 NR 32 TC 44 Z9 50 U1 0 U2 5 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PY 2004 VL 13 IS 4 BP 325 EP 338 DI 10.1191/0962280204sm369ra PG 14 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 844YR UT WOS:000223201100005 ER PT J AU Feuer, EJ Etzioni, R Cronin, KA Mariotto, A AF Feuer, EJ Etzioni, R Cronin, KA Mariotto, A TI The use of modeling to understand the impact of screening on US mortality: examples from mammography and PSA testing SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article ID PROSTATE-CANCER MORTALITY; EARLY BREAST-CANCER; UNITED-STATES; INTERPRETING TRENDS; SURVEILLANCE SERIES; RANDOMIZED-TRIALS; RECENT RISE; TAMOXIFEN; CARCINOMA; KINGDOM AB Surveillance data represent a vital resource for understanding the impact of cancer control interventions on the population cancer burden. However, population cancer trends are a complex product of many factors, and estimating the contribution of any one of these factors can be challenging. Surveillance modeling is a technique for estimating the contribution of one or more interventions of interest to trends in disease incidence and mortality. In this article, we present several approaches to surveillance modeling of cancer screening interventions. We classify models as biological or epidemiological, depending on whether they model the full unobservable aspects of disease onset and progression, or models which reduce the complex process to simpler terms by summarizing portions of the disease process using mostly observed population level measures. We also describe differences between macrolevel models, microsimulation models and mechanistic models. We discuss procedures for model calibration and validation, and methods for presenting model results which are robust with respect to certain types of biased model estimates. As examples, we present several models of the impact of mammography screening on breast cancer mortality, and PSA screening on prostate cancer mortality. Both these examples are appropriate uses of surveillance modeling, even though for mammography there is extensive (although somewhat controversial) randomized trial evidence, whereas for PSA this biomarker has seen extensive use as a screening test prior to any controlled trial evidence of its efficacy. Some of the models presented here were developed as part of the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network. C1 NCI, Stat Res & Applicat Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Feuer, EJ (reprint author), 6116 Execut Blvd,Room 5041,MSC 8317, Bethesda, MD 20892 USA. EM rf41u@nih.gov NR 38 TC 28 Z9 29 U1 0 U2 2 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PY 2004 VL 13 IS 6 BP 421 EP 442 DI 10.1191/0962280204sm376ra PG 22 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 871AU UT WOS:000225102100002 PM 15587432 ER PT J AU Hu, P Zelen, M AF Hu, P Zelen, M TI Planning of randomized early detection trials SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article ID BREAST-CANCER MORTALITY; FOLLOW-UP; SCREENING-PROGRAMS; DEATH RATES; MAMMOGRAPHY; DISEASE AB Consider a randomized clinical trial to evaluate the benefit of screening an asymptomatic population. Suppose that the subjects are randomized into a usual care and a study group. The study group receives one or more periodic early detection examinations aimed at diagnosing disease early, when there are no signs or symptoms. Early detection clinical trials differ from therapeutic trials in that power is affected by: i) the number of exams, ii) the time between exams and iii) the ages at which exams will be given. These design options do not exist in therapeutic trials. Furthermore; long-term follow-up may result in a reduction of power. In general, power increases with number of examinations, and the optimal follow-up time is dependent on the spacing between examinations. Clinical trials in which the usual care group receives benefit are also discussed. Two designs are discussed, for example the 'up-front design' in which all subjects receive an initial exam and then are randomized to the usual care and study groups and the 'close-out design' in which the usual care group receives an exam which is timed to be given at the same time as the last exam in the study group. Both families of designs significantly reduce the power. Power calculations are made for two clinical trials, which actually used these two designs. C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Hu, P (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM ph107y@nih.gov FU NCI NIH HHS [CA-88270] NR 23 TC 1 Z9 1 U1 1 U2 1 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PY 2004 VL 13 IS 6 BP 491 EP 506 DI 10.1191/0962280204sm379ra PG 16 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 871AU UT WOS:000225102100005 PM 15587435 ER PT J AU Zeng, XM Miura, T Luo, YQ Bhattacharya, B Condie, B Chen, J Ginis, I Lyons, I Mejido, J Puri, RK Rao, MS Freed, WJ AF Zeng, XM Miura, T Luo, YQ Bhattacharya, B Condie, B Chen, J Ginis, I Lyons, I Mejido, J Puri, RK Rao, MS Freed, WJ TI Properties of pluripotent human embryonic stem cells BG01 and BG02 SO STEM CELLS LA English DT Article DE embryonic stem cells; differentiation; microarray ID NEURAL PRECURSORS; GENE-EXPRESSION; LINES; DIFFERENTIATION; ESTABLISHMENT; CULTURE; GROWTH; CARDIOMYOCYTES; BLASTOCYSTS; ENRICHMENT AB Human ES (hES) cell lines have only recently been generated, and differences between human and mouse ES cells have been identified. In this manuscript we describe the properties of two human ES cell lines, BG01 and BG02. By immunocytochemistry and reverse transcription polymerase chain reaction, undifferentiated cells expressed markers that are characteristic of ES cells, including SSEA-3, SSEA-4, TRA-1-60, TRA-181, and OCT-3/4. Both cell lines were readily maintained in an undifferentiated state and could differentiate into cells of all three germ layers, as determined by expression of beta-tubulin III neuron-specific molecule (ectoderm), cardiac troponin I (cardiomyocytes, mesoderm), and alpha-fetoprotein (endoderm). A large-scale microarray (16,659 genes) analysis identified 373 genes that were expressed at three-fold or higher levels in undifferentiated BG01 and BG02 cells as compared with pooled human RNA. Ninety-two of these genes were also highly expressed in four other hES lines (TE05, GE01, GE09, and pooled samples derived from GE01, GE09, and GE07). Included in the list are genes involved in cell signaling and development, metabolism, transcription regulation, and many hypothetical proteins. Two focused arrays designed to examine transcripts associated with stem cells and with the transforming growth factor-beta superfamily were employed to examine differentially expressed genes. Several growth factors, receptors, and components of signaling pathways that regulate embryonic development, in particular the nodal signaling pathway, were detected in both BG01 and BG02. These data provide a detailed characterization and an initial gene expression profile for the BG01 and BG02 human ES cell lines. C1 NIDA, Dev & Plast Sect, Cellular Neurobiol Res Branch, DHHS, Baltimore, MD 21224 USA. BresaGen Inc, Athens, GA USA. US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Lab Mol Tumor Biol, Bethesda, MD USA. NIA, Neurosci Lab, DHHS, Baltimore, MD 21224 USA. RP Zeng, XM (reprint author), NIDA, Dev & Plast Sect, Cellular Neurobiol Res Branch, DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM xzeng@intra.nida.nih.gov; raomah@grc.nia.nih.gov FU NIDDK NIH HHS [R24DK063689] NR 36 TC 104 Z9 114 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 3 BP 292 EP 312 DI 10.1634/stemcells.22-3-292 PG 21 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 827AC UT WOS:000221869600010 PM 15153607 ER PT J AU Murga, M Yao, L Tosato, G AF Murga, M Yao, L Tosato, G TI Derivation of endothelial cells from CD34(-) umbilical cord blood SO STEM CELLS LA English DT Article DE endothelial progenitor cells; vasculogenesis; cord blood; CD34 ID RECEPTOR TYROSINE KINASE; PROGENITOR CELLS; SIALOMUCIN CD34; ANGIOGENESIS; GROWTH; DIFFERENTIATION; PRECURSORS; GENE; NEOVASCULARIZATION; INTERLEUKIN-12 AB CD34 is a transmembrane glycoprotein constitutively expressed on endothelial cells and hematopoietic stem cells. Use of CD34-recognizing antibodies has helped in the identification and isolation of CD34(+) endothelial precursors from embryonic and adult tissues. However, CD34-null mice display no vascular abnormalities, demonstrating that CD34 antigen expression is not required for normal vascular development. Here we show that a CD34(-) cell population that includes endothelial cell precursors can be isolated from cord blood. In the presence of angiogenic factors, these cells mature to express the endothelial cell markers vascular endothelial-cadherin, vascular endothelial growth factor receptor-1 and -2, Tie-1 and -2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains), von Willebrand factor, and CD31 while maintaining their CD34(-) status, and can be expanded in vitro for over 20 passages. Moreover, in functional studies, these cells can undergo extracellular matrix-dependent morphogenic changes into capillary-like tubular structures. When transplanted into immunodeficient mice in conjunction with tumor cells or with the pro-angiogenic factor basic fibroblast growth factor, these cells can form functional microvessels arising along with host blood cells. These studies provide strong evidence for the existence of CD34(-) endothelial cell precursors in cord blood and suggest the use of ex vivo-expanded cord blood CD34(-) cells as a unique tool for the investigation of postnatal lineage diversification. C1 NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Murga, M (reprint author), NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, Bldg 10,Room 12C207,10 Ctr Dr, Bethesda, MD 20892 USA. EM costama@mail.nih.gov NR 42 TC 31 Z9 38 U1 0 U2 1 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 3 BP 385 EP 395 DI 10.1634/stemcells.22-3-385 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 827AC UT WOS:000221869600018 PM 15153615 ER PT J AU Matrosova, VY Orlovskaya, IA Serobyan, N Khaldoyanidi, SK AF Matrosova, VY Orlovskaya, IA Serobyan, N Khaldoyanidi, SK TI Hyaluronic acid facilitates the recovery of Hematopoiesis following 5-fluorouracil administration SO STEM CELLS LA English DT Article DE bone marrow aplasia; chemotheraphy; cytokines; hematopoietic progenitor cells; microenvironment; hyaluronan ID BONE-MARROW MACROPHAGES; STEM-CELL NICHE; ADHESION RECEPTORS; PROGENITOR CELLS; CD44 PROTEINS; PROLIFERATION; EXPRESSION; TRANSPLANTATION; INTERLEUKIN-1; FIBROBLASTS AB The fate of hematopoietic stem cells (HSCs) is determined by microenvironmental niches, but the molecular structure of these local networks is not yet completely characterized. Our recent observation that glycosaminoglycan hyaluronic acid (HA), a major component of the bone marrow extracellular matrix, is required for in vitro hematopoiesis led us to suggest a role for HA in structuring the hematopoietic niche. Accordingly, HA deprivation induced by various treatments might lead to an imbalance of normal HSC homeostasis. Since 5-fluorouracil (5-FU) administration sharply decreases the amount of cell surface-associated HA in bone marrow, we examined whether the administration of exogenous HA enhances suppressed hematopoiesis in 5-FU-treated mice. HA administered to mice following 5-FU infusion facilitated the recovery of leukocytes and thrombocytes in the peripheral blood. Intravenously infused HA was found in the bone marrow, where it bound endothelial cells and resident macrophages and increased expression of the hematopoiesis-supportive cytokines interieukin-1 and interleukin-6. In agreement with these observations, enhanced hematopoietic activity was detected in the bone marrow, as measured by elevated counts of long-term culture-initiating cells (LTC-ICs), committed progenitors, and the total number of mature bone marrow cells. Overall, our results suggest that HA is required for regulation of the hematopoiesis-supportive function of bone marrow accessory cells and, therefore, participates in hematopoietic niche assembly. C1 La Jolla Inst Mol Med, Div Vasc Biol, San Diego, CA 92121 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Inst Clin Immunol, Novosibirsk, Russia. RP Khaldoyanidi, SK (reprint author), La Jolla Inst Mol Med, Div Vasc Biol, 4570 Execut Dr,Suite 100, San Diego, CA 92121 USA. EM sophia@ljimm.org FU NIDDK NIH HHS [R21 DK067084] NR 45 TC 38 Z9 39 U1 0 U2 6 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 4 BP 544 EP 555 DI 10.1634/stemcells.22-4-544 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 843GO UT WOS:000223066800011 PM 15277700 ER PT J AU Dermott, JM Gooya, JM Asefa, B Weiler, SR Smith, M Keller, JR AF Dermott, JM Gooya, JM Asefa, B Weiler, SR Smith, M Keller, JR TI Inhibition of growth by p205: A nuclear protein and putative tumor suppressor expressed during myeloid cell differentiation SO STEM CELLS LA English DT Article DE IFI-200; tumor suppressor; myeliod; differentiation ID INTERFERON-INDUCIBLE PROTEIN; NIH 3T3 CELLS; RETINOBLASTOMA PROTEIN; TRANSCRIPTION FACTORS; GENE-200 CLUSTER; DNA-SYNTHESIS; IFI 16; FAMILY; ANTIGEN; LOCALIZATION AB p205 belongs to a family of interferon-inducible proteins called the IFI-200 family, which have been implicated in the regulation of cell growth and differentiation. While p205 is induced in hematopoietic stem cells during myeloid cell differentiation, its function is not known. Therefore, the aim of this study was to determine the role of p205 in regulating proliferation in hematopoietic progenitor cells and in nonhematopoietic cell lines. We found that p205 localizes to the nucleus in hematopoietic and nonhematopoietic cell lines. Transient expression of p205 in murine IL-3-dependent BaF3 and 32D-C123 progenitor cell lines inhibited IL-3-induced growth and proliferation. The closely related IFI-200 family members, p204 and p202, similarly inhibited IL-3-dependent progenitor cell proliferation. p205 also inhibited the proliferation and growth of normal hematopoietic progenitor cells. In nonhematopoietic cell lines, p205 and p204 expression inhibited NIH3T3 cell colony formation in vitro, and microinjection of p205 expression vectors into NIH3T3 fibroblasts inhibited serum-induced proliferation. We have determined the functional domains of p205 necessary for activity, which were identified as the N-terminal domain in apoptosis and interferon response (DAPIN)/PYRIN domain, and the C-terminal retinoblastoma protein (Rb)-binding motif. In addition, we have demonstrated that a putative ataxia telangiectasia, mutated (ATM) kinase phosphorylation site specifically regulates the activity of p205. Taken together, these data suggest that p205 is a potent cell growth regulator whose activity is mediated by its protein-binding domains. We propose that during myelomonocytic cell differentiation, induction of p205 expression contributes to cell growth arrest, thus allowing progenitor cells to differentiate. C1 NCI, Basic Res Program, SAIC Frederick Inc, Canc Res Ctr, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Dana Farber Harvard Canc Ctr, Boston, MA USA. Invitrogen Corp, Carlsbad, CA USA. RP Keller, JR (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Canc Res Ctr, Bldg 560,Room 12-03, Frederick, MD 21702 USA. EM kellerj@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 52 TC 13 Z9 15 U1 0 U2 2 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 5 BP 832 EP 848 DI 10.1634/stemcells.22-5-832 PG 17 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 851FE UT WOS:000223670200019 PM 15342947 ER PT J AU Zeng, XM Cai, JL Chen, J Luo, YQ You, ZB Fotter, E Wang, Y Harvey, B Miura, T Backman, C Chen, GJ Rao, MS Freed, WJ AF Zeng, XM Cai, JL Chen, J Luo, YQ You, ZB Fotter, E Wang, Y Harvey, B Miura, T Backman, C Chen, GJ Rao, MS Freed, WJ TI Dopaminergic differentiation of human embryonic stem cells SO STEM CELLS LA English DT Article ID NEURONS IN-VITRO; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; SONIC HEDGEHOG; RAT MODEL; TYROSINE-HYDROXYLASE; NEURAL PRECURSORS; PROGENITOR CELLS; ES CELLS; RECEPTOR AB In this manuscript we report that human embryonic stem cells (hESCs) differentiated into dopaminergic neurons when cocultured with PA6 cells. After 3 weeks of differentiation, approximately 87% of hES colonies contained tyrosine hydroxylase (TH)-positive cells, and a high percentage of the cells in most of the colonies expressed TH. Differentiation was inhibited by exposure to BMP4 or serum. TH-positive cells derived from hESCs were postmitotic, as determined by bromodeoxyurindine colabeling. Differentiated cells expressed other markers of dopaminergic neurons, including the dopamine transporter, aromatic amino acid decarboxylase, and the transcription factors associated with neuronal and dopaminergic differentiation, Sox1, Nurr1, Ptx3, and Lmx1b. Neurons that had been differentiated on PA6 cells were negative for dopamine-p-hydroxylase, a marker of noradrenergic neurons. PA6-induced neurons were able to release dopamine and 3,4-dihydroxphe-hylacetic acid (DOPAC) but not noradrenalin when depolarized by high K+. When transplanted into 6-hydroxydopamine-treated animals, hES-derived dopaminergic cells integrated into the rat striatum. Five weeks after transplantation, surviving TH-positive cells were present but in very small numbers compared with the high frequency of TH-positive cells seen in PA6 coculture. Larger numbers of cells positive for smooth muscle actin, but no undifferentiated ES cells, were present after transplantation. Therefore, hESCs can be used to generate human dopaminergic cells that exhibit biochemical and functional properties consistent with the expected properties of mature dopaminergic neurons. C1 Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, Dev & Plast Sect, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Lab Neurosci, Natl Inst Aging, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Behav Neurosci Branch, Baltimore, MD 21224 USA. NIDA, Dept Hlth & Human Serv, Mol Neuropsychiat Branch, Baltimore, MD USA. RP Zeng, XM (reprint author), Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, Dev & Plast Sect, 333 Cassell Dr, Baltimore, MD 21224 USA. EM xzeng@intra.nida.nih.gov RI backman, cristina/C-1276-2013 NR 52 TC 240 Z9 258 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 6 BP 925 EP 940 DI 10.1634/stemcells.22-6-925 PG 16 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 870XX UT WOS:000225093300007 PM 15536184 ER PT J AU Hematti, P Tuchman, S Larochelle, A Metzger, ME Donahue, RE Tisdale, JF AF Hematti, P Tuchman, S Larochelle, A Metzger, ME Donahue, RE Tisdale, JF TI Comparison of retroviral transduction efficiency in CD34(+) cells derived from bone marrow versus G-CSF-mobilized or G-CSF plus stem cell factor-mobilized peripheral blood in nonhuman primates SO STEM CELLS LA English DT Article ID COLONY-STIMULATING FACTOR; SEVERE COMBINED IMMUNODEFICIENCY; FIBRONECTIN FRAGMENT CH-296; HUMAN BETA-GLOBIN; GENE-TRANSFER; REPOPULATING CELLS; PROGENITOR CELLS; THERAPY; DISEASE; CRISIS AB Hematopoietic stem cells (HSCs) are ideal targets for genetic manipulation in the treatment of several congenital and acquired disorders affecting the hematopoietic compartment. Although G-CSF-mobilized peripheral blood CD34(+) cells are the favored source of hematopoietic stem cells in clinical transplantation, this source of stem cells does not provide meaningful engraftment levels of genetically modified cells compared with G-CSF + stem cell factor (SCF)-mobilized cells in nonhuman primates. Furthermore, the use of G-CSF mobilization can have disastrous consequences in patients with sickle cell disease, a long-held target disorder for HSC-based gene therapy approaches. We therefore conducted a study to compare the levels of genetically modified cells attainable after retroviral transduction of CD34(+) cells collected from a bone marrow (BM) harvest with CD34(+) cells collected from a leukapheresis product after mobilization with G-CSF (n = 3) or G-CSF in combination with SCF (n = 3) in the rhesus macaque autologous transplantation model. Transductions were performed using retroviral vector supernatant on fibronectin-coated plates for 96 hours in the presence of stimulatory cytokines. BM was equal to or better than G-CSF-mobilized peripheral blood as a source of HSCs for retroviral transduction. Although the highest marking observed was derived from G-SCF + SCF-mobilized peripheral blood in two animals, marking in the third originated only from the BM fraction. These results demonstrate that steady-state BM is at least equivalent to G-CSF-mobilized peripheral blood as a source of HSCs for retroviral gene transfer and the only currently available source for patients with sickle cell disease. C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N116,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Johntis@intra.niddk.nih.gov NR 25 TC 13 Z9 14 U1 1 U2 2 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 6 BP 1062 EP 1069 DI 10.1634/stemcells.22-6-1062 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 870XX UT WOS:000225093300019 PM 15536196 ER PT J AU Choi, Y Ta, M Atouf, F Lumelsky, N AF Choi, Y Ta, M Atouf, F Lumelsky, N TI Adult pancreas generates multipotent stem cells and pancreatic and nonpancreatic progeny SO STEM CELLS LA English DT Article ID FIBRILLARY ACIDIC PROTEIN; DEVELOPING MOUSE PANCREAS; HEPATOCYTE GROWTH-FACTOR; IN-VITRO; TRANSCRIPTION FACTORS; DIABETES-MELLITUS; ENDOTHELIAL-CELLS; RADIAL GLIA; BETA-CELLS; DIFFERENTIATION AB Strategies designed to produce functional cells from stem cells or from mature cells hold great promise for treatment of different cell-degenerative diseases. Type 1 and type 2 diabetes are examples of such diseases. Although different in origin, both involve inadequate cell mass of insulin-producing beta cells, the most abundant cell type of pancreatic islets of Langerhans. Practical realization ofsuch strategies is highly dependent on the elucidation of physiological mechanisms responsible for generation of new beta cells in the pancreas, which at this time are poorly defined. The in vitro differentiation systems allowing generation of new beta cells provide a valuable experimental tool for studying these mechanisms. Few such systems are currently available. In this work, we present an in vitro differentiation system, derived from adult mouse pancreas, capable of generating insulin-producing beta-like cells, which self-organize into islet-like cell clusters (ILCCs) during the course of the culture. Surprisingly, we found that along with the ILCCs, multiple cell types with phenotypic characteristics of embryonic central nervous system and neural crest are also generated. Moreover, several embryonic stem cell-specific genes are induced during the course of these cultures. These results suggest that the adult pancreas may contain cells competent to give rise to new endocrine and neural cells. C1 NIDDKD, Islet & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Lumelsky, N (reprint author), NIDDKD, Islet & Autoimmun Branch, NIH, Bldg 10,CRC,Room 5-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM nadyal@intra.niddk.nih.gov NR 65 TC 50 Z9 56 U1 0 U2 0 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 6 BP 1070 EP 1084 DI 10.1634/stemcells.22-6-1070 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 870XX UT WOS:000225093300020 PM 15536197 ER PT J AU Brenner, S Whiting-Theobald, N Kawai, T Linton, GF Rudikoff, AG Choi, U Ryser, MF Murphy, PM Sechler, JMG Malech, HL AF Brenner, S Whiting-Theobald, N Kawai, T Linton, GF Rudikoff, AG Choi, U Ryser, MF Murphy, PM Sechler, JMG Malech, HL TI CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells SO STEM CELLS LA English DT Article DE engraftment; CXCR4; ex vivo gene transfer; hematopoietic stem cells (HSCs) ID BLOOD CD34(+) CELLS; NOD/SCID MICE; CXCR4; MOBILIZATION; SDF-1; PROLIFERATION; REPOPULATION; MIGRATION; VIVO AB Hematopoietic stem cells (HSCs) lose marrow reconstitution potential during ex vivo culture. HSC migration to stromal cell-derived factor (SDF)-1 (CXCL12) correlates with CXC chemokine receptor 4 (CXCR4) expression and marrow engraftment. We demonstrate that mobilized human CD34(+) peripheral blood stem cells (CD34(+) PBSCs) lose CXCR4 expression during prolonged culture. We transduced CD34(+) PBSCs with retrovirus vector encoding human CXCR4 and achieved 18-fold more CXCR4 expression in over 87% of CD34(+) cells. CXCR4-transduced cells yielded increased calcium flux and up to a 10-fold increase in migration to SDF-1. Six-day cultured CXCR4-transduced cells demonstrated significant engraftment in nonobese diabetic/severe combined immunodeficient mice under conditions in which control transduced cells resulted in low or no engraftment. We conclude that transduction-mediated overexpression of CXCR4 significantly improves marrow engraftment of cultured PBSCs. C1 Univ Clin Carl Gustav Carus, Dept Pediat, D-01307 Dresden, Germany. NIAID, Host Def Lab, NIH, Bethesda, MD USA. Jikei Univ, Sch Med, Dept Pediat, Tokyo, Japan. RP Brenner, S (reprint author), Univ Clin Carl Gustav Carus, Dept Pediat, Fetscherstr 74, D-01307 Dresden, Germany. EM Sebastian.Brenner@uniklinikum-dresden.de RI Brenner, Sebastian/D-7456-2013; OI Malech, Harry/0000-0001-5874-5775 NR 13 TC 71 Z9 78 U1 2 U2 2 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 7 BP 1128 EP 1133 DI 10.1634/stemcells.2003-0196 PG 6 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 879ZY UT WOS:000225759300002 PM 15579633 ER PT J AU Downing, GJ Battey, JF AF Downing, GJ Battey, JF TI Technical assessment of the first 20 years of research using mouse embryonic stem cell lines SO STEM CELLS LA English DT Review DE mouse embryonic stem cell; homologous recombination; discovery; technology ID GENETICALLY-ENGINEERED MICE; HUMAN TERATOCARCINOMA CELLS; ADULT SOMATIC-CELLS; ES CELLS; TARGETED DISRUPTION; NUCLEAR TRANSFER; ANIMAL-MODEL; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; CARCINOMA-CELLS AB This review assesses the effect that mouse embryonic stem (ES) cells have had on biomedical research during the 20 years that followed their isolation in 1981. Notable scientific discoveries enabled by these cell lines-including insights into cell cycle regulation, spatial and temporal relationships during development, and the roles of transcription factors and homeobox genes in developmental pathways-are discussed. The acceleration of basic discovery of gene function and the genetic basis of disease using a breakthrough technology (homologous recombination between modified gene constructs and the ES cell genome) became the principal enabling method to establish transgenic laboratory animals with single targeted genetic change. This review also examines the widespread influence of mouse ES cells as an enabling technology by highlighting their effect on drug development paradigms, directed differentiation to treat specific diseases, nuclear transfer protocols used in cloning, and establishment of methodologies for isolating non-rodent ES cells. This review concludes with a brief analysis of the most influential mouse ES cell lines of the first 20 years as viewed within the twin contexts of human disease application and contributions to the primary literature. C1 NCI, Off Technol & Ind Relat, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Downing, GJ (reprint author), NCI, Off Technol & Ind Relat, NIH, Bldg 31,Room 10A-52,MSC 2580,31 Ctr Dr, Bethesda, MD 20892 USA. EM downingg@mail.nih.gov NR 136 TC 38 Z9 40 U1 1 U2 3 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2004 VL 22 IS 7 BP 1168 EP 1180 DI 10.1634/stemcells.2004-0101 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 879ZY UT WOS:000225759300006 PM 15579637 ER PT S AU Mc Kay, R AF Mc Kay, R BE Gage, FH Bjorklund, A Prochiantz, A Christen, Y TI The importance of CNS stem cells in development and disease SO STEM CELLS IN THE NERVOUS SYSTEM: FUNCTIONAL AND CLINICAL IMPLICATIONS SE RESEARCH AND PERSPECTIVES IN NEUROSCIENCES LA English DT Proceedings Paper CT 12th Colloque on Medicine and Research in Neurosciences CY JAN 20, 2003 CL Paris, FRANCE SP Fdn Ipsen ID CENTRAL-NERVOUS-SYSTEM; EXPANDED MESENCEPHALIC PRECURSORS; NUCLEAR RECEPTOR NURR1; HIPPOCAMPAL-NEURONS; PROGENITOR CELLS; DOPAMINE NEURONS; IN-VITRO; NEURAL PROGENITORS; ADULT HIPPOCAMPUS; HUMAN BLASTOCYSTS C1 NIDS, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Mc Kay, R (reprint author), NIDS, Lab Mol Biol, NIH, Bldg 36 RM 5A29,Convent Dr MSC 4157, Bethesda, MD 20892 USA. NR 61 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0945-6082 BN 3-540-20558-6 J9 RES PER NEUROSCI JI Res. Perspect. Neurosci. PY 2004 BP 109 EP 116 PG 8 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA BY95U UT WOS:000189504400008 ER PT J AU Rakocevic, G Lyons, KE Wilkinson, SB Overman, JW Pahwa, R AF Rakocevic, G Lyons, KE Wilkinson, SB Overman, JW Pahwa, R TI Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria SO STEREOTACTIC AND FUNCTIONAL NEUROSURGERY LA English DT Article DE pallidotomy; glutaric aciduria; dystonia; child ID GENERALIZED DYSTONIA AB Glutaric aciduria type 1 is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase. This disorder mainly affects children. The majority of patients develop a dystonic-dyskinetic syndrome. The dystonia is painful and can cause significant disability. This report documents an 18-month-old child, the youngest reported, who underwent pallidotomy for disabling dystonia. The surgery improved dystonic symptoms, especially pain in this child with minor complications related to the procedure. Pallidotomy is a reasonable option for children with dystonic symptoms secondary to glutaric aciduria. Copyright (C) 2004 S. Karger AG, Basel. C1 Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66160 USA. Univ Kansas, Med Ctr, Dept Neurosurg, Kansas City, KS 66103 USA. NINDS, NIH, Bethesda, MD 20892 USA. KU Med Ctr Hosp, Kansas City, KS USA. RP Pahwa, R (reprint author), Univ Kansas, Med Ctr, Dept Neurol, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM rpahwa@kumc.edu NR 12 TC 12 Z9 12 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1011-6125 J9 STEREOT FUNCT NEUROS JI Stereotact. Funct. Neurosurg. PY 2004 VL 82 IS 2-3 BP 80 EP 83 DI 10.1159/000077405 PG 4 WC Neurosciences; Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 846NE UT WOS:000223321600004 PM 15305079 ER PT J AU Marcos, J Guo, LW Wilson, WK Porter, FD Shackleton, C AF Marcos, J Guo, LW Wilson, WK Porter, FD Shackleton, C TI The implications of 7-dehydrosterol-7-reductase deficiency (Smith-Lemli-Opitz syndrome) to neurosteroid production SO STEROIDS LA English DT Article DE neurosteroids; Smith-Lemli-Opitz syndrome; cholesterol biosynthetic disorders; GC/MS ID 7-DEHYDROCHOLESTEROL REDUCTASE GENE; CHROMATOGRAPHY MASS-SPECTROMETRY; DELTA-7-STEROL REDUCTASE; CHOLESTEROL-BIOSYNTHESIS; TISSUE DISTRIBUTION; MOLECULAR-CLONING; MUTATIONS; PLASMA; BRAIN; EXPRESSION AB Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation/mental retardation syndrome with an estimated incidence among individuals of European ancestry of I in 20,000 to 1 in 30,000. It is caused by inactivity of the enzyme 7-dehydrosterol-Delta(7)-reductase, which catalyses the terminal transformation in cholesterol synthesis. Patients show not only an increased level of 7-dehydrocholesterol in blood and tissues, but also increased 8-dehydrocholesterol because of the presence of an active Delta(8)-Delta(7) isomerase. A major consequence of these biochemical abnormalities is the alteration of normal embryonic and fetal somatic development causing postnatal abnormalities of growth, learning, language and behavior. While deficient cholesterol during early development is the primary cause of central nervous system (CNS) abnormalities and retardation, we questioned whether neurosteroids could also be involved since they can have a profound influence on behavioral characteristics. Disordered neurosteroidogenesis would be expected in SLOS and could be caused by a deficiency in classical neurosteroid synthesis secondary to cholesterol deficiency, or by synthesis from 7- and 8-dehydrocholesterol of novel neurosteroids with Delta(7) or Delta(8) unsaturation which may have altered activity compared with conventional neurosteroids. In particular we sought analogues of dehydroepiandrosterone sulfate, pregnenolone sulfate and the pregnanolone epimers. We targeted urine from post-pubertal females, as this type of sample would be most likely to yield identifiable amounts of the pregnanolone metabolites of progesterone. Analysis by GUMS of urinary steroids excreted by post-pubertal females confirmed the presence of neurosteroid-like compounds in SLOS patient's urine. Even though the new neuroactive steroids identified were unlikely to have been formed in the brain, it is likely that mechanisms for their synthesis are operable in this organ. (C) 2003 Elsevier Inc. All rights reserved. C1 Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77005 USA. NICHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Shackleton, C (reprint author), Childrens Hosp Oakland, Res Inst, 5700 Martin Luther Ling Jr Way, Oakland, CA 94609 USA. EM cshackleton@chori.org RI Marcos, Josep/F-3545-2015 OI Marcos, Josep/0000-0002-3624-108X FU NICHD NIH HHS [R03 HD-045302-01, R03 HD-39707] NR 40 TC 34 Z9 34 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD JAN PY 2004 VL 69 IS 1 BP 51 EP 60 DI 10.1016/j.steroids.2003.09.013 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 767VG UT WOS:000188494100006 PM 14715377 ER PT S AU Antani, S Xu, XQ Long, LR Thoma, GR AF Antani, S Xu, XQ Long, LR Thoma, GR BE Yeung, MM Lienhart, RW Li, CS TI Partial shape matching for CBIR of spine x-ray images SO STORAGE AND RETRIEVAL METHODS AND APPLICATIONS FOR MULTIMEDIA 2004 SE PROCEEDINGS OF THE SOCIETY OF PHOTO-OPTICAL INSTRUMENTATION ENGINEERS (SPIE) LA English DT Proceedings Paper CT Conference on Storage and Retrieval Methods and Applications for Multimedia CY JAN 20-22, 2003 CL San Jose, CA DE content-based image retrieval; medical image databases; partial shape matching; procrustes distance ID FOURIER DESCRIPTORS; RETRIEVAL AB Efficient content-based image retrieval (CBIR) of biomedical images is a challenging problem. Feature representation algorithms used in indexing medical images on the pathology of interest have to address conflicting goals of reducing feature dimensionality while retaining important and often subtle biomedical features. In case of the vertebra, its shape effectively describes various pathologies identified by medical experts as being consistently and reliably found in x-rays in the image collection. A suitable shape method must enable retrieval relevant to the pathology in question. An approach to enabling pathology based retrieval is to use partial shape matching techniques. This paper describes our research in the development of such methods and initial retrieval results and related issues. The research is a part of our ongoing effort in developing CBIR for digitized images of a collection of 17,000 cervical and lumbar spine x-rays taken as a part of the second National Health and Nutrition Examination Survey (NHANES II) at the Lister Hill National Center for Biomedical Communications, an intramural R&D division of the U.S. National Library of Medicine. C1 NIH, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20894 USA. RP Antani, S (reprint author), NIH, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20894 USA. OI Antani, Sameer/0000-0002-0040-1387 NR 10 TC 3 Z9 3 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-5210-6 J9 P SOC PHOTO-OPT INS PY 2004 VL 5307 BP 1 EP 8 PG 8 WC Computer Science, Artificial Intelligence; Imaging Science & Photographic Technology SC Computer Science; Imaging Science & Photographic Technology GA BY64A UT WOS:000189427700001 ER PT S AU Ingram, DK Anson, RM de Cabo, R Mamczarz, J Zhu, M Mattison, J Lane, MA Roth, GS AF Ingram, DK Anson, RM de Cabo, R Mamczarz, J Zhu, M Mattison, J Lane, MA Roth, GS BE DeGrey, ADN TI Development of calorie restriction mimetics as a prolongevity strategy SO STRATEGIES FOR ENGINEERED NEGLIGIBLE SENESCENCE: WHY GENUINE CONTROL OF AGING MAY BE FORESEEABLE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 10th Congress of the International-Association-of-Biomedical-Gerontology CY SEP 19-23, 2003 CL Cambridge, ENGLAND SP Int Assoc Biomed Gerontol DE metabolism; body temperature; stroke; MPTP; 2-deoxyglucose; metformin; insulin ID PROTECTS HIPPOCAMPAL-NEURONS; DIETARY RESTRICTION; LIFE-SPAN; STRESS RESISTANCE; DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; OXIDATIVE INJURY; RHESUS-MONKEYS; BRAIN-DAMAGE; LONGEVITY AB By applying calorie restriction (CR) at 30-50% below ad libitum levels, studies in numerous species have reported increased life span, reduced incidence and delayed onset of age-related diseases, improved stress resistance, and decelerated functional decline. Whether this nutritional intervention is relevant to human aging remains to be determined; however, evidence emerging from CR studies in nonhuman primates suggests that response to CR in primates parallels that observed in rodents. To evaluate CR effects in humans, clinical trials have been initiated. Even if evidence could substantiate CR as an effective antiaging strategy for humans, application of this intervention would be problematic due to the degree and length of restriction required. To meet this challenge for potential application of CR, new research to create "calorie restriction mimetics" has emerged. This strategy focuses on identifying compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. Microarray studies show that gene expression profiles of key enzymes in glucose (energy) handling pathways are modified by CR. Drugs that inhibit glycolysis (2-deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicity, enhanced dopamine action, and upregulated brain-derived neurotrophic factor. Further life span analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic, but this strategy now appears to offer a very promising and expanding research field. C1 NIA, Lab Expt Gerontol, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Ingram, DK (reprint author), NIA, Lab Expt Gerontol, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ingramd@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 63 TC 127 Z9 134 U1 0 U2 14 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-496-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1019 BP 412 EP 423 DI 10.1196/annals.1297.074 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Geriatrics & Gerontology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Cell Biology; Geriatrics & Gerontology; Science & Technology - Other Topics GA BAN77 UT WOS:000223002700074 PM 15247056 ER PT S AU Urbanski, HF Downs, JL Garyfallou, VT Mattison, JA Lane, MA Roth, GS Ingram, DK AF Urbanski, HF Downs, JL Garyfallou, VT Mattison, JA Lane, MA Roth, GS Ingram, DK BE DeGrey, ADN TI Effect of caloric restriction on the 24-hour plasma DHEAS and cortisol profiles of young and old male rhesus macaques SO STRATEGIES FOR ENGINEERED NEGLIGIBLE SENESCENCE: WHY GENUINE CONTROL OF AGING MAY BE FORESEEABLE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 10th Congress of the International-Association-of-Biomedical-Gerontology CY SEP 19-23, 2003 CL Cambridge, ENGLAND SP Int Assoc Biomed Gerontol DE dehydroepiandrosterone sulfate; adrenal gland; primate ID DIETARY RESTRICTION; MONKEYS; PRIMATE AB Although dietary caloric restriction (CR) can retard aging in laboratory rats and mice, it is unclear whether CR can exert similar effects in long-lived species, such as primates. Therefore, we tested the effect of CR on plasma levels of dehydroepiandrosterone sulfate (DHEAS), a reliable endocrine marker of aging. The study included six young (similar to10 years) and ten old (similar to25 years) male rhesus macaques, approximately half of the animals in each age group having undergone >4 years of 30% CR. Hourly blood samples were collected remotely for 24 hours, through a vascular catheter, and assayed for DHEAS and cortisol. Both of these adrenal steroids showed a pronounced diurnal plasma pattern, with peaks occurring in late morning, but only DHEAS showed an aging-related decline. More importantly, there was no significant difference in plasma DHEAS concentrations between the CR animals and age-matched controls. These data fail to support the hypothesis that CR can attenuate the aging-related decline in plasma DHEAS concentrations, at least not when initiated after puberty. C1 Oregon Natl Reg Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Urbanski, HF (reprint author), Oregon Natl Reg Primate Res Ctr, Div Neurosci, 505 NW 185th Ave, Beaverton, OR 97006 USA. EM urbanski@ohsu.edu FU NCRR NIH HHS [RR-14451, RR-00163]; NIA NIH HHS [AG-19914] NR 11 TC 23 Z9 25 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-496-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1019 BP 443 EP 447 DI 10.1196/annals.1297.081 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Geriatrics & Gerontology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Cell Biology; Geriatrics & Gerontology; Science & Technology - Other Topics GA BAN77 UT WOS:000223002700081 PM 15247063 ER PT S AU Zhu, M de Cabo, R Lane, MA Ingram, DK AF Zhu, M de Cabo, R Lane, MA Ingram, DK BE DeGrey, ADN TI Caloric restriction modulates early events in insulin signaling in liver and skeletal muscle of rat SO STRATEGIES FOR ENGINEERED NEGLIGIBLE SENESCENCE: WHY GENUINE CONTROL OF AGING MAY BE FORESEEABLE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 10th Congress of the International-Association-of-Biomedical-Gerontology CY SEP 19-23, 2003 CL Cambridge, ENGLAND SP Int Assoc Biomed Gerontol DE caloric restriction; aging; insulin signaling pathway; PTP-1B ID PROTEIN-TYROSINE PHOSPHATASE-1B; RECEPTOR; SENSITIVITY; OBESITY; MICE AB Mutations that extend life span in C elegans suggest that the insulin/IGF-1 signaling (IS) pathway may play a key role in retarding aging and extending life span by caloric restriction (CR). To evaluate this hypothesis, male rats were subjected to either AL (ad libitum) or CR (40% from AL) for 2 and 25 months, and then the effects of CR on the early events in the IS pathway in liver and muscle were assessed. The results indicated that aging was accompanied by a significant decline in insulin receptor tyrosine phosphorylation (pY-IR) upon insulin stimulation in both tissues, which was correlated with a significant increase in the activity of protein tyrosine phosphatase 1B (PTP-1B). However, these alterations with age were attenuated by 25CR. Parallel changes observed in liver mRNA of CR rats were upregulated insulin receptor (1R), IGF-1R and IRS-1, but increased expression of IR mRNA was dissociated with the IR protein in 25CR rats. The expression of liver mRNAs involved in lipid metabolism was also analyzed. In contrast to 25AL rats, the expression of mRNAs for PPARs (alpha, beta, and gamma) was significantly increased in 25CR rats. SREBP-1c and fatty acid synthase were reduced, and other genes were increased, including hormone-sensitive lipase and PGC-1 by CR. The data suggest that the normal function of insulin receptor in liver and muscle is required for successful aging. An altered expression of transcription of a number of genes involved in lipid metabolism may also contribute to modulation of the IS pathway by CR. C1 NIA, Gerontol Res Ctr, Lab Expt Gerontol, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Ingram, DK (reprint author), NIA, Gerontol Res Ctr, Lab Expt Gerontol, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM doni@vax.grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 11 TC 11 Z9 12 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-496-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1019 BP 448 EP 452 DI 10.1196/annals.1297.082 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Geriatrics & Gerontology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Cell Biology; Geriatrics & Gerontology; Science & Technology - Other Topics GA BAN77 UT WOS:000223002700082 PM 15247064 ER PT S AU Palkovits, M Dobolyi, A Helfferich, F Usdin, TB AF Palkovits, M Dobolyi, A Helfferich, F Usdin, TB BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Localization and chemical characterization of the audiogenic stress pathway SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE audiogenic stress; c-fos; tract-tracing; double immunostaining ID TUBEROINFUNDIBULAR PEPTIDE; HYPOTHALAMUS; RATS; NEUROENDOCRINE; CONNECTIONS; ACTIVATION; EXPRESSION; RESPONSES; INDUCTION; RESIDUES AB Neuronal pathways involved in stress responses to extreme somatosensory stimuli were investigated by immunostaining, viral tract tracing, and experimental brain surgery in rats. Acute audiogenic stress, which elicits an immediate marked elevation in plasma ACTH and corticosterone concentrations, was used as a model. Loud noise (105 dB, 30 min) elicited c-fos activation within neurons in all of the components of the auditory system and stress-sensitive brain nuclei, including corticotropin-releasing hormone-synthesizing parvicellular neurons in the hypothalamic paraventricular nucleus (PVN). c-Fos activation was also seen in the medial paralemniscal nucleus in the pons (MPL) and in the subparafascicular nucleus (SPF) in the midbrain. After injection of neurotropic virus (pseudorabies, Bartha strain) into the PVN, neurons in the MPL and the parvicellular portion of the SPF were retrogradely infected. It has been shown by immunostaining that MPL and SPF neurons express a newly discovered neuropeptide, tuberoinfundibular peptide of 39 residues (TIP39). TIP39 is present in a fine neuronal network in the PVN. Audiogenic stress-elicited c-fos activation in TIP39-containing neurons of the MPL and SPF. TIP39 immunoreactivity disappeared from the PVN after transection of MPL and SPF projections to the nucleus. These observations suggest that TIP39-containing MPL and SPF neurons may participate in mediating audiogenic stress responses. C1 Semmelweis Univ, Dept Anat, Neuromorphol Lab, H-1094 Budapest, Hungary. Hungarian Acad Sci, Neuromorphol Lab, Budapest, Hungary. NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Palkovits, M (reprint author), Semmelweis Univ, Dept Anat, Neuromorphol Lab, Tuzolto 58, H-1094 Budapest, Hungary. EM palkovits@ana.sote.hu RI Dobolyi, Arpad/B-9089-2008; Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 NR 12 TC 19 Z9 19 U1 1 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 16 EP 24 DI 10.1196/annals.1296.002 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800002 PM 15240348 ER PT S AU Saavedra, JM Ando, H Armando, I Baiardi, G Bregonzio, C Jezova, M Zhou, J AF Saavedra, JM Ando, H Armando, I Baiardi, G Bregonzio, C Jezova, M Zhou, J BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Brain angiotensin II, an important stress hormone: Regulatory sites and therapeutic opportunities SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE renin-angiotensin system; angiotensin II receptor types; AT(1) receptors; paraventricular nucleus; restraint stress; isolation stress; stress disorders ID PARAVENTRICULAR NUCLEUS; SUBFORNICAL ORGAN; RECEPTOR SUBTYPES; BINDING-SITES; RAT-BRAIN; PITUITARY; EXPRESSION; RESTRAINT; FOREBRAIN; INCREASES AB The presence of a brain Angiotensin II (Ang II) system, separated from and physiologically integrated with the peripheral, circulating renin-angiotensin system, is firmly established. Ang II is made in the brain and activates specific brain AT(1) receptors to regulate thirst and fluid metabolism. Some AT(1) receptors are located outside the blood-brain barrier and are sensitive to brain and circulating Ang II. Other AT(1) receptors, located inside the blood-brain barrier, respond to stimulation by Ang II of brain origin. AT(1) receptors in the subfornical organ, the hypothalamic paraventricular nucleus (PVN), and the median eminence are involved in the regulation of the stress response. In particular, AT(1) receptors in the PVN are under glucocorticoid control and regulate corticotrophin-releasing hormone (CRH) formation and release. In the PVN, restraint elicits a fast increase in AT(1) receptor mRNA expression. The expression of paraventricular AT(1) receptors is increased during repeated restraint and after 24 h of isolation stress, and their stimulation is essential for the hypothalamic-pituitary-adrenal axis activation, the hallmark of the stress response. Peripheral administration of an AT(1) receptor antagonist blocks peripheral and brain AT(1) receptors, prevents the sympathoadrenal and hormonal response to isolation stress, and prevents the gastric stress ulcers that are a characteristic consequence of cold-restraint stress. This evidence indicates that pharmacologic inhibition of the peripheral and brain Ang II system by AT(1) receptor blockade has a place in the prevention and treatment of stress-related disorders. C1 NIMH, Pharmacol Sect, DIRP, DHHS,NIH, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, DIRP, DHHS,NIH, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@intra.nimh.nih.gov NR 25 TC 34 Z9 35 U1 1 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 76 EP 84 DI 10.1196/annals.1296.009 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800009 PM 15240355 ER PT S AU Tjurmina, OA Armando, I Saavedra, JM Li, Q Murphy, DL AF Tjurmina, OA Armando, I Saavedra, JM Li, Q Murphy, DL BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Life-long serotonin reuptake deficiency results in complex alterations in adrenomedullary responses to stress SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE epinephrine; TH mRNA; Angiotensin II receptors; serotonin; SERT deficiency; stress ID ANGIOTENSIN-II AT(1); BINDING-SITES; TRANSPORTER; BRAIN; MICE; RECEPTORS AB This study examined whether serotonin transporter (SERT) deficiency influences adrenal serotonin (5-HT), catecholamine and Angiotensin II (Ang II) systems, and the hormonal response to acute restraint stress. Control SERT mice (+/+) expressed high numbers of SERT binding sites in adrenal medulla. Fifteen minutes of restraint stress increased adrenal 5-HT, adrenomedullary tyrosine hydroxylase (TH) mRNA expression and plasma epinephrine (EPI), and norepinephrine levels without alterations in adrenal catecholamine content. In SERT+/+, these responses coincided with a significant increase in adrenomedullary Ang II AT(2) receptor expression. SERT-deficient mice did not express SERT binding sites; their adrenal 5-HT was significantly depleted and further reduced after stress. They had exaggerated stress-induced EPI release into plasma, the increase in TH transcription did not occur, adrenal catecholamine content was decreased compared with SERT+/+, and stress induced a reduction rather than increase in the number of adrenomedullary AT(2) receptors. SERT-/- mice also possessed decreased pituitary 5-HT. Their pituitary ACTH was reduced after stress, but stress-induced increases in plasma ACTH and corticosterone were not different from those of SERT+/+ mice. Our results indicate that SERT function not only restrains stress-induced EPI release but also is required for the increase in adrenal catecholamine synthesis and AT(2) receptor expression. C1 NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NIMH, Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Tjurmina, OA (reprint author), NIMH, Clin Sci Lab, NIH, Bldg 10,Rm 3D41,10 Ctr Dr, Bethesda, MD 20892 USA. EM ot3d@nih.gov NR 14 TC 18 Z9 19 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 99 EP 104 DI 10.1196/annals.1296.011 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800011 PM 15240357 ER PT S AU Baiardi, G Bregonzio, C Jezova, M Armando, I Saavedra, JM AF Baiardi, G Bregonzio, C Jezova, M Armando, I Saavedra, JM BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Angiotensin II AT(1) receptor blockade prolongs the lifespan of spontaneously hypertensive rats and reduces stress-induced release of catecholamines, glucocorticoids, and vasopressin SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE isolation stress; angiotensin AT(1) receptors; catecholamines; corticosterone; SHR ID RESPONSES; AGE AB A 2-week pretreatment with an Angiotensin II AT(1) antagonist prevented the adrenomedullary and hormonal response to isolation stress. We studied the effect of life-long treatment with the AT(1) receptor antagonist candesartan, 10 mg/kg/day, or vehicle administered orally in the drinking water from 8 weeks of age on the response to stress of stress-sensitive spontaneously hypertensive rats (SHRs) and their normotensive controls, the Wistar Kyoto (WKY). Rats were submitted to 24-h isolation stress at different times during the treatment. Treatment with candesartan extended the lifespan of SHRs. AT(1) receptor blockade retained its capacity to blunt the response to isolation stress over a long period of treatment. The AT, antagonist inhibited epinephrine release in SHR but not in WKY rats during the first 3 months, corticosterone release in SHR and WKY rats during 10 months, and vasopressin release in SHR rats during 18 months of treatment when rats were submitted to isolation stress. There were no changes in vasopressin release in WKY rats during stress or after AT(1) receptor blockade. We conclude that the blockade of the stress response by the AT I receptor antagonist is long lasting and differs between stressprone SHR and WKY rats and that the specific components of the stress response (sympathoadrenal activity, hypothalamic-pituitary-adrenal axis activation, and vasopressin release) react differently to AT(1) receptor blockade. The long-term protective effects of AT(1) receptor blockade can be important in animals vulnerable to stress and, in conjunction with the normalization of blood pressure, can prolong lifespan through end-organ protection. C1 NIMH, Pharmacol Sect, NIH, DHHS, Bethesda, MD 20892 USA. RP Baiardi, G (reprint author), NIMH, Pharmacol Sect, NIH, DHHS, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM baiardig@intra.nimh.nih.gov NR 9 TC 16 Z9 17 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 131 EP 136 DI 10.1196/annals.1296.015 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800015 PM 15240361 ER PT S AU Eisenhofer, G Kopin, IJ Goldstein, DS AF Eisenhofer, G Kopin, IJ Goldstein, DS BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Leaky catecholamine stores: Undue waste or a stress response coping mechanism? SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE catecholamine turnover; metabolism; release; synthesis; vesicular leakage; vesicular monoamine transporters; tyrosine hydroxylase; exercise ID TYROSINE-HYDROXYLASE; NOREPINEPHRINE; DIHYDROXYPHENYLGLYCOL; METABOLISM; DISPOSITION; STIMULATION; EXERCISE; HUMANS; HEART; RAT AB Turnover of catecholamines, representing the constant loss and replenishment of neurotransmitter by synthesis, is usually considered to be driven exclusively by catecholamine release. This is incorrect. An important contribution of intraneuronal metabolism of norepinephrine to turnover, and dependence of this on leakage of norepinephrine from vesicular stores, was originally proposed by Kopin in 1964. Several years later, Maas and colleagues concluded that at least 75 % of norepinephrine turnover is due to intraneuronal metabolism without prior release at sympathetic nerve endings. More recently it was shown in the resting human heart that about 12% of norepinephrine turnover is due to extraneuronal uptake and metabolism or loss of the transmitter to the circulation, 15% is due to intraneuronal metabolism after re-uptake, and 73 % is due to intraneuronal metabolism of norepinephrine leaking from storage vesicles. Thus, contrary to usual depictions, vesicular stores of catecholamines do not exist in a static state simply waiting for exocytotic release. Rather, these stores exist in a highly dynamic equilibrium with the surrounding cytoplasm, with passive outward leakage of amines counterbalanced by inward active transport under the control of vesicular monoamine transporters. The large contribution of leakage to catecholamine turnover may seem inconsistent with cellular economy. In fact, this contribution provides an important mechanism for "gearing down" the requirement for increases in catecholamine synthesis to match increases in catecholamine release, and thereby provides sympathetic nerves with a capacity for a more extended range of sustainable release rates in response to stress than would otherwise be possible. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Eisenhofer, G (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM ge@box-g.nih.gov NR 14 TC 23 Z9 23 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 224 EP 230 DI 10.1196/annals.1296.027 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800027 PM 15240373 ER PT S AU Goldstein, DS AF Goldstein, DS BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Functional neuroimaging of sympathetic innervation of the heart SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE sympathetic; multiple system atrophy; Parkinson disease; autonomic failure; norepinephrine; dysautonomia ID IDIOPATHIC DILATED CARDIOMYOPATHY; CARDIAC NEURONAL FUNCTION; MULTIPLE SYSTEM ATROPHY; ACUTE MYOCARDIAL-INFARCTION; NEUROGENIC ORTHOSTATIC HYPOTENSION; PARKINSONS-DISEASE; AUTONOMIC FAILURE; I-123 METAIODOBENZYLGUANIDINE; ESSENTIAL-HYPERTENSION; DIABETIC-PATIENTS AB Many concepts about acute and chronic effects of stress depend on alterations in sympathetic nerves supplying the heart. Physiologic, pharmacologic, and neurochemical approaches have been used to evaluate cardiac sympathetic function. This article describes a fourth approach that is based on nuclear scanning to visualize cardiac sympathetic innervation and function and relationships between the neuroimaging findings and those from other approaches. Multiple-system atrophy with orthostatic hypotension (formerly the Shy-Drager syndrome) features normal cardiac sympathetic innervation and normal entry of norepinephrine into the coronary sinus (cardiac norepinephrine spillover), in contrast to Parkinson disease with orthostatic hypotension, which features neuroimaging and neurochemical evidence for loss of cardiac sympathetic nerves. This difference may have important implications not only for diagnosis but also for understanding the etiology of Parkinson disease. By analysis of curves relating myocardial radioactivity with time (time-activity curves) after injection of a sympathoneural imaging agent, it is possible to obtain information about cardiac sympathetic function. Abnormal time-activity curves are seen in common disorders such as heart failure and diabetic neuropathy and provide an independent, adverse prognostic index. Analogous abnormalities might help explain increased cardiovascular risk in psychiatric disorders such as melancholic depression. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov NR 114 TC 9 Z9 9 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 231 EP 243 DI 10.1196/annals.1296.028 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800028 PM 15240374 ER PT S AU Kaplan, BB Lavina, ZS Gioio, AE AF Kaplan, BB Lavina, ZS Gioio, AE BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Subcellular Compartmentation of neuronal protein synthesis: New insights into the biology of the neuron SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE protein synthesis; synaptosomes; axons; polyribosomes; novel mRNAs; nuclear-encoded mitochondrial mRNAs; cytoskeleton; squid ID SQUID GIANT-AXON; MESSENGER-RNA; GROWTH CONES; SYMPATHETIC NEURONS; ACTIVE POLYSOMES; BETA-TUBULIN; LOCALIZATION; DENDRITES; TRANSPORT; PHOSPHORYLATION AB During the past few years, it has become well established that the distal structural/functional domains of the neuron contain numerous mRNAs. However, there is a paucity of information on the composition and function of these unique mRNA populations. In this article, we review recent evidence to support the hypothesis that protein synthesis occurs in multiple subcellular compartments in the neuron, to include the axon and presynaptic nerve terminal. The studies we describe use the squid giant axon and photoreceptor neuron as model invertebrate motor and sensory systems, respectively. Initial cell-free translation studies and molecular hybridization analysis established that the giant axon contained a heterogeneous population of polyadenylated mRNAs. The application of differential mRNA display methodology greatly facilitated the isolation and identification of 29 of these mRNAs, which encode cytoskeletal proteins, molecular motors, translation factors, various nuclear-encoded mitochondrial mRNAs, and several novel mRNA species. RT-PCR analysis of RNA from squid brain synaptosomes confirmed the presence of these mRNAs in the presynaptic nerve terminal. The presence of these mRNAs in polysomes purified from the synaptosomal fraction establish that these messengers are actively translated in the terminal. Results of in vitro labeling studies demonstrate that a significant fraction of the nuclear-encoded mitochondrial protein derives from the local synthesis in the terminal. This finding calls attention to the intimacy of the relationship that has evolved between the nerve terminal and its energy-generating system. The role that local protein synthesis might play in the mammalian nervous system and in the neuronal response to stress is discussed. C1 NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kaplan, BB (reprint author), NIMH, Mol Biol Lab, NIH, 10 Ctr Dr,Rm 4N222, Bethesda, MD 20892 USA. EM barry.kaplan@nih.gov NR 30 TC 12 Z9 12 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 244 EP 254 DI 10.1196/annals.1296.029 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800029 PM 15240375 ER PT S AU Volpi, S Rabadan-Diehl, C Aguilera, G AF Volpi, S Rabadan-Diehl, C Aguilera, G BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Regulation of vasopressin V1b receptors and stress adaptation SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE vasopressin V1b receptor (V1bR) gene; V1bR regulation; transcription; translation ID TRANSCRIPTIONAL REGULATION; GAGA BOX; GENE; EXPRESSION; TRANSLATION; PROMOTER; RESPONSIVENESS; INVOLVEMENT; INITIATION; SECRETION AB Vasopressin (VP) regulates pituitary corticotroph function by acting upon plasma membrane G-protein receptors of the V1b subtype (V1bR), coupled to calcium-phospholipid signaling. The number of these receptors in the anterior pituitary varies during stress in direct correlation with corticotroph responsiveness, suggesting that the V1bR plays an important role during adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to stress. The molecular regulation of pituitary V1bR involves transcriptional and translational mechanisms. V1bR gene transcription, which is necessary to maintain V1bR mRNA levels, depends on a number of responsive elements in the promoter region, of which the stretch of GA repeats near the transcription start point (GAGA box) is essential. Although transcriptional activation is necessary to maintain V1bR mRNA levels, the lack of correlation between VP binding and V1bR mRNA suggests that V1bR content is mainly regulated at the translational level. Two potential mechanisms by which the 5' untranslated region (5'UTR) of the V1bR mediates negative and positive regulation of V1bR translation were identified. This includes the repressor effect of small open reading frames (ORF) present upstream of the main V1bR ORF, and an internal ribosome entry site (IRES), which activates V1bR translation. The existence of multiple loci of regulation for the V1bR at transcriptional and translational levels provides a mechanism to facilitate plasticity of regulation of the number of pituitary vasopressin receptors according to physiological demand. C1 NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10,Rm 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. EM greti@helix.nih.gov NR 36 TC 20 Z9 21 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 293 EP 301 DI 10.1196/annals.1296.035 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800035 PM 15240381 ER PT S AU Armando, I Jezova, M Bregonzio, C Baiardi, G Saavedra, JM AF Armando, I Jezova, M Bregonzio, C Baiardi, G Saavedra, JM BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Angiotensin II AT(1) and AT(2) receptor types regulate basal and stress-induced adrenomedullary catecholamine production through transcriptional regulation of tyrosine hydroxylase SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE renin-angiotensin system; Angiotensin II receptor types; AT(1) receptors; AT(2) receptors; tyrosine hydroxylase; transcription factors ID MEDULLARY CHROMAFFIN CELLS; PITUITARY-ADRENAL RESPONSE; IMMOBILIZATION STRESS; GENE-EXPRESSION; ACTIVATION; ELEMENT; BRAIN; PHOSPHORYLATION; FRA-2 AB The sympathoadrenal response to stress includes a profound increase in adrenomedullary catecholamine synthesis driven by stimulation of tyrosine hydroxylase (TH) transcription. We studied the role of Angiotensin 11 type 1 and 2 (AT(1) and AT(2)) receptors during isolation stress, and under basal conditions. Pretreatment of rats with the AT(1) receptor antagonist candesartan for 14 days prior to isolation completely prevented the stress-induced stimulation of catecholamine synthesis, decreasing tyrosine hydroxylase transcription by preventing the expression of the transcriptional factor, Fos-related antigen 2 (Fra-2). In addition, AT(1) receptor antagonism prevented the stress-induced increase in adrenomedullary AT(2) receptor binding and protein. Treatment of non-stressed, grouped animals under basal conditions with the AT(1) receptor or with PD 123319, an AT(2) receptor antagonist, decreased the adrenomedullary norepinephrine (NE) content and TH transcription. While AT(1) receptor antagonism decreased the levels of Fra-2 and the phosphorylated forms of cAMP responsive element binding protein (pCREB) and EKR2 (p-ERK2, phosphor-p42 MAP kinase), the AT(2) antagonist decreased Fra-2 with no change in the phosphorylation of CREB or EKR2. Our results demonstrate that both adrenomedullary AT(1) and AT(2) receptor types maintain and promote the adrenomedullary catecholamine synthesis and the transcriptional regulation of TH. Instead of opposing effects, however, our results indicate a complex synergistic regulation between the AT(1) and AT(2) receptor types. C1 NIMH, Pharmacol Sect, DIRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Armando, I (reprint author), NIMH, Pharmacol Sect, DIRP, NIH,DHHS, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM ArmandoI@intra.nimh.nih.gov NR 25 TC 22 Z9 28 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 302 EP 309 DI 10.1196/annals.1296.036 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800036 PM 15240382 ER PT S AU Ando, H Jezova, M Zhou, J Saavedra, JM AF Ando, H Jezova, M Zhou, J Saavedra, JM BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Angiotensin II AT(1) receptor blockade decreases brain artery inflammation in a stress-prone rat strain SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE angiotensin II AT(1) receptor; inflammation; brain microvessels; stress; eNOS; ICAM-1; macrophages ID SPONTANEOUSLY HYPERTENSIVE-RATS; ISCHEMIA; INJURY; PATHOGENESIS; MICROVESSELS; ANTAGONIST; EXPRESSION AB The spontaneously hypertensive rats (SHR) are a genetically hypertensive strain with vulnerability to brain ischemia and stress. In SHR, the brain Angiotensin 11 (Ang 11) system is chronically stimulated, resulting in brain artery remodeling and inflammation. Pretreatment with Ang II AT(1) receptor antagonists protects from brain ischemia and prevents the hormonal and sympathoadrenal response to stress. In addition, the anti-inflammatory effects of AT(1) receptor antagonists are partially responsible for preventing the development of stress-induced gastric ulcers. We asked whether AT(1) receptor antagonists could exert anti-inflammatory effects in the brain vasculature as a mechanism for their protective effects against ischemia. As determined by immunohistochemistry, long-term inhibition of brain AT(1) receptors by peripheral administration of the AT(1) receptor antagonist candesartan (0.3 mg/kg/day for 28 days) normalized the pathologic remodeling, decreased expression of the intercellular adhesion molecule-1 and the number of associated macrophages, and normalized the endothelial nitric oxide synthase expression in cerebral vessels of SHR. The anti-inflammatory effects of AT(1) receptor antagonists may be an important mechanism for protection against ischemia and could participate in the anti-stress properties of this class of compounds. C1 NIMH, Pharmacol Sect, DIRP, DHHS, Bethesda, MD 20892 USA. RP Ando, H (reprint author), NIMH, Pharmacol Sect, DIRP, DHHS, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@irp.nimh.nih.gov NR 12 TC 14 Z9 14 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 345 EP 350 DI 10.1196/annals.1296.043 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800043 PM 15240389 ER PT S AU Bregonzio, C Armando, I Ando, H Jezova, M Baiardi, G Saavedra, JM AF Bregonzio, C Armando, I Ando, H Jezova, M Baiardi, G Saavedra, JM BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Angiotensin II AT(1) receptor blockade prevents gastric ulcers during cold-restraint stress SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE stress ulcers; prevention and treatment; inflammation; angiotensin II receptors; AT(1) receptor antagonists ID HYPERTENSIVE RATS; INJURY; ANTAGONIST; ACTIVATION AB Cold-restraint stress reduces gastric blood flow and produces acute gastric ulcers. We studied the role of Angiotensin 11 (Ang 11) on gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats, a stress-sensitive strain, were pretreated for 14 days with the AT(1) receptor antagonist candesartan before cold-restraint stress. AT(1) blockade increased gastric blood flow 40 % to 50 %; prevented gastric ulcer formation by 70 % to 80 %; reduced the increase in adrenomedullary epinephrine and TH mRNA without preventing the stress-induced increase in adrenal corticosterone; decreased the stress-induced expression of tumor necrosis factor alpha (TNF-alpha) and adhesion protein ICAM-1 in arterial endothelium, and neutrophil infiltration in the gastric mucosa; and decreased PGE(2) content. AT(1) receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, anti-inflammatory effects with reduction in TNF-a, and ICAM-1 expression, leading to reduced neutrophil infiltration while maintaining the protective glucocorticoid effects and PGE(2) release. Ang 11 has a crucial role, through stimulation of AT(1) receptors, in the production and progression of stress-induced gastric injury, and AT(1) receptor antagonists could be of therapeutic benefit. C1 NIMH, Pharmacol Sect, DIRP, DHHS,NIH, Bethesda, MD 20892 USA. RP Bregonzio, C (reprint author), NIMH, Pharmacol Sect, DIRP, DHHS,NIH, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Bregonzc@intra.nimh.nih.gov NR 15 TC 21 Z9 21 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 351 EP 355 DI 10.1196/annals.1296.044 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800044 PM 15240390 ER PT S AU Pfeifer, K Boe, SP Rong, Q Ebert, SN AF Pfeifer, K Boe, SP Rong, Q Ebert, SN BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Generating mouse models for studying the function and fate of intrinsic cardiac adrenergic cells SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE dopamine-beta-hydroxylase; phenylethanolamine N-methyltransferase; green fluorescent protein gene ID PHENYLETHANOLAMINE N-METHYLTRANSFERASE; EMBRYONIC RAT-HEART; INNERVATION; EXPRESSION; SYSTEM AB Embryos lacking the ability to synthesize epinephrine and norepinephrine die (probably due to cardiac failure) without exogenous supplementation while mutant neonates can grow into fertile adults without supplementation. These experiments define a critical period during embryogenesis, when norepinephrine and/or epinephrine are essential for mouse development. The critical period is prior to sympathetic innervation of the heart and prior to synthesis of catecholamines by the adrenal medullae. Recent work indicates that the developing heart is likely to be a major source of catecholamines in the developing mammalian embryo. The spatial pattern of biosynthetic enzymes suggests an association of the intrinsic cardiac adrenergic cells with the developing pacemaker and cardiac conduction cells. To address the functional characteristics and the fate of these cardiac adrenergic cells, we have developed two mouse models that allow us to identify and to characterize the adrenergic cells and their descendants. C1 NICHHD, Lab Mamalian Genes & Dev, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. RP Pfeifer, K (reprint author), Bldg 6B,Room 206,9000 Rockville Pike, Bethesda, MD 20892 USA. EM pfeiferk@mail.nih.gov OI Pfeifer, Karl/0000-0002-0254-682X NR 11 TC 7 Z9 7 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 418 EP 423 DI 10.1196/annals.1296.051 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800051 PM 15240397 ER PT S AU Zhou, J Jezova, M Elkahloun, AG Saavedra, JM AF Zhou, J Jezova, M Elkahloun, AG Saavedra, JM BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Angiotensin II AT(1) receptor antagonism downregulates stress-related gene expression in brain microvessels from spontaneously hypertensive and normotensive rats SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE angiotensin II; AT(1) receptor antagonists; DNA microarray; brain microvessels; gene transcription; stress-related genes ID CELLS AB We studied the effect of treatment with the Angiotensin II AT(1) receptor antagonist candesartan (0.3 mg/kg/day via osmotic minipumps for 4 weeks compared with administration of vehicle) in brain microvessels in adult spontaneously hypertensive rats (SHR) that were vulnerable to stroke and normotensive control rats (WKY). At the dose administered, candesartan normalized blood pressure in SHR without significantly affecting blood pressure in WKY rats. We performed the gene expression analysis in rat brain microvessels using the Affymetrix Gene Chip Expression Analysis Technique. From a total of 8,799 probe array sets analyzed, we found abundant abnormalities in gene expression in SHR. Because stress has been suggested as a precipitant factor in brain ischemia and treatment with AT(1) receptor antagonist candesartan prevents the hormonal and sympathoadrenal reaction to isolation stress and protects from stress-induced gastric ulcers, we focused on the expression of stress-related genes. We found a higher number of probe array sets modified by candesartan treatment in normotensive WKY rats than in hypertensive SHR. AT(1) receptor blockade decreased the transcription levels of the stress-related tyrosine kinase receptor, stathmin, and fibroblast growth receptor genes in WKY and SHR rats. Our results indicate that Angiotensin II and its AT(1) receptors can influence gene expression independently of the effects on blood pressure. In addition, AT(1) receptor regulation of stress-related genes in brain microvessels may explain the proposed association between stress and ischemic disorders of the brain. C1 NIMH, Pharmacol Sect, DIRP, NIH,DHHS, Bethesda, MD 20892 USA. NHGRI, Microarray Unit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Zhou, J (reprint author), NIMH, Pharmacol Sect, DIRP, NIH,DHHS, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D57, Bethesda, MD 20892 USA. EM zhouj@intra.nimh.nih.gov NR 12 TC 4 Z9 4 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 480 EP 486 DI 10.1196/annals.1296.059 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800059 PM 15240405 ER PT S AU Eckelman, WC Rice, KC Contoreggi, C AF Eckelman, WC Rice, KC Contoreggi, C BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI New tools to monitor stress using non-invasive PET imaging SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE positron emission tomography; chronic myelogenous leukemia; tyrosine kinase; gastrointestinal stromal tumors; chemotherapy; imaging ID POSITRON-EMISSION-TOMOGRAPHY; GASTROINTESTINAL STROMAL TUMORS; CORTICOTROPIN-RELEASING-FACTOR; MUSCARINIC AGONIST; IMATINIB MESYLATE; ADDICTION; LIGAND; COMPETITION; WAY-100635; BINDING AB Noninvasive imaging using positron emission tomography (PET) is playing an increasing role in monitoring biochemical changes in vivo in various diseases. For example, many of the neurochemical systems activated by stress can be monitored using this technique. Examples of neurotransmitter interactions with CRH, serotonin, dopamine, and muscarinic cholinergic receptors demonstrate this approach. C1 NIH, PET Dept, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIDDKD, Med Chem Lab, NIH, DHHS, Bethesda, MD USA. NIDA, Imaging Branch, IRP, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Eckelman, WC (reprint author), NIH, PET Dept, Warren G Magnuson Clin Ctr, 10 Ctr Dr,Rm 1C401, Bethesda, MD 20892 USA. EM eckelman@nih.gov NR 30 TC 3 Z9 5 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 487 EP 494 DI 10.1196/annals.1296.060 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800060 PM 15240406 ER PT S AU Ilias, A Pacak, K AF Ilias, A Pacak, K BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Anatomical and functional imaging of metastatic pheochromocytoma SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE pheochromocytoma; computed tomography; magnetic resonance imaging; radionuclide imaging; octreotide; fluorine radioisotopes; positron emission tomography ID SOMATOSTATIN RECEPTOR SCINTIGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; METAIODOBENZYLGUANIDINE MIBG SCINTIGRAPHY; NEURAL CREST TUMORS; MALIGNANT PHEOCHROMOCYTOMA; I-131 MIBG; I-123 METAIODOBENZYLGUANIDINE; CATECHOLAMINE ASSAY; MAGNETIC-RESONANCE; ADRENAL-GLAND AB Although in the majority of patients with pheochromocytoma the tumor is localized in the adrenal, up to 26% of patients have malignant/metastatic disease. Metastatic disease should be ruled out before initial surgery is attempted. Anatomical imaging modalities (computed tomography or magnetic resonance imaging) should be done first over the adrenals, and if negative over the abdomen and if no tumor is found, then the chest and neck should be covered. Regardless of the anatomical imaging results functional imaging with [123-I]- or [131-I]-metaiodobenzylguanidine (MIBG) scintigraphy should be done to corroborate the diagnosis. Negative MIBG scans should be followed by positron emission tomography (PET) studies with specific ligands like [18-F]-dopamine. Persistently negative evaluations should be followed by PET studies with non-specific ligands such as [18-F]-deoxyglucose or somatostatin receptor scintigraphy. C1 NICHD, Unit Clin Neuroendocrinol, PREB, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHD, Unit Clin Neuroendocrinol, PREB, NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov; karel@mail.nih.gov NR 103 TC 24 Z9 24 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 495 EP 504 DI 10.1196/annals.1296.061 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800061 ER PT S AU Nedvidkova, J Haluzik, M Bartak, V Dostalova, I Vlcek, P Racek, P Taus, M Behanova, M Svacina, S Alesci, S Pacak, K AF Nedvidkova, J Haluzik, M Bartak, V Dostalova, I Vlcek, P Racek, P Taus, M Behanova, M Svacina, S Alesci, S Pacak, K BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Changes of noradrenergic activity and lipolysis in the subcutaneous abdominal adipose tissue of hypo- and hyperthyroid patients: An in vivo microdialysis study SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE lipolysis; isoprenaline; hypothyroidism; hyperthyroidism; microdialysis ID ACTIVATED PROTEIN-KINASE; FATTY-ACID OXIDATION; THYROID-HORMONE; GLUCOSE; BROWN; RECEPTORS; FLOW AB Thyroid function plays an important role in the regulation of overall metabolic rate and lipid metabolism. However, it is uncertain whether thyroid hormones directly affect lipolysis in adipose tissue and to what extent those changes contribute to overall metabolic phenotype. Our study was designed, using the microdialysis technique, to determine basal and isoprenaline-stimulated local lipolysis and to determine local concentrations of lipolysis-regulating catecholamines in abdominal subcutaneous adipose tissue in 12 patients with hypothyroidism, 6 patients with hyperthyroidism, and 12 healthy control subjects. Plasma norepinephrine (NE) concentrations in hypothyroid subjects were significantly higher than in the control and hyperthyroid groups. In contrast, systemic, adipose NE levels in hypothyroid patients were decreased relative to controls. Hyperthyroidism, on the other hand, resulted in four-fold higher adipose NE levels. Basal lipolysis measured by glycerol concentrations in adipose tissue was significantly attenuated in hypothyroid patients and markedly increased in hyperthyroid patients in comparison with the control group. In addition to differences in basal lipolysis, hypothyroidism resulted in attenuated, and hyperthyroidism in enhanced, lipolytic response to local stimulation with beta(1,2)-adrenergic agonist isoprenaline. These results demonstrate that lipolysis in abdominal subcutaneous adipose tissue is strongly modulated by thyroid function. We suggest that thyroid hormones regulate lipolysis primarily by affecting local NE concentration and/or adrenergic postreceptor signaling. C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Inst Endocrinol, Prague, Czech Republic. 1st Fac Med, Dept Med 3, Prague, Czech Republic. NIMH, NIH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42,10 Ctr Dr,MSC-1583, Bethesda, MD 20892 USA. EM karel@mail.nih.gov; karel@mail.nih.gov RI Svacina, Stepan/C-1962-2017 OI Svacina, Stepan/0000-0002-0894-4116 NR 22 TC 12 Z9 13 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 541 EP 549 DI 10.1196/annals.1296.067 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800067 PM 15240413 ER PT S AU Macho, L Koska, J Ksinantova, L Vigas, M Blazicek, P Noskov, VB Grigoriev, AI Pacak, K Kvetnansky, A AF Macho, L Koska, J Ksinantova, L Vigas, M Blazicek, P Noskov, VB Grigoriev, AI Pacak, K Kvetnansky, A BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Effects of real and simulated microgravity on response of sympathoadrenal system to various stress stimuli SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE catecholamines; microgravity; space flight; bed rest; work load; psychic; metabolic; mental stressors ID SPACE-FLIGHT; ENDOCRINE SYSTEM; HORMONAL CHANGES; PLASMA; CATECHOLAMINES; SPACEFLIGHT; COSMONAUTS; INSULIN; HUMANS; LOADS AB Changes in plasma levels of epinephrine (EPI) and norepinephrine (NE) were investigated in humans exposed to physical exercise (WL), to psychic stressor (mental arithmetic test, MAT), and to oral glucose administration (oGTT) before and during a stay in microgravity (real space flight, SF) or in simulated microgravity (head-down bed rest, HDBR). A permanent cannula inserted into the cubital vein and a special appliance, Plasma-03, were used for blood collection, plasma separation, and freezing of samples during SF. Plasma EPI, NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylalanine (DOPA) levels were measured by the high-pressure liquid chromatography (HPLC) method. Basal plasma EPI, NE, DHPG, and DOPA levels were found within the range of control values during SF. Preflight WL produced high increase in plasma NE and moderate elevation of plasma EPI, DHPG, and DOPA levels. Exaggerated exercise induced increases in plasma NE, DHPG, EPI, and DOPA levels were demonstrated in real microgravity. A return to preflight responses of sympathoadrenal system was seen after the landing. Plasma EPI, NE, and DHPG responses to MAT were relatively small, but increased during SF. During the oGTT the plasma EPI levels were slightly reduced in microgravity. Similarly as in SF, WL in HDBR was followed by significantly exaggerated responses of plasma catecholamines. These results show that both somatic and psychological stressors are able to induce an increased activation of sympathoadrenal system during SF or simulated microgravity in HDBR. C1 Slovak Acad Sci, Inst Expt Endocrinol, Bratislava 83306, Slovakia. Hosp Minist Def, Bratislava, Slovakia. RAS, State Res Ctr, Inst Medicobiol Problems, Moscow 117901, Russia. NIH, Bethesda, MD USA. RP Macho, L (reprint author), Slovak Acad Sci, Inst Expt Endocrinol, Vlarska 3, Bratislava 83306, Slovakia. EM ueenlaco@savba.sk NR 25 TC 2 Z9 4 U1 1 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 550 EP 561 DI 10.1196/annals.1296.068 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800068 PM 15240414 ER PT S AU Koska, J Ksinantova, L Kvetnansky, R Hamar, D Martinkovic, M Vigas, A AF Koska, J Ksinantova, L Kvetnansky, R Hamar, D Martinkovic, M Vigas, A BE Pacak, K Aguilera, B Saban, E Kvetnansky, R TI Effects of endurance training on endocrine response to physical exercise after 5 days of bed rest in healthy male subjects SO STRESS: CURRENT NEUROENDOCRINE AND GENETIC APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 8th Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN 28-JUL 03, 2003 CL Smolenice Castle, SLOVENIA SP Abbott Labs, Ajinomoto Co Inc, Aventis Pharmaceut, CNS, Catecholamine Fdn, Ctr Excellence European Commiss EU, LDN Labor Diagnost Nord GmbH & Co, Lundbeck Co, NICHHD, Nippon Zoki Pharmaceut Co Ltd, Sanofi Synthelabo, Slovak Acad Sci DE exercise; training; bed rest; norepinephrine; epinephrine; cortisol; PRA ID HEAD-DOWN TILT; SIMULATED WEIGHTLESSNESS; PHYSIOLOGICAL-RESPONSES; ADRENAL-MEDULLA; PLASMA-RENIN; NOREPINEPHRINE; MEN; RESPONSIVENESS; MICROGRAVITY; HEMODYNAMICS AB The study was designed to evaluate how a bout of endurance training (ET) influences the endocrine response after head-down bed rest (HDBR). Eleven healthy males completed the study, which consisted of a 6-wk ET followed by 5 days of -6degrees head-down HDBR. Treadmill exercise at 80% of pre-training maximal aerobic capacity (VO2max) was performed before and after ET as well as after HDBR. ET increased VO2max by 13%. The response of norepinephrine was attenuated after ET and exaggerated after HDBR (P<0.001). The differences in epinephrine responses were not statistically significant. The responses of cortisol and plasma renin activity (PRA) were unchanged after ET and were enhanced after HDBR (P<0.001). The response of growth hormone after HDBR was reduced (P<0.05). Only the change in cortisol response was associated with the increment of VO2max after ET (r = 0.68, P<0.01). Endurance training failed to completely prevent changes in endocrine responses seen after HDBR. Improvement of physical fitness was associated with an enhancement of the cortisol response to exercise following the period of bed rest. C1 Slovak Acad Sci, Inst Expt Endocrinol, Bratislava, Slovakia. Comenius Univ, Fac Phys Educ & Sports, Bratislava, Slovakia. Hosp Minist Def, Bratislava, Slovakia. RP Koska, J (reprint author), NIDDKD, NIH, 4212 N 16Th St,Rm 5-33, Phoenix, AZ 85016 USA. EM jkoska@mail.nih.gov NR 29 TC 1 Z9 1 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-494-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1018 BP 569 EP 575 DI 10.1196/annals.1296.070 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BAN76 UT WOS:000223000800070 PM 15240416 ER PT J AU Ding, JZ Eigenbrodt, ML Mosley, TH Hutchinson, RG Folsom, AR Harris, TB Nieto, FJ AF Ding, JZ Eigenbrodt, ML Mosley, TH Hutchinson, RG Folsom, AR Harris, TB Nieto, FJ TI Alcohol intake and cerebral abnormalities on magnetic resonance imaging in a community-based population of middle-aged adults - The Atherosclerosis Risk in Communities (ARIC) Study SO STROKE LA English DT Article DE alcohol drinking; atrophy; cerebral infarction; magnetic resonance imaging ID WHITE-MATTER LESIONS; CARDIOVASCULAR HEALTH; LONGITUDINAL CHANGES; ISCHEMIC STROKE; CLINICAL STROKE; FOLLOW-UP; CONSUMPTION; BRAIN; MORTALITY; MEN AB Background and Purpose - Although the risks associated with heavy drinking for increased stroke and neurodegenerative changes are well established, the effects on the brain of low to moderate alcohol intake are unclear. Subclinical cerebral abnormalities identified on MRI have been associated with neurocognitive decline and incident stroke. We examined the associations of alcohol intake with MRI-defined cerebral abnormalities in a middle-aged, population-based cohort. Methods - During 1993 - 1994, a total of 1909 middle-aged adults (40% men and 49% blacks) from 2 communities in the Atherosclerosis Risk in Communities (ARIC) Study (Forsyth County, North Carolina, and Jackson, Miss) underwent a cerebral MRI examination. Trained neuroradiologists coded the images for the presence of infarction and the extent (10-point scale) of white matter lesions, ventricular size, and sulcal size. Results - In logistic regression analyses, there was no association between alcohol intake and the presence of MRI infarction. In linear regression analyses, alcohol intake was not associated with white matter grade. However, intake of each additional alcoholic drink per week was associated with a 0.01 grade greater ventricular size ( P = 0.03) and a 0.009 grade greater sulcal size ( P = 0.02) after adjustment for age, sex, race, body mass index, smoking, income, sports index, and diabetes. The positive associations of alcohol intake with ventricular and sulcal size were consistent across sex and race subgroups. Conclusions - A protective effect of low to moderate alcohol intake on cerebral infarction was not found; moreover, increased alcohol intake was associated with brain atrophy. C1 Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Univ Arkansas, Coll Publ Hlth, Dept Epidemiol, Little Rock, AR 72204 USA. Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Med, Dept Populat Hlth Sci, Madison, WI USA. RP Ding, JZ (reprint author), Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, 615 N Wolfe St,Room 6009, Baltimore, MD 21205 USA. FU NHLBI NIH HHS [N01-HC-55016, N01-HC-55018, N01-HC-55021, N01-HC-55015, N01-HC-55019, N01-HC-55020, N01-HC-55022] NR 23 TC 64 Z9 64 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 16 EP 21 DI 10.1161/01.STR.0000105929.88691.8E PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500004 PM 14657449 ER PT J AU Oparil, S Davis, BR Nwachuku, C Pressel, S deLeon, B AF Oparil, S Davis, BR Nwachuku, C Pressel, S deLeon, B TI Stroke results in the antihypertensive and lipid-lowering treatment to prevent heart attack trial SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 Univ Texas, Hlth Sci Ctr, Houston, TX USA. Univ Alabama, Birmingham, AL USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 235 EP 235 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500053 ER PT J AU Kang, DW Chalela, JA Warach, S AF Kang, DW Chalela, JA Warach, S CA NIH-Suburban Stroke Cntr Investigat TI Screening MRI prior to standard alteplase therapy is feasible and safe SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, Bethesda, MD 20892 USA. NIH, Suburban Stroke Investigators, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 236 EP 237 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500059 ER PT J AU Kidwell, CS Saver, JL Latour, LL Starkman, S Alger, JR Jahan, R Duckwiler, G Ovbiagele, B Fredieu, A Suzuki, S Vinuela, F Gobin, YP AF Kidwell, CS Saver, JL Latour, LL Starkman, S Alger, JR Jahan, R Duckwiler, G Ovbiagele, B Fredieu, A Suzuki, S Vinuela, F Gobin, YP CA UCLA IA Thrombolysis MERCI Investi TI Reduced incidence of HARM following mechanical thrombectomy compared to intra-arterial thrombolysis in acute stroke SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. NINDS, Sect Stroke Diagnost & Therapeut, Stroke Branch, Bethesda, MD 20892 USA. New York Presbyterian Weill Cornell Med Coll, New York, NY USA. Univ Calif Los Angeles, IA Thrombolysis, Los Angeles, CA USA. MERCI Investigators, Los Angeles, CA USA. RI Gobin, Yves/A-8008-2008 NR 0 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 236 EP 236 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500058 ER PT J CA NINDS rt-PA Stroke Study Grp TI Tissue plasminogen activator for minor strokes: The NINDS rt-PA stroke study experience SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, Rt PA Stroke Study Grp, Bethesda, MD USA. Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 241 EP 241 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500082 ER PT J AU Elkins, JS O'Meara, ES Longstreth, WT Carlson, MC Manolio, TA Johnston, SC AF Elkins, JS O'Meara, ES Longstreth, WT Carlson, MC Manolio, TA Johnston, SC TI Stroke risk factors and high cognitive function in the elderly without stroke or TIA SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 UCSF, Med Ctr, San Francisco, CA USA. Univ Washington, Seattle, WA 98195 USA. Johns Hopkins Univ, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. UCSF, Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 244 EP 244 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500098 ER PT J AU Kang, DW Lattimore, SU Latour, LL Chalela, JA Warach, S AF Kang, DW Lattimore, SU Latour, LL Chalela, JA Warach, S TI Asymptomatic ischemic lesion recurrence on MRI predicts subsequent clinical events SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 247 EP 247 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500115 ER PT J AU Meschia, JF Brott, TG Hardy, J Brown, RD Kissela, BM Brown, WM Rich, SS AF Meschia, JF Brott, TG Hardy, J Brown, RD Kissela, BM Brown, WM Rich, SS CA SWISS Investigators TI Susceptibility to ischemic stroke subtype may not be genetically determined: the SWISS study SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 Mayo Clin, Jacksonville, FL 32224 USA. NIA, Bethesda, MD 20892 USA. Mayo Clin, Rochester, MN USA. Univ Cincinnati, Cincinnati, OH USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 251 EP 251 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500135 ER PT J AU Lynch, JK Han, CJ Nelson, KB AF Lynch, JK Han, CJ Nelson, KB TI Candidate single nucleotide polymorphisms in children with stroke SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 252 EP 252 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500140 ER PT J AU Chalela, JA Kang, DW Luby, M Ezzeddine, MA Latour, LL Todd, JW Dunn, W Warach, S AF Chalela, JA Kang, DW Luby, M Ezzeddine, MA Latour, LL Todd, JW Dunn, W Warach, S TI Ultra-early MRI findings in patients receiving tissue plasminogen activator predict clinical outcome: New insights into the pathophysiology of acute stroke in the thrombolysis era SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 260 EP 260 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500180 ER PT J AU Han, CJ Lynch, JK Nee, LE Nelson, KB AF Han, CJ Lynch, JK Nee, LE Nelson, KB TI Health-related quality of life in children with stroke. SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. NINDS, Family Studies Unit, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 288 EP 288 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500316 ER PT J AU Wright, VL Horvath, R Chalela, JA Dambrosia, J Yu, H Kang, DW Ezzeddine, M Moore, D Sharma, A Baird, AE AF Wright, VL Horvath, R Chalela, JA Dambrosia, J Yu, H Kang, DW Ezzeddine, M Moore, D Sharma, A Baird, AE TI Early prediction of stroke recovery using CT SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 300 EP 300 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500379 ER PT J AU Hague, S Brown, WM Rich, SS Hardy, J Brott, TG Brown, RD Kissela, BM Crook, R Singleton, A Meschia, JF AF Hague, S Brown, WM Rich, SS Hardy, J Brott, TG Brown, RD Kissela, BM Crook, R Singleton, A Meschia, JF CA SWISS Investigators TI Absence of linkage of the STRK1 locus to ischemic stroke in the North American population: The SWISS study SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NIA, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Mayo Clin, Jacksonville, FL 32224 USA. Mayo Clin, Rochester, MN USA. Univ Cincinnati, Cincinnati, OH USA. RI Singleton, Andrew/C-3010-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 312 EP 312 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500437 ER PT J AU Nadareishvili, Z Li, H Wright, V Maric, D Barker, JL Hallenbeck, JM Dambrosia, J Baird, AE AF Nadareishvili, Z Li, H Wright, V Maric, D Barker, JL Hallenbeck, JM Dambrosia, J Baird, AE TI CD4(+)CD28(-) cells: A potential biomarker of stroke recurrence and death. SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. NINDS, Stroke Neurosci Unit, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 314 EP 314 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500450 ER PT J AU Qureshi, AI Suri, FK Kirmani, JF Lynch, JK AF Qureshi, AI Suri, FK Kirmani, JF Lynch, JK TI Hyperuricemia and risk of stroke and myocardial infarction: A pooled analysis of the First National Health or Nutrition Examination Survey epidemiologic follow-up study and the Framingham Study. SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 Univ Med & Dent New Jersey, Newark, NJ 07103 USA. NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 314 EP 314 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500448 ER PT J AU Seshadri, S Beiser, A Vasan, RS DeCarli, C Wang, TJ Au, R Larson, MG Levy, D Wolf, PA AF Seshadri, S Beiser, A Vasan, RS DeCarli, C Wang, TJ Au, R Larson, MG Levy, D Wolf, PA TI Association of plasma atrial and B-type natriuretic peptides with silent cerebral infarcts and white matter hyperintensity on brain magnetic resonance imaging. SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 Boston Univ, Sch Med, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RI DeCarli, Charles/B-5541-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 314 EP 314 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500451 ER PT J AU Mohammad, Y Qureshi, AI Suri, MFK Xavier, AR Kirmani, JF Lynch, JK AF Mohammad, Y Qureshi, AI Suri, MFK Xavier, AR Kirmani, JF Lynch, JK TI Is pre-hypertension a risk factor for stroke and myocardial infarction? SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 Ohio State Univ, Columbus, OH 43210 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 316 EP 316 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500458 ER PT J AU Goldstein, LB Samsa, GP Matchar, DB Hoff-Lindquist, J Horner, RD AF Goldstein, LB Samsa, GP Matchar, DB Hoff-Lindquist, J Horner, RD TI Validation of the Charlson Index for Ischemic Stroke. SO STROKE LA English DT Meeting Abstract CT 29th International Stroke Conference CY FEB 05-07, 2004 CL SAN DIEGO, CALIFORNIA SP Amer Heart Assoc C1 Duke Univ, Med Ctr, Durham, NC USA. Durham VA Med Ctr, Durham, NC USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2004 VL 35 IS 1 BP 323 EP 323 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 758JH UT WOS:000187630500494 ER PT J AU Barry, DG Daly, NL Bokesch, HR Gustafson, KR Craik, DJ AF Barry, DG Daly, NL Bokesch, HR Gustafson, KR Craik, DJ TI Solution structure of the cyclotide palicourein: Implications for the development of a pharmaceutical framework SO STRUCTURE LA English DT Article ID NMR STRUCTURE CALCULATION; SPIN COUPLING-CONSTANTS; POLYPEPTIDE KALATA B1; PLANT CYCLOTIDES; CYSTINE KNOT; MACROCYCLIC POLYPEPTIDES; 3-DIMENSIONAL STRUCTURE; BACKBONE CYCLIZATION; CHASSALIA-PARVIFOLIA; IN-VIVO AB The cyclotides are a family of disulfide-rich proteins from plants. They have the characteristic structural features of a circular protein backbone and a knotted arrangement of disulfide bonds. Structural and biochemical studies of the cyclotides suggest that their unique physiological stability can be loaned to bioactive peptide fragments for pharmaceutical and agricultural development. In particular, the cyclotides incorporate a number of solvent-exposed loops that are potentially suitable for epitope grafting applications. Here, we determine the structure of the largest known cyclotide, palicourein, which has an atypical size and composition within one of the surface-exposed loops. The structural data show that an increase in size of a palicourein loop does not perturb the core fold, to which the thermodynamic and chemical stability has been attributed. The cyclotide core fold, thus, can in principle be used as a framework for the development of useful pharmaceutical and agricultural bioactivities. C1 Univ Queensland, Inst Mol Biosci, Queensland Biosci Precint, Brisbane, Qld 4072, Australia. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Mol Targets Dev Program, Frederick, MD 21702 USA. RP Craik, DJ (reprint author), Univ Queensland, Inst Mol Biosci, Queensland Biosci Precint, Brisbane, Qld 4072, Australia. EM d.craik@imb.uq.edu.au RI Daly, Norelle/D-4302-2013; Craik, David/B-1695-2010 OI Craik, David/0000-0003-0007-6796 FU NCI NIH HHS [N01-CO-12400] NR 50 TC 33 Z9 34 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JAN PY 2004 VL 12 IS 1 BP 85 EP 94 DI 10.1016/j.str.2003.11.019 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 820ZY UT WOS:000221430000013 PM 14725768 ER PT J AU Bischoff, JF White, JF AF Bischoff, JF White, JF TI Torrubiella piperis sp nov (Clavicipitaceae, Hypocreales), a new teleomorph of the Lecanicillium complex SO STUDIES IN MYCOLOGY LA English DT Article DE Barro Colorado Island; Coccoidea; Cordyceps; Lecanicillium; Piperaceae; scale insect; Verticillium ID VERTICILLIUM SECTION PROSTRATA; REVISION; GENUS; DNA; IDENTIFICATION; SEQUENCES; MODEL AB Recent publications have distinguished clavicipitaceous Verticillium sensu lato anamorphs into six genera. One genus, Lecanicillium, includes the majority of these taxa, including the anamorphs of Cordyceps militaris and Torrubiella confragosa. Torrubiella confragosa has been linked to Lecanicillium lecanii (= Verticillium lecanii). During a recent collection trip to Panama a Torrubiella sp. that produced a Verticillium-like anamorph was found on the corpses of scale insects attached to Piperaceae. It could be distinguished from Torrubiella confragosa based on presence of a true stroma, immersed perithecia, conidial size (3-5 x 1-2 mu m), and phialide size (10-30 x 1-2 mu m). Thus we describe this new collection as Torrubiella piperis sp. nov. In addition, based on the morphological observations and phylogentic analyses using partial LSU rDNA data we determined it to belong to the Lecanicillium group (100 % posterior probability). C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. USDA ARS, Insect Biocontrol Lab, Beltsville, MD 20705 USA. Rutgers State Univ, Cook Coll, Dept Plant Biol & Pathol, New Brunswick, NJ 08901 USA. RP Bischoff, JF (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 45 Ctr Dr,MSC 6510,Room 6AN 32D-21, Bethesda, MD 20892 USA. EM bischoff@ncbi.nlm.nih.gov RI White, James/C-2280-2009 NR 24 TC 5 Z9 6 U1 0 U2 4 PU CENTRAALBUREAU SCHIMMELCULTURE PI BAARN PA PO BOX 273, 3740 AG BAARN, NETHERLANDS SN 0166-0616 J9 STUD MYCOL JI Stud. Mycol. PY 2004 IS 50 SI SI BP 89 EP 94 PN 1 PG 6 WC Mycology SC Mycology GA 915JK UT WOS:000228300300011 ER PT J AU Robin, RW Saremi, A Albaugh, B Hanson, RL Williams, D Goldman, D AF Robin, RW Saremi, A Albaugh, B Hanson, RL Williams, D Goldman, D TI Validity of the SMAST in two American Indian tribal populations SO SUBSTANCE USE & MISUSE LA English DT Article DE alcoholism; American Indian; native American; MAST; assessment; shame; alcohol use screen ID ALCOHOLISM SCREENING-TEST; WOMEN AB The standardized evaluation of alcoholism and other psychopathologies in minority populations, particularly American Indians, has long been questioned. This study investigated the validity of one of the most commonly applied assessments for alcoholism-the Short Michigan Alcohol Screening Test (SMAST)-in two distinct American Indian tribal groups. We analyzed data collected from 1989 to 1995 from largely community representative samples of 456 Southwestern and 214 Plains Indians ages 21 or older. For comparison, alcohol dependence was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R) criteria from a detailed, modified version of the Schedule for Affective Disorders and Schizophrenia-Lifetime (SADS-L). Accuracy of the SMAST was quantified as sensitivity, specificity, likelihood ratios, and the area under the curve for receiver operating characteristics, using the DSM-III-R diagnosis as the reference. The standard SMAST cutoff score of greater than or equal to3 had a demonstrated sensitivity 86% to 95%, but did not perform well in terms of specificity (23%-47%). Significantly higher cutoff scores (greater than or equal to5 for both genders in the Southwestern tribe and 8 and greater than or equal to6 for men and women in the Plains tribe) were required to demonstrate acceptable levels of specificity in both tribes. The findings suggest that the SMAST is not a valid tool to screen for alcohol misuse in these two tribal populations. The highly elevated and different thresholds required from one population to the next and from one gender to the next constitute a significant obstacle to the use of the instrument. C1 Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. NIDDK, Phoenix, AZ USA. Ctr Human Behav Studies, Oklahoma City, OK USA. NIAAA, Neurogenet Lab, Rockville, MD USA. RP Robin, RW (reprint author), Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. EM rwrobin@ptialaska.net RI Hanson, Robert/O-3238-2015; Goldman, David/F-9772-2010 OI Hanson, Robert/0000-0002-4252-7068; Goldman, David/0000-0002-1724-5405 NR 47 TC 2 Z9 2 U1 2 U2 3 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PY 2004 VL 39 IS 4 BP 601 EP 624 DI 10.1081/JA-120030062 PG 24 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 813UH UT WOS:000220931500004 PM 15115215 ER PT J AU Shi, ZD Liu, HP Zhang, MC Yang, DJ Burke, TR AF Shi, ZD Liu, HP Zhang, MC Yang, DJ Burke, TR TI Synthesis of the first alpha-fluoro-phosphotyrosyl mimetic SO SYNTHETIC COMMUNICATIONS LA English DT Article DE chiral induction; enantioselective; phosphotyrosyl mimetic; fluorination ID O-PHOSPHOTYROSINE; PEPTIDE-SYNTHESIS; AMINO-ACIDS; DOMAIN; DESIGN; INHIBITORS; ANALOGS; LIGANDS AB The diastereoselective preparation of (2S)-2-fluoro-4-1[bis(l, l-dimethylethoxy)phosphinyl]methyl] benzenepropanoic acid (5) is presented as. new phosphotyrosyl (pTyr) mimetic suitably protected for incorporation into peptides. Synthesis of 5 utilized electrophilic fluorination under chiral induction provided by the commercially available Evans auxiliary, (S)-(+)-4-phenyl-2-oxazolidinone. In order to demonstrate its synthetic utility, analogue 5 was employed to prepare a signal transduction-directed tripeptide. The design considerations for this peptide and its preliminary biological evaluation are included. C1 NCI, Ctr Canc Res, Lab Med Chem, NIH, Frederick, MD 20702 USA. Univ Michigan, Sch Med, Dept Hematol Oncol, Ann Arbor, MI USA. RP Burke, TR (reprint author), NCI, Ctr Canc Res, Lab Med Chem, NIH, POB B Bldg 376 Boyles St, Frederick, MD 20702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 NR 14 TC 8 Z9 8 U1 0 U2 0 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0039-7911 J9 SYNTHETIC COMMUN JI Synth. Commun. PY 2004 VL 34 IS 21 BP 3883 EP 3889 DI 10.1081/SCC-200034770 PG 7 WC Chemistry, Organic SC Chemistry GA 868WF UT WOS:000224943100006 ER PT B AU Seeff, LB AF Seeff, LB BE Omata, M Okita, K TI Management and treatment of hepatitis C SO THERAPY FOR VIRAL HEPATITIS AND PREVENTION OF HEPATOCELLULAR CARCINOMA LA English DT Proceedings Paper CT 1st Single-Topic Conference on Therapy of Viral Hepatitis and Prevention of Hepatocellular Carcinoma CY NOV 14-15, 2002 CL TOKYO, JAPAN SP Japan Soc Hepatol, Ajinomoto Co Inc, GlaxosmithKline K K, Otsuka Pharmaceut Co Ltd, Schering-Plough K K C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Seeff, LB (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG TOKYO PI TOKYO PA 37-3, HONGO 3-CHOME BONKYO-KU, TOKYO, 113, JAPAN BN 4-431-40280-2 PY 2004 BP 189 EP 198 PG 10 WC Oncology; Gastroenterology & Hepatology; Virology SC Oncology; Gastroenterology & Hepatology; Virology GA BY41S UT WOS:000189200100018 ER PT J AU Romieu, I Sienra-Monge, JJ Ramirez-Aguilar, M Moreno-Macias, H Reyes-Ruiz, NI del Rio-Navarro, BE Hernandez-Avila, M London, SJ AF Romieu, I Sienra-Monge, JJ Ramirez-Aguilar, M Moreno-Macias, H Reyes-Ruiz, NI del Rio-Navarro, BE Hernandez-Avila, M London, SJ TI Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City SO THORAX LA English DT Article ID S-TRANSFERASE M1; CANCER AB Background: We recently reported that antioxidant supplementation with vitamins C and E mitigated ozone related decline in forced expiratory flow (FEF25-75) in 158 asthmatic children in an area with high ozone exposure in Mexico City. Methods: A study was undertaken to determine whether deletion of glutathione S-transferase M1 (GSTM1 null genotype), a gene involved in response to oxidative stress, influences ozone related decline in FEF25-75 and the benefit of antioxidant supplementation. Results: GSTM1 null children receiving placebo had significant ozone related decrements in FEF25-75 (percentage change per 50 ppb of ozone 2.9 (95% CI -5.2 to -0.6), p = 0.01); GSTM1 positive children did not. Conversely, the effect of antioxidants was stronger in children with the GSTM1 null genotype. Conclusions: Asthmatic children with a genetic deficiency of GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant supplementation. C1 Inst Nacl Salud Publ, Cuernavaca 62508, Morelos, Mexico. Hosp Infantil Federico Gomez, Mexico City, DF, Mexico. NIEHS, Res Triangle Pk, NC 27709 USA. RP Romieu, I (reprint author), Inst Nacl Salud Publ, 655 Avenida Univ, Cuernavaca 62508, Morelos, Mexico. OI London, Stephanie/0000-0003-4911-5290 NR 7 TC 175 Z9 182 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD JAN 1 PY 2004 VL 59 IS 1 BP 8 EP 10 PG 3 WC Respiratory System SC Respiratory System GA 756ZP UT WOS:000187515900005 PM 14694237 ER PT J AU Ton, TVT Hong, HHL Anna, CH Dunnick, JK Devereux, TR Sills, RC Kim, Y AF Ton, TVT Hong, HHL Anna, CH Dunnick, JK Devereux, TR Sills, RC Kim, Y TI Predominant K-ras codon 12 G -> A transition in chemically induced lung neoplasms in B6C3F1 mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE 2,2-bis(bromomethyl)-1,3-propanediol; tetranitromethane; alveolar bronchiolar adenoma; alveolar bronchiolar carcinoma; K-ras mutations; K-ras codon 12 G -> A transition; B6C3F1 mouse ID PROTOONCOGENE ACTIVATION; A/J MICE; TUMORS; MUTATIONS; DNA; MOUSE; ADENOCARCINOMA; POLYMERASE; RESISTANT; ONCOGENE AB Based on long-term toxicity and carcinogencity studies in B6C3F1 mice conducted by the National Toxicology Program, 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) and tetranitromethane (TNM) have been identified as carcinogens. Following 2 yr of exposure to 312, 625, or 1,250 ppm BMP in feed, or exposure to 0.5 or 2 ppm TNM by inhalation, increased incidences of lung neoplasms were observed in B6C3F1 mice at all exposure concentrations compared to unexposed mice. The present study characterizes genetic alterations in the K-ras protooncogene in BMP- and TNM-induced lung neoplasms, respectively, and compares the findings to spontaneous lung neoplasms from corresponding control mice. The frequencies of the K-ras mutations were 57% (29/51) in BMP- induced lung neoplasms compared to 15% (3/20) in lung neoplasms from dosed feed control mice, and 54% (14/26) in TNM-induced lung neoplasms compared to 60% (3/5) in lung neoplasms from inhalation control mice. G. A transitions at the second base of the K-ras codon 12 (GGT-->GAT) were the most frequent pattern of K-ras mutations identified in BMP- induced (20/29) and TNM-induced lung neoplasms (13/14), which differed from the mutational patterns identified in the lung neoplasms from unexposed control mice. These results indicate that mutations in the K-ras gene are involved in B6C3F1 lung carcinogenesis following BMP- and TNM-exposure, and the high frequency and specificity of the ras mutation profile in lung neoplasms (G-->A transition) may be due to in vivo genotoxicity by the parent compounds or their metabolites. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Environm Carcinogenesis Program, Res Triangle Pk, NC 27709 USA. RP Kim, Y (reprint author), NIEHS, MD B3-06,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM kim16@niehs.nih.gov NR 32 TC 7 Z9 7 U1 1 U2 3 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 JAN-FEB PY 2004 VL 32 IS 1 BP 16 EP 21 DI 10.1080/01926230490260682 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 763GU UT WOS:000188067200003 PM 14713543 ER PT J AU Long, PH Herbert, RA Nyska, A AF Long, PH Herbert, RA Nyska, A TI Hexachlorobenzene-induced incisor degeneration in Sprague-Dawley rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE rat; hexachlorobenzene; incisor; pulp; odontoblast; dentin; degeneration ID DEVELOPMENTAL DENTAL DEFECTS; MOLAR TOOTH DEVELOPMENT; ACTINOMYCIN-D; DENTINOGENESIS; EXPOSURE; MICE; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; CYCLOPHOSPHAMIDE; TEETH; ODONTOBLASTS AB Hexachlorobenzene (HCB) was administered to female Sprague-Dawley rats in a 13-week toxicity study conducted for the National Toxicology Program (NTP). Groups of 10 rats were treated by gavage with 0.0, 0.03, 0.1, 0.3, 1.0, 3.0, 10, or 25 mg/kg HCB in corn oil 5 days/week for 13 weeks. Dose-dependent, region-specific, maxillary incisor degeneration was observed in animals given HCB at doses of 1.0 mg/kg/day and higher. Treatment with 1.0 mg/kg/day resulted in focal mesenchymal cell vacuolation and focal osteodentin formation within the pulp. Lesions were restricted to a short linear region subjacent to the odontoblast layer along the lateral aspect of the incisor at the level of the dentin-enamel interface. When observed in both incisors, lesions were bilaterally symmetric. Treatment with 3.0 mg/kg/day resulted in lateral and medial pulp lesions and focal odontoblast degeneration with dentin niche formation along the lateral incisor margin in some animals. Treatment with 10 mg/kg/day resulted in a higher incidence of lateral dentin niches and a low incidence of medial dentin niches. In animals treated with 25 mg/kg/day, a high incidence of bilaterally symmetric, lateral and medial, dentin niches were observed. The morphology and distribution of HCB-induced incisor lesions in rats are consistent with injury to a selective population of preodontoblasts. C1 Pathol Associates Inc, W Chester, OH 45069 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Long, PH (reprint author), Pathol Associates Inc, 6217 Cent Pk Dr, W Chester, OH 45069 USA. EM plong2@cinci.rr.com NR 32 TC 4 Z9 4 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 JAN-FEB PY 2004 VL 32 IS 1 BP 35 EP 40 DI 10.1080/01926230490260871 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 763GU UT WOS:000188067200006 PM 14713546 ER PT J AU Tani, Y Maronpot, RR Foley, JF Haseman, JK Walker, NJ Nyska, A AF Tani, Y Maronpot, RR Foley, JF Haseman, JK Walker, NJ Nyska, A TI Follicular epithelial cell hypertrophy induced by chronic oral administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE thyroid; follicular epithelial cells; hypertrophy; dioxin; TCDD; morphometry ID MINICHROMOSOME MAINTENANCE PROTEINS; SMOOTH-MUSCLE-CELLS; DIBENZO-P-DIOXINS; THYROID-HORMONE; CANCER MORTALITY; DNA-REPLICATION; INHIBITS EXPRESSION; RISK ASSESSMENT; TIME-COURSE; 2,3,7,8-TCDD AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) affects the thyroid morphologically and/or functionally in adult animals. Recently, the National Toxicology Program conducted a 2-year gavage study of TCDD in female Harlan Sprague-Dawley rats. The only treatment-related alterations found in thyroid follicles were decreased luminal size and increased height of the follicular epithelial cells, without prominent protrusion into the lumen. The present study elucidated the nature of these follicular lesions. Thyroid glands of 10 rats each from the control, high (100 ng/kg/day)-dose, and stop-study (100 ng/kg/day, 30 weeks; vehicle to study termination) groups in the 2-year study were evaluated microscopically. Twenty randomly selected follicles were measured morphometrically in each animal. TCDD treatment significantly decreased the mean ratio of luminal/epithelial areas and increased the mean sectional epithelial height of the high-dose group compared to controls. Thyroid sections were immunostained with antibody against minichromosome maintenance (MCM) proteins, a novel cell-cycle biomarker. The MCM labeling index of the high-dose group was significantly higher than that of the control; however, the TUNEL labeling index was also higher in the high-dose group than the control. All data from the stop group were comparable to those from controls. These results indicate that the follicular cell response was hypertrophic and reversible. This information should contribute to diagnosis of nonneoplastic thyroid follicular lesions in rats. C1 NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Computat Biol & Risk Anal, NIH, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, NIH, POB 12233,Mail Drop B3-06, Res Triangle Pk, NC 27709 USA. EM nyska@niehs.nih.gov RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 NR 49 TC 13 Z9 13 U1 0 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 JAN-FEB PY 2004 VL 32 IS 1 BP 41 EP 49 DI 10.1080/01926230490260952 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 763GU UT WOS:000188067200007 PM 14713547 ER PT J AU Gallardo-Williams, MT Chapin, RE King, PE Moser, GJ Goldsworthy, TL Morrison, JP Maronpot, RR AF Gallardo-Williams, MT Chapin, RE King, PE Moser, GJ Goldsworthy, TL Morrison, JP Maronpot, RR TI Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice SO TOXICOLOGIC PATHOLOGY LA English DT Article ID BORIC-ACID; DIETARY BORON; ANTIGEN; PROTEASE; CANCER; RATS AB Prostate-specific antigen (PSA) is a serine protease and one of the most abundant proteins secreted by the human prostate epithelium. PSA is used as a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3), providing increased local levels of IGF-1, leading to tumor growth. Separately, there are data that suggest an enzymatic regulatory role for dietary boron, which is a serine protease inhibitor. In this study we have addressed the use of boric acid as a PSA inhibitor in an animal study. We have previously reported that low concentrations (6 ug/mL) of boric acid can partially inhibit the proteolytic activity of purified PSA towards a synthetic fluorogenic substrate. Also, by Western blot we have followed the degradation of fibronectin by enzymatically active PSA and have found significant inhibition in the presence of boric acid. We proposed that dietary supplementation with boric acid would inhibit PSA and reduce the development and proliferation of prostate carcinomas in an animal model. We tested this hypothesis using nude mice implanted subcutaneously with LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric acid solutions (1.7, 9.0 mgB/kg/day) by gavage. Control group received only water. Tumor sizes were measured weekly for 8 weeks. Serum PSA and IGF-1 levels were determined at terminal sacrifice. The size of tumors was decreased in mice exposed to the low and high dose of boric acid by 38% and 25%, respectively. Serum PSA levels decreased by 88.6% and 86.4%, respectively, as compared to the control group. There were morphological differences between the tumors in control and boron-dosed animals, including a significantly lower incidence of mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were not different among groups, though expression of IGF-1 in the tumors was markedly reduced by boron treatment, which we have shown by immunohistochemistry. These data indicate that low-level dietary boron supplementation reduced tumor size and content of a tumor trophic factor, IGF-1. This promising model is being evaluated in further studies. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Mol Toxicol, Res Triangle Pk, NC 27709 USA. ILS Inc, Res Triangle Pk, NC USA. Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14853 USA. RP Maronpot, RR (reprint author), NIEHS, Lab Expt Pathol, POB 12233,MD B3-06, Res Triangle Pk, NC 27709 USA. EM maronpot@niehs.nih.gov OI Chapin, Robert/0000-0002-5997-1261 NR 20 TC 41 Z9 44 U1 1 U2 5 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 JAN-FEB PY 2004 VL 32 IS 1 BP 73 EP 78 DI 10.1080/01926230490260899 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 763GU UT WOS:000188067200011 PM 14713551 ER PT J AU Barlow, NJ McIntyre, BS Foster, PMD AF Barlow, NJ McIntyre, BS Foster, PMD TI Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl) phthalate SO TOXICOLOGIC PATHOLOGY LA English DT Article DE di(n-butyl); phthalate; in utero exposure; male reproductive development; testes; Leydig cell adenoma; testicular dysgenesis ID PROLIFERATIVE LESIONS; DEVELOPMENTAL EXPOSURE; ANOGENITAL DISTANCE; NIPPLE RETENTION; LATE-GESTATION; URINARY-TRACT; MALE-RAT; MICE; DIETHYLSTILBESTROL; MALFORMATIONS AB In utero exposure of male rats to the antiandrogen di(n-butyl) phthalate (DBP) leads to decreased anogenital distance (AGD) on postnatal day (PND) 1, increased areolae retention on PND 13, malformations in the male reproductive tract, and histologic testicular lesions including marked seminiferous epithelial degeneration and a low incidence of Leydig cell (LC) adenomas on PND 90. One objective of this study was to determine the incidence and persistence of decreased AGD, increased areolae retention, and LC adenomas in adult rats following in utero DBP exposure. A second objective was to determine whether AGD and areolae retention during the early postnatal period are associated with lesions in the male reproductive tract. Pregnant Crl:CD(SD) BR rats were gavaged with corn oil or DBP at 100 or 500 mg/kg/day, 10 dams per group. Three replicates of rats (n=30 rats per replicate) were exposed from gestation day 12 to 21 and the male offspring allowed to mature to 6, 12, or 18 months of age. Gross malformations in the male reproductive tract and histologic lesions in the testes were similar to those previously described. However, testicular dysgenesis, a lesion of proliferating LCs and aberrant tubules that has not been previously described in DBP-exposed testes, was diagnosed. The incidence of this lesion was approximately 20% unilateral and 7-18% bilateral in the high-dose group and was similar among all ages examined, implicating a developmental alteration rather than an age-related change. AGD and areolae retention were found to be permanent changes following in utero exposure to 500 mg/kg/day of DBP. Decreased AGD was a sensitive predictor of lesions in the male reproductive tract, relatively small changes in AGD were associated with a significant incidence of male reproductive malformations. In utero DBP exposure induced proliferative developmental lesions, some of which would have been diagnosed as LC adenomas by the morphological criteria set forth by the Society of Toxicologic Pathology. However, these lesions were dissimilar to traditional LC adenomas as the LCs were poorly differentiated and the lesions contained aberrant seminiferous tubules. While the morphology and incidence of this DBP-induced testicular developmental lesion has been fully characterized by this study, the detailed pathogenesis warrants further investigation. C1 NIEHS, Res Triangle Pk, NC 27709 USA. CIIT Ctr Hlth Res, Res Triangle Pk, NC USA. Aventis Inc, Bridgewater, NJ USA. Schering Plough Corp, Res Inst, Lafayette, NJ USA. RP Foster, PMD (reprint author), NIEHS, POB 12233 MD E1-06, Res Triangle Pk, NC 27709 USA. EM foster2@niehs.nih.gov NR 30 TC 83 Z9 84 U1 0 U2 3 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 JAN-FEB PY 2004 VL 32 IS 1 BP 79 EP 90 DI 10.1080/01926230490265894 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA 763GU UT WOS:000188067200012 PM 14713552 ER PT J AU Wallace, KB Hausner, E Herman, E Holt, GD MacGregor, JT Metz, AL Murphy, E Rosenblum, IY Sistare, FD York, MJ AF Wallace, KB Hausner, E Herman, E Holt, GD MacGregor, JT Metz, AL Murphy, E Rosenblum, IY Sistare, FD York, MJ TI Serum troponins as biomarkers of drug-induced cardiac toxicity SO TOXICOLOGIC PATHOLOGY LA English DT Review ID CREATINE-KINASE-MB; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; JOINT EUROPEAN-SOCIETY; HUMAN SKELETAL-MUSCLE; AMINO-ACID-SEQUENCE; HEART-FAILURE; SUBARACHNOID HEMORRHAGE; RELEASE KINETICS C1 Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20852 USA. US FDA, Ctr Drug Evaluat & Res, Laurel, MD 20708 USA. Oxford GlycoSci, Montgomery Village, MD 20886 USA. US FDA, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. Pfizer Inc, Ann Arbor Labs, Drug Safety Evaluat, Global Res & Dev, Ann Arbor, MI 48105 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Schering Plough Corp, Res Inst, Gen Toxicol, Drug Safety & Metab, Lafayette, NJ 07848 USA. GlaxoSmithKline, Clin Pathol Lab, Preclin Safety Sci, Ware SG12 0DP, Herts, England. RP Wallace, KB (reprint author), Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, 1035 Univ Dr, Duluth, MN 55812 USA. EM kwallace@d.umn.edu NR 144 TC 81 Z9 89 U1 1 U2 5 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 JAN-FEB PY 2004 VL 32 IS 1 BP 106 EP 121 DI 10.1080/01926230490261302 PG 16 WC Pathology; Toxicology SC Pathology; Toxicology GA 763GU UT WOS:000188067200015 PM 14713555 ER PT J AU Crissman, JW Goodman, DG Hildebrandt, PK Maronpot, RR Prater, DA Riley, JH Seaman, WJ Thake, DC AF Crissman, JW Goodman, DG Hildebrandt, PK Maronpot, RR Prater, DA Riley, JH Seaman, WJ Thake, DC TI Best practices guideline: T6oxicologic histopathology SO TOXICOLOGIC PATHOLOGY LA English DT Article DE toxicology; histopathology; methods; best practice; pathology; microscopy; guideline ID TOXICOLOGIC PATHOLOGY; RECOMMENDATIONS; PERSPECTIVE C1 Pfizer Inc, Kalamazoo, MI 49001 USA. Dow Corning Corp, Hlth & Environm Sci, Midland, MI 48686 USA. Covance Labs Inc, Vienna, VA 22182 USA. Pathco Inc, Frederick, MD 21702 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. US FDA, Ctr Vet Med, Rockville, MD 20855 USA. Estuary Pharmaceut, Cambridge, MA 02139 USA. RP Seaman, WJ (reprint author), Pfizer Inc, 301 Henrietta St, Kalamazoo, MI 49001 USA. EM william.j.seaman@pfizer.com NR 20 TC 134 Z9 144 U1 1 U2 3 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 JAN-FEB PY 2004 VL 32 IS 1 BP 126 EP 131 DI 10.1080/0192623049026875 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 763GU UT WOS:000188067200018 PM 14713558 ER PT J AU Dill, JA Lee, KM Mellinger, KH Bates, DJ Burka, LT Roycroft, JH AF Dill, JA Lee, KM Mellinger, KH Bates, DJ Burka, LT Roycroft, JH TI Lung deposition and clearance of inhaled vanadium pentoxide in chronically exposed F344 rats and B6C3F1 mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE vanadium; vanadium pentoxide (V2O5); lung deposition; clearance; chronic inhalation; toxicokinetics AB Female F344 rats and B6C3F1 mice were exposed to vanadium pentoxide (V2O5) at concentrations of 0, 0.5, 1, or 2 mg/m(3) (rats) and 0, 1, 2, or 4 mg/m(3) (mice) for 6 h/day, 5 days/week (for up to 18 months), by whole-body inhalation. Lung weights and lung burdens of vanadium were determined for exposed animals after 1, 5, and 12 days and after 1, 2, 6, 12, and 18 months of V2O5 exposure. Blood vanadium concentrations were determined at 1, 2, 6, 12, and 18 months for all animals including controls. A model that assumed a first-order deposition rate and a first-order elimination rate for vanadium was employed to fit the lung burden data. Comparisons between exposed groups indicated a progressive increase in lung weight with exposure concentration and time on exposure for both species. The vanadium lung burdens appeared to reach steady state in the lowest exposure groups (0.5 and 1 mg/m(3) for rats and mice, respectively) but showed a decline in the higher exposure groups. This deposition pattern was similar between rats and mice but the maximum lung burdens were observed at different times (1 or 2 months in mice vs. 6 months in rats). The vanadium deposition rate decreased faster in mice, while the elimination half-lives of vanadium lung burdens were about six- to nine-fold shorter in mice than in rats at 1 and 2 mg/m(3). Thus, the retention of vanadium in the lungs at 18 months was lower in mice (similar to2% retained) compared with rats (13-15% retained) at the common exposure concentrations of 1 and 2 mg/m(3). The lung burden data were approximately proportional to the exposure concentration in both species, likely due to concomitant decreases in deposition and elimination to a similar extent with increasing exposure. The area under the lung burden versus time curves and the area under the blood concentration (control-normalized) versus time curves were also proportional to exposure concentration. The progression of pathological changes in the lung with exposure and time is thought to affect the pattern and/or extent of vanadium deposition in the lungs following repeated exposures to V2O5. C1 Battelle Mem Inst, Toxicol NW, Richland, WA 99352 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Dill, JA (reprint author), Battelle Mem Inst, Toxicol NW, MS K4-16,POB 999, Richland, WA 99352 USA. EM dillj@battelle.org NR 17 TC 16 Z9 16 U1 1 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 JAN PY 2004 VL 77 IS 1 BP 6 EP 18 DI 10.1093/toxsci/kfh005 PG 13 WC Toxicology SC Toxicology GA 762NJ UT WOS:000187988800004 PM 14600283 ER PT J AU Caruccio, L Walkovich, K Bettinotti, M Schuller, R Stroncek, D AF Caruccio, L Walkovich, K Bettinotti, M Schuller, R Stroncek, D TI CD177 polymorphisms: correlation between high-frequency single nucleotide polymorphisms and neutrophil surface protein expression SO TRANSFUSION LA English DT Article ID POLYCYTHEMIA RUBRA VERA; SIGNAL PEPTIDE VARIANT; ANTIGEN NB1; BIOCHEMICAL-CHARACTERIZATION; MONOCLONAL-ANTIBODIES; GENE-FREQUENCIES; MOLECULAR-BASIS; GLYCOPROTEIN; RECEPTOR; PRV-1 AB BACKGROUND: Human neutrophil antigen-2a (NB1) is located on NB1 glycoprotein, which is expressed on subpopulations of neutrophils. PRV-1 is a gene that is over-expressed in neutrophils from patients with polycythemia rubra vera. The gene encoding NB1 differs from PRV-1 at four nucleotides. The purpose of this study was to determine if PRV-1 and NB1 are alleles of the same gene or two separate genes; and, moreover, if they are alleles, to explore potential correlations to NB1 glycoprotein expression. STUDY DESIGN AND METHODS: Primer pairs were used to amplify WBC DNA in the regions surrounding the four NB1 polymorphic sites. The four resulting amplicons were sequenced. The size of the neutrophil population in each donor that stained brightly with CD177 antibody was assessed by flow cytometry. RESULTS: If PRV-1 and NB1 are separate genes, then all people should be heterozygous for the PRV-1/NB1 polymorphisms. Because 11 of 23 donors were homozygous for PRV-1 polymorphisms at all four sites, PRV-1 and NB1 are alleles of the same gene, CD177. When the sequenced exons were compared with PRV-1, 13 single nucleotide polymorphisms (SNPs) that result in amino acid changes were found. The G42C NB1 polymorphism, found in 10 donors, was the most common SNP. The size of the CD177 bright-staining neutrophil population was greater in 42C/C donors than in 42G/G donors (66 +/- 20% vs. 41 +/- 21%, p = 0.004). CONCLUSIONS: PRV-1 and NB1 are alleles of the polymorphic gene CD177. The most common SNP in bp 42 predicted an amino acid change that may have an effect on protein expression. C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Amer Red Cross, N Cent Blood Serv, St Paul, MN USA. RP Stroncek, D (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C711,10 Ctr Dr MSC-1184, Bethesda, MD 20892 USA. EM dstroncek@dtm.cc.nih.gov NR 20 TC 17 Z9 21 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JAN PY 2004 VL 44 IS 1 BP 77 EP 82 DI 10.1046/j.0041-1132.2004.00606.x PG 6 WC Hematology SC Hematology GA 761HY UT WOS:000187896500013 PM 14692971 ER PT J AU Nirenberg, M AF Nirenberg, M TI Historical review: Deciphering the genetic code - a personal account SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID AMINO ACID CODE; FREE PROTEIN SYNTHESIS; SYNTHETIC POLYNUCLEOTIDES; RNA CODEWORDS; E-COLI; ESCHERICHIA-COLI; NUCLEOTIDE SEQUENCES; RIBONUCLEIC ACID; TEMPLATE RNA; RIBOSOMES AB This is an autobiographical description of the events that led to the breaking of the genetic code and the subsequent race to decipher the code. The code was deciphered in two stages over a five-year period between 1961 and 1966. During the first stage, the base compositions of codons were deciphered by the directing cell-free protein synthesis with randomly ordered RNA preparations. During the second phase, the nucleotide sequences of RNA codons were deciphered by determining the species of aminoacyl-tRNA that bound to ribosomes in response to trinucleotides of known sequence. Views on general topics such as how to pick a research problem and competition versus collaboration also are discussed. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Nirenberg, M (reprint author), NHLBI, Lab Biochem Genet, NIH, 9000 Rockville Pike,MSC-1654,Bldg 10,Room 7N-315, Bethesda, MD 20892 USA. EM mnirenberg@nih.gov NR 48 TC 52 Z9 58 U1 3 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD JAN PY 2004 VL 29 IS 1 BP 46 EP 54 DI 10.1016/j.tibs.2003.11.009 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 770XZ UT WOS:000188757800010 PM 14729332 ER PT J AU Furano, AV Duvernell, DD Boissinot, S AF Furano, AV Duvernell, DD Boissinot, S TI L1 (LINE-1) retrotransposon diversity differs dramatically between mammals and fish SO TRENDS IN GENETICS LA English DT Editorial Material ID CYTOSINE METHYLATION; ECTOPIC RECOMBINATION; POSITIVE SELECTION; MOUSE GENOME; EVOLUTION; ELEMENTS; SEQUENCES; LINEAGES; GENE; DROSOPHILA AB L1 retrotransposons replicate (amplify) by copying (reverse transcribing) their RNA transcript into genomic DNA. The evolutionary history of L1 in mammals has been unique. In mice and humans similar to80 million years of L1 evolution and replication produced a single evolutionary lineage of L1 elements while generating similar to20% of the genomic mass in each species. By contrast, zebrafish contain >30 distinct L1 lineages that have generated approximately one-tenth as much DNA. We contend that, by becoming far more permissive of interspersed repeated DNA than other organisms, mammals are conducive to competition between L1 families for replicative dominance, and that this competition, perhaps for the host factors required for L1 replication, results in a single L1 lineage. C1 NIH, Bethesda, MD 20892 USA. So Illinois Univ, Dept Biol Sci, Edwardsville, IL 62026 USA. CUNY Queens Coll, Dept Biol, Flushing, NY 11367 USA. RP Furano, AV (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM avf@helix.nih.gov OI Duvernell, David/0000-0003-2478-6522 NR 48 TC 83 Z9 88 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JAN PY 2004 VL 20 IS 1 BP 9 EP 14 DI 10.1016/j.tig.2003.11.006 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 764VF UT WOS:000188226200003 PM 14698614 ER PT J AU Banke, TG Traynelis, SF AF Banke, TG Traynelis, SF TI Response to Gibb: NMDA receptor subunit gating - uncovered SO TRENDS IN NEUROSCIENCES LA English DT Editorial Material C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30233 USA. RP Banke, TG (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bldg 49,49 Convent Dr,MSC 4495, Bethesda, MD 20892 USA. EM banket@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JAN PY 2004 VL 27 IS 1 BP 10 EP 10 DI 10.1016/j.tins.2003.10.009 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 768YP UT WOS:000188599100004 ER PT J AU Yao, PJ AF Yao, PJ TI Synaptic frailty and clathrin-mediated synaptic vesicle trafficking in Alzheimer's disease SO TRENDS IN NEUROSCIENCES LA English DT Editorial Material ID ASSEMBLY PROTEIN AP180; TRANSGENIC MICE; CAENORHABDITIS-ELEGANS; SYNAPTOTAGMIN MUTANTS; FRONTAL-CORTEX; EXPRESSION PROFILE; AXONAL-TRANSPORT; COATED VESICLES; NEURONAL LOSS; MOUSE MODEL AB Loss of synapses contributes to the progressive cognitive impairment in Alzheimer's disease. Emerging evidence suggests that synapses are not functioning optimally even before structural deterioration. Expression of synapse-specific proteins, including that of some involved in synaptic vesicle trafficking, is affected in the disease. This article reviews current understanding of these components in presynaptic functions and explores possible roles for aberrant synaptic vesicle trafficking in the dysregulation of synaptic function, an important aspect in the neuropathology of Alzheimer's disease. The inability of neurons to form synaptic vesicles properly could have direct consequences on the functionality of neuronal circuits. Further studies focusing on this possibility would be useful for understanding the disease process and could lead to therapeutic strategies that can modify the function of persistent synapses. C1 NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov NR 69 TC 38 Z9 43 U1 2 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JAN PY 2004 VL 27 IS 1 BP 24 EP 29 DI 10.1016/j.tins.2003.10.012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 768YP UT WOS:000188599100009 PM 14698607 ER PT J AU Shah, BH Catt, KJ AF Shah, BH Catt, KJ TI GPCR-mediated transactivation of RTKs in the CNS: mechanisms and consequences SO TRENDS IN NEUROSCIENCES LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; PROTEIN-COUPLED RECEPTORS; ADENOSINE A(2A) RECEPTOR; LONG-TERM POTENTIATION; CENTRAL-NERVOUS-SYSTEM; MU-OPIOID RECEPTOR; SIGNALING PATHWAYS; MATRIX METALLOPROTEINASES; TYROSINE KINASES; EGF RECEPTOR AB G protein-coupled receptors (GPCRs) mediate cellular responses to a diverse array of extracellular messenger molecules. Recent studies have shown that GPCR-mediated signaling pathways include transactivation of receptor tyrosine kinases (RTKs), such as receptors for epidermal growth factor, platelet-derived growth factor, neurotrophins and fibroblast growth factor. Cross-communication between GPCRs and RTKs is a complex process, and utilizes sets of signalling molecules that are primarily determined by cell context and the types of receptors activated. The differential involvement of RTKs and downstream signaling pathways activated in response to GPCR-mediated stimulation elicits a variety of cellular effects during development, proliferation, differentiation, survival, repair and synaptic transmission in the CNS. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. EM catt@helix.nih.gov NR 66 TC 82 Z9 85 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JAN PY 2004 VL 27 IS 1 BP 48 EP 53 DI 10.1016/j.tins.2003.11.003 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 768YP UT WOS:000188599100012 PM 14698610 ER PT J AU Lyons, MJ Yoshimura, T McMurray, DN AF Lyons, MJ Yoshimura, T McMurray, DN TI Interleukin (IL)-8 (CXCL8) induces cytokine expression and superoxide formation by guinea pig neutrophils infected with Mycobacterium tuberculosis SO TUBERCULOSIS LA English DT Article DE neutrophils; IL-8; guinea pig ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; PULMONARY TUBERCULOSIS; GENE-EXPRESSION; CDNA CLONING; HOST-DEFENSE; TNF-ALPHA; INDUCTION; PEPTIDE; MODEL; MICE AB Setting: Interleukin (IL)-8, a neutrophil attracting chemokine, is known to be made by a variety of leukocyte populations following stimulation by Mycobacterium tuberculosis. Objective: The effect of recombinant guinea pig IL-8 on the ability of neutrophits to generate a cytokine response after infection with M. tuberculosis H37Ra was examined. Design: Recombinant gpIL-8 was produced by subcloning the gene into Escherichia coli and purification over a nickel column. The identity of the rgpIL-8 was confirmed by sequencing. Neutrophils were harvested from the blood of non-vaccinated or M. bovis BCG-vaccinated guinea pigs and tested for their ability to migrate toward media alone, 10 mug/ml PPD, f-Met-Leu-Phe (f-MLP), or rgpIL-8 in 96-well chemotactic chambers. Neutrophits were also pre-stimutated with rgpIL-8 then restimulated with LPS (10 mug/ml) or infected in vitro with M. tuberculosis H37Ra (MOI 1:1). Results: Recombinant gpIL-8 and f-MLP induced significant chemotaxis in neutrophils from both non-vaccinated and BCG-vaccinated guinea pigs, with the best chemotaxis occuring at a concentration of 10(-7) M. Real-time PCR analysis revealed that pre-treatment of neutrophils induced elevated levels of IL-8 and TNF-alpha mRNA and protein as well as superoxide, but not mRNA for MCP-1, IFN-gamma, or TGF-beta when compared to neutrophils pre-stimutated with media alone. Conclusions: The presence of IL-8 early in the host response to M. tuberculosis infection may be an important contributor to a successful immune response. How essential a role IL-8 plays remains unknown and merits further study. (C) 2003 Elsevier Ltd. All rights reserved. C1 Texas A&M Univ, Syst Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. NCI Frederick, Mol Immunoregulat Lab, Ft Detrick, MD 21702 USA. RP McMurray, DN (reprint author), Texas A&M Univ, Syst Hlth Sci Ctr, Dept Med Microbiol & Immunol, 407 Reynolds Med Bldg,Univ Dr, College Stn, TX 77843 USA. EM dmcmurray@tamu.edu FU NIAID NIH HHS [R01-AI-15495] NR 37 TC 33 Z9 33 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PY 2004 VL 84 IS 5 BP 283 EP 292 DI 10.1016/j.tube.2003.09.003 PG 10 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 836LT UT WOS:000222557900001 PM 15207803 ER PT S AU Robbins, JB Schneerson, R AF Robbins, JB Schneerson, R BE Kaler, SG Rennert, OM TI Future vaccine development at NICHD SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE capsular polysaccharide; O-specific polysaccharide; serum IgG; capsular polypeptide; pertussis toxin ID INFLUENZAE TYPE-B; O-SPECIFIC POLYSACCHARIDE; AERUGINOSA RECOMBINANT EXOPROTEIN; VI-CAPSULAR POLYSACCHARIDE; SUB-SAHARAN AFRICA; SHIGELLA-DYSENTERIAE TYPE-1; 2-TO 4-YEAR-OLD CHILDREN; ESCHERICHIA-COLI O157; HEMOPHILUS-INFLUENZAE; CONJUGATE VACCINE AB Using published data and the results of our studies, we hypothesized that a critical level of serum IgG antibodies to the surface structures of invasive pathogens (capsular polysaccharides of Haemophilus influenzae type b, pneumococcus, meningococcus, Salmonella typhi, Escherichia coli, and Staphylococcus aureus, the O-specific polysaccharide LPS domain of the LPS of Shigella, non-typhoidal Salmonella, and E. coli, and the capsular polypeptide of Bacillus anthraces) confer immunity to these pathogens. Covalent attachment to a protein increases their immunogenicity and bestows T-cell properties to these antigens. We have also shown that a critical level of serum IgG antibodies to pertussis toxin alone induces immunity on both an individual and on a community basis (herd immunity) to Bordetella pertussis. It is likely that all the above conjugates and pertussis toxoid will be incorporated into vaccines for routine infant immunization. C1 NICHD, Lab Dev & Mol Immun, Sect Bacterial Dis Pathogenesis & Immun, NIH, Bethesda, MD 20892 USA. RP Robbins, JB (reprint author), NICHD, Lab Dev & Mol Immun, Sect Bacterial Dis Pathogenesis & Immun, NIH, Bldg 6,Room 436, Bethesda, MD 20892 USA. EM robbinsj@nichd.nih.gov; schneerr@mail.nih.gov NR 61 TC 8 Z9 9 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 49 EP 59 DI 10.1196/annals.1315.011 PG 11 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300005 PM 15838097 ER PT S AU Hinnebusch, AG Asano, K Olsen, DS Phan, L Nielsen, KH Valasek, L AF Hinnebusch, AG Asano, K Olsen, DS Phan, L Nielsen, KH Valasek, L BE Kaler, SG Rennert, OM TI Study of translational control of eukaryotic gene expression using yeast SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE translation; regulation; GCN4; initiation factor; ribosome; protein kinase ID IN-VIVO; MULTIFACTOR COMPLEX; MEDIATE BINDING; INITIATION; EIF3; EXCHANGE AB Eukaryotic cells respond to starvation by decreasing the rate of general protein synthesis while inducing translation of specific mRNAs encoding transcription factors GCN4 (yeast) or ATF4 (humans). Both responses are elicited by phosphorylation of translation initiation factor 2 (eIF2) and the attendant inhibition of its nucleotide exchange factor eIF2B-decreasing the binding to 40S ribosomes of methionyl initiator tRNA in the ternary complex (TC) with eIF2 and GTP. The reduction in TC levels enables scanning ribosomes to bypass the start codons of upstream open reading frames in the GCN4 mRNA leader and initiate translation at the authentic GCN4 start codon. We exploited the fact that GCN4 translation is a sensitive reporter of defects in TC recruitment to identify the catalytic and regulatory subunits of eIF2B. More recently, we implicated the C-terminal domain of eIF1A in 40S-binding of TC in vivo. Interestingly, we found that TC resides in a multifactor complex (MFC) with eIF3, eIF1, and the GTPase-activating protein for eIF2, known as eIF5. Our biochemical and genetic analyses indicate that physical interactions between MFC componens enhance TC binding to 40S subunits and are required for wild-type translational control of GCN4. MFC integrity and eIF3 function also contribute to post-assembly steps in the initiation pathway that impact GCN4 expression. Thus, apart from its critical role in the starvation response, GCN4 regulation is a valuable tool for dissecting the contributions of multiple translation factors in the eukaryotic initiation pathway. C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI Valasek, Leos/I-5743-2014 NR 12 TC 18 Z9 19 U1 0 U2 6 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 60 EP 74 DI 10.1196/annals.1315.012 PG 15 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300006 PM 15838098 ER PT S AU Dawid, IB AF Dawid, IB BE Kaler, SG Rennert, OM TI Developmental biology of zebrafish SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE gene expression; zebrafish; genetics; signal transduction; Sef; fibroblast growth factor (FGF) AB The biology and genetics of zebrafish has become a very popular system in developmental biology especially because of their suitability for genetics and the transparent embryo of this small tropical fish. Studies reported briefly here demonstrate that one can use gene expression in the zebrafish embryo to find new components of important and well-studied developmental mechanisms and signal transduction pathways. The study of zebrafish developmental genetics has proven invaluable in determining many aspects of vertebrate development. Further use of this model organism promises to generate many interesting and useful data. C1 NICHD, Genet Mol Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHD, Genet Mol Lab, Div Intramural Res, NIH, Bldg 6B,Room 413, Bethesda, MD 20892 USA. EM dawidi@mail.nih.gov NR 6 TC 8 Z9 8 U1 0 U2 6 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 88 EP 93 DI 10.1196/annals.1315.015 PG 6 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300009 PM 15838101 ER PT S AU Lewis, EB AF Lewis, EB BE Kaler, SG Rennert, OM TI Developmental genetics of Drosophila SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE Drosophila; history of genetics; development; homeobox genes AB Drosophila melanogaster is one of the most valuable organisms in biological research, particularly in the areas of genetics and developmental biology. Drosophila has been used as a model organism in research for almost a century. The organism is easy to breed and has a short life cycle, making it ideal for the study of genetic mutations. The importance to human health and development lies in the homology of Drosophila genes to those in man, e.g., the homeobox gene complex. C1 CALTECH, Pasadena, CA 91125 USA. RP Lewis, EB (reprint author), NICHD, Sect Drosophila Gene Regulat, Mol Genet Lab, Div Intramural Res,NIH, Bldg 6B,Room 331,6 Ctr Dr, Bethesda, MD 20892 USA. EM jim_kennison@nih.gov NR 0 TC 0 Z9 0 U1 7 U2 24 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 94 EP 97 DI 10.1196/annals.1315.016 PG 4 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300010 PM 15838102 ER PT S AU Bonifacino, JS AF Bonifacino, JS BE Kaler, SG Rennert, OM TI Insights into the biogenesis of lysosome-related organelles from the study of the Hermansky-Pudlak syndrome SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE lysosomes; endosomes; clathrin; pigmentation; sorting signals; melanine ID AP-3 ADAPTER COMPLEX; VESICLE FORMATION; PIGMENT GRANULE; PROTEINS; TRAFFICKING; TYROSINASE; EXPRESSION; MUTATIONS; SUBUNIT; GENES AB Lysosome-related organelles (LROs) are a family of cell-type-specific organelles that include melanosomes, platelet dense bodies, and cytotoxic T cell granules. The name, LRO, recognizes the fact that all of these organelles contain subsets of lysosomal proteins in addition to cell-type-specific proteins. The recent identification of genetic disorders that cause combined defects in several of these organelles indicates that they share common biogenetic pathways. Studies of one of these disorders, the Hermansky-Pudlak syndrome (HPS), have provided helpful insights into the molecular machinery involved in LRO biogenesis. HPS is a genetically heterogeneous disorder caused by mutations in any of 7 genes in humans and 15 genes in mice. These genes encode subunits of 4 multi-protein complexes named AP-3, BLOC-1, BLOC-2 and BLOC-3, in addition to miscellaneous components of the general protein trafficking machinery. The AP-3 complex is a coat protein involved in vesicle formation and cargo selection in the endosomal-lysosomal system. One of these cargo molecules is the melanosomal enzyme, tyrosinase, the missorting of which may explain the defective melanosomes in AP-3-deficient humans and mice. The function of the BLOC complexes is unknown, although they are thought to mediate either vesicle tethering/fusion or cytoplasmic dispersal of LROs. Further studies of these complexes should contribute to the elucidation of the mechanisms of LRO biogenesis and the pathogenesis of HPS. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural NIH HHS NR 17 TC 44 Z9 45 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 103 EP 114 DI 10.1196/annals.1315.018 PG 12 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300012 PM 15838104 ER PT S AU Lippincott-Schwartz, J AF Lippincott-Schwartz, J BE Kaler, SG Rennert, OM TI Dynamics of secretory membrane trafficking SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE GFP; Golgi apparatus; ER; secretory; membrane traffic; photohleaching ID LIVING CELLS; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; IN-VIVO; GOLGI; ER; TRANSPORT; PROTEINS; RETENTION; COPI AB The study of intracellular membrane trafficking and organelle dynamics has been revolutionized with the advent of GFP technology, which allows individual proteins to be tagged with GFP and monitored in living cells. Using GFP-based techniques such as selective photobleaching and time-lapse imaging of different GFP color variants, it is now possible to address a host of questions related to protein retention within the organelles, the origin and fate of transport intermediates, and the extent of trafficking through different transport pathways. This has provided unexpected new insights into the organization and function of secretory and endocytic pathways within cells. C1 NICHD, Sect Organelle Biol, Cell Biol & Metab Branch, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHD, Sect Organelle Biol, Cell Biol & Metab Branch, Div Intramural Res,NIH, Bldg 18T,Room 101,18 Lib Dr, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov NR 22 TC 12 Z9 13 U1 0 U2 4 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 115 EP 124 DI 10.1196/annals.1315.019 PG 10 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300013 PM 15838105 ER PT S AU Mayer, M AF Mayer, M BE Kaler, SG Rennert, OM TI Structure and function of glutamate receptors SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE glutamate receptors; neurons; synaptic plasticity; neurotransmitters AB Understanding how glutamate receptors, a group of molecules that mediate information between neurons in the brain, work at the molecular level has been the focus of my research. The key role of glutamate receptors is to mediate excitatory synaptic transmission throughout the brain and spinal cord. To understand the mechanisms by which this occurs requires a molecular understanding of the receptor proteins. Our experimental approach required breaking down the receptor into smaller assemblies that are easier to work with. We ended up, after a few years, with the first molecular model for how ion channel gating occurs. C1 NICHD, Lab Cellular & Mol Neurophysiol, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Mayer, M (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Div Intramural Res, NIH, Bldg 36,Room 2D02,MSC 4066,36 Convent Dr, Bethesda, MD 20892 USA. EM mm18a@nih.gov RI Mayer, Mark/H-5500-2013 NR 5 TC 2 Z9 2 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 125 EP 130 DI 10.1196/annals.1315.020 PG 6 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300014 PM 15838106 ER PT S AU Vaitukaitis, JL AF Vaitukaitis, JL BE Kaler, SG Rennert, OM TI Development of the home pregnancy test SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE home pregnancy test; reproductive endocrinology; human chorionic gonadotropin; hCG ID HUMAN CHORIONIC-GONADOTROPIN; TUMOR MARKER; BETA-SUBUNIT; HCG; RADIOIMMUNOASSAY; ANTISERA; HORMONE; IMPLANTATION AB The home pregnancy testworks by measuring human chorionic gonadotropin (hCG) hormone in urine. This hormone was initially studied in NICHD intramural laboratories as a reliable marker of certain tumors. Refinement of the assay for hCG detection to enhance specificity enabled its ready application to pregnancy detection. C1 Natl Res Resources, NIH, Bethesda, MD 20892 USA. RP Vaitukaitis, JL (reprint author), Natl Res Resources, NIH, Bldg 31,Room 3B11,9000 Rockville Pike, Bethesda, MD 20892 USA. EM judyv@ncrr.nih.gov NR 19 TC 6 Z9 6 U1 0 U2 5 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 220 EP 222 DI 10.1196/annals.1315.030 PG 3 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300024 PM 15838116 ER PT S AU Garcia, CR AF Garcia, CR BE Kaler, SG Rennert, OM TI Development of the pill SO UNDERSTANDING AND OPTIMIZING HUMAN DEVELOPMENT:: FROM CELLS TO PATIENTS TO POPULATIONS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 40th Scientific Symposium of the National-Institute-of-Child-Health-and-Human-Development CY SEP 08, 2003 CL Bethesda, MD SP NICHD DE oral contraceptive; reproduction; progesterone; estrogen; public health AB The history of development of the first oral contraceptive reveals the coalescence of scientific and social forces in the late 1950s that led to his major advance in reproductive freedom for women. Improved knowledge of basic reproductive endocrinology, the development of oral compounds by pharmaceutical companies, and careful clinical trials to document efficacy each played pivotal roles in the story. In addition to industry, the National Institute of Child Health and Human Development and the U.S. Food and Drug Administration provided the research and regulatory support structures to nurture the field along its ultimately highly successful path. Still, it remains important to note that more than 500,000 women die each year from complications of child-bearing, a problem that is particularly acute in Africa. A significant portion of this mortality would be prevented by better knowledge of and access to oral contraceptives. C1 Hosp Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. RP Garcia, CR (reprint author), Natl Inst Child Hlth & Human Dev, Intramural Res Program, NIH, Bldg 10,Room 9S-261,10 Ctr Dr,MSC 1834, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-520-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1038 BP 223 EP 226 DI 10.1196/annals.1315.031 PG 4 WC Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine; Science & Technology - Other Topics GA BCN49 UT WOS:000230169300025 PM 15838117 ER PT B AU Dean, J AF Dean, J BE Filicori, M TI Mouse models provide insights into folliculogenesis and fertilization SO UPDATES IN INFERTILITY TREATMENT 2004 LA English DT Proceedings Paper CT Conference on Updates in Infertility Treatment CY JAN 22-24, 2004 CL Marco Isl, FL DE sperm binding; zona pellucida; mouse fertilization; sperm-egg interaction; induction of acrosome reaction ID PELLUCIDA GLYCOPROTEIN ZP3; ZONA-PELLUCIDA; SPERM RECEPTORS; COORDINATE EXPRESSION; TARGETED DISRUPTION; FIG-ALPHA; EGG-COAT; MICE; GENE; LACKING AB Perinatally, mouse oocytes become surrounded by a single layer of flattened granulose cells to form primordial follicles that represent the full complement of germ cells available to the female. Subsequent, yet to be defined signals, select cohorts to enter into a growth phase after which the eggs undergo meiotic maturation and are ovulated into the oviduct. Exploiting the appearance of the zona pellucida as a biochemical marker of folliculogenesis, a transcription factor, FIGalpha (Factor In the Germline, alpha) required for zona gene expression has been identified. Mice lacking FIGa do not form primordial follicles and are sterile. Additional gene products expressed by the oocytes are required for follicular growth and meiotic progression to metaphase II. After ovulation, eggs are fertilized in the ampulla of the oviduct by capacitated sperm. Although the molecular biology of the zona pellucida is increasingly well understood, the basis of sperm binding to the zona matrix remains enigmatic. Using targeted mutagenesis and transgenesis, mouse lines have been established that lack each of the three mouse zona proteins (Zp1, Zp2, Zp3 null mice) or contain human ZP2, human ZP3 or both in lieu of the endogenous mouse proteins (huZP2, huZP3, huZP2/ZP3 rescue mice). Normally following fertilization, ZP2 is cleaved, sperm no longer bind to embryos, and there is an effective block to sperm penetration of the zona pellucida. Surprisingly, mice with zonae containing human proteins (human ZP2, human ZP3 or both) remain fertile, but do not support human sperm binding. Also unexpected, mouse sperm continue to bind at the two-cell stage to chimeric zonae containing human ZP2, a phenotype that correlates with intact ZP2. These observations support a model in which sperm bind to a three-dimensional zona structure formed ad minimum by ZP2/ZP3, and the cleavage of ZP2 following fertilization alters the matrix so that it is no longer permissive for sperm binding. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 36 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND PUBLISHING CO PI BOLOGNA PA VIA RUBBIANI 6/2, 40124 BOLOGNA, ITALY BN 88-7587-088-8 PY 2004 BP 65 EP 75 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA BBR45 UT WOS:000227356900006 ER PT S AU Ottolenghi, C Uda, M Hamatani, T Crisponi, L Garcia, JE Ko, M Pilia, G Sforza, C Schlessinger, D Forabosco, A AF Ottolenghi, C Uda, M Hamatani, T Crisponi, L Garcia, JE Ko, M Pilia, G Sforza, C Schlessinger, D Forabosco, A BE Bulleti, C DeZiegler, D Flamigni, C TI Aging of oocyte, ovary, and human reproduction SO UTERUS AND HUMAN REPRODUCTION SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 5th Conference on the Uterus and Human Reproduction CY JUN 03-05, 2004 CL Marignano, ITALY SP Italian Minist Educ, Higher Educ & Res, Italian Minist Hlth, Alma Mater Studiorum, Univ Bologna DE histogenesis; meiotic competence; developmental competence; premature ovarian failure; POF; oocyte quality; follicle endowment; follicle dynamics ID FOLLICULAR DEVELOPMENT; MAMMALIAN OVARY; MATERNAL AGE; DEVELOPMENTAL COMPETENCE; EMBRYONIC-DEVELOPMENT; FEMALE FECUNDITY; GENE-EXPRESSION; MOUSE OVARY; STEM-CELLS; GERM-CELLS AB We review age-related changes in the ovary and their effect on female fertility, with particular emphasis on follicle formation, follicle dynamics, and oocyte quality. The evidence indicates that the developmental processes leading to follicle formation set the rules determining follicle quiescence and growth. This regulatory system is maintained until menopause and is directly affected in at least some models of premature ovarian failure (POF), most strikingly in the Foxl2 mouse knockout, a model of human POF with monogenic etiology (blepharophimosis/ptosis/epicanthus inversus syndrome). Several lines of evidence indicate that if the ovarian germ cell lineage maintains regenerative potential, as recently suggested in the mouse, a role in follicle dynamics for germ stem cells, if any, is likely indirect or secondary. In addition, agerelated variations in oocyte quality in animal models suggest that reproductive competence is acquired progressively and might depend on parallel growth and differentiation of follicle cells and stroma. Genomewide analyses of the mouse oocyte transcriptome have begun to be used to systematically investigate the mechanisms of reproductive competence that are altered with aging. Investigative and therapeutic strategies can benefit from considering the role of continuous interactions between follicle cells and oocytes from the beginning of histogenesis to full maturation. C1 NIA, IRP, Genet Lab, Triad Technol Ctr,NIH, Baltimore, MD 21224 USA. Univ Modena, Dept Mother & Child, I-41100 Modena, Italy. Univ Cagliari, CNR, Ist Neurogenet & Neuroanat, Cagliari, Italy. Univ Milan, Fac Med, Dept Human Anat, Funct Anat Res Ctr, Milan, Italy. RP Ottolenghi, C (reprint author), NIA, IRP, Genet Lab, Triad Technol Ctr,NIH, Suite 3000,333 Cassell Dr, Baltimore, MD 21224 USA. EM ottolenghich@grc.nia.nih.gov RI Ko, Minoru/B-7969-2009; sforza, chiarella/C-3008-2015 OI Ko, Minoru/0000-0002-3530-3015; sforza, chiarella/0000-0001-6532-6464 NR 109 TC 51 Z9 52 U1 0 U2 8 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-535-4 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2004 VL 1034 BP 117 EP 131 DI 10.1196/annals.1335.015 PG 15 WC Multidisciplinary Sciences; Obstetrics & Gynecology; Reproductive Biology SC Science & Technology - Other Topics; Obstetrics & Gynecology; Reproductive Biology GA BBW46 UT WOS:000228130100011 PM 15731305 ER PT B AU Berzofsky, JA Belyakov, IM AF Berzofsky, JA Belyakov, IM BE DeQuadros, CA TI Mucosal vaccines to induce cellular immunity against HIV and other viral infections SO VACCINES: PREVENTING DISEASE AND PROTECTING HEALTH SE PAN AMERICAN HEALTH ORGANIZATION SCIENTIFIC PUBLICATION LA English DT Proceedings Paper CT Conference on Vaccines, Prevention and Public Health CY NOV 25-27, 2002 CL Pan Amer Hlth Org, Washington, DC HO Pan Amer Hlth Org ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; COLONY-STIMULATING FACTOR; ANTIBODY-RESPONSES; INTRANASAL IMMUNIZATION; ENVELOPE GLYCOPROTEIN; ALPHA SYNERGIZE; PEPTIDE VACCINE; MICE; IL-12 C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NR 32 TC 0 Z9 0 U1 0 U2 1 PU PAN AMERICAN HEALTH ORGANIZATION PI WASHINGTON PA 525 TWENTY-THIRD ST NW, WASHINGTON, DC 20037 USA BN 92-75-11596-6 J9 PAHO SCI P PY 2004 IS 596 BP 223 EP 237 PG 15 WC Public, Environmental & Occupational Health; Immunology; Infectious Diseases SC Public, Environmental & Occupational Health; Immunology; Infectious Diseases GA BAE77 UT WOS:000221907000029 ER PT J AU McDermott, MM Greenland, P Guralnik, JM Ferrucci, L Green, D Liu, K Criqui, MH Schneider, JR Chan, C Ridker, P Pearce, WH Martin, G Clark, E Taylor, L AF McDermott, MM Greenland, P Guralnik, JM Ferrucci, L Green, D Liu, K Criqui, MH Schneider, JR Chan, C Ridker, P Pearce, WH Martin, G Clark, E Taylor, L TI Inflammatory markers, D-dimer, pro-thrombotic factors, and physical activity levels in patients with peripheral arterial disease SO VASCULAR MEDICINE LA English DT Article DE C-reactive protein; D-dimer; intermittent claudication; peripheral arterial disease; physical activity; physical functioning ID ISCHEMIC-HEART-DISEASE; C-REACTIVE PROTEIN; NECROSIS-FACTOR-ALPHA; PLASMA-FIBRINOGEN; PLASMINOGEN-ACTIVATOR; HEMOSTATIC FACTORS; SKELETAL-MUSCLE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION AB Men and women with lower extremity peripheral arterial disease (PAD) have reduced physical activity levels compared with persons without PAD. We describe associations between physical activity levels with D-dimer, pro-coagulant factors, and inflammatory markers in patients with PAD. Participants were 188 patients with PAD identified from non-invasive vascular laboratories. Physical activity was measured over 7 days with a vertical accelerometer. We measured the ankle-brachial index (ABI) and levels of D-dimer, C-reactive protein (CRP), fibrinogen, serum amyloid A (SAA), prothrombin 1.2, t-PA antigen, PAI-1, and the t-PA antigen/PAI-1 ratio. Adjusting for age, sex, race, body mass index, ABI, comorbidities, smoking, total cholesterol/HDL ratio and statin use (for CRP only), we found significant inverse linear associations between physical activity levels and log D-dimer (p = 0.002), log CRP (p < 0.001), fibrinogen (p = 0.014), and log SAA (p = 0.012). There were no significant associations between physical activity levels and other blood factors. In an analysis adjusting for all blood factors simultaneously along with known and potential confounders, log D-dimer was the only blood factor associated significantly with physical activity levels (p = 0.036). Based on these findings, future studies should assess whether interventions to increase physical activity in patients with PAD reduce levels of D-dimer and inflammatory markers. C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Northwestern Univ, Evanston Hosp, Evanston, IL 60201 USA. Harvard Univ, Sch Med, Boston, MA USA. St Josephs Med Ctr, Chicago, IL USA. Oregon Hlth & Sci Univ, Portland, OR USA. RP McDermott, MM (reprint author), Northwestern Feinberg Sch Med, Dept Med, Ste 18-200,675 N St Clair St, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU NCRR NIH HHS [RR-00048]; NHLBI NIH HHS [R01-HL58099, R01-HL64739] NR 54 TC 20 Z9 21 U1 0 U2 2 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PY 2004 VL 9 IS 2 BP 107 EP 115 DI 10.1191/1358863x04vm525oa PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 856RO UT WOS:000224062600003 PM 15521700 ER PT J AU Cardillo, C Mettimano, M Mores, N Koh, KK Campia, U Panza, JA AF Cardillo, C Mettimano, M Mores, N Koh, KK Campia, U Panza, JA TI Plasma levels of cell adhesion molecules during hyperinsulinemia and modulation of vasoactive mediators SO VASCULAR MEDICINE LA English DT Article DE cell adhesion molecules; endothelin; endothelium; insulin; nitric oxide ID INSULIN-RESISTANCE; ENDOTHELIAL-CELLS; NITRIC-OXIDE; METABOLIC SYNDROME; DIABETES-MELLITUS; EXPRESSION; ACTIVATION; RECEPTOR; OBESITY; POTENT AB Endothelial expression of cell adhesion molecules (CAMs) plays an important role in atherosclerosis. Atherosclerosis is increased in hyperinsulinemic states, but whether insulin per se is proatherogenic remains unclear. To investigate the effects of hyperinsulinemia on CAM expression, plasma levels of ICAM-1, VCAM-1 and E-selectin were measured before and after forearm infusion of insulin in healthy subjects. Insulin administration for 2 h resulted in significant hyperinsulinemia, whereas no significant change was observed in soluble CAMs (all p > 0.05). Because insulin stimulates endothelial release of both endothelin-1 (ET-1) and nitric oxide ( NO), which may modulate the expression of CAMs, we also investigated the response of CAMs to ET-1 receptor blockade, alone and in combination with NO synthesis inhibition. ET-1 receptor blockade during hyperinsulinemia resulted in a vasodilator response, but did not affect soluble CAMs (all p > 0.05). Superimposition of NO inhibition by L-NMMA reversed the vasodilator effect of ET-1 blockade, without affecting soluble CAMs (all p > 0.05). In conclusion, acute hyperinsulinemia, alone or during ET-1 and NO pathway blockade, does not affect soluble CAMs. These results do not support a direct effect of insulin on endothelial cells to affect leukocyte adhesiveness to the vascular wall. C1 NHLBI, Bethesda, MD 20892 USA. Catholic Univ, Rome, Italy. Gachon Med Ctr, Inchon, South Korea. Cardiovasc Res Inst, Washington, DC USA. RP Panza, JA (reprint author), Washington Hosp Ctr, 110 Irving St NW,Suite 2A 74, Washington, DC 20010 USA. EM julio.a.panza@medstar.net OI Campia, Umberto/0000-0002-7894-3565; MORES, Nadia/0000-0002-4197-0914 NR 27 TC 2 Z9 2 U1 0 U2 0 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PY 2004 VL 9 IS 3 BP 185 EP 188 DI 10.1191/1358863x04vm546oa PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 885VM UT WOS:000226185300004 PM 15675182 ER PT J AU Sahagun-Ruiz, A Sierra-Honigmann, AM Krause, P Murphy, PM AF Sahagun-Ruiz, A Sierra-Honigmann, AM Krause, P Murphy, PM TI Simian cytomegalovirus encodes five rapidly evolving chemokine receptor homologues SO VIRUS GENES LA English DT Article DE chemokine; cytomegalovirus; genomics; herpesvirus; inflammation; receptor ID PROTEIN-COUPLED RECEPTOR; KAPOSIS-SARCOMA; MOLECULAR MIMICRY; US28; GENE; IDENTIFICATION; PATHOGENESIS; EXPRESSION; DELETION; SYSTEM AB Many herpesviruses, poxviruses and retroviruses encode proteins related to chemokines and chemokine receptors. The first one discovered, US28 of human cytomegalovirus ( HCMV), is a 7-transmembrane domain G protein-coupled chemokine receptor able to activate diverse cellular responses, including cell migration and gene expression. A related ORF named US27 is adjacent to US28, but no functions have been defined yet. Recently ORFs 3-7, a cluster of five concatenated ORFs with highest homology to US28 and mammalian chemokine receptors, were sequenced from a prototype "stealth virus'', an African green monkey simian CMV (SCMV)-related entity with unusual fungal, bacterial and mammalian gene homologues. Stealth viruses have not yet been independently replicated in tissue culture, and therefore their biological significance remains unclear. ORF3, ORF4, ORF5 and ORF6 are complete ORFs whereas the sequence of ORF7 is incomplete. In the present study, we identified five corresponding ORFs in the genome of a clinical isolate of bona. de simian CMV ( SCMV), strain 9610. We found substantial differences between the SCMV and "stealth virus'' ORFs, especially for ORF5 where there are 31% nonidentities at the amino acid level. Four conserved genes unrelated to chemokines (64K/CAP, DNBI, UL32, and IE2) in SCMV and HCMV had on average 52% identity at the deduced amino acid level, whereas the corresponding values for the SCMV ORFs versus US28 ranged from 21% to 30%, suggesting rapid gene diversification in this cluster. Consistent with this, the amino acid identity for any pairwise comparison among the SCMV ORFs is only 21 - 52%. The chemokine receptor homologues are estimated to comprise similar to 2 - 3% of the SCMV genome. HCMV US27 and US28 homologues have also been identified in the chimpanzee CMV genome, whereas mouse and rat CMV lack chemokine receptor homologues. This genomic analysis indicates that SCMV has an unusually high concentration of US28-related chemokine receptor homologues that have arisen by gene duplication and have diverged extensively from their closest relatives in mammals and other beta herpesviruses. The rate of divergence appears to be very rapid compared to other known SCMV genes, suggesting strong positive selection. C1 NIAID, Mol Signalling Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Mol Signalling Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. EM pmm@nih.gov NR 27 TC 17 Z9 19 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-8569 J9 VIRUS GENES JI Virus Genes PD JAN PY 2004 VL 28 IS 1 BP 71 EP 83 DI 10.1023/B:VIRU.0000012265.33168.b5 PG 13 WC Genetics & Heredity; Virology SC Genetics & Heredity; Virology GA 764NU UT WOS:000188213600006 PM 14739653 ER PT J AU Bernier, M He, HJ Kwon, YK Jang, HJ AF Bernier, M He, HJ Kwon, YK Jang, HJ TI The roles of phospholipase C-gamma 1 and actin-binding protein filamin A in signal transduction of the insulin receptor SO VITAMINS AND HORMONES - ADVANCES IN RESEARCH AND APPLICATIONS, VOL 69 SE VITAMINS AND HORMONES-ADVANCES IN RESEARCH AND APPLICATIONS LA English DT Review ID PLECKSTRIN HOMOLOGY DOMAIN; GROWTH-FACTOR RECEPTOR; TYROSINE KINASE-ACTIVITY; FACTOR-I RECEPTOR; C-GAMMA; 3T3-L1 ADIPOCYTES; BETA-SUBUNIT; SH2 DOMAIN; SERINE PHOSPHORYLATION; CYTOPLASMIC DOMAINS C1 NIA, Diabet Sect, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Diabet Sect, Baltimore, MD 21224 USA. RI jang, hyeung jin/C-8022-2013; OI Bernier, Michel/0000-0002-5948-368X NR 113 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0083-6729 J9 VITAM HORM PY 2004 VL 69 BP 221 EP 247 DI 10.1016/S0083-6729(04)69008-X PG 27 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA BAR08 UT WOS:000223227200008 PM 15196884 ER PT J AU Heesch, KC Masse, LC AF Heesch, KC Masse, LC TI Lack of time for physical activity: Perception or reality for African American and Hispanic women? SO WOMEN & HEALTH LA English DT Article DE exercise; correlates; health promotion; barriers ID LIFE-STYLE; MINORITY WOMEN; EXERCISE; PREVENTION; DISEASE; HEALTH; LEISURE AB Lack of time is a well-known barrier to physical activity. It is not known, however, whether this barrier reflects actual time commitments. This study examined time commitments of women and assessed the relationship between time commitments and perceived lack of time for physical activity. Participants were 249 African American and Hispanic women, aged 45 to 70 years. These women devoted much of their time to their responsibilities as workers, housekeepers, mothers and wives. They also spent 28 hours per week in sedentary leisure-time activity. Actual time commitments did not predict perceived lack of time for physical activity. These findings can be used to address the misperceptions of women about time available to them for physical activity. C1 Univ Oklahoma, Dept Hlth & Sport Sci, Norman, OK 73019 USA. NCI, Div Canc Control & Populat Sci, Hlth Promot Res Branch, Behav Res Program, Bethesda, MD 20892 USA. RP Heesch, KC (reprint author), Univ Oklahoma, Dept Hlth & Sport Sci, HHC 119, Norman, OK 73019 USA. EM kheesch@ou.edu RI Heesch, Kristi/B-7863-2009; Heesch, Kristiann/J-1288-2012 OI Heesch, Kristiann/0000-0003-1931-3683 FU ODCDC CDC HHS [U48/CC609653] NR 32 TC 19 Z9 19 U1 1 U2 6 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0363-0242 J9 WOMEN HEALTH JI Women Health PY 2004 VL 39 IS 3 BP 45 EP 62 DI 10.1300/j013v39n03_04 PG 18 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 855QY UT WOS:000223990000004 PM 15256355 ER PT B AU Casper, LA King, RB AF Casper, LA King, RB BE Crouter, AC Booth, A TI Changing families, shifting economic fortunes, and meeting basic needs SO WORK-FAMILY CHALLENGES FOR LOW-INCOME PARENTS AND THEIR CHILDREN- LA English DT Proceedings Paper CT Symposium on Work Family Challenges for Low Income Parents and Their Children CY OCT 10-11, 2003 CL PENN STATE UNIV, UNIVERSITY PK, PA HO PENN STATE UNIV ID INEQUALITY C1 NICHHD, Bethesda, MD 20892 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU LAWRENCE ERLBAUM ASSOC PUBL PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430 USA BN 0-8058-4600-X PY 2004 BP 55 EP 79 PG 25 WC Economics; Family Studies; Industrial Relations & Labor; Public Administration SC Business & Economics; Family Studies; Public Administration GA BY39F UT WOS:000189159900004 ER PT B AU Salicrup, LA Rohrbaugh, M AF Salicrup, LA Rohrbaugh, M GP MEDIMOND TI Partnerships in technology transfer - An innovative way apply to HIV/AIDS research into policy and program implementation SO XV INTERNATIONAL AIDS CONFERENCE: POLICY AND PROGRAM IMPLEMENTATION LA English DT Proceedings Paper CT 15th International AIDS Conference CY JUL 11-17, 2004 CL Bangkok, THAILAND AB As part of the U.S. National Institutes of Health (NIH)' s mission of biomedical research to extend healthy life by reducing the burdens of illness and as part of a coordinated effort to address some of the existing gaps related to the availability to the general public of NIH inventions, the NIH ' s Office of Technology Transfer (OTT) is currently working on ways to enhance the process of transferring technologies to developing countries. OTT is identifying biomedical research institutions, foundations and companies in Africa, Asia, Latin America, the Caribbean, the Middle East, and some of the transitional economies from Central and Eastern Europe where we have learned by working with institutions in those countries, international organizations and private foundations that there is a need and potential to transfer different Public Health Service technologies including those related to HIV/AIDS and tuberculosis. OTT has already had some initial success in transferring technologies to India, China and Mexico and some countries in Sub-Saharan Africa. Additional negotiations are currently going on with public and private institutions in Brazil, South Africa, India, and China. This effort is helping OTT/NIH meet an important part of its mission reducing the burden of diseases in developing countries. It is also expected that participating institutions would be able to address some of their crucial public health needs and to enhance the prevention and care of HIV/AIDS and related-diseases by having access and availability to key technologies. technologies including those related to HIV/AIDS and tuberculosis. By working with institutions in those countries, international organizations and private foundations, OTT has identified needs and opportunities to transfer NIH technologies including those related to HIV/AIDS, tuberculosis, and other endemic or neglected diseases malaria, dengue, rotavirus, meningitis, West Nile Virus, pertussis, and diabetes. C1 NIH, Off Technol Transfer, Rockville, MD USA. RP Salicrup, LA (reprint author), NIH, Off Technol Transfer, Rockville, MD USA. NR 4 TC 0 Z9 0 U1 1 U2 2 PU MEDIMOND PUBLISHING CO PI BOLOGNA PA VIA RUBBIANI 6/2, 40124 BOLOGNA, ITALY BN 88-7587-065-9 PY 2004 BP 55 EP 58 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BBR14 UT WOS:000227337900012 ER PT J AU Weinstein, BM AF Weinstein, Brant M. TI Something's Fishy in Bethesda: Zebrafish in the NIH Intramural Program SO ZEBRAFISH LA English DT Article AB The NIH intramural program has roots more than a century old, but in the past few years it has seen tens of thousands of new arrivals to its Bethesda campus: zebrafish. This review discusses the origins of the NIH intramural program and zebrafish research on the NIH campus, and highlights the work of some of the intramural zebrafish laboratories. 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. EM flyingfish@nih.gov FU National Institute of Child Health and Human Development FX The author gratefully acknowledges the assistance of the NIH intramural researchers listed in this review for generously providing information about each of their laboratories for use in this article. They are Peter Aplan, Shawn Burgess, Settara Chandrasekharappa, Ajay Chitnis, Igor Dawid, Ben Feldman, Dennis Hickstein, Paul Liu, Ralph Nelson, Joram Piatigorsky, and Ramani Ramchandran. The author gratefully acknowledges the support of the National Institute of Child Health and Human Development for making it possible for him to offer this perspective on zebrafish research at the NIH. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 J9 ZEBRAFISH JI Zebrafish PY 2004 VL 1 IS 1 BP 12 EP 20 DI 10.1089/154585404774101635 PG 9 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA V18CU UT WOS:000207983700004 PM 18248201 ER PT J AU Henken, DB Rasooly, RS Javois, L Hewitt, AT AF Henken, Deborah B. Rasooly, Rebekah S. Javois, Lorette Hewitt, A. Tyl CA Natl Inst Hlth Trans-NIH Zebrafish TI The National Institutes of Health and the Growth of the Zebrafish as an Experimental Model Organism SO ZEBRAFISH LA English DT Review AB The National Institutes of Health (NIH), an agency in the Department of Health and Human Services (DHHS), is a strong advocate of zebrafish and other animal model systems for biomedical and behavior research. In part because of strong funding support from NIH, zebrafish research is now providing fundamental insights into physiology, behavior, and the mechanisms of human disease. Over the past few years, the NIH has established a research infrastructure for the zebrafish community that includes genomic resources and tools for genetic analysis in this system. In addition, the NIH supports community resources such as the Zebrafish International Resource Center (ZIRC) and the Zebrafish Information Network (ZFIN). With the importance of zebrafish research now well-established, NIH will continue to fund a broad array of investigator-initiated studies that focus on issues critical to human health using this model system. C1 [Henken, Deborah B.] NICHHD, Dev Biol Genet & Teratol Branch, NIH, Bethesda, MD 20892 USA. [Rasooly, Rebekah S.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Henken, DB (reprint author), NICHHD, Dev Biol Genet & Teratol Branch, NIH, Execut Bldg,Room 4B01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dh50g@nih.gov NR 8 TC 7 Z9 8 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 J9 ZEBRAFISH JI Zebrafish PY 2004 VL 1 IS 2 BP 105 EP 110 DI 10.1089/zeb.2004.1.105 PG 6 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA V18CV UT WOS:000207983800004 PM 18248222 ER PT J AU Kamei, M Isogai, S Weinstein, BM AF Kamei, M Isogai, S Weinstein, BM TI Imaging blood vessels in the zebrafish SO ZEBRAFISH: 2ND EDITION CELLULAR AND DEVELOPMENTAL BIOLOGY SE METHODS IN CELL BIOLOGY LA English DT Review ID TRANSGENIC ZEBRAFISH; VASCULAR DEVELOPMENT; IN-VIVO; EMBRYOS; VASCULOGENESIS; VERTEBRATE; EXPRESSION; NOTOCHORD C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Iwate Med Univ, Dept Anat 1, Sch Med, Morioka, Iwate 0208505, Japan. RP Kamei, M (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. OI Kamei, Makoto/0000-0002-1438-0783 NR 24 TC 15 Z9 16 U1 0 U2 2 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-679X J9 METHOD CELL BIOL PY 2004 VL 76 BP 51 EP 74 PG 24 WC Cell Biology SC Cell Biology GA BBS32 UT WOS:000227571500004 PM 15602871 ER PT J AU Schriml, LM Sprague, J AF Schriml, LM Sprague, J TI Data mining the zebrafish genome SO ZEBRAFISH:2ND EDITION GENETICS GENOMICS AND INFORMATICS SE METHODS IN CELL BIOLOGY LA English DT Review ID INFORMATION; UPDATE C1 Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Univ Oregon, ZFIN, Eugene, OR 97403 USA. RP Schriml, LM (reprint author), Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. OI Schriml, Lynn/0000-0001-8910-9851 FU NHGRI NIH HHS [P41HG002659] NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-679X J9 METHOD CELL BIOL PY 2004 VL 77 BP 415 EP 437 PG 23 WC Cell Biology SC Cell Biology GA BBL01 UT WOS:000225969100023 PM 15602925 ER PT J AU Golen, JA Williard, PG Ram, S Sachdeva, YP Wilson, DK Zhar, S Verma, RK AF Golen, JA Williard, PG Ram, S Sachdeva, YP Wilson, DK Zhar, S Verma, RK TI Crystal structure of 5-hydroxy-2,3,8,8-tetramethyl-4H,8H-benzo[1,2-b : 5,4-b ']dipyran-4-one, C16H16O4 SO ZEITSCHRIFT FUR KRISTALLOGRAPHIE-NEW CRYSTAL STRUCTURES LA English DT Article AB C16H16O4, monoclinic, P12(1)/c1 (no. 14), a = 9.149(2) Angstrom, b = 13.029(3) Angstrom, c = 11.608(2) Angstrom, beta = 99.90(3)degrees, V= 1363.1 Angstrom(3), Z = 4, R-gt(F) = 0.046, wR(ref)(F-2) = 0. 122, T= 296 K. C1 Univ Massachusetts, Dept Chem & Biochem, N Dartmouth, MA 02747 USA. Brown Univ, Dept Chem, Providence, RI 02912 USA. Pharm Eco Labs Inc, Lexington, MA 02173 USA. NCI, Pharmaceut Res Branch, NIH, Bethesda, MD 20892 USA. RP Golen, JA (reprint author), Univ Massachusetts, Dept Chem & Biochem, N Dartmouth, MA 02747 USA. EM jgolen@umassd.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU R OLDENBOURG VERLAG PI MUNICH PA LEKTORAT MINT, POSTFACH 80 13 60, D-81613 MUNICH, GERMANY SN 1433-7266 J9 Z KRIST-NEW CRYST ST JI Z. Krist.-New Cryst. Struct. PY 2004 VL 219 IS 4 BP 405 EP 406 PG 2 WC Crystallography SC Crystallography GA 893EU UT WOS:000226702900033 ER PT J AU Burks, KD Mellen, JD Miller, GW Lehnhardt, J Weiss, A Figueredo, AJ Maple, TL AF Burks, KD Mellen, JD Miller, GW Lehnhardt, J Weiss, A Figueredo, AJ Maple, TL TI Comparison of two introduction methods for African elephants (Loxodonta africana) SO ZOO BIOLOGY LA English DT Article DE aggression; behavioral management; socialization; group formation ID SQUIRREL-MONKEYS; BEHAVIOR AB Managers must consider an animal's potential for aggression when they decide to change or form a captive social group formation. In this study we compared two introduction methods (termed "sequential" and "nonsequential" introductions) in African elephants to assess their effectiveness in managing aggression and minimizing stress. Both introduction methods included four phases: baseline, visual contact, limited tactile contact, and physical introduction. In the sequential introduction, these steps were followed sequentially, and empirical data were considered during decision-making. In the nonsequential introduction, these steps were not followed sequentially, and decision-making was based primarily on intuitive assessments by animal managers. Behavioral data and fecal corticoid concentrations were measured throughout both types of introduction. The behavior categories measured included active aggression, passive aggression, submissive behavior, undesirable/stress-related behavior, and affiliative behavior. While the role of affiliative behavior was surprising, general behavior patterns were characterized by increases in behavior as animals progressed to the next phase of introduction regardless of introduction type. These increases then attenuated over time during each phase. Overall, less behavior was observed during the sequential introduction, as predicted. The data suggest that the sequential introduction managed aggression more effectively. Similar patterns were predicted for undesirable/stress-related behavior and fecal corticoid concentration. Undesirable/stress-related behavior was a poor predictor of observed behavior patterns. Although the patterns differed from those predicted, higher concentrations of fecal corticoids were measured during the nonsequential introduction and correlated significantly only with submissive behavior. While more investigation is warranted, the data indicate that the nonsequential introduction brought about an increased physiological response. Overall, the sequential introduction method appeared to manage aggression and stress better than the nonsequential technique. Every introduction is subject to factors that can influence success, such as staff experience, the design of the facility, and the animals' social histories. It is hoped that the rigorous sequential protocol will be a useful tool in the animal manager's "toolbox" for planning and implementing introductions. Applications of this introduction method are also discussed. (C) 2004 Wiley-Liss, Inc. C1 Disneys Anim Kingdom, Lake Buena Vista, FL 32830 USA. Univ Cent Florida, Dept Biol, Orlando, FL USA. Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. NIA, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. Georgia Inst Technol, Sch Psychol, Atlanta, GA 30332 USA. Zoo Atlanta, TECHLab, Atlanta, GA USA. RP Burks, KD (reprint author), Disneys Anim Kingdom, POB 10000, Lake Buena Vista, FL 32830 USA. EM kyle.burks@disney.com NR 30 TC 9 Z9 9 U1 3 U2 14 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0733-3188 J9 ZOO BIOL JI Zoo Biol. PY 2004 VL 23 IS 2 BP 109 EP 126 DI 10.1002/zoo.10132 PG 18 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 817OM UT WOS:000221186800002 ER PT J AU Almasy, L Amos, CI Bailey-Wilson, JE Cantor, RM Jaquish, CE Martinez, M Neuman, RJ Olson, JM Palmer, LJ Rich, SS Spence, MA Maccluer, JW AF Almasy, L Amos, CI Bailey-Wilson, JE Cantor, RM Jaquish, CE Martinez, M Neuman, RJ Olson, JM Palmer, LJ Rich, SS Spence, MA Maccluer, JW TI Genetic analysis workshop 13: Analysis of longitudinal family data for complex diseases and related risk factors SO BMC GENETICS LA English DT Editorial Material C1 SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78245 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77025 USA. NHGRI, NIH, Baltimore, MD 21224 USA. Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Hop St Louis, INSERM, F-91034 Evry, France. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Case Western Reserve Univ, Dept Biostat & Epidemiol, Cleveland, OH 44109 USA. Western Australia Inst Med Res, Genet Epidemiol Grp, Perth, WA 6000, Australia. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27517 USA. Univ Calif Irvine, Med Ctr, Dept Pediat, Orange, CA 92868 USA. RP Almasy, L (reprint author), SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78245 USA. EM almasy@darwin.sfbr.org; camos@request.mdacc.tmc.edu; jebw@nhgri.nih.gov; rcantor@mednet.ucla.edu; jaquishc@nhlbi.nih.gov; maria@evry.inserm.fr; roz@gretta.wustl.edu; olson@darwin.epbi.cwru.edu; lpalmer@cyllene.uwa.edu.au; srich@wfubmc.edu; maspence@uci.edu; jean@darwin.sfbr.org RI Palmer, Lyle/K-3196-2014; Martinez, Maria/B-3111-2013 OI Palmer, Lyle/0000-0002-1628-3055; Martinez, Maria/0000-0003-2180-4537 NR 0 TC 7 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S1 DI 10.1186/1471-2156-4-S1-S1 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900001 ER PT J AU Bergen, AW Yang, XHR Bai, Y Beerman, MB Goldstein, AM Goldin, LR AF Bergen, AW Yang, XHR Bai, Y Beerman, MB Goldstein, AM Goldin, LR TI Genomic regions linked to alcohol consumption in the Framingham Heart Study SO BMC GENETICS LA English DT Article; Proceedings Paper CT 13th Genetic Analysis Workshop CY NOV 11-14, 2002 CL NEW ORLEANS, LOUISIANA ID WIDE SEARCH; GENETIC-LINKAGE; SUBSTANCE-ABUSE; DEPENDENCE; RISK; VULNERABILITY; LOCI; NICOTINE; TOBACCO; SMOKING AB Background: Pedigree, demographic, square-root transformed maximum alcohol (SRMAXAPD) and maximum cigarette (MAXCPD) consumption, and genome-wide scan data from the Framingham Heart Study (FHS) were used to investigate genetic factors that may affect alcohol and cigarette consumption in this population-based sample. Results: A significant sister: sister correlation greater than spouse correlation was observed for MAXCPD only. Single-point sib-pair regression analysis provided nominal evidence for linkage of loci to both SRMAXAPD and MAXCPD consumption traits, with more significant evidence of linkage to SRMAXAPD than to MAXCPD. One genomic region, chr9q21.11, exhibits significant multi-point sib-pair regression to SRMAXAPD. Conclusion: SRMAXAPD exhibits greater evidence for genetic linkage than does MAXCPD in the FHS sample. Four regions of the genome exhibiting nominal evidence for linkage to SRMAXAPD in the FHS sample correspond to regions of the genome previously identified as linked to alcoholism or related traits in the family data set ascertained on individuals affected with alcohol dependence known as COGA. C1 NCI, Core Genotyping Facil, Ctr Adv Technol, NIH,DHHS, Gaithersburg, MD USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Gaithersburg, MD USA. SAIC Frederick Inc, Core Genotyping Facil, Frederick, MD USA. RP Bergen, AW (reprint author), NCI, Core Genotyping Facil, Ctr Adv Technol, NIH,DHHS, Gaithersburg, MD USA. EM bergena@mail.nih.gov; royang@mail.nih.gov; baiy@mail.nih.gov; beermanm@mail.nih.gov; goldstea@mail.nih.gov; goldinl@mail.nih.gov OI Bergen, Andrew/0000-0002-1237-7644 FU NCRR NIH HHS [P41 RR003655, P41 RR03655] NR 23 TC 42 Z9 43 U1 4 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S101 DI 10.1186/1471-2156-4-S1-S101 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900101 PM 14975169 ER PT J AU Cupples, LA Yang, Q Demissie, S Copenhafer, D Levy, D AF Cupples, LA Yang, Q Demissie, S Copenhafer, D Levy, D CA Framingham Heart Study Investigato TI Description of the Framingham Heart Study data for Genetic Analysis Workshop 13 SO BMC GENETICS LA English DT Article; Proceedings Paper CT 13th Genetic Analysis Workshop CY NOV 11-14, 2002 CL NEW ORLEANS, LOUISIANA C1 Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA. RP Cupples, LA (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. EM adrienne@bu.edu; qyang@bu.edu; demissie@bu.edu; dcopenha@math.bu.edu; dan@fram.nhlbi.nih.gov RI Yang, Qiong/G-5438-2014 NR 2 TC 13 Z9 13 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S2 DI 10.1186/1471-2156-4-S1-S2 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900002 PM 14975070 ER PT J AU Klein, AP Kovac, I Sorant, AJM Baffoe-Bonnie, A Doan, BQ Ibay, G Lockwood, E Mandal, D Santhosh, L Weissbecker, K Woo, J Zambelli-Weiner, A Zhang, J Naiman, DQ Malley, J Bailey-Wilson, JE AF Klein, AP Kovac, I Sorant, AJM Baffoe-Bonnie, A Doan, BQ Ibay, G Lockwood, E Mandal, D Santhosh, L Weissbecker, K Woo, J Zambelli-Weiner, A Zhang, J Naiman, DQ Malley, J Bailey-Wilson, JE TI Importance sampling method of correction for multiple testing in affected sib-pair linkage analysis SO BMC GENETICS LA English DT Article; Proceedings Paper CT 13th Genetic Analysis Workshop CY NOV 11-14, 2002 CL NEW ORLEANS, LOUISIANA ID SCANS AB Using the Genetic Analysis Workshop 13 simulated data set, we compared the technique of importance sampling to several other methods designed to adjust p-values for multiple testing: the Bonferroni correction, the method proposed by Feingold et al., and naive Monte Carlo simulation. We performed affected sib-pair linkage analysis for each of the 100 replicates for each of five binary traits and adjusted the derived p-values using each of the correction methods. The type I error rates for each correction method and the ability of each of the methods to detect loci known to influence trait values were compared. All of the methods considered were conservative with respect to type I error, especially the Bonferroni method. The ability of these methods to detect trait loci was also low. However, this may be partially due to a limitation inherent in our binary trait definitions. C1 NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Johns Hopkins Med Sch, CIDR, Baltimore, MD USA. Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA USA. Tulane Univ, Dept Psychiat & Neurol, New Orleans, LA 70118 USA. Tulane Univ, Hayward Genet Program, New Orleans, LA 70118 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Dept Math Sci, Baltimore, MD 21218 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Bailey-Wilson, JE (reprint author), NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. EM aklein@nhgri.nih.gov; ikovac@nhgri.nih.gov; ajms@nhgri.nih.gov; a_bonnie@fccc.edu; bdoan@jhsph.edu; gibay@nhgri.nih.gov; elock1@umbc.edu; dmanda@lsuhsc.edu; leksparv@cidr.nhgri.nih.gov; kremer@tulane.edu; jagwoo@yahoo.com; azambell@jhsph.edu; jiezhang@cidr.jhmi.edu; daniel.naiman@jhu.edu; jmalley@helix.nih.gov; jebw@nhgri.nih.gov FU NCRR NIH HHS [RR03655, P41 RR003655] NR 11 TC 4 Z9 4 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S73 DI 10.1186/1471-2156-4-S1-S73 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900073 PM 14975141 ER PT J AU Lin, JP AF Lin, JP TI Genome-wide scan on plasma triglyceride and high density lipoprotein cholesterol levels, accounting for the effects of correlated quantitative phenotypes SO BMC GENETICS LA English DT Article; Proceedings Paper CT 13th Genetic Analysis Workshop CY NOV 11-14, 2002 CL NEW ORLEANS, LOUISIANA ID TRAIT LINKAGE ANALYSIS; MAJOR LOCUS; FRAMINGHAM; DISEASE; RATIO; GENE AB Background: Plasma triglyceride and high density lipoprotein cholesterol levels are inversely correlated and both are genetically related. Two correlated traits may be influenced both by shared and unshared genes. The power to detect unshared trait-specific genes may be increased by incorporating correlated traits as covariates. The power to localize the shared genes may be improved by bivariate analysis. Univariate genome scans were carried out on triglyceride ( high density lipoprotein cholesterol) with and without using high density lipoprotein cholesterol ( triglyceride) as a covariate, and bivariate linkage analysis on triglyceride and high density lipoprotein cholesterol using the 330 Framingham pedigrees of the Genetic Analysis Workshop 13 data. The results of five genome scans were compared to determine the chromosomal regions which may harbor the genes influencing variation specific to triglycerides, specific to high density lipoprotein cholesterol, or the covariation of both triglyceride and high density lipoprotein cholesterol. Results: The results of our five genome scans identified some chromosomal regions with possible quantitative trait loci (QTL) that may specifically influence one trait, such as the regions on chromosome 1 ( at 1 cM near marker 280we5), on high density lipoprotein cholesterol, or control the covariation of both traits, such as the regions on chromosome 7 ( at 169 cM near marker GATA30D09), chromosome 12 ( at 3 cM near marker GATA4H03), chromosome 20 ( at 49 cM near marker GATA29F06), chromosome 2 ( at 146 cM near marker GATA8H05), and chromosome 6 ( at 148 cM near marker GATA184A08) on triglyceride and high density lipoprotein cholesterol. The one on chromosome 6 had a LOD score of 3.1 with the bivariate linkage analysis. Conclusion: There is strong evidence for a QTL on chromosome 6 near marker GATA184A08 appearing to influence the variation of high density lipoprotein cholesterol and triglycerides in the Framingham population. C1 NHLBI, Off Biostat Res, DECA, NIH, Bethesda, MD 20892 USA. RP Lin, JP (reprint author), NHLBI, Off Biostat Res, DECA, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM linj@nhlbi.nih.gov NR 11 TC 6 Z9 6 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S47 DI 10.1186/1471-2156-4-S1-S47 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900047 PM 14975115 ER PT J AU Mathias, RA Roy-Gagnon, MH Justice, CM Papanicolaou, GJ Fan, YT Pugh, EW Wilson, AF AF Mathias, RA Roy-Gagnon, MH Justice, CM Papanicolaou, GJ Fan, YT Pugh, EW Wilson, AF TI Comparison of year-of-exam- and age-matched estimates of heritability in the Framingham Heart Study data SO BMC GENETICS LA English DT Article; Proceedings Paper CT 13th Genetic Analysis Workshop CY NOV 11-14, 2002 CL NEW ORLEANS, LOUISIANA AB Several different approaches can be used to examine generational and temporal trends in family studies. The measurement of offspring and parents can be made over a short period of time with parents and offspring having quite different ages, or measurements can be made at the same ages but with decades between parent and offspring measures. A third approach, used in the Framingham Heart Study, has repeated examinations across a broad range of age and time, and provides a unique opportunity to compare these approaches. Parents and offspring were matched both on ( year of exam) and on age. Heritability estimates for systolic blood pressure, body mass index, height, weight, cholesterol, and glucose were obtained by regressing offspring on midparent values with and without adjustment for age. Higher estimates of heritability were obtained for age-matched than for year-of-exam-matched data for all traits considered. For most traits, estimates of the heritability of the change over time ( slope) of the trait were near zero. These results suggest that the optimal design to identify genetic effects in traits with large age-related effects may be to measure parents and offspring at similar ages and not to rely on age-adjustment or longitudinal measures to account for these temporal effects. C1 NHGRI, Genometr Sect, NIH, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Ctr Inherited Dis Res, Baltimore, MD USA. RP Wilson, AF (reprint author), NHGRI, Genometr Sect, NIH, 333 Cassell Dr, Baltimore, MD USA. EM rmathias@nhgri.nih.gov; mrgagnon@jhsph.edu; cmj@nhgri.nih.gov; gjp@nhgri.nih.gov; rfan@cidr.jhmi.edu; ewp@cidr.jhmi.edu; afw@nhgri.nih.gov NR 2 TC 13 Z9 13 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S36 DI 10.1186/1471-2156-4-S1-S36 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900036 PM 14975104 ER PT J AU Moslehi, R Goldstein, AM Beerman, M Goldin, L Bergen, AW AF Moslehi, R Goldstein, AM Beerman, M Goldin, L Bergen, AW TI A genome-wide linkage scan for body mass index on Framingham Heart Study families SO BMC GENETICS LA English DT Article; Proceedings Paper CT 13th Genetic Analysis Workshop CY NOV 11-14, 2002 CL NEW ORLEANS, LOUISIANA ID QUANTITATIVE-TRAIT LOCI; LEPTIN LEVELS; PIMA-INDIANS; OBESITY; PHENOTYPES; AMERICANS; FAT AB Background: Genome-wide scan data from a community-based sample was used to identify the genetic factors that affect body mass index (BMI). BMI was defined as weight (kg) over the square of height (m), where weight and height were obtained from the first measurement available between the ages of 40 and 50 years. Results: Significant familial correlations were observed in mother: father (spouse) relative pairs and in all relative pairs examined except parent: daughter pairs. Single-point sib-pair regression analysis provided nominal evidence for linkage (p < 0.05) of loci to BMI at 23 markers. Multi-point sib-pair regression analysis provided nominal evidence for linkage to BMI at 42 loci on 12 chromosomes. Empirical p-values showed results consistent with the multi-point results; all but three of the loci identified by multi-point analysis were also significant. Conclusion: The largest regions of nominally significant linkage were found on chromosomes 2, 3, and 11. The most significant evidence for linkage was obtained with markers D2S1788, D2S1356, D2S1352, D3S1744, and D11S912 from multi-point sib-pair single-trait regression analysis. Our results are in agreement with some of the recently published reports on BMI using various data sets including the Framingham Heart Study data. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Core Genotyping Facil, Ctr Adv Technol, NIH,DHHS, Gaithersburg, MD USA. RP Moslehi, R (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. EM moslehir@mail.nih.gov; goldstea@mail.nih.gov; beermanm@mail.nih.gov; goldin1@mail.nih.gov; bergena@mail.nih.gov FU NCRR NIH HHS [1 P41 RR03655, P41 RR003655] NR 16 TC 15 Z9 15 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S97 DI 10.1186/1471-2156-4-S1-S97 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900097 PM 14975165 ER PT J AU Wu, CO Zheng, G Leifer, E Follmann, D Lin, JP AF Wu, CO Zheng, G Leifer, E Follmann, D Lin, JP TI A statistical method for adjusting covariates in linkage analysis with sib pairs SO BMC GENETICS LA English DT Article; Proceedings Paper CT 13th Genetic Analysis Workshop CY NOV 11-14, 2002 CL NEW ORLEANS, LOUISIANA AB Background: We propose a statistical method that includes the use of longitudinal regression models and estimation procedures for adjusting for covariate effects in applying the Haseman-Elston ( HE) method for linkage analysis. Our methodology, which uses the covariate adjusted trait, contains three steps: a) modelling the covariate-adjusted population means of quantitative traits through regression; b) estimating the value of covariate-adjusted quantitative traits; and c) evaluating the linkage between the adjusted trait values and the markers based on alleles shared identically by descent. Results: We applied our adjusted HE method and the standard HE method in S. A. G. E. to the sib-pair subset of the Framingham Heart Study distributed by Genetic Analysis Workshop 13 with systolic blood pressure as the quantitative trait. Both methods gave similar patterns for the LOD scores, and exhibited highest multipoint LOD scores near location 70 cM of chromosome 12. Conclusion: The adjusted HE method has two major advantages over the standard HE method used in S. A. G. E.: a) it has the capability to handle longitudinal data; b) it provides a more natural approach for adjusting the repeatedly measured covariates from each subject. C1 NHLBI, Off Biostat, DECA, Bethesda, MD 20892 USA. RP Wu, CO (reprint author), NHLBI, Off Biostat, DECA, 2 Rockledge Ctr, Bethesda, MD 20892 USA. EM wuc@nhlbi.nih.gov; zhengg@nhlbi.nih.gov; leifere@nhlbi.nih.gov; dfollmann@niaid.nih.gov; linj@nhlbi.nih.gov FU NCRR NIH HHS [P41 RR003655, RR03655] NR 10 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD DEC 31 PY 2003 VL 4 SU 1 AR S51 DI 10.1186/1471-2156-4-S1-S51 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 765ZL UT WOS:000188320900051 PM 14975119 ER PT J AU Brossi, A AF Brossi, A TI Preface of the special issue "30 years heterocycles" SO HETEROCYCLES LA English DT Editorial Material C1 Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. NIH, Bethesda, MD 20892 USA. RP Brossi, A (reprint author), Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0385-5414 J9 HETEROCYCLES JI Heterocycles PD DEC 31 PY 2003 VL 61 BP 3 EP 3 PG 1 WC Chemistry, Organic SC Chemistry GA 763CJ UT WOS:000188053700002 ER PT J AU Yu, QS Luo, WM Holloway, HW Utsuki, T Perry, TA Lahiri, DK Greig, NH Brossi, A AF Yu, QS Luo, WM Holloway, HW Utsuki, T Perry, TA Lahiri, DK Greig, NH Brossi, A TI Racemic N(1)-norphenserine and its enantiomers: Unpredicted inhibition of human acetyl- and butyrylcholinesterase and beta-amyloid precursor protein in vitro SO HETEROCYCLES LA English DT Article DE racemic; N '-norphenserine; enantiomer; acetyl- and butyrylcholinesterases; beta-amyloid precursor ID ALZHEIMER DRUG PHENSERINE; ANTICHOLINESTERASE ACTIVITY; FACILE PREPARATION; ANTIPODAL ISOMERS; CARBAMATE ANALOGS; DISEASE; (-)-PHYSOSTIGMINE; (-)-ESEROLINE; PHYSOSTIGMINE; TARGETS AB The optically pure enantiomers of N'-norphenserine (15, 16) were synthesized and its racemate 17 was prepared by mixing equal parts of each enantiomer. (-)-N'-Norphenserine (15) was prepared by partial synthesis initiated from the natural product, (-)-physostigmine (1). (+)-N'-Norphenserine (16) was prepared by total synthesis using the Julian oxindole route, with modifications. The in vitro inhibitory activities of 15-17 were quantified against human erythrocyte AChE and plasma BChE as well as against human neuroblastoma cell beta-amyloid precursor protein secretion in cell culture. All were active. Racemic compound (17) with a high AChE and beta-amyloid precursor protein inhibitory action may warrant further assessment in Alzheimer's disease models. C1 NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM GreigN@vax.nia.nih.gov NR 33 TC 13 Z9 14 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0385-5414 J9 HETEROCYCLES JI Heterocycles PD DEC 31 PY 2003 VL 61 BP 529 EP + PG 12 WC Chemistry, Organic SC Chemistry GA 763CJ UT WOS:000188053700058 ER PT J AU Khidekel, N Arndt, S Lamarre-Vincent, N Lippert, A Poulin-Kerstien, KG Ramakrishnan, B Qasba, PK Hsieh-Wilson, LC AF Khidekel, N Arndt, S Lamarre-Vincent, N Lippert, A Poulin-Kerstien, KG Ramakrishnan, B Qasba, PK Hsieh-Wilson, LC TI Chemoenzymatic approach toward the rapid and sensitive detection of O-GlcNAc posttranslational modifications SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LINKED N-ACETYLGLUCOSAMINE; PROTEINS; IDENTIFICATION; GLYCOPROTEINS; GLYCOSYLATION C1 CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. SAIC Frederic Inc, NCI, Struct Glycobiol Sect, Lab Expt & Computat Biol,CCR, Ft Detrick, MD 21702 USA. RP Hsieh-Wilson, LC (reprint author), CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. EM lhw@caltech.edu NR 24 TC 134 Z9 139 U1 7 U2 35 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 DEC 31 PY 2003 VL 125 IS 52 BP 16162 EP 16163 DI 10.1021/ja038545r PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 757RG UT WOS:000187574800003 PM 14692737 ER PT J AU Cheng, SY AF Cheng, SY TI Thyroid hormone receptor mutations in cancer SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Conference on Thyroid and Gonadal Hormones in Health and Disease CY JUN, 2002 CL HEINRICH FABRI INST, BLAUBEUREN ULM, GERMANY SP European Union HO HEINRICH FABRI INST DE thyroid hormone receptor mutations; thyroid cancer; metastasis; microarrays; mouse models; carcinogenesis ID DOMINANT-NEGATIVE ACTIVITY; SECRETING PITUITARY-TUMOR; CLEAR-CELL CARCINOMA; HEPATOCELLULAR-CARCINOMA; TRANSCRIPTIONAL ACTIVITY; NUCLEAR RECEPTORS; V-ERBA; SIGNALING PATHWAYS; LIGAND-BINDING; SUPPRESSOR P53 AB The thyroid hormone receptors (TRs) mediate the pleiotropic activities of the thyroid hormone (T3) in growth, development, and differentiation and in maintaining metabolic homeostasis. They are ligand-dependent transcription factors and are members of the steroid hormone/retionic acid receptor superfamily. Two TR genes, alpha and beta, located on human chromosomes 17 and 3, respectively, have been identified. That they are cellular homologs of the retroviral v-erbA oncogene suggests their possible involvement in carcinogenesis. Recent studies showed altered expression of TRs at both the mRNA and protein levels and identified somatic mutations of TRs in several human cancers. Furthermore, male transgenic mice overexpressing v-erbA oncogene develop hepatocellular carcinoma. Importantly, a targeted germline mutation of the TRbeta gene leads to the occurrence of metastatic thyroid carcinoma in homozygous mutant mice. These findings provide evidence to support the critical role of TRs in human cancer. Published by Elsevier Ireland Ltd. C1 NCI, Gene Regulat Sect, Mol Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Gene Regulat Sect, Mol Biol Lab, Canc Res Ctr, Bldg 37,Room 5128,37 Convent Dr MSC 4264, Bethesda, MD 20892 USA. EM sycheng@helix.nih.gov NR 52 TC 32 Z9 32 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD DEC 31 PY 2003 VL 213 IS 1 SI SI BP 23 EP 30 DI 10.1016/j.mce.2003.10.051 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 773DG UT WOS:000188882000004 PM 15062571 ER PT J AU Obsil, T Ghirlando, R Anderson, DE Hickman, AB Dyda, F AF Obsil, T Ghirlando, R Anderson, DE Hickman, AB Dyda, F TI Two 14-3-3 binding motifs are required for stable association of forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding SO BIOCHEMISTRY LA English DT Article ID MULTIPLE SIGNALING PATHWAYS; FACTOR AFX; CRYSTAL-STRUCTURE; KINASE-B; PHOSPHORYLATION SITES; NUCLEAR-LOCALIZATION; CELL-CYCLE; FKHR; TRANSACTIVATION; IDENTIFICATION AB dThe 14-3-3 proteins, a family of dimeric regulatory proteins, are involved in many biologically important processes. The common feature of 14-3-3 proteins is their ability to bind to other proteins in a phosphorylation-dependent manner. Through these binding interactions, 14-3-3 proteins work as molecular scaffolds, modulating the biological functions of their partners. 14-3-3 proteins recognize short motifs containing a phosphorylated serine or threonine residue. In this study, we have quantitatively characterized the in vitro interactions among 14-3-3, the Forkhead transcription factor FOXO4, and its target DNA, the insulin response element. Phosphorylation of FOXO4 (residues 11-213) by protein kinase B at Thr-28 and Ser-193 creates two 14-3-3 binding motifs. Analytical gel filtration and sedimentation equilibrium experiments indicate that doubly phosphorylated FOXO4 and 14-3-3 form a complex with 1:2 molar stoichiometry and a K-D of less than 30 nM. In contrast, singly phosphorylated FOXO4 mutants bind 14-3-3zeta with significantly lower affinity while retaining the ability to bind DNA. An active role for 14-3-3 in the disassembly of the FOXO4/DNA complex is demonstrated by the fact that, in the presence of 14-3-3, two phosphorylated 14-3-3 binding motifs are needed for the complete inhibition of FOX04 binding to its target DNA. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDKD, Mol Biol Lab, NIH, 5 Ctr Dr,MSC 0560, Bethesda, MD 20892 USA. RI Ghirlando, Rodolfo/A-8880-2009; Obsil, Tomas/B-7142-2012 OI Obsil, Tomas/0000-0003-4602-1272 NR 37 TC 60 Z9 63 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 30 PY 2003 VL 42 IS 51 BP 15264 EP 15272 DI 10.1021/bi0352724 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 758LB UT WOS:000187634900028 PM 14690436 ER PT J AU Moore, DF Altarescu, G Barker, WC Patronas, NJ Herscovitch, P Schiffmann, R AF Moore, DF Altarescu, G Barker, WC Patronas, NJ Herscovitch, P Schiffmann, R TI White matter lesions in Fabry disease occur in 'prior' selectively hypometabolic and hyperperfused brain regions SO BRAIN RESEARCH BULLETIN LA English DT Article DE cerebral blood flow; perfusion; stroke; MRI ID CEREBRAL-BLOOD-FLOW; GLUCOSE-UTILIZATION; NERVOUS-SYSTEM; LEUKOARAIOSIS; HYPOPERFUSION; INVOLVEMENT; INTENSITY; STROKE; AGE AB Fabry disease is an X-linked disorder associated with early onset stroke. We previously found a significantly elevated cerebral blood flow (CBF) in patients with Fabry disease. We set to determine whether elevated resting CBF in Fabry disease is primarily a cerebrovascular abnormality or is secondary to enhanced neuronal metabolism. The relationship of cerebral metabolism and blood flow to Fabry leukoencephalopathy was also investigated. We measured the global and regional cerebral metabolic rate of glucose using 18-fluoro-deoxyglucose (FDG) and PET in 16 patients with Fabry disease (7 patients with leukoaraiotic lesions and 9 without) and in 7 control subjects. MRI fluid attenuated inversion recovery (FLAIR) studies were also performed in the patient and control groups. All control subjects had normal MRI FLAIR studies with no high-signal deep white matter lesions (WML). Patients were partitioned into FLAIR lesion and non-FLAIR lesion groups. We found no evidence of cerebral glucose hypermetabolism in Fabry disease. On the contrary, significantly decreased regional cerebral glucose metabolism (rCMRGlu) was found particularly in the deep white matter in the Fabry non-lesion group and exacerbated in the lesion group. Lesion-susceptible regions were relatively hyperperfused in non-lesion patients compared to the control group. We conclude that the elevated rCBF and decreased white matter rCMRGlu indicates a dissociation between metabolism and blood flow suggesting chronic deep white matter metabolic insufficiency. Published by Elsevier Inc. C1 NINDS, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. PET Dept, Bethesda, MD USA. NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. EM RS4e@nih.gov NR 40 TC 67 Z9 68 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD DEC 30 PY 2003 VL 62 IS 3 BP 231 EP 240 DI 10.1016/j.brainresbull.2003.09.021 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 763EM UT WOS:000188062000007 PM 14698356 ER PT J AU Smeyne, RJ Pollock, JD AF Smeyne, RJ Pollock, JD TI Role of prenatal drugs of abuse on neuronal development - Special issue - Foreword SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Editorial Material C1 St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. Natl Inst Drug Abuse, Genet & Mol Neurobiol Res Branch, NIH, Bethesda, MD USA. RP Smeyne, RJ (reprint author), St Jude Childrens Res Hosp, Dept Dev Neurobiol, 332 N Lauderdale, Memphis, TN 38105 USA. EM richard.smeyne@stjude.org RI Pollock, Jonathan/B-1554-2009; OI Smeyne, Richard/0000-0002-8459-5472 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD DEC 30 PY 2003 VL 147 IS 1-2 BP 1 EP 2 DI 10.1016/j.devbrainres.2003.11.004 PG 2 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 803QT UT WOS:000220246300001 ER PT J AU Riddle, R Pollock, JD AF Riddle, R Pollock, JD TI Making connections: the development of mesencephalic dopaminergic neurons SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Review DE dopamine neuron; mesencephalon; development; embryogenesis; transcription factor; growth factor; proliferation; early patterning; early neurite specification; process outgrowth; navigation; target selection; axonal guidance; synapse maturation; substantia nigra; ventral tegmental area; Parkinson's disease; substance abuse; addiction ID GLIAL-CELL LINE; ORPHAN NUCLEAR RECEPTOR; NAIL-PATELLA SYNDROME; PRENATAL COCAINE EXPOSURE; HYDROXYLASE-IMMUNOREACTIVE NEURONS; METABOTROPIC GLUTAMATE RECEPTORS; CENTRAL-NERVOUS-SYSTEM; RETINOID-X-RECEPTOR; GDNF FAMILY LIGANDS; LIM-HOMEOBOX GENES AB The disorders of two adjacent sets of mesencephalic dopaminergic neurons (MDNs) are associated with two significant health problems: Parkinson's disease and drug addiction. Because of this, a great deal of research has focused on understanding the growth, development and maintenance of MDNs. Many transcription factors and signaling pathways are known to be required for normal MDNs formation, but a unified model of MDN development is still unclear. The long-term goal is to design therapeutic strategies to: (i) nurture and/or heal endogenous MDNs, (ii) replace the affected tissue with exogenous MDNs from in vitro cultivated stem cells and (iii) restore normal connectivity. Recent developmental biology studies show great promise in understanding how MDNs develop both in vivo and in vitro. This information has great therapeutic value and may provide insight into how environmental and genetic factors increase vulnerability to addiction. (C) 2003 Elsevier B.V All rights reserved. C1 Natl Inst Drug Abuse, Genet & Mol Neurobiol Res Branch, Div Neurosci & Behav Res, Bethesda, MD 20892 USA. RP Riddle, R (reprint author), Natl Inst Drug Abuse, Genet & Mol Neurobiol Res Branch, Div Neurosci & Behav Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM riddler@nida.nih.gov RI Pollock, Jonathan/B-1554-2009 NR 204 TC 36 Z9 36 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD DEC 30 PY 2003 VL 147 IS 1-2 BP 3 EP 21 DI 10.1016/j.devbrainres.2003.09.010 PG 19 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 803QT UT WOS:000220246300002 ER PT J AU Noailles, PAH Becker, KG Wood, WH Teichberg, D Cadet, JL AF Noailles, PAH Becker, KG Wood, WH Teichberg, D Cadet, JL TI Methamphetamine-induced gene expression profiles in the striatum of male rat pups exposed to the drug in utero SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE METH; development; neurogenesis; gene expression; microarray ID HIPPOCAMPAL AXONS; DENDRITIC SPINES; MOUSE-BRAIN; CDNA ARRAY; PREGNANCY; ABUSE; MOTOR; MICE; PATTERNS; SPECTRIN AB Methamphetamine is a neurotoxic pychostimulant which affects monoaminergic and non-monoaminergic systems in the brain. Clinical studies in humans have found that exposure to methamphetamine in the developing embryo can cause significant behavioral and cognitive anomalies later in life. Exposure of animals to methamphetamine (METH) in utero can cause neurobehavioral effects that do not become apparent until young adulthood. In the present study, we sought to determine the effects of in utero METH exposure on the striata of perinatal rat pups using a recently developed 17 k cDNA microarray. We found that METH administration caused alterations in 913 genes according to strict criteria. These alterations include changes in genes that participate in signal transduction, heat shock responses and neuronal development. The majority of the changes in gene expression were more prominent at the 7-day time point. These observations suggest that in utero METH exposure might initiate molecular programs that significantly impact gene expression during the developmental period long after the last exposure to this drug. Thus, during development, METH exposure in utero might cause significant long-term changes in gene expression that might constitute, in part, some of the substrates for the behavioral and cognitive anomalies reported in the literature. Published by Elsevier B.V. C1 NIDA, Mol Neuropsychiat Branch, NIH, Baltimore, MD 21224 USA. NIA, Gene Express & Genom Unit, Res Resources Branch, NIH, Baltimore, MD USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM JCADET@intra.nida.nih.gov OI Becker, Kevin/0000-0002-6794-6656 NR 36 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD DEC 30 PY 2003 VL 147 IS 1-2 BP 153 EP 162 DI 10.1016/j.devbrainres.2003.11.003 PG 10 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 803QT UT WOS:000220246300015 ER PT J AU Backman, C Zhang, YJ Hoffer, BJ Tomas, AC AF Backman, C Zhang, YJ Hoffer, BJ Tomas, AC TI Short interfering RNAs (siRNAs) for reducing dopaminergic phenotypic markers SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE RNA interference; RNAi; short interfering RNA; siRNA; dopamine; midbrain; Nurr1; cRet; tyrosine hydroxylase ID DOUBLE-STRANDED-RNA; CAENORHABDITIS-ELEGANS; GENETIC INTERFERENCE; TARGETED DISRUPTION; NEUROTROPHIC FACTOR; MAMMALIAN-CELLS; MESSENGER-RNA; EXPRESSION; NEURONS; MICE AB Short interfering RNAs (siRNAs) are double-stranded RNAs of similar to19-29 nucleotides designed to suppress the expression of homologous genes by a process known as RNA interference (RNAi). In this study we have characterized several short interfering RNAs to reduce (knockdown) the expression of genes related to the dopaminergic system of the ventral mesencephalon. We report here effective suppression of all targeted genes, tyrosine hydroxylase (TH), the transcription factor Nr4a2 (Nurr1) and the GDNF receptor moiety cRet, by co-transfection of plasmids expressing gene specific siRNAs under control of the human U6 promoter with a reporter plasmid coding for firefly luciferase and fused in tandem to the cDNA for the gene of interest. The effective suppression of Nr4a2, cRet and tyrosine hydroxylase suggest that the U6 expression cassette could be used to deliver siRNA to mammalian cells in vivo and actively suppress the expression of dopamine related mammalian genes. The characterization of highly effective siRNAs for DA phenotypic markers may open new avenues for loss-of-function phenotypic analysis, and may lead to new approaches for gene therapy. (C) 2003 Elsevier B.V. All rights reserved. C1 NIDA, Cellular Neurobiol Branch, NIH, Baltimore, MD 21224 USA. RP Tomas, AC (reprint author), NIDA, Cellular Neurobiol Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI backman, cristina/C-1276-2013 NR 24 TC 8 Z9 10 U1 0 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD DEC 30 PY 2003 VL 131 IS 1-2 BP 51 EP 56 DI 10.1016/S0165-0270(03)00236-X PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 759EM UT WOS:000187725400006 PM 14659823 ER PT J AU Gulley, JL Dahut, WL AF Gulley, JL Dahut, WL TI Novel approaches to treating the asymptomatic hormone-refractory prostate cancer patient SO UROLOGY LA English DT Article ID PHASE-II TRIAL; PROTEIN-KINASE-C; COLONY-STIMULATING FACTOR; DOCETAXEL TAXOTERE; DEFINITIVE RADIOTHERAPY; ANGIOGENESIS INHIBITOR; PELVIC LYMPHADENECTOMY; RADICAL PROSTATECTOMY; TECHNOLOGY EVALUATION; ANDROGEN SUPPRESSION AB For >50 years, the standard treatment for advanced prostate cancer has been hormonal therapy. However, all such treated patients eventually develop disease refractory to androgen suppression as manifested by increasing prostate-specific antigen (PSA) levels, progressive disease on radiographic imaging, and ultimately, symptomatic deterioration. Historical perceptions that treatment of hormone-refractory prostate cancer was a largely futile venture have faded over the past decade with the advances in new therapeutic strategies. With the use of PSA values to follow the progress of patients after definitive therapy, physicians are seeing more patients who have failed hormonal therapy yet have no symptoms from their disease. There are standard therapies available for patients who require palliation for symptoms, but there is no consensus on treatment for asymptomatic patients. To date, there has been no definitive increase in survival with any therapy in this group of patients. In addition, several novel drugs have advanced through preclinical testing into early clinical trials. It is these drugs-alone or in combination-that are designed to target strategic tumor pathways in these patients. This article will review a selection of agents that may be potentially useful in this population. (C) 2003 Elsevier Inc. C1 NCI, Ctr Canc Res, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, Genitourinary Clin Res Sect, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Ctr Canc Res, Tumor Immunol & Biol Lab, 10 Ctr Dr,8B07 MSC 1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 76 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 0090-4295 J9 UROLOGY JI Urology PD DEC 29 PY 2003 VL 62 IS 6B SU S BP 147 EP 154 DI 10.1016/j.urology.2003.08.003 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 808TR UT WOS:000220591900018 PM 14747053 ER PT J AU Spence, SL Dey, BR Terry, C Albert, P Nissley, P Furlanetto, RW AF Spence, SL Dey, BR Terry, C Albert, P Nissley, P Furlanetto, RW TI Interaction of 14-3-3 proteins with the insulin-like growth factor I receptor (IGFIR): evidence for a role of 14-3-3 proteins in IGFIR signaling SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE 14-3-3 proteins; insulin-like growth factor I receptor; insulin receptor; protein kinase C; yeast two-hybrid; transformation; PMA ID TRANSFORMING ACTIVITIES; CYTOPLASMIC DOMAINS; MUTATIONS AB We have extended our previous yeast two-hybrid findings to show that 14-3-3beta also interacts with the insulin-like growth factor I receptor (IGFIR) in mammalian cells overexpressing both proteins and that the interaction involves serine 1283 and is dependent on receptor activation. Treatment of cells with the phorbol ester PMA stimulates the interaction of 14-3-3beta with the IGFIR in the absence of receptor tyrosine phosphorylation, suggesting that receptor activation leads to activation of an endogenous protein kinase that catalyzes the phosphorylation of serine 1283. To investigate the role of 14-3-3 proteins in IGF signal transduction, IGFIR structure-function studies were performed. Mutation of serine 1283 alone (S1283A) (a mutation that decreases but does not abolish the interaction of the IGFIR with 14-3-3) did not affect anchorage-independent growth of NIH 3T3 fibroblasts overexpressing the mutant receptor. However, the simultaneous mutation of this residue and the truncation of the G terminal 27 residues of the receptor (Delta1310/S1283A) abolished the interaction of the receptor with 14-3-3 and reversed the enhanced colony formation observed with the IGFIR truncation mutation alone (Delta1310). The difference between the Delta1310 and Delta1310/S1283A transfectants in the soft agar assay was confirmed by tumorigenesis experiments. These findings suggest that 14-3-3 proteins interact with the IGFIR in vivo and that this interaction may play a role in a transformation pathway signaled by the IGFIR. Published by Elsevier Inc. C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. RP Nissley, P (reprint author), NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [1R01 DK51657] NR 26 TC 10 Z9 10 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 26 PY 2003 VL 312 IS 4 BP 1060 EP 1066 DI 10.1016/j.bbrc.2003.11.043 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 753VW UT WOS:000187252300029 PM 14651979 ER PT J AU Xiao, XD Chakraborti, S Dimitrov, AS Gramatikoff, K Dimitrov, DS AF Xiao, XD Chakraborti, S Dimitrov, AS Gramatikoff, K Dimitrov, DS TI The SARS-CoV S glycoprotein: expression and functional characterization SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE SARS-CoV; S glycoprotein; receptor; binding; fusion; inhibitor; vaccine ID ACUTE RESPIRATORY SYNDROME; CORONAVIRUS; RECEPTOR; BIOLOGY; ENTRY AB We have cloned, expressed, and characterized the full-length and various soluble fragments of the SARS-CoV (Tor2 isolate) S glycoprotein. Cells expressing S fused with receptor-expressing cells at neutral pH suggesting that the recombinant glycoprotein is functional, its membrane fusogenic activity does not require other viral proteins, and that low pH is not required for triggering membrane fusion; fusion was not observed at low receptor concentrations. S and its soluble ectodomain, S-e, were not cleaved to any significant degree. They ran at about 180-200 kDa in SDS gels suggesting post-translational modifications as predicted by previous computer analysis and observed for other coronaviruses. Fragments containing the N-terminal amino acid residues 17-537 and 272537 but not 17-276 bound specifically to Vero E6 cells and purified soluble receptor, ACE2, recently identified by M. Farzan and coworkers [Nature 426 (2003) 450-454]. Together with data for inhibition of binding by antibodies developed against peptides from S, these findings suggest that the receptor-binding domain is located between amino acid residues 303 and 537. These results also confirm that ACE2 is a functional receptor for the SARS virus and may help in the elucidation of the mechanisms of SARS-CoV entry and in the development of vaccine immunogens and entry inhibitors. Published by Elsevier Inc. C1 NCI, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. Abgent, San Diego, CA 92121 USA. RP Dimitrov, DS (reprint author), NCI, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. NR 10 TC 180 Z9 206 U1 2 U2 10 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 DEC 26 PY 2003 VL 312 IS 4 BP 1159 EP 1164 DI 10.1016/j.bbrc.2003.11.054 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 753VW UT WOS:000187252300044 PM 14651994 ER PT J AU Bera, TK Hahn, Y Lee, BK Pastan, IH AF Bera, TK Hahn, Y Lee, BK Pastan, IH TI TEPP, a new gene specifically expressed in testis, prostate, and placenta and well conserved in chordates SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE EST database; tissue specific gene; secreted protein ID SUBCELLULAR-LOCALIZATION; DNA-SEQUENCE; PROGRAM; PROTEINS; CANCER AB We have combined computer-based screening and experimental expression analysis to identify genes that are expressed in normal prostate and/or prostate cancer but not in essential human tissues. Using this approach we identified a new gene that is specifically expressed in testis, prostate, and placenta. The gene has one major transcript of 1.0 kb in size and encodes for a protein of 30.7 kDa molecular weight. We named this gene TEPP (expressed in testis, prostate, and placenta). The amino acid sequence analysis of TEPP using SignalP program shows that it has a signal peptide with a predicted cleavage site between amino acids 19 and 20, indicating that it might be a secreted protein. Analysis of the predicted TEPP orthologs from different species shows that these proteins are highly conserved in chordates. In addition we have identified a splice variant of TEPP, which encodes a 37 kDa protein. In conclusion, a combination of bioinformatic and molecular approaches is useful in the identification of genes expressed in specific tissues. Selective expression of TEPP in testis, prostate, and in placenta and its high conservation among different species indicate that TEPP might have a role in reproductive biology. Published by Elsevier Inc. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, IH (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov NR 15 TC 4 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 26 PY 2003 VL 312 IS 4 BP 1209 EP 1215 DI 10.1016/j.bbrc.2003.11.031 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 753VW UT WOS:000187252300052 PM 14652002 ER PT J AU Aravind, L Iyer, LM Wellems, TE Miller, LH AF Aravind, L Iyer, LM Wellems, TE Miller, LH TI Plasmodium biology: Genomic gleanings SO CELL LA English DT Review ID APICOMPLEXAN PARASITES; MALARIA PARASITES; GENE FAMILY; PROTEIN SEQUENCES; TOPOISOMERASE-VI; DNA-BINDING; LIFE-CYCLE; FALCIPARUM; EVOLUTION; RNA AB The highly A+T rich genomes of human and rodent malarial parasites offer unprecedented glimpses of a lineage that is distinct from other model organisms. Plasmodium is distinguished by the presence of numerous low complexity inserts within globular domains of proteins. It displays several peculiarities in its transcription apparatus, and its DNA repair system appears to favor a certain innate level of mutability. Plasmodium possesses many cell surface molecules with "animal-like" adhesion modules. Potential genetic footprints of the ancestral eukaryotic algal precursor of the apicoplast are also detectable in its genome. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov; lmiller@niaid.nih.gov NR 83 TC 207 Z9 217 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD DEC 26 PY 2003 VL 115 IS 7 BP 771 EP 785 DI 10.1016/S0092-8674(03)01023-7 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 758RV UT WOS:000187664700003 PM 14697197 ER PT J AU Vargason, JM Szittya, G Burgyan, J Hall, TMT AF Vargason, JM Szittya, G Burgyan, J Hall, TMT TI Size selective recognition of siRNA by an RNA silencing suppressor SO CELL LA English DT Article ID BUSHY-STUNT-VIRUS; SHORT INTERFERING RNA; NICOTIANA-BENTHAMIANA; VIRAL SUPPRESSOR; PROTEIN; PLANTS; DNA; EXPRESSION; INDUCTION; SYSTEM AB RNA silencing in plants likely exists as a defense mechanism against molecular parasites such as RNA viruses, retrotransposons, and transgenes. As a result, many plant viruses have adapted mechanisms to evade and suppress gene silencing. Tombusviruses express a 19 kDa protein (p19), which has been shown to suppress RNA silencing in vivo and bind silencing-generated and synthetic small interfering RNAs (siRNAs) in vitro. Here we report the 2.5 Angstrom crystal structure of p19 from the Carnation Italian ringspot virus (CIRV) bound to a 21 nt siRNA and demonstrate in biochemical and in vivo assays that CIRV p19 protein acts as a molecular caliper to specifically select siRNAs based on the length of the duplex region of the RNA. C1 NIEHS, Lab Struct Biol, NIH, Res Triangle Pk, NC 27709 USA. Plant Biol Inst, Agr Biotechnol Ctr, Godollo, Hungary. RP Hall, TMT (reprint author), NIEHS, Lab Struct Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Szittya, Gyorgy/A-2905-2012; Burgyan, Jozsef/C-7511-2012 NR 66 TC 323 Z9 347 U1 2 U2 24 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD DEC 26 PY 2003 VL 115 IS 7 BP 799 EP 811 DI 10.1016/S0092-8674(03)00984-X PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 758RV UT WOS:000187664700005 PM 14697199 ER PT J AU Shen, X Woodgate, R Goodman, MF AF Shen, X Woodgate, R Goodman, MF TI Escherichia coli DNA polymerase V subunit exchange - A post-SOS mechanism to curtail error-prone DNA synthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UMUD MUTAGENESIS PROTEIN; RECA PROTEIN; ULTRAVIOLET-LIGHT; BIOCHEMICAL BASIS; CLEAVAGE; PURIFICATION; DEFICIENT; MUTATIONS; COMPLEX; MUTANTS AB DNA polymerase V consisting of a heterotrimer composed of one molecule of UmuC and two molecules of UmuD' (UmuD'C-2) is responsible for SOS damage-induced mutagenesis in Escherichia coli. Here we show that although the UmuD'C-2 complex remains intact through multiple chromatographic steps, excess UmuD, the precursor to UmuD', displaces UmuD' from UmuD'C-2 by forming a UmuDD' heterodimer, while UmuC concomitantly aggregates as an insoluble precipitate. Although soluble UmuD'C-2 is readily detected when the two genes are co-transcribed and translated in vitro, soluble UmuD(2)C or UmuDD'C are not detected. The subunit exchange between UmuD'C-2 and UmuD offers a biological means to inactivate error-prone polymerase V following translesion synthesis, thus preventing mutations from occurring on undamaged DNA. C1 Univ So Calif, Dept Chem & Biol Sci, Hedco Mol Biol Labs, Los Angeles, CA 90089 USA. NICHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Biol Sci, SHS Rm 172,Univ Pk, Los Angeles, CA 90089 USA. FU NIGMS NIH HHS [GM42554, GM21422] NR 34 TC 16 Z9 16 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 DEC 26 PY 2003 VL 278 IS 52 BP 52546 EP 52550 DI 10.1074/jbc.M310127200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 756LX UT WOS:000187480700071 PM 14573598 ER PT J AU Rambaratsingh, RA Stone, JC Blumberg, PM Lorenzo, PS AF Rambaratsingh, RA Stone, JC Blumberg, PM Lorenzo, PS TI RasGRP1 represents a novel non-protein kinase C phorbol ester signaling pathway in mouse epidermal keratinocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SKIN TUMOR PROMOTION; PROTEIN-KINASE; EXCHANGE FACTOR; DIFFERENTIATION MARKERS; RAS ACTIVATION; DIACYLGLYCEROL; CELLS; CALCIUM; EXPRESSION; INDUCTION AB The mouse skin model of carcinogenesis has been instrumental in our appreciation of the multistage nature of carcinogenesis. In this system, tumor promotion is a critical step in the generation of tumors and is usually achieved by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Although it is generally assumed that protein kinase C (PKC) is the sole receptor for TPA in this system, we sought to evaluate whether non-PKC pathways could also contribute to the effects of phorbol esters in skin. We documented expression of the high affinity non-PKC phorbol ester receptor and Ras activator RasGRP1 in mouse primary keratinocytes. Overexpression of RasGRP1 in keratinocytes increased the level of active GTP-loaded Ras. TPA treatment further elevated this Ras activation in a PKC-independent manner and induced the translocation and down-regulation of RasGRP1. Overexpression of RasGRP1 in keratinocytes also caused apoptosis. Finally, induction of keratinocyte differentiation by elevation of extracellular calcium suppressed expression of endogenous RasGRP1, whereas overexpression of RasGRP1 inhibited expression of the differentiation markers keratins 1 and 10 induced by high calcium in the medium. Taken together, our results demonstrate that RasGRP1 is an additional diacylglycerol/phorbol ester receptor in epidermal keratinocytes and suggest that activation of this novel receptor may contribute to some of the phorbol ester- and Ras-mediated effects in mouse epidermis. C1 Univ Hawaii, Canc Res Ctr Hawaii, Nat Prod Program, Honolulu, HI 96813 USA. Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. RP Lorenzo, PS (reprint author), Univ Hawaii, Canc Res Ctr Hawaii, Nat Prod Program, Rm 315,1236 Lauhala St, Honolulu, HI 96813 USA. FU NCI NIH HHS [R55 CA096841-01, R55-CA96841-01] NR 49 TC 29 Z9 32 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 DEC 26 PY 2003 VL 278 IS 52 BP 52792 EP 52801 DI 10.1074/jbc.M308240200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 756LX UT WOS:000187480700098 PM 14532295 ER PT J AU Knights, CD Liu, YG Appella, E Kulesz-Martin, M AF Knights, CD Liu, YG Appella, E Kulesz-Martin, M TI Defective p53 post-translational modification required for wild type p53 inactivation in malignant epithelial cells with mdm2 gene amplification SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALTERNATIVELY SPLICED P53; TUMOR-SUPPRESSOR PROTEIN; MOUSE EPIDERMAL-CELLS; DNA-BINDING; IN-VITRO; PHOSPHORYLATION; ACETYLATION; DAMAGE; ACTIVATION; KINASE AB Mdm2 gene amplification occurs in benign and chemotherapy-responsive malignant tumors with wtp53 genes as well as in breast and epithelial cancers. Mdm2 amplification in benign tumors suggests that it is not sufficient for p53 inactivation in cancer, implying that other defects in the p53 pathway are required for malignancy. We investigated mechanisms of wtp53 protein inactivation in malignant conversion of epithelial cells by comparing clonally related initiated cells with their derivative cancerous cells that have mdm2 amplification. Deficiencies in p53 accumulation and activities in response to DNA damage were not due simply to Mdm2 destabilization of p53 protein, but to continued association of DNA-bound p53 with Mdm2 protein and lack of binding and acetylation by p300 protein. The aberrant interactions were not because of mdm2 amplification alone, because DNA-bound p53 protein from initiated cells failed to bind ectopically expressed Mdm2 or endogenous overexpressed Mdm2 from cancerous cells. Phosphorylations of endogenous p53 at Ser(18), -23, or -37 were insufficient to dissociate Mdm2, because each was induced by UV in cancerous cells. Interestingly, phospho-mimic p53-T21E did dissociate the Mdm2 protein from DNA-bound p53 and recovered p300 binding and p21 induction in the cancerous cells. Thus wtp53 in malignant cells with mdm2 amplification can be inactivated by continued association of DNA-bound p53 protein with Mdm2 and failure of p300 binding and acetylation, coupled with a defect in p53 phosphorylation at Thr(21). These findings suggest therapeutic strategies that address both p53/Mdm2 interaction and associated p53 protein defects in human tumors that have amplified mdm2 genes. C1 Oregon Hlth Sci Univ, Dept Dermatol, Portland, OR 97239 USA. SUNY Buffalo, Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. SUNY Buffalo, Roswell Pk Canc Inst, Program Biochem, Buffalo, NY 14263 USA. NCI, Cell Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Kulesz-Martin, M (reprint author), Oregon Hlth Sci Univ, Dept Dermatol, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. FU NCI NIH HHS [CA69533, CA31101] NR 54 TC 20 Z9 22 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 DEC 26 PY 2003 VL 278 IS 52 BP 52890 EP 52900 DI 10.1074/jbc.M300279200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 756LX UT WOS:000187480700110 PM 14555661 ER PT J AU von Kobbe, C Thoma, NH Czyzewski, BK Pavletich, NP Bohr, VA AF von Kobbe, C Thoma, NH Czyzewski, BK Pavletich, NP Bohr, VA TI Werner syndrome protein contains three structure-specific DNA binding domains SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BLOOM-SYNDROME PROTEINS; RECQ FAMILY HELICASES; SYNDROME GENE-PRODUCT; WRN PROTEIN; IN-VITRO; EXONUCLEASE; REPLICATION; INTERACTS; COMPLEX; DAMAGE AB Werner syndrome (WS) is a premature aging syndrome caused by mutations in the WS gene (WRN) and a deficiency in the function of the Werner protein (WRN). WRN is a multifunctional nuclear protein that catalyzes three DNA-dependent reactions: a 3'-5'-exonuclease, an ATPase, and a 3'-5'-helicase. Deficiency in WRN results in a cellular phenotype of genomic instability. The biochemical characteristics of WRN and the cellular phenotype of WRN mutants suggest that WRN plays an important role in DNA metabolic pathways such as recombination, transcription, replication, and repair. The catalytic activities of WRN have been extensively studied and are fairly well understood. However, much less is known about the domain-specific interactions between WRN and its DNA substrates. This study identifies and characterizes three distinct WRN DNA binding domains using recombinant truncated fragments of WRN and five DNA substrates (long forked duplex, blunt-ended duplex, single-stranded DNA, 5'-overhang duplex, and Holliday junction). Substrate-specific DNA binding activity was detected in three domains, one N-terminal and two different C-terminal WRN fragments (RecQ conserved domain and helicase RNase D conserved domain-containing domains). The substrate specificity of each DNA binding domain may indicate that each protein domain has a distinct biological function. The importance of these results is discussed with respect to proposed roles for WRN in distinct DNA metabolic pathways. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 43 TC 94 Z9 94 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 DEC 26 PY 2003 VL 278 IS 52 BP 52997 EP 53006 DI 10.1074/jbc.M308338200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 756LX UT WOS:000187480700123 PM 14534320 ER PT J AU Phetsuksiri, B Jackson, M Scherman, H McNeil, M Besra, GS Baulard, AR Slayden, RA DeBarber, AE Barry, CE Baird, MS Crick, DC Brennan, PJ AF Phetsuksiri, B Jackson, M Scherman, H McNeil, M Besra, GS Baulard, AR Slayden, RA DeBarber, AE Barry, CE Baird, MS Crick, DC Brennan, PJ TI Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLOPROPENE FATTY-ACIDS; POSITIONAL DISTRIBUTION; COFACTOR REQUIREMENTS; THERMAL ADAPTATION; STEAROYL-COENZYME; PHLEI; BIOSYNTHESIS; INHIBITION; DESATURATION; ETHIONAMIDE AB The thiourea isoxyl (thiocarlide; 4,4'-diisoamyloxydiphenylthiourea) is known to be an effective anti-tuberculosis drug, active against a range of multidrug-resistant strains of Mycobacterium tuberculosis and has been used clinically. Little was known of its mode of action. We now demonstrate that isoxyl results in a dose-dependent decrease in the synthesis of oleic and, consequently, tuberculostearic acid in M. tuberculosis with complete inhibition at 3 mug/ml. Synthesis of mycolic acid was also affected. The anti-bacterial effect of isoxyl was partially reversed by supplementing growth medium with oleic acid. The specificity of this inhibition pointed to a Delta9-stearoyl desaturase as the drug target. Development of a cell-free assay for Delta9-desaturase activity allowed direct demonstration of the inhibition of oleic acid synthesis by isoxyl. Interestingly, sterculic acid, a known inhibitor of Delta9-desaturases, emulated the effect of isoxyl on oleic acid synthesis but did not affect mycolic acid synthesis, demonstrating the lack of a relationship between the two effects of the drug. The three putative fatty acid desaturases in the M. tuberculosis genome, desA1, desA2, and desA3, were cloned and expressed in Mycobacterium bovis BCG. Cell-free assays and whole cell labeling demonstrated increased Delta9-desaturase activity and oleic acid synthesis only in the desA3-overexpressing strain and an increase in the minimal inhibitory concentration for isoxyl, indicating that DesA3 is the target of the drug. These results validate membrane-bound Delta9-desaturase, DesA3, as a new therapeutic target, and the thioureas as anti-tuberculosis drugs worthy of further development. C1 Colorado State Univ, Dept Microbiol Pathol & Immunol, Ft Collins, CO 80523 USA. NIAID, NIH, Rockville, MD 20852 USA. Univ Wales, Dept Chem, Bangor LL57 2UW, Gwynedd, Wales. RP Brennan, PJ (reprint author), Colorado State Univ, Dept Microbiol Pathol & Immunol, Ft Collins, CO 80523 USA. RI Baird, Mark/A-2470-2009; Barry, III, Clifton/H-3839-2012; Slayden, Richard/O-8626-2016; Jackson, Mary/D-5345-2017; OI Slayden, Richard/0000-0001-6857-7277; Besra, Gurdyal/0000-0002-5605-0395; Baird, Mark/0000-0001-5340-8745 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [AI-18357, AI38087, P01 AI046393, R01 AI018357, R37 AI018357] NR 56 TC 97 Z9 109 U1 0 U2 11 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 DEC 26 PY 2003 VL 278 IS 52 BP 53123 EP 53130 DI 10.1074/jbc.M311209200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 756LX UT WOS:000187480700137 PM 14559907 ER PT J AU Chmielewski, MK Marchan, V Cieslak, J Grajkowski, A Livengood, V Munch, U Wilk, A Beaucage, SL AF Chmielewski, MK Marchan, V Cieslak, J Grajkowski, A Livengood, V Munch, U Wilk, A Beaucage, SL TI Thermolytic carbonates for potential 5 '-hydroxyl protection of deoxyribonucleosides SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SOLID-PHASE SYNTHESIS; LIGHT-DIRECTED SYNTHESIS; OLIGONUCLEOTIDE SYNTHESIS; DEOXYNUCLEOSIDE PHOSPHORAMIDITES; DNA-SYNTHESIS; OLIGODEOXYRIBONUCLEOTIDE SYNTHESIS; OLIGORIBONUCLEOTIDE SYNTHESIS; NUCLEOTIDE CHEMISTRY; MICROARRAYS; NUCLEOSIDES AB Thermolytic groups structurally related to well-studied heat-sensitive phosphate/thiophosphate protecting groups have been evaluated for 5'-hydroxyl protection of deoxyribonucleosides as carbonates and for potential use in solid-phase oligonucleotide synthesis. The spatial arrangement of selected functional groups forming an asymmetric nucleosidic 5'-O-carbonic acid ester has been designed to enable heat-induced cyclodecarbonation reactions, which would result in the release of carbon dioxide and the generation of a nucleosidic 5'-hydroxyl group. The nucleosidic 5'-O-carbonates 3-8, 10-15, and 19-21 were prepared and were isolated in yields ranging from 45 to 83%. Thermolytic deprotection of these carbonates is preferably performed in aqueous organic solvent at 90 degreesC under near neutral conditions. The rates of carbonate deprotection are dependent on the nucleophilicity of the functional group involved in the postulated cyclodecarbonation reaction and on solvent polarity. Deprotection kinetics increase according to the following order: 4 < 5 < 10 < 6 < 12 < 7 < 13 < 8 < 14 congruent to 19-21 and CCl4 < dioxane < MeCN < t-BuOH < MeCN:phosphate buffer (3:1 v/v, pH 7.0) < EtOH:phosphate buffer (1:1 v/v, pH 7.0). Complete thermolytic deprotection of carbonates 7, 8, 13, and 14 is achieved within 20 min to 2 h under optimal conditions in phosphate buffer-MeCN. The 2-(2-pyridyl)amino-1-phenylethyl and 2-[N-methyl-N-(2-pyridyl)]aminoethyl groups are particularly promising for 5'-hydroxyl protection of deoxyribonucleosides as thermolytic carbonates. C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Beaucage, SL (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM beaucage@cber.fda.gou RI Marchan, Vicente/K-9751-2014 OI Marchan, Vicente/0000-0002-1905-2156 NR 49 TC 20 Z9 21 U1 2 U2 7 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 DEC 26 PY 2003 VL 68 IS 26 BP 10003 EP 10012 DI 10.1021/jo035089g PG 10 WC Chemistry, Organic SC Chemistry GA 755TL UT WOS:000187427500017 PM 14682694 ER PT J AU Zhang, RX Lao, LX Qiao, JT Ruda, MA AF Zhang, RX Lao, LX Qiao, JT Ruda, MA TI Strain differences in pain sensitivity and expression of preprodynorphin mRNA in rats following peripheral inflammation SO NEUROSCIENCE LETTERS LA English DT Article DE nociceptive response; spinal dynorphin expression; hyperalgesia; inflammatory pain; strain-dependent difference; rats ID NEUROPATHIC PAIN; SPINAL-CORD; GENETIC-DIFFERENCES; THERMAL NOCICEPTION; LOCUS-CERULEUS; HYPERALGESIA; MORPHINE; INJURY; MECHANISMS; BEHAVIORS AB The experience of pain is highly variable among individuals, which may be due in part to the effects of genetic factors on the central transmission and modulation of noxious inputs. This study examined behavioral responses and the expression of preprodynorphin (PPD) mRNA at the spinal level during complete Freund's adjuvant-induced inflammation of the unilateral hind paw in male Fischer 344 (F344), Sprague-Dawley (SD), and Lewis (LEW) rats. Experiments showed that F344 rats exhibited stronger hind paw hyperalgesia and greater spinal PPD mRNA induction than SD or LEW rats. These results indicate that genetic factors that determine the spinal PPD mRNA and dynorphin production underlie strain-dependent differences in pain perception. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 NIDCR, Cellular Neurosci Sect, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. Shanxi Med Univ, Dept Neurobiol, Taiyuan 030001, Shanxi, Peoples R China. Univ Maryland, Sch Med, Ctr Integrat Med, Baltimore, MD 21201 USA. RP Zhang, RX (reprint author), Ctr Integrat Med, 3rd Floor,James Kernan Hosp Mans,2200 Kernan Dr, Baltimore, MD 21207 USA. RI Lao, Lixing/I-7979-2013; OI Lao, Lixing/0000-0003-0198-9714 NR 32 TC 14 Z9 14 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 26 PY 2003 VL 353 IS 3 BP 213 EP 216 DI 10.1016/j.neulet.2003.09.043 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 754XN UT WOS:000187358900015 PM 14665419 ER PT J AU Fudala, PJ Bridge, TP Chiang, CN AF Fudala, PJ Bridge, TP Chiang, CN TI Office-based treatment of opiate addiction - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NIH, Bethesda, MD 20892 USA. RP Fudala, PJ (reprint author), Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NR 0 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 DEC 25 PY 2003 VL 349 IS 26 BP 2567 EP 2568 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 757BT UT WOS:000187529500028 ER PT J AU Miclet, E O'Neil-Cabello, E Nikonowicz, EP Live, D Bax, A AF Miclet, E O'Neil-Cabello, E Nikonowicz, EP Live, D Bax, A TI H-1-H-1 dipolar couplings provide a unique probe of RNA backbone structure SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PULSE SEQUENCES; NMR; PROTEINS; MACROMOLECULES; METHYLENE; C-13; DNA C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77251 USA. Univ Minnesota, Dept Biochem, Minneapolis, MN 55455 USA. RP Bax, A (reprint author), NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NR 18 TC 22 Z9 22 U1 3 U2 6 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 DEC 24 PY 2003 VL 125 IS 51 BP 15740 EP 15741 DI 10.1021/ja0388212 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 755XF UT WOS:000187436200028 PM 14677953 ER PT J AU Paulson, EK Morcombe, CR Gaponenko, V Dancheck, B Byrd, RA Zilm, KW AF Paulson, EK Morcombe, CR Gaponenko, V Dancheck, B Byrd, RA Zilm, KW TI Sensitive high resolution inverse detection NMR spectroscopy of proteins in the solid state SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ROTATING SOLIDS; CHEMICAL-SHIFTS; N-15 NMR; C-13 NMR; H-1; MAS; ENHANCEMENT; SPECTRA; FIELD AB A new indirect detection scheme for obtaining N-15/H-1 shift correlation spectra in crystalline proteins is described. Excellent water suppression is achieved without the need for pulsed field gradients, and using only a 2-step phase cycle. Careful attention to overall NMR instrument stability was found critical for obtaining the best resolution and sensitivity. Magnetic dilution by deuteration of the protein in combination with highspeed magic angle spinning produces H-1 resonances averaging only 0.22 ppm in width, and in some cases lines as narrow as 0.17 ppm are obtained. In application to two different polymorphs of ubiquitin, structure dependent differences in both N-15 and H-1 amide chemical shifts are observed. In one case, distinct shifts for different molecules in the asymmetric unit are seen, and all differ substantially from solution NMR shifts. A gain of 7 in sensitivity makes the method competitive with solution NMR as long as nanocrystalline samples are available. C1 Yale Univ, Dept Chem, New Haven, CT 06520 USA. Natl Canc Inst, Struct Biophys Lab, Ft Detrick, MD 21702 USA. RP Zilm, KW (reprint author), Yale Univ, Dept Chem, POB 208107, New Haven, CT 06520 USA. RI Paulson, Eric/I-1816-2012; Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 NR 26 TC 126 Z9 127 U1 8 U2 38 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 DEC 24 PY 2003 VL 125 IS 51 BP 15831 EP 15836 DI 10.1021/ja037315+ PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 755XF UT WOS:000187436200049 PM 14677974 ER PT J AU de Alba, E Weiler, S Tjandra, N AF de Alba, E Weiler, S Tjandra, N TI Solution structure of human saposin c: pH-dependent interaction with phospholipid vesicles SO BIOCHEMISTRY LA English DT Article ID SPHINGOLIPID ACTIVATOR PROTEIN; MAGNETIC-RESONANCE RELAXATION; ELEVATED LYSOSOMAL PH; MODEL-FREE APPROACH; ORIENTED MACROMOLECULES; CRYSTAL-STRUCTURE; GAUCHER DISEASE; NMR-SPECTRA; NK-LYSIN; HYDROGEN-EXCHANGE AB Saposin C binds to membranes to activate lipid degradation in lysosomes. To get insights into saposin C's function, we have determined its three-dimensional structure by NMR and investigated its interaction with phospholipid vesicles. Saposin C adopts the saposin-fold common to other members of the family. In contrast, the electrostatic surface revealed by the NMR structure is remarkably different. We suggest that charge distribution in the protein surface can modulate membrane interaction leading to the functional diversity of this family. We find that the binding of saposin C to phospholipid vesicles is a pH-controlled reversible process. The pH dependence of this interaction is sigmoidal, with an apparent pK(a), for binding close to 5.3. The pK(a), values of many solvent-exposed Glu residues are anomalously high and close to the binding pK(a). Our NMR data are consistent with the absence of a conformational change prior to membrane binding. All this information suggests that the negatively charged electrostatic surface of saposin C needs to be partially neutralized to trigger membrane binding. We have studied the membrane-binding behavior of a mutant of saposin C designed to decrease the negative charge of the electrostatic surface. The results support our conclusion on the importance of protein surface neutralization in binding. Since saposin C is a lysosomal protein and pH gradients occur in lysosomes, we propose that lipid degradation in the lysosome could be switched on and off by saposin C's reversible binding to membranes. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, 50 Ctr Dr, Bethesda, MD 20892 USA. NR 82 TC 57 Z9 57 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 23 PY 2003 VL 42 IS 50 BP 14729 EP 14740 DI 10.1021/bi0301338 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 755KL UT WOS:000187402000003 PM 14674747 ER PT J AU Jones, JM Gellert, M AF Jones, JM Gellert, M TI Autoubiquitylation of the V(D)J recombinase protein RAG1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID UBIQUITIN-CONJUGATING ENZYME; MULTIUBIQUITIN CHAIN; TERMINAL REGION; RING FINGER; ACTIVE-SITE; COMPLEX; LIGASE; DOMAIN; TRANSPOSITION; MUTATIONS AB V(D)J recombination, the rearrangement of gene segments to assemble Ig and T cell receptor coding regions, is vital to B and T lymphocyte development. Here, we demonstrate that the V(D)J recombinase protein RAG1 undergoes ubiquitylation in cells. In vitro,the RING finger domain of RAG1 acts as a ubiquitin ligase that mediates its own ubiquitylation at a highly conserved K residue in the RAG1 amino-terminal region. Ubiquitylation is best supported by a specific ubiquitin-conjugating enzyme, UbcH3/CDC34, and requires an intact RAG1 RING finger motif. Disruption of the RING finger and certain RAG1 N-terminal truncations are associated with immunodeficiency in human patients, suggesting that RAG1's ubiquitin ligase is required for its biological role in lymphocyte development. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Room 241, Bethesda, MD 20892 USA. NR 51 TC 45 Z9 47 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 DEC 23 PY 2003 VL 100 IS 26 BP 15446 EP 15451 DI 10.1073/pnas.2637012100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600031 PM 14671314 ER PT J AU Yu, YK Wootton, JC Altschul, SF AF Yu, YK Wootton, JC Altschul, SF TI The compositional adjustment of amino acid substitution matrices SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN SEQUENCES; PSI-BLAST; DATABASE; PERSPECTIVE; GENERATION; EVOLUTION AB Amino acid substitution matrices are central to protein-comparison methods. In most commonly used matrices, the substitution scores take a log-odds form, involving the ratio of "target" to "background" frequencies derived from large, carefully curated sets of protein alignments. However, such matrices often are used to compare protein sequences with amino acid compositions that differ markedly from the background frequencies used for the construction of the matrices. Of course, the target frequencies should be adjusted in such cases, but the lack of an appropriate way to do this has been a long-standing problem. This article shows that if one demands consistency between target and background frequencies, then a log-odds substitution matrix implies a unique set of target and background frequencies as well as a unique scale. Standard substitution matrices therefore are truly appropriate only for the comparison of proteins with standard amino acid composition. Accordingly, we present and evaluate a rationale for transforming the target frequencies implicit in a standard matrix to frequencies appropriate for a nonstandard context. This rationale yields asymmetric matrices for the comparison of proteins with divergent compositions. Earlier approaches are unable to deal with this case in a fully consistent manner. Composition-specific substitution matrix adjustment is shown to be of utility for comparing compositionally biased proteins, including those of organisms with nucleotide-biased, and therefore codon-biased, genomes or isochores. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Florida Atlantic Univ, Dept Phys, Boca Raton, FL 33431 USA. RP Altschul, SF (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 23 TC 55 Z9 55 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 DEC 23 PY 2003 VL 100 IS 26 BP 15688 EP 15693 DI 10.1073/pnas.2533904100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600073 PM 14663142 ER PT J AU Costantino, N Court, DL AF Costantino, N Court, DL TI Enhanced levels of lambda red-mediated recombinants in mismatch repair mutants SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; BETA-PROTEIN; BACTERIOPHAGE-LAMBDA; HOMOLOGOUS RECOMBINATION; PHAGE-LAMBDA; SYNTHETIC OLIGONUCLEOTIDES; INTERSPECIES RECOMBINATION; GENE REPLACEMENT; IN-VITRO AB Homologous recombination can be used to generate recombinants on episomes or directly on the Escherichia coli chromosome with PCR products or synthetic single-stranded DNA (ssDNA) oligonucleotides (oligos). Such recombination is possible because bacteriophage lambda-encoded functions, called Red, efficiently recombine linear DNA with homologies as short as 20-70 bases. This technology, termed recombineering, provides ways to modify genes and segments of the chromosome as well as to study homologous recombination mechanisms. The Red Beta function, which binds and anneals ssDNA to complementary ssDNA, is able to recombine 70-base oligos with the chromosome. In E. coli, methyl-directed mismatch repair (MMR) can affect these ssDNA recombination events by eliminating the recombinant allele and restoring the original sequence. In so doing, MMR can reduce the apparent recombination frequency by >100-fold. In the absence of MMR, Red-mediated oligo recombination can incorporate a single base change into the chromosome in an unprecedented 25% of cells surviving electroporation. Our results show that Beta is the only bacteriophage function required for this level of recombination and suggest that Beta directs the ssDNA to the replication fork as it passes the target sequence. C1 NCI, Mol Control & Genet Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP NCI, Mol Control & Genet Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Bldg 539,POB B, Frederick, MD 21702 USA. EM court@ncifcrf.gov NR 60 TC 125 Z9 131 U1 3 U2 26 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 DEC 23 PY 2003 VL 100 IS 26 BP 15748 EP 15753 DI 10.1073/pnas.243959100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600083 PM 14673109 ER PT J AU Hughes, AL Packer, B Welch, R Bergen, AW Chanock, SJ Yeager, M AF Hughes, AL Packer, B Welch, R Bergen, AW Chanock, SJ Yeager, M TI Widespread purifying selection at polymorphic sites in human protein-coding loci SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; MOLECULAR EVOLUTION; DISEASE; POPULATIONS; SNPS; GENE; SUBSTITUTIONS; MUTATIONS; RESOURCES; GENOME AB Estimation of gene diversity (heterozygosity) at 1,442 single-nucleoticle polymorphism (SNP) loci in an ethnically diverse sample of humans revealed consistently reduced gene diversities at SNP loci causing amino acid changes, particularly those causing amino acid changes predicted to be disruptive to protein structure. The reduction of gene diversity at these SNP loci, in comparison to SNPs in the same genes not affecting protein structure, is evidence that negative natural selection (purifying selection) has reduced the population frequencies of deleterious SNP alleles. This, in turn, suggests that slightly deleterious mutations are widespread in the human population and that estimation of gene diversity even in a sample of modest size can help guide the search for disease-associated genes. C1 Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA. NCI, Sci Applicat Int Corp, SAIC Frederick, Frederick, MD 21702 USA. NCI, Core Genotyping Facil, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Sect Genomic Variat, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Hughes, AL (reprint author), Univ S Carolina, Dept Biol Sci, Coker Life Sci Bldg,700 Sumter St, Columbia, SC 29208 USA. OI Bergen, Andrew/0000-0002-1237-7644 FU NCI NIH HHS [N01CO12400]; NIGMS NIH HHS [R01 GM043940, GM43940]; PHS HHS [N01-C0-12400] NR 30 TC 80 Z9 80 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 DEC 23 PY 2003 VL 100 IS 26 BP 15754 EP 15757 DI 10.1073/pnas.2536718100 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600084 PM 14660790 ER PT J AU Chang, KT Shi, YJ Min, KT AF Chang, KT Shi, YJ Min, KT TI The Drosophila homolog of Down's syndrome critical region 1 gene regulates learning: Implications for mental retardation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DEPENDENT PROTEIN-KINASE; LONG-TERM-MEMORY; INHIBITS CALCINEURIN; STRIATED-MUSCLES; MUSHROOM BODIES; EXPRESSION; MELANOGASTER; DSCR1; IDENTIFICATION; SYSTEM AB Mental retardation is the most common phenotypic abnormality seen in Down's syndrome (DS) patients, yet the underlying mechanism remains mysterious. DS critical region 1 (DSCR1), located on chromosome 21, is overexpressed in the brain of DS fetus and encodes an inhibitor of calcineurin, but its physiological significance is unknown. To study its functional importance and role in mental retardation in DS, we generated Drosophila mutants of nebula, an ortholog of human DSCR1. Here, we report that both nebula loss-of-function and overexpression mutants exhibit severe learning defects that are attributed by biochemical perturbations rather than maldevelopment of the brain. These results, combined with our data showing that the same biochemical signaling pathway is altered in human DS fetal brain tissue overexpressing DSCR1, suggest that alteration of DSCR1 expression could contribute to mental retardation in DS. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Min, KT (reprint author), NINDS, Neurogenet Branch, NIH, MSC1250,10-3B12, Bethesda, MD 20892 USA. OI min, kyung-tai/0000-0003-0983-4258 NR 36 TC 83 Z9 84 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 DEC 23 PY 2003 VL 100 IS 26 BP 15794 EP 15799 DI 10.1073/pnas.2536696100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600091 PM 14668437 ER PT J AU Zhu, P Chertova, E Bess, J Lifson, JD Arthur, LO Liu, J Taylor, KA Roux, KH AF Zhu, P Chertova, E Bess, J Lifson, JD Arthur, LO Liu, J Taylor, KA Roux, KH TI Electron tomography analysis of envelope glycoprotein trimers on HIV and simian immunodeficiency virus virions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OLIGOMERIC STRUCTURE; TYPE-1; GP120; PROTEIN; SURFACE; GP41; NEUTRALIZATION; CD4; INACTIVATION; DETERMINANT AB We used electron tomography to directly visualize trilobed presumptive envelope (env) glycoprotein structures on the surface of negatively stained HIV type 1 (HIV-1) and simian immunodeficiency virus (SIV) virions. Wild-type HIV-1 and SIV virions had an average of 8-10 trimers per virion, consistent with predictions based on biochemical evidence. Mutant SIVs, biochemically demonstrated to contain high levels of the viral env proteins, averaged 70-79 trimers per virion in tomograms. These correlations strongly indicate that the visualized trimers represent env spikes. The env trimers were without obvious geometric distribution pattern or preferred rotational orientation. Combined with biochemical analysis of gag/env ratios in virions, these trimer counts allow calculation of the number of gag molecules per virion, yielding an average value of approximate to1,400. Virion and env dimensions were also determined. Image-averaging analysis of SIV env trimers revealed a distinct chirality and strong concordance with recent molecular models. The results directly demonstrate the presence of env trimers on the surface of AIDS virus virions, albeit at numbers much lower than generally appreciated, and have important implications for understanding virion formation, virus interactions with host cells, and virus neutralization. C1 Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Roux, KH (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. RI Bess, Jr., Julian/B-5343-2012 FU NIAID NIH HHS [R01 AI055461, R01 AI 055461, R21 AI44291]; NIGMS NIH HHS [GM 30598, R01 GM030598]; PHS HHS [N01-C0-124000] NR 42 TC 207 Z9 210 U1 2 U2 16 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 DEC 23 PY 2003 VL 100 IS 26 BP 15812 EP 15817 DI 10.1073/pnas.26334931100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600094 PM 14668432 ER PT J AU Kullberg, MC Andersen, JF Gorelick, PL Caspar, P Suerbaum, S Fox, JG Cheever, AW Jankovic, D Sher, A AF Kullberg, MC Andersen, JF Gorelick, PL Caspar, P Suerbaum, S Fox, JG Cheever, AW Jankovic, D Sher, A TI Induction of colitis by a CD4(+) T cell clone specific for a bacterial epitope SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; RESIDENT INTESTINAL FLORA; HEPATICUS-INDUCED COLITIS; HELICOBACTER-HEPATICUS; MICE; ANTIGEN; INFECTION; INTERLEUKIN-10; AUTOIMMUNITY; TOLERANCE AB It is now well established that the intestinal flora plays an important role in the pathogenesis of inflammatory bowel disease (IBD). However, whether bacteria serve as the sole target of the immune response in this process or whether they act indirectly by triggering an anti-self response is still unclear. We have previously shown that specific pathogen-free IL-10-deficient (IL-10 KO) mice develop a T helper (Th1)-cytokine associated colitis after experimental infection with Hehcobacter hepaticus. We here show that H. hepaticus Ag (SHelAg)-specificCD4(+) Th1 clones transfer disease to H. hepaticus-infected T cell-deficient RAG KO hosts. Importantly, uninfected recipients of the SHelAg-specific clones did not develop intestinal inflammation, and a control Schistosoma mansonispecific Th1 clone did not induce colitis upon transfer to infected RAG KO mice. The disease-inducing T cell clones recognized antigen(s) (Ag) specifically expressed by certain Helicobacter species as they responded when stimulated in vitro with H. hepaticus and Helicobacter typhlonius Ag, but not when cultured with Ag preparations from Helicobacter pylori, various non-helicobacter bacteria, or with cecal bacterial lysate from uninfected mice. Characterization of the Ag specificity of one of the clones showed that it reacts uniquely with a 15-mer peptide epitope on the flagellar hook protein (FlgE) of H. hepaticus presented by I-A(b). Together, our results demonstrate that colitis can be induced by clonal T cell populations that are highly specific for target Ag on intestinal bacteria, suggesting that an aberrant T cell response directed against gut flora is sufficient to trigger IBD. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lab Malaria & Vector Res, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, SAIC, Lab Anim Sci Program, Anim Hlth Diagnost Lab, Frederick, MD 21702 USA. Univ Wurzburg, Inst Hyg & Microbiol, D-97080 Wurzburg, Germany. MIT, Div Comparat Med, Cambridge, MA 02139 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Kullberg, MC (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU NCI NIH HHS [R01 CA067529, R01-CA67529] NR 31 TC 48 Z9 49 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 DEC 23 PY 2003 VL 100 IS 26 BP 15830 EP 15835 DI 10.1073/pnas.2534546100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600097 PM 14673119 ER PT J AU Matsuda, J Suzuki, O Oshima, A Yamamoto, Y Noguchi, A Takimoto, K Itoh, M Matsuzaki, Y Yasuda, Y Ogawa, S Sakata, Y Nanba, E Higaki, K Ogawa, Y Tominaga, L Ohno, K Iwasaki, H Watanabe, H Brady, RO Suzuki, Y AF Matsuda, J Suzuki, O Oshima, A Yamamoto, Y Noguchi, A Takimoto, K Itoh, M Matsuzaki, Y Yasuda, Y Ogawa, S Sakata, Y Nanba, E Higaki, K Ogawa, Y Tominaga, L Ohno, K Iwasaki, H Watanabe, H Brady, RO Suzuki, Y TI Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OCTYL-BETA-VALIENAMINE; ALPHA-GALACTOSIDASE; N-BUTYLDEOXYNOJIRIMYCIN; LYSOSOMAL STORAGE; GLUCOCEREBROSIDASE INHIBITORS; BIOLOGICAL EVALUATION; FABRY DISEASE; MOUSE; GANGLIOSIDES; DERIVATIVES AB We synthesized a galactose derivative, N-octyl-4-epi-beta-valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, beta-galactosidosis (G(M1)-gangliosidosis and Morquio 8 disease). It is a potent inhibitor of lysosomal beta-galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOW to a model mouse of juvenile G(M1)-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of G(M1), and G(A1) in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass biochemical analysis did not show the substrate reduction observed histochemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical chaperone therapy may be useful for certain patients with beta-gal-actosidosis and potentially other lysosomal storage diseases with central nervous system involvement. C1 Int Univ Hlth & Welf, Clin Res Ctr, Otawara 3248501, Japan. Natl Inst Infect Dis, Dept Vet Sci, Shinjuku Ku, Tokyo 1628640, Japan. Natl Inst Infect Dis, Div Expt Anim Res, Shinjuku Ku, Tokyo 1628640, Japan. Natl Inst Neurosci, Dept Mental Retardat & Birth Defect Res, Natl Ctr Neurol & Psychiat, Kodaira, Tokyo 1878502, Japan. Seikagaku Corp, Cent Res Labs, Tokyo 2070021, Japan. Keio Univ, Fac Sci & Technol, Dept Biosci & Informat, Kohoku Ku, Yokohama, Kanagawa 2238522, Japan. Tottori Univ, Res Ctr Biosci & Technol, Div Funct Genom, Yonago, Tottori 6838503, Japan. Tottori Univ, Fac Med, Div Child Neurol, Yonago, Tottori 6838504, Japan. Nasu Inst Dev Disabil, Otawara 3240011, Japan. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Suzuki, Y (reprint author), Int Univ Hlth & Welf, Clin Res Ctr, Room L-423,2600-1 Kita Kanemaru, Otawara 3248501, Japan. RI Matsuzaki, Yumi/H-2476-2013 NR 31 TC 169 Z9 177 U1 1 U2 12 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 DEC 23 PY 2003 VL 100 IS 26 BP 15912 EP 15917 DI 10.1073/pnas.2536657100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600111 PM 14676316 ER PT J AU Panchal, RG Ruthel, G Kenny, TA Kallstrom, GH Lane, D Badie, SS Li, LM Bavari, S Aman, MJ AF Panchal, RG Ruthel, G Kenny, TA Kallstrom, GH Lane, D Badie, SS Li, LM Bavari, S Aman, MJ TI In vivo oligomerization and raft localization of Ebola virus protein VP40 during vesicular budding SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE rafts; FIAsH; TSG101; filovirus ID MATRIX PROTEIN; LIPID RAFTS; BINDING PROPERTIES; MEMBRANE; CELLS; DOMAINS; TRAFFICKING; TSG101; CHOLESTEROL; FILOVIRUSES AB The matrix protein VP40 plays a critical role in Ebola virus assembly and budding, a process that utilizes specialized membrane domains known as lipid rafts. Previous studies with purified protein suggest a role for oligomerization of VP40 in this process. Here, we demonstrate VP40 oligomers in lipid rafts of mammalian cells, virus-like particles, and in the authentic Ebola virus. By mutagenesis, we identify several critical C-terminal sequences that regulate oligomerization at the plasma membrane, association with detergent-resistant membranes, and vesicular release of VP40, directly linking these phenomena. Furthermore, we demonstrate the active recruitment of TSG101 into lipid rafts by VP40. We also report the successful application of the biarsenic fluorophore, FlAsH, combined with a tetracysteine tag for imaging of Ebola VP40 in live cells. C1 USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. NCI, Dev Therapeut Program, Target Struct Based Drug Discovery Grp, Sci Applicat Int Corp, Ft Detrick, MD 21702 USA. Clin Res Management Inc, Ft Detrick, MD 21702 USA. Funct Genet Inc, Rockville, MD 20852 USA. RP Aman, MJ (reprint author), USA, Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD 21702 USA. NR 29 TC 127 Z9 129 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 23 PY 2003 VL 100 IS 26 BP 15936 EP 15941 DI 10.1073/pnas.2533915100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600115 PM 14673115 ER PT J AU Belland, RJ Nelson, DE Virok, D Crane, DD Hogan, D Sturdevant, D Beatty, WL Caldwell, HD AF Belland, RJ Nelson, DE Virok, D Crane, DD Hogan, D Sturdevant, D Beatty, WL Caldwell, HD TI Transcriptome analysis of chlamydial growth during IFN-gamma-mediated persistence and reactivation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microarray analysis; chlamydia; genomics; latency; stimulon ID TRACHOMATIS INFECTION; DEVELOPMENTAL CYCLE; PHOSPHOLIPASE-D; IMMUNITY; CELLS; PROTEIN; GENE AB Chlamydia trachomatis is an obligatory intracellular prokaryotic parasite that causes a spectrum of clinically important chronic inflammatory diseases of humans. Persistent infection may play a role in the pathophysiology of chlamydial disease. Here we describe the chlamydial transcriptome in an in vitro model of IFN-gamma-mediated persistence and reactivation from persistence. Tryptophan utilization, DNA repair and recombination, phospholipid utilization, protein translation, and general stress genes were. up-regulated during persistence. Down-regulated genes included chlamydial late genes and genes involved in proteolysis, peptide transport, and cell division. Persistence was characterized by altered but active biosynthetic processes and continued replication of the chromosome. On removal of IFN-gamma, chlamydiae rapidly reentered the normal developmental cycle and reversed transcriptional changes associated with cytokine treatment. The coordinated transcriptional response to IFN-gamma implies that a chlamydial response stimulon has evolved to control the transition between acute and persistent growth of the pathogen. In contrast to the paradigm of persistence as a general stress response, our findings suggest that persistence is an alternative life cycle used by chlamydiae to avoid the host immune response. C1 NIAID, Rocky Mt Lab, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Lab, Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. RP Caldwell, HD (reprint author), NIAID, Rocky Mt Lab, Intracellular Parasites Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 24 TC 125 Z9 134 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 23 PY 2003 VL 100 IS 26 BP 15971 EP 15976 DI 10.1073/pnas.2535394100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 757GL UT WOS:000187554600121 PM 14673075 ER PT J AU Wagner, WG Hammer, JA AF Wagner, WG Hammer, JA TI Myosin V and the endoplasmic reticulum: the connection grows SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material DE actin; myosin V; endoplasmic reticulum; yeast; dendritic spines ID SACCHAROMYCES-CEREVISIAE; LIVING CELLS; DENDRITIC SPINES; ACTIN-FILAMENTS; PURKINJE-CELLS; TRANSPORT; RECEPTOR; PROTEIN; COMPLEX; YEAST AB In this issue, Estrada et al. (2003) provide new and important insights into how the endoplasmic reticulum (ER) of budding yeast cells is inherited. Together with other studies in plant and animal cells, the results of Estrada et al. (2003) support the idea that myosin V acts as a universal motor for the transport of ER membranes. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, NIH Bldg 50,Room 2523,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov NR 42 TC 14 Z9 14 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 DEC 22 PY 2003 VL 163 IS 6 BP 1193 EP 1196 DI 10.1083/jcb.200311077 PG 4 WC Cell Biology SC Cell Biology GA 757WB UT WOS:000187583500002 PM 14691131 ER PT J AU Janvier, K Kato, Y Boehm, M Rose, JR Martina, JA Kim, BY Venkatesan, S Bonifacino, JS AF Janvier, K Kato, Y Boehm, M Rose, JR Martina, JA Kim, BY Venkatesan, S Bonifacino, JS TI Recognition of dileucine-based sorting signals from HIV-1 Nef and LIMP-II by the AP-1 gamma-sigma 1 and AP-3 delta-sigma 3 hemicomplexes SO JOURNAL OF CELL BIOLOGY LA English DT Article DE clathrin; adaptors; coats; endocytosis; endosomes ID ADAPTER PROTEIN COMPLEXES; DI-LEUCINE MOTIF; CLATHRIN-COATED PITS; CD4 DOWN-REGULATION; CYTOPLASMIC TAIL; INVARIANT CHAIN; ACIDIC-CLUSTER; SUBUNIT INTERACTIONS; TARGETING SIGNALS; MEMBRANE-PROTEINS AB The sorting of transmembrane proteins to endosomes and lysosomes is mediated by signals present in the cytosolic tails of the proteins. A subset of these signals conform to the [DE]XXXL[LI] consensus motif and mediate sorting via interactions with heterotetrameric adaptor protein (AP) complexes. However, the identity of the AP subunits that recognize these signals remains controversial. We have used a yeast three-hybrid assay to demonstrate that [DE]XXXL[LI]-type signals from the human immunodeficiency virus negative factor protein and the lysosomal integral membrane protein II interact with comb nations of the gamma and sigma1 subunits of AP-1 and the 8 and sigma3 subunits of AP-3, but not the analogous combinations of AP-2 and AP-4 subunits. The sequence requirements for these interactions are similar to those for binding to the whole AP complexes in vitro and for function of the signals in vivo. These observations reveal a novel mode of recognition of sorting signals involving the gamma/delta and sigma subunits of AP-1 and AP-3. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. RI KATO, Yukio/D-8396-2015 NR 66 TC 155 Z9 160 U1 0 U2 4 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 DEC 22 PY 2003 VL 163 IS 6 BP 1281 EP 1290 DI 10.1083/jc6.200307157 PG 10 WC Cell Biology SC Cell Biology GA 757WB UT WOS:000187583500011 PM 14691137 ER PT J AU Chu, JW Trout, BL Brooks, BR AF Chu, JW Trout, BL Brooks, BR TI A super-linear minimization scheme for the nudged elastic band method SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID OPTIMIZING LARGE MOLECULES; MINIMUM ENERGY PATHS; C-H ACTIVATION; TRANSITION-STATES; SADDLE-POINTS; OXIDATION; MECHANISMS; DYNAMICS; SOLVENT; ROTATION AB In this article, we present a superlinear minimization scheme for the nudged elastic band (NEB) method, which determines a minimum-energy path (MEP) of a reaction via connecting intermediate "replicas'' between the reactant and the product. The minimization scheme is based on a quasi-Newton method: the adopted basis Newton-Raphson (ABNR) minimization scheme. In each step of ABNR minimization, the Newton-Raphson procedure is performed in a subspace of a user-defined dimension. The tangent directions of the path at a new Newton-Raphson step are determined self-consistently in the subspace. The acceleration of the proposed scheme over the quenched molecular-dynamic minimization, the current practice for minimizing a path using NEB, is demonstrated in three nontrivial test cases: isomerization of an alanine dipeptide, alpha-helix to pi-helix transition of an alanine decapeptide, and oxidation of dimethyl sulfide. New features are also added such that the distances between replicas can be defined in the root of mean squared (RMS) best-fit space with flexible weighting options. This offers a way to incorporate the effects of a mobile solvent in the process with a finite number of replicas. MEPs obtained from various initial structures can be used to investigate different proposed reaction mechanisms, and the speedup of minimizing a path enhances the applicability of the NEB method. The combination of NEB force projection procedures, the flexible distance definition in the RMS best fit space with arbitrary weighting options, and the superlinear minimization scheme provides a framework to aid in the study of transition processes of biological molecules as such proteins. (C) 2003 American Institute of Physics. C1 MIT, Dept Chem Engn, Cambridge, MA 02139 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM trout@mit.edu; brb@nih.gov RI Chu, Jhih-Wei/D-2257-2012; Chu, Jhih-Wei/M-2870-2013 OI Chu, Jhih-Wei/0000-0003-3842-2893 NR 53 TC 115 Z9 115 U1 1 U2 19 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD DEC 22 PY 2003 VL 119 IS 24 BP 12708 EP 12717 DI 10.1063/1.1627754 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 757RY UT WOS:000187576300004 ER PT J AU Cao, XL Ito, YC AF Cao, XL Ito, YC TI Supercritical fluid extraction of grape seed oil and subsequent separation of free fatty acids by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE supercritical fluid extraction; counter-current chromatography; preparative chromatography; oils; grapes; fatty acids AB Supercritical fluid extraction (SFE) of grape seed oil was performed to study the effect of various parameters such as pressure, temperature and the particle size of the sample on the yield and composition of oil using an analytical-scale SFE system. Then the extraction was scaled up by 125 times using a preparative SFE system under the optimized conditions of high pressure (30-40 MPa) and low temperature (35-40 degreesC) with medium particle size (20-40 mesh). The maximum yield of the oil can reach 6.2% with pure supercritical CO2 and 4.0% more oil can be obtained by adding 10% of ethanol as modifier. The unsaturated fatty acids (UFSs) make up about 70% in the oil on the basis of free fatty acids. The grape seed oil was then subjected to separation and purification for free fatty acids after saponification by high-speed counter-current chromatography coupled with evaporative light scattering detection (ELSD). The separation of 1.0 g of oil can yield about 430 mg pure linoleic acid at 99% purity. The fatty acids were analyzed by HPLC-ELSD. (C) 2003 Elsevier B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Beijing Technol & Business Univ, Beijing Key Lab Plant Resource Res & Dev, Beijing 100037, Peoples R China. RP Ito, YC (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Room 3334,50 South Dr, Bethesda, MD 20892 USA. EM itoy@nhlbi.nih.gov NR 9 TC 91 Z9 98 U1 5 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD DEC 22 PY 2003 VL 1021 IS 1-2 BP 117 EP 124 DI 10.1016/j.chroma.2003.09.001 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 758QW UT WOS:000187662500011 PM 14735980 ER PT J AU Moro, S Deflorian, F Spalluto, G Pastorin, G Cacciari, B Kim, SK Jacobson, KA AF Moro, S Deflorian, F Spalluto, G Pastorin, G Cacciari, B Kim, SK Jacobson, KA TI Demystifying the three dimensional structure of G protein-coupled receptors (GPCRs) with the aid of molecular modeling SO CHEMICAL COMMUNICATIONS LA English DT Article ID A(3) ADENOSINE RECEPTOR; SITE-DIRECTED MUTAGENESIS; LIGAND RECOGNITION; A(3)-ADENOSINE RECEPTOR; CRYSTAL-STRUCTURE; ANTAGONISTS; DERIVATIVES; BINDING; RHODOPSIN; AFFINITY AB We review our recent work on adenosine receptors, a family of GPCRs; focusing our attention on A(3) adenosine receptor, we have demonstrated that the reciprocal integration of different theoretical and experimental disciplines can be very useful for the successful protein-based design of new, potent and selective receptor ligands. C1 Univ Padua, Dept Pharmaceut Sci, Mol Modeling Sect, Padua, Italy. Univ Trieste, Dept Pharmaceut Sci, Trieste, Italy. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. NIDDK, Mol Recognit Sect, LBC, NIH, Bethesda, MD USA. RP Moro, S (reprint author), Univ Padua, Dept Pharmaceut Sci, Mol Modeling Sect, Padua, Italy. RI Jacobson, Kenneth/A-1530-2009; Moro, Stefano/A-2979-2012; Pastorin, Giorgia/B-5907-2015 OI Jacobson, Kenneth/0000-0001-8104-1493; Moro, Stefano/0000-0002-7514-3802; NR 39 TC 40 Z9 41 U1 0 U2 3 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1359-7345 J9 CHEM COMMUN JI Chem. Commun. PD DEC 21 PY 2003 IS 24 BP 2949 EP 2956 DI 10.1039/b303439a PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 755PV UT WOS:000187418800001 PM 14703805 ER PT J AU Smith-Warner, SA Spiegelman, D Yaun, SS Albanes, D Beeson, WL van den Brandt, PA Feskanich, D Folsom, AR Fraser, GE Freudenheim, JL Giovannucci, E Goldbohm, RA Graham, S Kushi, LH Miller, AB Pietinen, P Rohan, TE Speizer, FE Willett, WC Hunter, DJ AF Smith-Warner, SA Spiegelman, D Yaun, SS Albanes, D Beeson, WL van den Brandt, PA Feskanich, D Folsom, AR Fraser, GE Freudenheim, JL Giovannucci, E Goldbohm, RA Graham, S Kushi, LH Miller, AB Pietinen, P Rohan, TE Speizer, FE Willett, WC Hunter, DJ TI Fruits, vegetables and lung cancer: A pooled analysis of cohort studies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE fruit; vegetables; lung neoplasms; cohort studies; pooling ID FOOD FREQUENCY QUESTIONNAIRE; MISSOURI WOMENS HEALTH; BETA-CAROTENE; UNITED-STATES; DIETARY FACTORS; RISK-FACTORS; VITAMIN-C; CARDIOVASCULAR-DISEASE; NONSMOKING WOMEN; NUTRIENT INTAKE AB Inverse associations between fruit and vegetable consumption and lung cancer risk have been consistently reported. However, identifying the specific fruits and vegetables associated with lung cancer is difficult because the food groups and foods evaluated have varied across studies. We analyzed fruit and vegetable groups using standardized exposure and covariate definitions in 8 prospective studies. We combined study-specific relative risks (RRs) using a random effects model. In the pooled database, 3,206 incident lung cancer cases occurred among 430,281 women and men followed for up to 6-16 years across studies. Controlling for smoking habits and other lung cancer risk factors, a 16-23% reduction in lung cancer risk was observed for quintiles 2 through 5 vs. the lowest quintile of consumption for total fruits (RR = 0.77; 95% CI = 0.67-0.87 for quintile 5; p-value, test for trend < 0.001) and for total fruits and vegetables (RR = 0.79; 95% CI = 0.69-0.90; p-value, test for trend = 0.001). For the same comparison, the association was weaker for total vegetable consumption (RR = 0.88; 95% CI = 0.78-1.00; p-value, test for trend = 0.12). Associations were similar between never, past, and current smokers. These results suggest that elevated fruit and vegetable consumption is associated with a modest reduction in lung cancer risk, which is mostly attributable to fruit, not vegetable, intake. However, we cannot rule out the possibility that our results are due to residual confounding by smoking. The primary focus for reducing lung cancer incidence should continue to be smoking prevention and cessation. (C) 2003 Wiley-Liss, Inc. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NCI, Div Clin Sci, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Loma Linda Univ, Sch Med, Ctr Hlth Res, Loma Linda, CA 92354 USA. Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. TNO, Nutr & Food Res Inst, Dept Epidemiol, NL-3700 AJ Zeist, Netherlands. Kaiser Permanente, Div Res, Oakland, CA USA. Univ Toronto, Fac Med, Dept Publ Hlth Sci, Toronto, ON, Canada. Natl Publ Hlth Inst, Dept Hlth Promot & Epidemiol, Helsinki, Finland. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Harvard Univ, Ctr Canc Prevent, Boston, MA 02115 USA. RP Smith-Warner, SA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. RI Albanes, Demetrius/B-9749-2015; OI Kushi, Lawrence/0000-0001-9136-1175 FU NCI NIH HHS [CA 55075, CA 78548] NR 99 TC 101 Z9 104 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 20 PY 2003 VL 107 IS 6 BP 1001 EP 1011 DI 10.1002/ijc.11490 PG 11 WC Oncology SC Oncology GA 744GJ UT WOS:000186619300019 PM 14601062 ER PT J AU Ferrari, MG Stevceva, L Markham, P Franchini, G AF Ferrari, MG Stevceva, L Markham, P Franchini, G TI Species-specific transformation of T cells by HVMNE SO VIROLOGY LA English DT Article DE EBV-like virus; HVMNE; nonhuman primate virus; T cell transformation ID EPSTEIN-BARR-VIRUS; CUTANEOUS LYMPHOPROLIFERATIVE DISORDERS; HERPESVIRUS-PAPIO; NONHUMAN-PRIMATES; CONSTITUTIVE ACTIVATION; MYCOSIS-FUNGOIDES; EBV-DNA; LYMPHOMA; INFECTION; DISEASE AB HVMNE is an Epstein-Barr virus (EBV)-like lymphocryptovirus (LCV) originally isolated from a Macaca nemestrina with CD8(+) T cell mycosis fungoides/cutaneous T cell lymphoma (Blood 98 (2001), 2193). HVMNE transforms rabbit T cells in vitro and causes T cell lymphoma in New Zealand white rabbits. Here we demonstrate that HVMNE also immortalizes T cells from mustached tamarins but not those from owl monkeys, common marmosets, squirrel monkeys, black-capped capuchins, and humans. Cytogenetic and FACS analysis revealed the true origin and T cell lineage of the transformed tamarin T cell lines. Tamarin T cells contained HVMNE DNA sequence and displayed a decreased requirement for the IL-2 cytokine for growth. Thus, this EBV-like virus from M. nemestrina differs from the other EBV-like viruses found in nonhuman primates inasmuch as it appears to preferentially transform T cells. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. Adv Biosci Labs, Kensington, MD 20895 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, 41-D804, Bethesda, MD 20892 USA. OI Stevceva, Liljana/0000-0002-3761-2460 NR 52 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 2003 VL 317 IS 2 BP 299 EP 307 DI 10.1016/j.virol.2003.08.030 PG 9 WC Virology SC Virology GA 759UM UT WOS:000187755300010 PM 14698668 ER PT J AU Guedes, SD Vitorino, R Tomer, K Domingues, MRM Correia, AJF Amado, F Domingues, P AF Guedes, SD Vitorino, R Tomer, K Domingues, MRM Correia, AJF Amado, F Domingues, P TI Drosophila melanogaster larval hemolymph protein mapping SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE two-dimensional gel electrophoresis; proteomics; Drosophila; hemolymph larvae; MALDI-TOF/TOF ID ASSISTED-LASER-DESORPTION/IONIZATION; ANTIMICROBIAL HOST-DEFENSE; MOSQUITO IMMUNE-RESPONSES; INNATE IMMUNITY; FLIGHT-MUSCLE; GEL-ELECTROPHORESIS; MASS SPECTROMETRY; IDENTIFICATION; GENE; THIOREDOXIN AB With the completion of the genome sequence of Drosophila melanogaster the importance of constructing a proteome map is to be considered. Therefore, with the application of recent advances in proteomic analysis approaches, a protein map of D. melanogaster larvae hemolymph proteins was obtained using 2-DE in the range of pH 3-10. After Coomassie colloidal detection of 289 spots, a total of 105 were excised from the gel and digested with trypsin. Identification was done based on a combination of MALDI-TOF/TOF MS and MS/MS spectra. The 99 proteins identified using this approach include a large number of metabolic enzymes, translational apparatus components, and structural proteins. Among these we emphasize the identification of proteins with molecular chaperone properties (heat shock proteins and PPIases) and protein spots involved in defense responses such as antioxidant and immunological defense mechanisms (thioredoxin, prophenoloxidase, and serine proteases), as well as in signal transduction pathways. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Aveiro, Dept Chem, P-3800 Aveiro, Portugal. Natl Inst Environm Hlth Sci, DHHS, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. RP Domingues, P (reprint author), Univ Aveiro, Dept Chem, P-3800 Aveiro, Portugal. EM pedrom@dq.ua.pt RI Tomer, Kenneth/E-8018-2013; Domingues, Pedro/E-5202-2010; Vitorino, Rui/G-7356-2014; Domingues, Rosario/K-7444-2014; Amado, Francisco/M-5337-2015; OI Domingues, Pedro/0000-0002-8060-7675; Vitorino, Rui/0000-0003-3636-5805; Domingues, Rosario/0000-0001-5357-3601; Amado, Francisco/0000-0001-8256-1749; Guedes, Sofia de Morais/0000-0001-9556-3639 NR 40 TC 33 Z9 36 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 19 PY 2003 VL 312 IS 3 BP 545 EP 554 DI 10.1016/j.bbrc.2003.10.156 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 750WK UT WOS:000187021300003 PM 14680800 ER PT J AU Chen, HL Lein, PJ Wang, JY Gash, D Hoffer, BJ Chiang, YH AF Chen, HL Lein, PJ Wang, JY Gash, D Hoffer, BJ Chiang, YH TI Expression of bone morphogenetic proteins in the brain during normal aging and in 6-hydroxydopamine-lesioned animals SO BRAIN RESEARCH LA English DT Article DE bone morphogenetic proteins; aging; substantia nigra; 6-hydroxydopamine ID SERINE/THREONINE KINASE RECEPTORS; MIDBRAIN DOPAMINERGIC-NEURONS; ENHANCES DENDRITIC GROWTH; DORSAL NEURAL-TUBE; OSTEOGENIC PROTEIN-1; NERVOUS-SYSTEM; II RECEPTOR; PARKINSONS-DISEASE; GABAERGIC NEURONS; CORTICAL-NEURONS AB Bone morphogenetic proteins (BMPs), BMP receptors (BMPRs), and endogenous BMP antagonists have been found to be critically important for the development of the central nervous system (CNS) and peripheral organs in mammals. There is also increasing evidence that this system has significant activity in the adult CNS. Accordingly, we studied the regional distribution of endogenous BMP ligand proteins, receptors, and antagonists during aging and after lesion of the midbrain dopamine pathways produced by 6-hydroxydopamine (6-OHDA). We found that there were only small changes in the levels of these molecules as a function of age. Interestingly, levels of BMP 7 and noggin, a BMP antagonist, were uniquely elevated in substantia nigra. Moreover, after lesions of the midbrain dopamine system by 6-hydroxydopamine, there was a marked reduction in levels of all BMP ligands, receptors and antagonists bilaterally in both substantia nigra and hippocampus. There were also differential changes in BMP ligands, receptors, and antagonists in the cortex and striatum after such lesions. Taken together, our results indicate significant expression of BMP-related molecules in the adult and aging brain, and suggest a dynamic and differential regulation of these molecules after perturbations. (C) 2003 Elsevier B.V. All rights reserved. C1 Natl Def Univ, Natl Def Med Ctr, Grad Inst Life Sci, Taipei, Taiwan. NIDA, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. RP Chiang, YH (reprint author), Tri Serv Gen Hosp, Dept Neurosurg, 325 Cheng Kung Rd,Sec 2, Taipei 114, Taiwan. NR 62 TC 30 Z9 35 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 19 PY 2003 VL 994 IS 1 BP 81 EP 90 DI 10.1016/j.brainres.2003.09.020 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 753UT UT WOS:000187249500009 PM 14642451 ER PT J AU Goldstein, S Russo, A Samuni, A AF Goldstein, S Russo, A Samuni, A TI Reactions of PTIO and carboxy-PTIO with (NO)-N-center dot, (NO2)-N-center dot, and O-2(center dot) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE; NITRONYL NITROXIDES; SUPEROXIDE-DISMUTASE; PULSE-RADIOLYSIS; NITROGEN-DIOXIDE; AQUEOUS-SOLUTION; HUMAN-CELLS; CENTER-DOT; NO; PEROXYNITRITE AB Nitronyl nitroxides, such as derivatives of 2- phenyl-4,4,5,5,- tetramethylimidazoline- 1- oxyl 3- oxide ( PTIOs), react with (.) NO to form the corresponding imino nitroxides ( PTIs) and (.) NO2. PTIOs are considered as monitors of (NO)-N-., stoichiometric sources of (NO2)-N-., biochemical and physiological effectors, specific tools for the elimination of (NO)-N-., and potential therapeutic agents. However, a better understanding of the chemical properties of PTIOs, especially following their reaction with (NO)-N-., is necessary to resolve many of the reported discrepancies surrounding the effects of PTIOs and to better characterize their potential therapeutic activity. We have generated electrochemically the oxidized and reduced forms of PTIO and carboxy- PTIO ( C- PTIO), characterized their absorption spectra, and determined the reduction potentials for the oxoammonium/ nitroxide and nitroxide/ hydroxylamine couples. The rate constants for the reaction of (NO2)-N-. with PTIO and C- PTIO to form the corresponding oxoammonium cations ( PTIO (+) s) and nitrite were determined to be ( 1.5 - 2) x 10(7) M-1 s(-1). We have also shown that the reactions of PTIO(+)s with (NO)-N-. form PTIOs and NO2-. The rate constants for these reactions are approximately 30- fold higher than those for the reactions of PTIOs with (NO)-N-. or O-2. The present results show that ( i) the reaction of PTIOs with (NO)-N-. forms solely PTIs and NO2- where [NO2-]/[ PTI] varies between 1 and 2 depending on the steady- state concentrations of (NO)-N-.. Consequently, quantitation of (NO)-N-. is valid only at sufficiently low fluxes of (NO)-N-.; ( ii) the reaction of PTIOs with (NO)-N-. can be used as a valid source of (NO2)-N-. only when the latter is effectively scavenged by an appropriate reductant; and ( iii) the formation of peroxynitrite cannot be efficiently inhibited by PTIOs even under relatively low fluxes of (NO)-N-. and O-2. and millimolar levels of PTIOs. C1 Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Biol, IL-91120 Jerusalem, Israel. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Goldstein, S (reprint author), Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. NR 44 TC 92 Z9 94 U1 6 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 19 PY 2003 VL 278 IS 51 BP 50949 EP 50955 DI 10.1074/jbc.M308317200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 752ZM UT WOS:000187206300016 PM 12954619 ER PT J AU Chan, FKM Shisler, J Bixby, JG Felices, M Zheng, LX Appel, M Orenstein, J Moss, B Lenardo, MJ AF Chan, FKM Shisler, J Bixby, JG Felices, M Zheng, LX Appel, M Orenstein, J Moss, B Lenardo, MJ TI A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEATH DOMAIN KINASE; NF-KAPPA-B; ADAPTIVE IMMUNE-RESPONSES; CELL-DEATH; INDUCED APOPTOSIS; T-LYMPHOCYTES; TNF RECEPTORS; FACTOR-ALPHA; RIP; FAS AB Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are potent regulators of apoptosis, a process that is important for the maintenance of immune homeostasis. Recent evidence suggests that TNFR-1 and Fas and TRAIL receptors can also trigger an alternative form of cell death that is morphologically distinct from apoptosis. Because distinct molecular components including the serine/threonine protein kinase receptor-interacting protein ( RIP) are required, we have referred to this alternative form of cell death as "programmed necrosis." We show that TNFR-2 signaling can potentiate programmed necrosis via TNFR-1. When cells were pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, enhanced cell death and recruitment of RIP to the TNFR-1 complex were observed. However, TNF-induced programmed necrosis was normally inhibited by caspase-8 cleavage of RIP. To ascertain the physiological significance of RIP and programmed necrosis, we infected Jurkat cells with vaccinia virus (VV) and found that VV-infected cells underwent programmed necrosis in response to TNF, but deficiency of RIP rescued the infected cells from TNF-induced cytotoxicity. Moreover, TNFR-2(-/-) mice exhibited reduced inflammation in the liver and defective viral clearance during VV infection. Interestingly, death effector domain-containing proteins such as MC159, E8, K13, and cellular FLIP, but not the apoptosis inhibitors Bcl-x(L), p35, and XIAP, potently suppressed programmed necrosis. Thus, TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition and may play a role in controlling viral infection. C1 Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Div Diabet, Worcester, MA 01655 USA. George Washington Univ, Dept Pathol, Washington, DC 20037 USA. RP Chan, FKM (reprint author), Univ Massachusetts, Sch Med, Dept Pathol, Rm S2-125,55 Lake Ave N, Worcester, MA 01655 USA. RI Chan, Francis/E-9647-2014; Chan, Francis K. L./F-4851-2010 OI Chan, Francis/0000-0002-4803-8353; Chan, Francis K. L./0000-0001-7388-2436 FU NIDDK NIH HHS [DK32520] NR 33 TC 240 Z9 250 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 DEC 19 PY 2003 VL 278 IS 51 BP 51613 EP 51621 DI 10.1074/jbc.M305633200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 752ZM UT WOS:000187206300095 PM 14532286 ER PT J AU Nagarajan, M Xiao, XS Antony, S Kohlhagen, G Pommier, Y Cushman, M AF Nagarajan, M Xiao, XS Antony, S Kohlhagen, G Pommier, Y Cushman, M TI Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CALF THYMUS DNA; TRANSPORT-SYSTEM; MAMMALIAN-CELLS; BINDING; CONDENSATION; CHLORIDE; ANALOG; CYTOTOXICITY; HOMOLOGATION; RECOGNITION AB The indenoisoquinolines are a class of noncamptothecin topoisomerase I inhibitors that display significant cytotoxicity in human cancer cell cultures. They offer a number of potential advantages over the camptothecins, including greater chemical stability, formation of more persistent cleavage complexes, and induction of a unique pattern of DNA cleavage sites. Molecular modeling has suggested that substituents on the indenoisoquinoline lactam nitrogen would protrude out of the DNA duplex in the ternary cleavage complex through the major groove. This indicates that relatively large substituents in that location would be tolerated without compromising biological activity. As a strategy for increasing the potencies and potential therapeutic usefulness of the indenoisoquinolines, a series of compounds was synthesized containing polyamine side chains on the lactam nitrogen. The rationale for the synthesis of these compounds was that the positively charged ammonium cations would increase DNA affinity through electrostatic binding to the negatively charged DNA backbone, and the polyamines might also facilitate cellular uptake by utilization of polyamine transporters. The key step in the synthesis involved the condensation of Schiff bases, containing protected amine side chains, with substituted homophthalic anhydrides, to afford cis-3-aryl-4-carboxy-1-isoquinolones. These isoquinolones were then converted to indenoisoquinolines with thionyl chloride. Although monoamines were much more potent than the lead compound, no significant increase in potency was observed through incorporation of additional amino groups in the side chain. However, one of the monoamine analogues, which features a bis(2-hydroxyethyl)amino group in the side chain, proved to be one of the most cytotoxic indenoisoquinoline synthesized to date, with a GI50 mean-graph midpoint (MGM) of 0.07 muM in the NIH human cancer cell culture screen, and topoisomerase I inhibitory activity comparable to that of camptothecin. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, 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. EM cushman@pharmacy.purdue.edu FU NCI NIH HHS [U01 CA 89566, 5T32 CA 09634, N01 CO 56000] NR 44 TC 113 Z9 114 U1 0 U2 11 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 DEC 18 PY 2003 VL 46 IS 26 BP 5712 EP 5724 DI 10.1016/jm030313f PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 753RE UT WOS:000187243700017 PM 14667224 ER PT J AU Gibbs, RA Belmont, JW Hardenbol, P Willis, TD Yu, FL Yang, HM Ch'ang, LY Huang, W Liu, B Shen, Y Tam, PKH Tsui, LC Waye, MMY Wong, JTF Zeng, CQ Zhang, QR Chee, MS Galver, LM Kruglyak, S Murray, SS Oliphant, AR Montpetit, A Hudson, TJ Chagnon, F Ferretti, V Leboeuf, M Phillips, MS Verner, A Kwok, PY Duan, SH Lind, DL Miller, RD Rice, JP Saccone, NL Taillon-Miller, P Xiao, M Nakamura, Y Sekine, A Sorimachi, K Tanaka, T Tanaka, Y Tsunoda, T Yoshino, E Bentley, DR Deloukas, P Hunt, S Powell, D Altshuler, D Gabriel, SB Qiu, RZ Ken, A Dunston, GM Kato, K Niikawa, N Knoppers, BM Foster, MW Clayton, EW Wang, VO Watkin, J Gibbs, RA Belmont, JW Sodergren, E Weinstock, GM Wilson, RK Fulton, LL Rogers, J Birren, BW Han, H Wang, HG Godbout, M Wallenburg, JC L'Archeveque, P Bellemare, G Todani, K Fujita, T Tanaka, S Holden, AL Lai, EH Collins, FS Brooks, LD McEwen, JE Guyer, MS Jordan, E Peterson, JL Spiegel, J Sung, LM Zacharia, LF Kennedy, K Dunn, MG Seabrook, R Shillito, M Skene, B Stewart, JG Valle, DL Clayton, EW Jorde, LB Belmont, JW Chakravarti, A Cho, MK Duster, T Foster, MW Jasperse, M Knoppers, BM Kwok, PY Licinio, J Long, JC Marshall, PA Ossorio, PN Wang, VO Rotimi, CN Royal, CDM Spallone, P Terry, SF Lander, ES Lai, EH Nickerson, DA Abecasis, GR Altshuler, D Bentley, DR Boehnke, M Cardon, LR Daly, MJ Deloukas, P Douglas, JA Gabriel, SB Hudson, RR Hudson, TJ Kruglyak, L Kwok, PY Nakamura, Y Nussbaum, RL Royal, CDM Schaffner, SF Sherry, ST Stein, LD Tanaka, T AF Gibbs, RA Belmont, JW Hardenbol, P Willis, TD Yu, FL Yang, HM Ch'ang, LY Huang, W Liu, B Shen, Y Tam, PKH Tsui, LC Waye, MMY Wong, JTF Zeng, CQ Zhang, QR Chee, MS Galver, LM Kruglyak, S Murray, SS Oliphant, AR Montpetit, A Hudson, TJ Chagnon, F Ferretti, V Leboeuf, M Phillips, MS Verner, A Kwok, PY Duan, SH Lind, DL Miller, RD Rice, JP Saccone, NL Taillon-Miller, P Xiao, M Nakamura, Y Sekine, A Sorimachi, K Tanaka, T Tanaka, Y Tsunoda, T Yoshino, E Bentley, DR Deloukas, P Hunt, S Powell, D Altshuler, D Gabriel, SB Qiu, RZ Ken, A Dunston, GM Kato, K Niikawa, N Knoppers, BM Foster, MW Clayton, EW Wang, VO Watkin, J Gibbs, RA Belmont, JW Sodergren, E Weinstock, GM Wilson, RK Fulton, LL Rogers, J Birren, BW Han, H Wang, HG Godbout, M Wallenburg, JC L'Archeveque, P Bellemare, G Todani, K Fujita, T Tanaka, S Holden, AL Lai, EH Collins, FS Brooks, LD McEwen, JE Guyer, MS Jordan, E Peterson, JL Spiegel, J Sung, LM Zacharia, LF Kennedy, K Dunn, MG Seabrook, R Shillito, M Skene, B Stewart, JG Valle, DL Clayton, EW Jorde, LB Belmont, JW Chakravarti, A Cho, MK Duster, T Foster, MW Jasperse, M Knoppers, BM Kwok, PY Licinio, J Long, JC Marshall, PA Ossorio, PN Wang, VO Rotimi, CN Royal, CDM Spallone, P Terry, SF Lander, ES Lai, EH Nickerson, DA Abecasis, GR Altshuler, D Bentley, DR Boehnke, M Cardon, LR Daly, MJ Deloukas, P Douglas, JA Gabriel, SB Hudson, RR Hudson, TJ Kruglyak, L Kwok, PY Nakamura, Y Nussbaum, RL Royal, CDM Schaffner, SF Sherry, ST Stein, LD Tanaka, T CA Int HapMap Consortium TI The International HapMap Project SO NATURE LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; LINKAGE-DISEQUILIBRIUM; HUMAN GENOME; ESTIMATING RECOMBINATION; SEQUENCE VARIATION; GENETIC-VARIATION; CROHNS-DISEASE; SUSCEPTIBILITY; DIVERSITY; COMPLEX C1 Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA. ParAllele Biosci, San Francisco, CA 94080 USA. Chinese Acad Sci, Beijing Genom Inst, Beijing 100300, Peoples R China. Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. Chinese Natl Human Genome Ctr Shanghai, Shanghai 201203, Peoples R China. Chinese Natl Human Genome Ctr Beijing, Beijing Econ & Technol Dev Zone, Beijing 100176, Peoples R China. Univ Hong Kong, Genome Res Ctr, Pokfulam, Hong Kong, Peoples R China. Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. Chinese Univ Hong Kong, Dept Biochem, Shatin, Hong Kong, Peoples R China. Hong Kong Univ Sci & Technol, Dept Biochem, Knowloon, Hong Kong, Peoples R China. Illumina, San Diego, CA 92121 USA. McGill Univ, Montreal, PQ H3A 1A4, Canada. Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada. Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Washington Univ, Sch Med, St Louis, MO 63110 USA. Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan. RIKEN, SNP Res Ctr, Tsurumi Ku, Kanagawa 2300045, Japan. RIKEN, Technol Transfer & Res Coordinat Div, Wako, Saitama 35101, Japan. Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. Whitehead Inst MIT, Ctr Genome Res, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beijing Normal Univ, Beijing 100875, Peoples R China. Hlth Sci Univ Hokkaido, Ezuko Inst Dev Disabil, Kumamoto 575, Japan. Shinshu Univ, Sch Med, Dept Med Genet, Matsumoto, Nagano 3908621, Japan. Univ Tsukuba, Eubios Eth Inst, Tsukuba, Ibaraki 3058691, Japan. Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Univ Ibadan, Coll Med, Ibadan, Oyo, Nigeria. Case Western Reserve Univ, Sch Med, Dept Bioeth, Cleveland, OH 44106 USA. Univ Utah, Dept Human Genet, Eccles Inst Human Genet, Salt Lake City, UT 84112 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. Univ Oxford, Dept Stat, Oxford OX1 3TG, England. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. NIH, NHGRI, Bethesda, MD 20892 USA. NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Chinese Acad Social Sci, Ctr Appl Eth, Beijing 100054, Peoples R China. Genet Interest Grp, London N1 3QP, England. Kyoto Univ, Inst Res Human, Sakyo Ku, Kyoto 6068501, Japan. Nagasaki Univ, Grad Sch Biomed Sci, Dept Human Genet, Nagasaki 8528523, Japan. Univ Montreal, Publ Law Res Ctr, CRDP, Montreal, PQ H3C 3J7, Canada. Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA. Vanderbilt Univ, Ctr Genet & Hlth Policy, Nashville, TN 37232 USA. Wellcome Trust Res Labs, London NW1 2BE, England. Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO 63108 USA. Whitehead Inst MIT, Ctr Genome Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. Chinese Acad Sci, Beijing 100864, Peoples R China. Chinese Minist Sci & Technol, Beijing 100862, Peoples R China. Genome Canada, Ottawa, ON K2P 1P1, Canada. McGill Univ, Off Technol Transfer, Montreal, PQ H3A 2A7, Canada. Genome Quebec, Montreal, PQ H3B 1S6, Canada. Minist Educ Culture Sports Sci & Technol, Chiyoda Ku, Tokyo, Japan. Hiraka & Associates, Minato Ku, Tokyo 1050001, Japan. SNP Consortium, Deerfield, IL 60015 USA. GlaxoSmithKline, Res Triangle Pk, NC 27709 USA. NIH, NHGRI, Bethesda, MD 20892 USA. Fdn Natl Inst Hlth, Bethesda, MD 20892 USA. NIH, Off Technol Transfer, Rockville, MD 20852 USA. Univ Maryland, Sch Law, Baltimore, MD 21201 USA. Exchange House, London EC2A 2HS, England. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. Stanford Ctr Biomed Eth, Palo Alto, CA 94304 USA. NYU, Dept Sociol, New York, NY 10003 USA. Univ Calif Berkeley, Dept Sociol, Berkeley, CA 94720 USA. Univ New Mexico, Hlth Sci Ctr, Gallup, NM 87301 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Wisconsin, Sch Law, Madison, WI 53706 USA. Univ London London Sch Econ & Polit Sci, London WC2A 2AE, England. Genet Alliance, Washington, DC 20008 USA. Univ Washington, Dept Genome Sci, Washington, DC 98125 USA. Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. NIH, NHGRI, Bethesda, MD 20892 USA. RP Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, 1 Baylor Plaza, Houston, TX 77030 USA. EM drb@sanger.ac.uk; fost1848@msmailhub.oulan.ou.edu RI Tam, Paul/C-4405-2009; Abecasis, Goncalo/B-7840-2010; Altshuler, David/A-4476-2009; Tsui, Lap-chee/A-1081-2010; Schaffner, Stephen/D-1189-2011; Deloukas, Panos/B-2922-2013; Kwok, Pui-Yan/F-7725-2014; Tsunoda, Tatsuhiko/K-2061-2014; Waye 韋妙宜教授, Mary Miu Yee /A-9674-2008; Tanaka, Toshihiro/J-9310-2014; Licinio, Julio/L-4244-2013; OI Belmont, John/0000-0001-7409-3578; Abecasis, Goncalo/0000-0003-1509-1825; Adebamowo, Clement/0000-0002-6571-2880; Altshuler, David/0000-0002-7250-4107; Deloukas, Panos/0000-0001-9251-070X; Kwok, Pui-Yan/0000-0002-5087-3059; Waye 韋妙宜教授, Mary Miu Yee /0000-0002-2582-4917; Tanaka, Toshihiro/0000-0001-6201-9784; Licinio, Julio/0000-0001-6905-5884; Cunningham, Fiona/0000-0002-7445-2419; Thorisson, Gudmundur/0000-0001-5635-1860 NR 68 TC 3294 Z9 3391 U1 18 U2 198 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 18 PY 2003 VL 426 IS 6968 BP 789 EP 796 DI 10.1038/nature02168 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 754QM UT WOS:000187342000046 ER PT J AU Ganesh, L Burstein, E Guha-Nijogi, A Louder, MK Mascola, JR Klomp, LWJ Wijmenga, C Duckett, CS Nabel, GJ AF Ganesh, L Burstein, E Guha-Nijogi, A Louder, MK Mascola, JR Klomp, LWJ Wijmenga, C Duckett, CS Nabel, GJ TI The gene product Murr1 restricts HIV-1 replication in resting CD4(+) lymphocytes SO NATURE LA English DT Article ID NF-KAPPA-B; HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELLS; UBIQUITINATION; ACTIVATION; ALPHA; TRANSCRIPTION; INFECTION; COMPLEX; PHOSPHORYLATION AB Although human immunodeficiency virus-1 (HIV-1) infects quiescent and proliferating CD4(+) lymphocytes, the virus replicates poorly in resting T cells(1-6). Factors that block viral replication in these cells might help to prolong the asymptomatic phase of HIV infection(7); however, the molecular mechanisms that control this process are not fully understood. Here we show that Murr1, a gene product known previously for its involvement in copper regulation(8,9), inhibits HIV-1 growth in unstimulated CD4(+) T cells. This inhibition was mediated in part through its ability to inhibit basal and cytokine-stimulated nuclear factor (NF)-kappaB activity. Knockdown of Murr1 increased NF-kappaB activity and decreased IkappaB-alpha concentrations by facilitating phospho-IkappaB-alpha degradation by the proteasome. Murr1 was detected in CD4(+) T cells, and RNA-mediated interference of Murr1 in primary resting CD4(+) lymphocytes increased HIV-1 replication. Through its effects on the proteasome, Murr1 acts as a genetic restriction factor that inhibits HIV-1 replication in lymphocytes, which could contribute to the regulation of asymptomatic HIV infection and the progression of AIDS. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Med Ctr Utrecht, NL-3584 EA Utrecht, Netherlands. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC-3005,40 Convent Dr, Bethesda, MD 20892 USA. RI Wijmenga, Cisca/D-2173-2009; Burstein, Ezra/B-7247-2016; OI Burstein, Ezra/0000-0003-4341-6367; Wijmenga, Cisca/0000-0002-5635-1614 NR 31 TC 157 Z9 163 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 DEC 18 PY 2003 VL 426 IS 6968 BP 853 EP 857 DI 10.1038/nature02171 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 754QM UT WOS:000187342000062 PM 14685242 ER PT J AU McConnell, JD Roehrborn, CG Bautista, OM Andriole, GL Dixon, CM Kusek, JW Lepor, H McVary, KT Nyberg, LM Clarke, HS Crawford, ED Diokno, A Foley, JP Foster, HE Jacobs, SC Kaplan, SA Kreder, KJ Lieber, MM Lucia, MS Miller, GJ Menon, M Milam, DF Ramsdell, JW Schenkman, NS Slawin, KM Smith, JA Kusek, JW Nyberg, LM Briggs, JP McConnell, JD Crawford, ED Homan, K Donohue, R Parker, D Easterday, K Robertson, K Kaplan, S Wentland, M Hardy, L Roehrborn, C Ahrens, A McConnell, J Hall, D Cutts, D Carter, S Waldrep, K Schenkman, N Sanetrik, K Sihelnik, S Zorn, B McLeod, D Moul, J Peay, K Szkutnik, A Travis, J Brawer, M Earl, D Mayo, M Dixon, C Hirschfield, S Lepor, H Hoffman, D Brassil, D Castro, M Kramer, P Slawin, K Pavlik, V Morton, R Miles, B Harrison, S Valdez, R Foley, J Jones, A Thompson, I Morey, A Canby-Hagino, E Dobbs, R Rozanski, T Sloat, G Ramsdell, J Parman, Z Schmidt, J Albo, M Guy, H Eskew, D Sparks, D Menon, M David, C Kirkemo, A Diokno, A Burks, D Stricker, H Peabody, J Littleton, R Leemon, B Steinert, B Kuzara, J Peabody, M Lieber, M Smith, J Patterson, D Blute, M Van Oort, C Fitch, D Mann, D Hyland, K Wieland, H McVary, K Perez, E Grayhack, J Bushman, W Haldes, K Manzera, M Smith, J Hughes, B Milam, D Sisk, P Andriole, G Faust, J Sundaram, C Nicolai, C Johnson, A Shelly, N Foster, H Martin, T Anderson, K Puklin, C Chodkowshi, D Alfano, S Sopp, K Clarke, H Lopez, B Tenover, L Elmer, S Lachenmeyer, K Kreder, K Fearing, M See, W Ziegler, B Schultz, S Tuftee, T Jacobs, S Hershner, M Naslund, M Greene, B Markowitz, G Miller, GJ Lucia, MS Lepoff, R Covey-Magnuson, C Johnson, G Torkko, K Bautista, O Burrows, P Gersnoviez, R Bain, R Greenhouse, S Bamdad, J Mason, W Sherif, H Temprosa, M Minkoff, N Barry, M Bruskewitz, R Cockett, A Litwin, M Mostwin, J Reda, D Roberts, R Rous, S Williford, W Smith-West, D Greene, P Round, E Gormley, G Mallen, S Sigel, R Grossman, E AF McConnell, JD Roehrborn, CG Bautista, OM Andriole, GL Dixon, CM Kusek, JW Lepor, H McVary, KT Nyberg, LM Clarke, HS Crawford, ED Diokno, A Foley, JP Foster, HE Jacobs, SC Kaplan, SA Kreder, KJ Lieber, MM Lucia, MS Miller, GJ Menon, M Milam, DF Ramsdell, JW Schenkman, NS Slawin, KM Smith, JA Kusek, JW Nyberg, LM Briggs, JP McConnell, JD Crawford, ED Homan, K Donohue, R Parker, D Easterday, K Robertson, K Kaplan, S Wentland, M Hardy, L Roehrborn, C Ahrens, A McConnell, J Hall, D Cutts, D Carter, S Waldrep, K Schenkman, N Sanetrik, K Sihelnik, S Zorn, B McLeod, D Moul, J Peay, K Szkutnik, A Travis, J Brawer, M Earl, D Mayo, M Dixon, C Hirschfield, S Lepor, H Hoffman, D Brassil, D Castro, M Kramer, P Slawin, K Pavlik, V Morton, R Miles, B Harrison, S Valdez, R Foley, J Jones, A Thompson, I Morey, A Canby-Hagino, E Dobbs, R Rozanski, T Sloat, G Ramsdell, J Parman, Z Schmidt, J Albo, M Guy, H Eskew, D Sparks, D Menon, M David, C Kirkemo, A Diokno, A Burks, D Stricker, H Peabody, J Littleton, R Leemon, B Steinert, B Kuzara, J Peabody, M Lieber, M Smith, J Patterson, D Blute, M Van Oort, C Fitch, D Mann, D Hyland, K Wieland, H McVary, K Perez, E Grayhack, J Bushman, W Haldes, K Manzera, M Smith, J Hughes, B Milam, D Sisk, P Andriole, G Faust, J Sundaram, C Nicolai, C Johnson, A Shelly, N Foster, H Martin, T Anderson, K Puklin, C Chodkowshi, D Alfano, S Sopp, K Clarke, H Lopez, B Tenover, L Elmer, S Lachenmeyer, K Kreder, K Fearing, M See, W Ziegler, B Schultz, S Tuftee, T Jacobs, S Hershner, M Naslund, M Greene, B Markowitz, G Miller, GJ Lucia, MS Lepoff, R Covey-Magnuson, C Johnson, G Torkko, K Bautista, O Burrows, P Gersnoviez, R Bain, R Greenhouse, S Bamdad, J Mason, W Sherif, H Temprosa, M Minkoff, N Barry, M Bruskewitz, R Cockett, A Litwin, M Mostwin, J Reda, D Roberts, R Rous, S Williford, W Smith-West, D Greene, P Round, E Gormley, G Mallen, S Sigel, R Grossman, E CA MTOPS Res Grp TI The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE URINARY RETENTION; AMERICAN-UROLOGICAL-ASSOCIATION; GOODNESS-OF-FIT; CONTROLLED TRIAL; TRACT SYMPTOMS; DOUBLE-BLIND; EFFICACY; MEN; PLACEBO; SAFETY AB BACKGROUND: Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alpha-blockers) or 5(alpha)-reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. METHODS: We conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia. RESULTS: The risk of overall clinical progression -- defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection -- was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. CONCLUSIONS: Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy. C1 Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. George Washington Univ, Rockville, MD USA. Washington Univ, St Louis, MO USA. NYU, New York, NY USA. NIDDKD, Bethesda, MD 20892 USA. Northwestern Univ, Chicago, IL 60611 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Brooke Army Med Ctr, Ft Sam Houston, TX 78234 USA. Yale Univ, New Haven, CT USA. Univ Maryland, Baltimore, MD 21201 USA. New York Presbyterian Hosp, New York, NY USA. Univ Iowa, Iowa City, IA USA. Mayo Clin, Rochester, MN USA. Henry Ford Hosp, Detroit, MI 48202 USA. Vanderbilt Univ, Nashville, TN USA. Univ Calif San Diego, San Diego, CA 92103 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Roehrborn, CG (reprint author), Univ Texas, SW Med Ctr, 5323 Harry Hines Blvd,J8-130, Dallas, TX 75390 USA. RI Litwin, Mieczyslaw/C-3868-2012; Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NIDDK NIH HHS [U01 DK-49880, U01 DK-49960, U01 DK41418, U01 DK46416, U01 DK46429, U01 DK46431, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49912, U01 DK49951, U01 DK49954, U01 DK49963, U01 DK49964, U01 DK49971, U01 DK49977, U01 DK49980] NR 42 TC 904 Z9 979 U1 4 U2 32 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 DEC 18 PY 2003 VL 349 IS 25 BP 2387 EP 2398 DI 10.1056/NEJMoa030656 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 754PJ UT WOS:000187326200004 PM 14681504 ER PT J AU Wolff, L Garin, MT Koller, R Bies, J Liao, W Malumbres, M Tessarollo, L Powell, D Perella, C AF Wolff, L Garin, MT Koller, R Bies, J Liao, W Malumbres, M Tessarollo, L Powell, D Perella, C TI Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15(Ink4b)-defficient mice SO ONCOGENE LA English DT Article DE tumor suppressor; myeloid leukemia; hypermethylation; retrovirus; Ink4b ID KINASE INHIBITOR P15(INK4B); TUMOR-SUPPRESSOR; C-MYB; METHYLATION; P16(INK4A); P19(ARF); CELLS; DIFFERENTIATION; TUMORIGENESIS; INACTIVATION AB The Ink4b gene (Cdkn2b) encodes p15(Ink4b), a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. The evidence is twofold: (1) retrovirus-induced myeloid leukemias of the myelomonocytic phenotype were found to have hypermethylation of the 5' CpG island of the Ink4b gene, and this could be correlated with reduced mRNA expression, as demonstrated by TaqMan real-time PCR. p15(Ink4b) mRNA expression in a leukemia cell line, with hypermethylation at the locus, was induced following treatment with 5-aza-2'-deoxycytidine.(2) Targeted deletion of one allele in mice by removal of exon 2 increases their susceptibility to retrovirus-induced myeloid leukemia. Mice deficient in both alleles were not more susceptible to myeloid disease than those deficient in one allele, raising the possibility that there are opposing forces related to the development of myeloid leukemia in Ink4b null mice. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Ctr Nacl Invest Oncol, E-28029 Madrid, Spain. NCI, SAIC Frederick, Bethesda, MD 20892 USA. NCI, Data Management Serv, Frederick, MD 21701 USA. RP Wolff, L (reprint author), NCI, Ctr Canc Res, NIH, Bldg 37,Room 4124A,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. RI Malumbres, Marcos/E-8834-2011 OI Malumbres, Marcos/0000-0002-0829-6315 NR 31 TC 32 Z9 32 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 18 PY 2003 VL 22 IS 58 BP 9265 EP 9274 DI 10.1038/sj.onc.1207092 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 755JU UT WOS:000187400400008 PM 14681685 ER PT J AU Ghali, JK Krause-Steinrauf, HJ Adams, KF Khan, SS Rosenberg, YD Yancy, CW Young, JB Goldman, S Peberdy, MA Lindenfeld, J AF Ghali, JK Krause-Steinrauf, HJ Adams, KF Khan, SS Rosenberg, YD Yancy, CW Young, JB Goldman, S Peberdy, MA Lindenfeld, J TI Gender differences in advanced heart failure: Insights from the BEST study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR FUNCTION; ACUTE MYOCARDIAL-INFARCTION; POSTMENOPAUSAL WOMEN; CLINICAL-TRIALS; MORTALITY; HYPERTROPHY; ESTROGEN; HYPERTENSION; BISOPROLOL; EXCLUSION AB OBJECTIVES The goal of this study was to determine the influence of gender on baseline characteristics, response to treatment, and prognosis in patients with heart failure (HF) and impaired left ventricular ejection fraction (LVEF). BACKGROUND Under-representation of women in HF clinical trials has limited our understanding of gender-related differences in patients with HF. METHODS The impact of gender was assessed in the Beta-Blocker Evaluation of Survival Trial (BEST) which randomized 2,708 patients with New York Heart Association class III/IV and LVEF less than or equal to 0.35 to bucindolol versus placebo. Women (n = 593) were compared with men (n = 2,115). Mean follow-up period was two years. RESULTS Significant differences in baseline clinical and laboratory characteristics were found. Women were younger, more likely to be black, had a higher prevalence of nonischemic etiology, higher right and left ventricular ejection fraction, higher heart rate, greater cardiothoracic ratio, higher prevalence of left bundle branch block, lower prevalence of atrial fibrillation, and lower plasma norepinephrine level. Ischemic etiology and measures of severity of HF were found to be predictors of prognosis in women and men. However, differences in the predictive values of various variables were noted; most notably, coronary artery disease and LVEF appear to be stronger predictors of prognosis in women. In the nonischemic patients, women had a significantly better survival rate compared with men. CONCLUSIONS In HF patients with impaired LVEF, significant gender differences are present, and the prognostic predictive values of some variables vary in magnitude between women and men. The survival advantage of women is confined to patients with nonischemic etiology. (J Am Coll Cardiol 2003;42:2128-34) (C) 2003 by the American College of Cardiology Foundation. C1 Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Vet Affairs Med Ctr, Tucson, AZ USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Texas SW, Dallas, TX USA. Cedars Sinai Med Ctr, Los Angeles, CA USA. Univ N Carolina, Chapel Hill, NC USA. NHLBI, Bethesda, MD 20892 USA. Cardiac Ctr Louisiana, Shreveport, LA USA. RP Ghali, JK (reprint author), Cardiac Ctr Louisiana LLC, 2551 Greenwood Rd,Suite 350, Shreveport, LA 71103 USA. NR 34 TC 130 Z9 135 U1 1 U2 3 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 DEC 17 PY 2003 VL 42 IS 12 BP 2128 EP 2134 DI 10.1016/j.jacc.2003.05.012 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 753ER UT WOS:000187219600017 PM 14680739 ER PT J AU Twizere, JC Kruys, V Lefebvre, L Vanderplasschen, A Collete, D Debacq, C Lai, WS Jauniaux, JC Bernstein, LR Semmes, OJ Burny, A Blackshear, PJ Kettmann, R Willems, L AF Twizere, JC Kruys, V Lefebvre, L Vanderplasschen, A Collete, D Debacq, C Lai, WS Jauniaux, JC Bernstein, LR Semmes, OJ Burny, A Blackshear, PJ Kettmann, R Willems, L TI Interaction of retroviral tax oncoproteins with tristetraprolin and regulation of tumor necrosis factor-alpha expression SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID VIRUS TYPE-I; BOVINE-LEUKEMIA-VIRUS; NF-KAPPA-B; T-CELL ACTIVATION; COLONY-STIMULATING FACTOR; MESSENGER-RNA TURNOVER; AU-RICH ELEMENTS; TYPE-1 TAX; HTLV-1 TAX; GM-CSF AB Background: The Tax oncoproteins are transcriptional regulators of viral expression involved in pathogenesis induced by complex leukemogenic retroviruses (or delta-retroviruses, i.e., primate T-cell leukemia viruses and bovine leukemia virus). To better understand the molecular pathways leading to cell transformation, we aimed to identify cellular proteins interacting with Tax. Methods: We used a yeast two-hybrid system to identify interacting cellular proteins. Interactions between Tax and candidate interacting cellular proteins were confirmed by glutathione S-transferase (GST) pulldown assays, co-immunoprecipitation, and confocal microscopy. Functional interactions between Tax and one interacting protein, tristetraprolin (TTP), were assessed by analyzing the expression of tumor necrosis factor-alpha (TNF-alpha), which is regulated by TTP, in mammalian cells (HeLa, D17, HEK 293, and RAW 264.7) transiently transfected with combinations of intact and mutant Tax and TTP. Results: We obtained seven interacting cellular proteins, of which one, TTP, was further characterized. Tax and TTP were found to interact specifically through their respective carboxyl-terminal domains. The proteins colocalized in the cytoplasm in a region surrounding the nucleus of HeLa cells. Furthermore, coexpression of Tax was associated with nuclear accumulation of TTP. TTP is an immediate-early protein that inhibits expression of TNF-alpha at the post-transcriptional level. Expression of Tax reverted this inhibition, both in transient transfection experiments and in stably transfected macrophage cell lines. Conclusion: Tax, through its interactions with the TTP repressor, indirectly increases TNF-alpha expression. This observation is of importance for the cell transformation process induced by leukemogenic retroviruses, because TNF-a. overexpression plays a central role in pathogenesis. C1 Fac Univ Sci Agron Gembloux, B-5030 Gembloux, Belgium. Free Univ Brussels, Inst Biol Mol & Med, Gosselies, Belgium. Univ Liege, Fac Med Vet, Liege, Belgium. NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. Texas A&M Univ, Dept Pathol & Lab Med, College Stn, TX USA. Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23501 USA. RP Willems, L (reprint author), Fac Univ Sci Agron Gembloux, 13 Ave Marechal Juin, B-5030 Gembloux, Belgium. FU NCI NIH HHS [5 R29 CA73783, R01 CA076595] NR 98 TC 36 Z9 39 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 DEC 17 PY 2003 VL 95 IS 24 BP 1846 EP 1859 DI 10.1093/jnci/djg118 PG 14 WC Oncology SC Oncology GA 754GX UT WOS:000187308700009 PM 14679154 ER PT J AU Le Grice, SFJ AF Le Grice, SFJ TI "In the beginning": Initiation of minus strand DNA synthesis in retroviruses and LTR-containing retrotransposons SO BIOCHEMISTRY LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMER-BINDING-SITE; HIV-1 REVERSE TRANSCRIPTION; ROUS-SARCOMA-VIRUS; RNA SECONDARY STRUCTURE; MATURE TRANSFER-RNA; LAC UV5 PROMOTER; PSI-C LOOP; EFFICIENT INITIATION; IN-VITRO AB Sequestering a host-coded tRNA for initiation of minus (-) strand DNA synthesis is central to the reverse transcription cycle of a number of retroviruses and long terminal repeat (LTR) retrotransposons. However, "self-priming" from a hydrolysis product of the viral genome has been observed for the LTR retrotransposon Tf1 and most likely exists for related elements. Furthermore, in contrast to retroviruses, where DNA synthesis is initiated from the 3'-terminus of the cognate tRNA primer, examples are available where nucleotides of the tRNA anticodon domain are complementary to the viral primer binding site (PBS), necessitating internal cleavage of the primer to provide the appropriate 3'-OH for DNA synthesis. Thus, although the ensuing steps of reverse transcription are common to these elements, several variations in which the replication primer is used have been exploited. In addition, the PBS of the viral RNA genome can vary in size from an 11 nt sequence, through a bipartite cis-acting element, to 18 contiguous nucleotides complementary to the 3'-end of the replication primer. These diverse tRNA-viral RNA interactions, and their consequences for initiation of (-) strand DNA synthesis, are the subject of this review. C1 NCI, Reverse Transcriptase Biochem Sect, Resistance Mech Lab, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, Reverse Transcriptase Biochem Sect, Resistance Mech Lab, HIV Drug Resistance Program, Frederick, MD 21702 USA. NR 64 TC 35 Z9 36 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 DEC 16 PY 2003 VL 42 IS 49 BP 14349 EP 14355 DI 10.1021/bi030201q PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 753PU UT WOS:000187240400001 PM 14661945 ER PT J AU Aviles, RJ Martin, DO Apperson-Hansen, C Houghtaling, PL Rautaharju, P Kronmal, RA Tracy, RP Van Wagoner, DR Psaty, BM Lauer, MS Chung, MK AF Aviles, RJ Martin, DO Apperson-Hansen, C Houghtaling, PL Rautaharju, P Kronmal, RA Tracy, RP Van Wagoner, DR Psaty, BM Lauer, MS Chung, MK TI Inflammation as a risk factor for atrial fibrillation SO CIRCULATION LA English DT Article DE atrial flutter; fibrillation; inflammation; arrhythmia ID C-REACTIVE PROTEIN; CARDIOVASCULAR HEALTH; EPIDEMIOLOGIC FEATURES; MARKERS; ARRHYTHMIAS; PREVALENCE; ADULTS AB Background - The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort. Methods and Results - CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9 +/- 1.6 ( median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile ( < 0.97 mg/L), subjects in the fourth quartile ( > 3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P = 0.002). Of 5491 subjects without AF at baseline, 897 ( 16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF ( fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P = 0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF ( adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P < 0.001). Conclusions - CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF. C1 Cleveland Clin Fdn, Dept Cardiovasc Med, Cleveland, OH 44951 USA. Cleveland Clin Fdn, Dept Biostat, Cleveland, OH 44951 USA. Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Vermont, Dept Pathol & Biochem, Colchester, VT USA. CHS Coordinating Ctr, Seattle, WA USA. RP Aviles, RJ (reprint author), NHLBI, Cardiovasc Branch, NIH, 10 Ctr Dr,Bldg 10,Room 2C713,MSC 1538, Bethesda, MD 20892 USA. RI Van Wagoner, David/C-6783-2008; Lauer, Michael/L-9656-2013; OI Van Wagoner, David/0000-0001-8250-9828; Lauer, Michael/0000-0002-9217-8177; Apperson-Hansen, Carolyn/0000-0001-9057-3037 FU NHLBI NIH HHS [N01-HC-85083, HL-65412, N01 HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85084, N01-HC-85085, N01-HC-85086] NR 25 TC 694 Z9 764 U1 5 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 DEC 16 PY 2003 VL 108 IS 24 BP 3006 EP 3010 DI 10.1161/01.CIR.0000103131.70301.4F PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 754CZ UT WOS:000187286300012 PM 14623805 ER PT J AU Hirsch, GA Heldman, AW Wittstein, IS Schulman, SP Gerstenblith, G AF Hirsch, GA Heldman, AW Wittstein, IS Schulman, SP Gerstenblith, G TI ST-segment elevation in an unresponsive patient SO CIRCULATION LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. RP Hirsch, GA (reprint author), NHLBI, NIH, 10 Ctr Dr,MSC-1061,Bldg 10,Room B1D-416, Bethesda, MD 20892 USA. RI Heldman, Alan/K-8784-2012 NR 0 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 16 PY 2003 VL 108 IS 24 BP E165 EP E166 DI 10.1161/01.CIR.0000109202.90989.99 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 754CZ UT WOS:000187286300020 PM 14676137 ER PT J AU Sverdlov, AV Rogozin, IB Babenko, VN Koonin, EV AF Sverdlov, AV Rogozin, IB Babenko, VN Koonin, EV TI Evidence of splice signal migration from exon to intron during intron evolution SO CURRENT BIOLOGY LA English DT Article ID SITES; RNA; POSITIONS; SEQUENCES; ANCIENT; MODEL; GENES; CONSERVATION; INFORMATION; FAMILIES AB A comparison of the nucleotide sequences around the splice junctions that flank old (shared by two or more major lineages of eukaryotes) and new (lineage-specific) introns in eukaryotic genes reveals substantial differences in the distribution of information between introns and exons. Old introns have a lower information content in the exon regions adjacent to the splice sites than new introns but have a corresponding higher information content in the intron itself. This suggests that introns insert into nonrandom (proto-splice) sites but, during the evolution of an intron after insertion, the splice signal shifts from the flanking exon regions to the ends of the intron itself. Accumulation of information inside the intron during evolution suggests that new introns largely emerge de novo rather than through propagation and migration of old introns. C1 Natl Lib Med, Natl Inst Hlth, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Inst Hlth, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RI Babenko, Vladimir/K-5609-2014; OI Babenko, Vladimir/0000-0002-3077-9559 NR 32 TC 30 Z9 30 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 DEC 16 PY 2003 VL 13 IS 24 BP 2170 EP 2174 DI 10.1016/j.cub.2003.12.003 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 756GB UT WOS:000187456500023 PM 14680632 ER PT J AU Thayer, JF Merritt, MM Sollers, JJ Zonderman, AB Evans, MK Yie, S Abernethy, DR AF Thayer, JF Merritt, MM Sollers, JJ Zonderman, AB Evans, MK Yie, S Abernethy, DR TI Effect of angiotensin-converting enzyme insertion/deletion polymorphism DD genotype on high-frequency heart rate variability in African Americans SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; DELETION POLYMORPHISM; MYOCARDIAL-INFARCTION; GENE POLYMORPHISMS; SPECTRAL-ANALYSIS; DISEASE; ASSOCIATION; HUMANS AB Seventy-nine African-American participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) pilot study were genotyped for the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and had spectral power of their high-frequency (HF) heart rate variability (HRV). determined by fast-Fourier transformation. HF HRV was highest in 11,- intermediate in ID, and lowest in DD (11 vs DD, p <0.043) genotypes, thus making an association of the ACE I/D DD genotype with -decreased HF HRV that is consistent with the hypothesis that the DD genotype confers susceptibility to increased c ' ardiovascularrisk. The urban African-American population we studied had a particularly high cardiovascular risk, and these findings suggest that ACE I/D genotypes may modify that risk. 02003 by Excerpta Medica, Inc. C1 NIA, Intramural Res Program, Natl Ctr Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Div Geriatr Med, Baltimore, MD USA. RP Abernethy, DR (reprint author), NIA, Intramural Res Program, Natl Ctr Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. OI Zonderman, Alan B/0000-0002-6523-4778 NR 20 TC 25 Z9 26 U1 1 U2 3 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 DEC 15 PY 2003 VL 92 IS 12 BP 1487 EP 1490 DI 10.1016/j.amjcard.2003.08.069 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 753ZD UT WOS:000187277500028 PM 14675596 ER PT J AU Johnston, JJ Olivos-Glander, I Turner, J Aleck, K Bird, LM Mehta, L Schimke, RN Heilstedt, H Spence, JE Blancato, J Biesecker, LG AF Johnston, JJ Olivos-Glander, I Turner, J Aleck, K Bird, LM Mehta, L Schimke, RN Heilstedt, H Spence, JE Blancato, J Biesecker, LG TI Clinical and molecular delineation of the greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE GLI3; GCPS; acrocallosal ID GLI3; MUTATIONS; DISORDERS; SPECTRUM AB Greig cephalopolysyndactyly syndrome (GCPS) is caused by haploinsufficiency of GLI3 on 7p13. Features of GCPS include polydactyly, macrocephaly, and hypertelorism, and may be associated with cognitive deficits and abnormalities of the corpus callosum. GLI3 mutations in GCPS patients include point, frameshift, translocation, and gross deletion mutations. FISH and STRP analyses were applied to 34 patients with characteristics of GCPS. Deletions were identified in 11 patients and the extent of their deletion was determined. Nine patients with deletions had mental retardation (MR) or developmental delay (DD) and were classified as severe GCPS. These severe GCPS patients have manifestations that overlap with the acrocallosal syndrome (ACLS). The deletion breakpoints were analyzed in six patients whose deletions ranged in size from 151 kb to 10.6 Mb. Junction fragments were found to be distinct with no common sequences flanking the breakpoints. We con-clude that patients with GCPS caused by large deletions that include GLI3 are likely to have cognitive deficits, and we hypothesize that this severe GCPS phenotype is caused by deletion of contiguous genes. Published 2003 Wiley-Liss, Inc. C1 NHGRI, NIH, Bethesda, MD 20892 USA. GeneDx Corp, Gaithersburg, MD USA. Univ Arizona, Coll Med, Phoenix, AZ USA. Childrens Hosp & Hlth Ctr, San Diego, CA USA. N Shore Univ Hosp, Manhasset, NY USA. Univ Kansas, Sch Med, Kansas City, KS USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Carolinas Med Ctr, Charlotte, NC 28203 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bldg 49,Room 4A80, Bethesda, MD 20892 USA. NR 16 TC 27 Z9 28 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC 15 PY 2003 VL 123A IS 3 BP 236 EP 242 DI 10.1002/ajmg.a.20318 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 747UL UT WOS:000186823200003 PM 14608643 ER PT J AU Taveira-DaSilva, AM Stylianou, MP Hedin, CJ Kristof, AS Avila, NA Rabel, A Travis, WD Moss, J AF Taveira-DaSilva, AM Stylianou, MP Hedin, CJ Kristof, AS Avila, NA Rabel, A Travis, WD Moss, J TI Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE interstitial lung disease; maximal oxygen uptake; diffusion capacity; computed tomography scan; lung histology ID HEALTHY NONSMOKING ADULTS; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; CAPACITY AB Lymphangioleiomyomatosis (LAM), a disease that occurs primarily in women, is characterized by cystic lung lesions causing respiratory failure, which may require lung transplantation. Lung diffusion (DLCO) and/or FEV1 are decreased, but frequently not in parallel with each other. Because cardiopulmonary exercise testing (CPET) provides information that is not obtainable from resting cardiopulmonary tests, we performed CPET in 217 LAM patients and correlated exercise data with clinical markers of severity, computed tomography scans, lung function, and histology. (V) over dot O(2)max was decreased in 162 patients, of whom 28 did not reach anaerobic threshold; 29 had low oxygen uptake at anaerobic threshold, and 54 developed hypoxemia. Hypoxemia occurred even in patients with near normal DLCO and FEV1. (V) over dot O(2)max decreased with an increasing score of histologic LAM severity and was correlated with computed tomography scans, the use of oxygen, and resting Pa-O2. DLCO and FEV1, however, were the only significant predictors of (V)over dot O(2)max. We conclude that CPET uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and determining supplemental oxygen requirements in patients with LAM. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. RP NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Room 6D05,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov NR 19 TC 46 Z9 49 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 15 PY 2003 VL 168 IS 12 BP 1427 EP 1431 DI 10.1164/rccm.200203-593OC PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 753DB UT WOS:000187215700010 PM 12958050 ER PT J AU Ward, MM Sundaramurthy, S Lotstein, D Bush, TM Neuwelt, CM Street, RL AF Ward, MM Sundaramurthy, S Lotstein, D Bush, TM Neuwelt, CM Street, RL TI Participatory patient-physician communication and morbidity in patients with systemic lupus erythematosus SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE patient-physician communication; systemic lupus erythematosus; morbidity; socioeconomic status; health disparities ID LONGITUDINAL DATA-ANALYSIS; DISEASE-ACTIVITY; SOCIOECONOMIC-STATUS; MEDICAL CONSULTATIONS; METABOLIC CONTROL; ACTIVITY INDEXES; DECISION-MAKING; SELF-MANAGEMENT; DAMAGE INDEX; CARE AB Objective. To examine associations between active patient-physician communication and measures of morbidity in patients with systemic lupus erythematosus (SLE). Methods. Audiotapes of routine visits between 79 women with SLE and their rheumatologists were coded for active patient participation and the degree of patient-centered communication of the physician, using a validated coding scheme. Measures of SLE activity, functional disability, and permanent organ damage were recorded at the same visit. Permanent organ damage was reassessed in 68 patients after a median of 4.7 years. Results. Patients who participated more actively in their visits had less permanent organ damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and tended to accrue less organ damage over time. There were no associations between either active patient participation or physicians' patient-centered communication scores and measures of SLE activity or functional disability. Conclusions. Patients with SLE who participated more actively in their visits had less permanent organ damage, suggesting that involving patients more in their care may decrease morbidity. C1 Vet Affairs Palo Alto Hlth Care Syst, Stanford, CA USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Santa Clara Valley Med Ctr, San Jose, CA 95128 USA. Alameda Cty Med Ctr, Oakland, CA USA. Texas A&M Univ, College Stn, TX USA. RP Ward, MM (reprint author), NIAMS, NIH, IRP, Bldg 10,Room 9S205,10 Ctr Dr,MSC 1828, Bethesda, MD 20892 USA. NR 64 TC 49 Z9 49 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD DEC 15 PY 2003 VL 49 IS 6 BP 810 EP 818 DI 10.1002/art.11467 PG 9 WC Rheumatology SC Rheumatology GA 753LK UT WOS:000187232700011 PM 14673968 ER PT J AU Jun, DY Rue, SW Han, KH Taub, D Lee, YS Bae, YS Kim, YH AF Jun, DY Rue, SW Han, KH Taub, D Lee, YS Bae, YS Kim, YH TI Mechanism underlying cytotoxicity of thialysine, lysine analog, toward human acute leukemia Jurkat T cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE lysine analog; thialysine; apoptosis; mitochondrial cytochrome c; caspase cascade; Bcl-xL; cell-cycle arrest; cdks; cyclins ID DRUG-INDUCED APOPTOSIS; APO-1/FAS RECEPTOR/LIGAND SYSTEM; L-CANAVANINE; CYTOCHROME-C; BCL-XL; CANCER-CHEMOTHERAPY; ECTOPIC EXPRESSION; GROWTH-INHIBITION; CYCLE CONTROL; CHO CELLS AB We first report the mechanism for the inhibitory effect of the lysine analog, thialysine on human acute leukemia Jurkat T cells. When Jurkat T cells were treated with thialysine (0.32-2.5 mM), apoptotic cell death along with several biochemical events such as mitochondrial cytochrome c release, caspase-9 activation, caspase-3 activation, degradation of poly (ADP-ribose) polymerase, and DNA fragmentation was induced in a dose- and time-dependent manner. However, these thialysine-induced apoptotic events were significantly abrogated by an ectopic expression of Bcl-xL, which is known to block mitochondrial cytochrome c release. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, also suppressed thialysine-induced apoptotic events. Comparison of the thialysine-induced alterations in the cell cycle distribution between Jurkat T cells transfected with Bcl-xL gene (J/Bcl-xL) and Jurkat T cells transfected with vector (J/Neo) revealed that the apoptotic cells were mainly derived from the cells accumulated in S and G2/M phases following thialysine treatment. The interruption of cell cycle progression in the presence of thialysine was accompanied by a significant decline in the protein level of cdk4, cdk6, cdc2, cyclin A, cyclin B 1, and cyclin E. These results demonstrate that the cytotoxic activity of thialysine toward Jurkat T cells is attributable to not only apoptotic cell death mediated by a mitochondria-dependent death signaling pathway, but also interruption of cell cycle progression by a massive down-regulation in the level of cdks and cyclins. (C) 2003 Elsevier Inc. All rights reserved. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Microbiol, Immunobiol Lab, Taegu 702701, South Korea. NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Kyungpook Natl Univ, Coll Nat Sci, Dept Biochem, Taegu 702701, South Korea. RP Kim, YH (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Microbiol, Immunobiol Lab, Taegu 702701, South Korea. NR 45 TC 18 Z9 18 U1 1 U2 1 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 DEC 15 PY 2003 VL 66 IS 12 BP 2291 EP 2300 DI 10.1016/j.bcp.2003.08.030 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 749KL UT WOS:000186919000003 PM 14637187 ER PT J AU Volkow, ND Insel, TR AF Volkow, ND Insel, TR TI What are the long-term effects of methylphenidate treatment? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; ORAL METHYLPHENIDATE; ABUSE; SENSITIZATION; AMPHETAMINE; CHILDREN; COCAINE; RATS; ADHD C1 NIDA, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, 6001 Execut Blvd,Room 5274,MSC9581, Bethesda, MD 20892 USA. NR 21 TC 82 Z9 82 U1 2 U2 10 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 DEC 15 PY 2003 VL 54 IS 12 BP 1307 EP 1309 DI 10.1016/j.biopsych.2003.10.019 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 753UW UT WOS:000187249800001 PM 14675792 ER PT J AU Ingjaldsson, JT Laberg, JC Thayer, JF AF Ingjaldsson, JT Laberg, JC Thayer, JF TI Reduced heart rate variability in chronic alcohol abuse: Relationship with negative mood, chronic thought suppression, and compulsive drinking SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cue reactivity; thought suppression; craving; Obsessive Compulsive Drinking Scale; White Bear Thought Suppression Inventory; heart rate variability ID CUE-REACTIVITY; POLYVAGAL THEORY; DRUG-USE; STIMULI; RESPONSES; DISORDER; ANXIETY; MODEL; SCALE; BEHAVIOR AB Background: Previous research suggests that heart rate variability (HRV) may be an important factor in various maladaptive psychological conditions. Methods: This study was conducted to investigate vagal tone assessed as tonic vagally mediated heart rate variability in alcoholic (n = 49) and control subjects (n = 45). Results: Alcoholic subjects had faster heart rate and lower preimaginary exposure levels of HRV compared with the control group. An increase in HRV was observed in the alcoholic group when subjects were exposed to an imaginary alcohol script. Tonic HRV was found to be related inversely to negative mood and chronic thought suppression and positively to positive mood. Furthermore, the compulsive subscale of the Obsessive Compulsive Drinking Scale (OCDS) was inversely related to HRV during the imaginary alcohol exposure. Conclusions: It is concluded that the findings are in agreement with the neurovisceral integration model of affective regulation, which claims that dysfunctional psychologic states are rooted in an impaired inhibitory mechanism that is associated with low HRV. C1 Univ Bergen, Dept Clin Psychol, N-5012 Bergen, Norway. Univ Bergen, Dept Psychosocial Sci, N-5012 Bergen, Norway. NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. RP Ingjaldsson, JT (reprint author), Univ Bergen, Dept Clin Psychol, Christiesgate 12, N-5012 Bergen, Norway. NR 66 TC 116 Z9 119 U1 4 U2 18 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 DEC 15 PY 2003 VL 54 IS 12 BP 1427 EP 1436 DI 10.1016/S0006-3223(02)01926-1 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 753UW UT WOS:000187249800017 PM 14675808 ER PT J AU Orlic, D AF Orlic, D TI Adult stem cells: can they transdifferentiate? SO BLOOD LA English DT Editorial Material ID MYOCARDIAL-INFARCTION; TRANSPLANTATION; REGENERATION C1 NIH, Bethesda, MD USA. RP Orlic, D (reprint author), NIH, Bethesda, MD USA. NR 5 TC 1 Z9 1 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 DEC 15 PY 2003 VL 102 IS 13 BP 4249 EP 4250 DI 10.1182/blood-2003-09-3306 PG 2 WC Hematology SC Hematology GA 751ZT UT WOS:000187122000005 ER PT J AU Tisdale, JF AF Tisdale, JF TI Modeling human hematopoiesis: of mice and monkeys SO BLOOD LA English DT Editorial Material C1 NIH, Bethesda, MD USA. RP Tisdale, JF (reprint author), NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 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 DEC 15 PY 2003 VL 102 IS 13 BP 4254 EP 4254 DI 10.1182/blood-2003-09-3214 PG 1 WC Hematology SC Hematology GA 751ZT UT WOS:000187122000011 ER PT J AU Gomez, G Sitkovsky, MV AF Gomez, G Sitkovsky, MV TI Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; CONCANAVALIN-A; ANTIINFLAMMATORY MECHANISM; A(3) RECEPTORS; LIVER-INJURY; CEREBROSPINAL-FLUID; INDUCED HEPATITIS; ALPHA PRODUCTION; ENDOTOXIC-SHOCK; HUMAN MONOCYTES AB Inosine is an endogenous nucleoside with immunosuppressive properties that is known to inhibit the accumulation of proinflammatory cytokines and protect mice from endotoxin-induced inflammation and lung tissue damage. There are no known receptors specific for inosine, but A3 adenosine receptors (A3Rs) have been shown to bind inosine, resulting in mast cell degranulation and increased vascular permeability. The present study specifically addresses the requirement for A2aR and/or A3R for the protective effect of inosine in 2 experimental in vivo models of inflammatory disease. The data show that A3R is essential for protection against ConA-induced fulminant hepatitis since only MR-expressing mice were protected by inosine whereas wild-type and A2aR-deficient mice exhibited severe liver damage even after administration of inosine. In addition, we show in a model of LPS-induced endotoxemia that inosine protected both A2aR(-/-) and A3R(-/-) mice from inflammation, but not A2aA3R double-null mice, indicating that in this model both A2aR and A3R were used by inosine. Thus, we demonstrate that A2a and A3 adenosine receptors are differentially utilized by inosine for the downregulation of tissue damage under different inflammatory conditions in vivo. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sitkovsky, MV (reprint author), NIAID, Immunol Lab, NIH, 10-11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. NR 54 TC 60 Z9 66 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 DEC 15 PY 2003 VL 102 IS 13 BP 4472 EP 4478 DI 10.1182/blood-2002-11-3624 PG 7 WC Hematology SC Hematology GA 751ZT UT WOS:000187122000043 PM 12947007 ER PT J AU Chandra, J Hackbarth, J Le, S Loegering, D Bone, N Bruzek, LM Narayanan, VL Adjei, AA Kay, NE Tefferi, A Karp, JE Sausville, EA Kaufmann, SH AF Chandra, J Hackbarth, J Le, S Loegering, D Bone, N Bruzek, LM Narayanan, VL Adjei, AA Kay, NE Tefferi, A Karp, JE Sausville, EA Kaufmann, SH TI Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; ABL TYROSINE KINASE; BCR-ABL; IN-VITRO; PHILADELPHIA-CHROMOSOME; HEMATOPOIETIC-CELLS; IMATINIB MESYLATE; TYRPHOSTIN AG957; ARSENIC TRIOXIDE AB Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/ abl(-) cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned. C1 Mayo Clin, Div Oncol Res, Dept Oncol, Rochester, MN 55901 USA. Mayo Clin, Dept Internal Med, Rochester, MN 55901 USA. Mayo Grad Sch, Dept Biochem & Mol Biol, Rochester, MN USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. Univ Maryland, Greenbaum Canc Ctr, Baltimore, MD 21201 USA. RP Kaufmann, SH (reprint author), Mayo Clin, Div Oncol Res, Dept Oncol, Guggenheim 1301,200 1st SW, Rochester, MN 55901 USA. FU NCI NIH HHS [F32 CA93055, R01 CA 85972, R01 CA91542] NR 42 TC 57 Z9 61 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 DEC 15 PY 2003 VL 102 IS 13 BP 4512 EP 4519 DI 10.1182/blood-2003-02-0562 PG 8 WC Hematology SC Hematology GA 751ZT UT WOS:000187122000049 PM 12920036 ER PT J AU Kurzrock, R Kantarjian, HM Cortes, JE Singhania, N Thomas, DA Wilson, EF Wright, JJ Freireich, EJ Talpaz, M Sebti, SM AF Kurzrock, R Kantarjian, HM Cortes, JE Singhania, N Thomas, DA Wilson, EF Wright, JJ Freireich, EJ Talpaz, M Sebti, SM TI Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting SO BLOOD LA English DT Article ID GERANYLGERANYLTRANSFERASE-I INHIBITORS; PROTEIN TRANSFERASE INHIBITOR; ACUTE MYELOGENOUS LEUKEMIA; RAS SIGNALING PATHWAY; GTP-BINDING PROTEINS; N-RAS; K-RAS; H-RAS; TRANSGENIC MICE; TUMOR-GROWTH AB R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-weekoff schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/ schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras, 3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. Fill 15777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-alpha (TNF-alpha) levels by day 7 showed a trend toward correlation with response (P =.09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS. C1 Univ Texas, MD Anderson Canc Ctr, Dept Bioimmunotherapy, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. Univ Colorado, Hlth Sci Ctr, Dept Internal Med, Denver, CO 80202 USA. Univ S Florida, Drug Discovery Program, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. NCI, Bethesda, MD 20892 USA. RP Kurzrock, R (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Bioimmunotherapy, Unit 422,1515 Holcombe Blvd, Houston, TX 77030 USA. FU NCI NIH HHS [1R21CA91518-1] NR 57 TC 96 Z9 104 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 DEC 15 PY 2003 VL 102 IS 13 BP 4527 EP 4534 DI 10.1182/blood-2002-11-3359 PG 8 WC Hematology SC Hematology GA 751ZT UT WOS:000187122000051 PM 12947010 ER PT J AU Tamura, T Kong, HJ Tunyaplin, C Tsujimura, H Calame, K Ozato, K AF Tamura, T Kong, HJ Tunyaplin, C Tsujimura, H Calame, K Ozato, K TI ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells SO BLOOD LA English DT Article ID SEQUENCE-BINDING-PROTEIN; CHRONIC MYELOGENOUS LEUKEMIA; C-MYC TRANSCRIPTION; TERMINAL MACROPHAGE DIFFERENTIATION; BCR-ABL; CLINICAL-FEATURES; INTERFERON-ALPHA; DENDRITIC CELLS; IN-VIVO; EXPRESSION AB Interferon consensus sequence binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) is a transcription factor that controls myeloid cell development. ICSBF-/- mice develop a chronic myelogenous leukemia (CML)-like syndrome. Several observations on patients and mouse models have implicated ICSBP in the pathogenesis of CML. In this paper, we investigated whether ICSBP modulates the growth-promoting activity of Bcr/Abl, the causal oncoprotein for CIVIL. When transformed with p210 Bcr/Abl, ICSBP-/- myeloid progenitor cells lost growth factor dependence and grew in the absence of granulocyte-macrophage colony-stimulating factor. When ICSBP was ectopically expressed, Bcr/Abl-transformed cells underwent complete growth arrest and differentiated into mature, functional macrophages without inhibiting the kinase activity of Bcr/Abl. Providing a mechanistic basis for the growth arrest, ICSBP markedly repressed c-Myc messenger RNA (mRNA)expression, a downstream target of Bcr/Abl. A further analysis with the ICSBP/estrogen receptor chimera showed that ICSBP repression of c-Myc is indirect and is mediated by another gene(s). We identified Blimp-1 and METS/PE1, potent c-Myc repressors, as direct targets of ICSBP activated in these cells. Consistent with this, ectopic Blimp-1 repressed c-Myc expression and inhibited cell growth. These results indicate that ICSBP inhibits growth of Bcr/Abl-transformed myeloid progenitor cells by activating several genes that interfere with the c-Myc pathway. (C) 2003 by The American Society of Hematology. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Microbiol, New York, NY USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Rm 2A01,6 Ctr Dr MSC 2753, Bethesda, MD 20892 USA. NR 51 TC 47 Z9 47 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 DEC 15 PY 2003 VL 102 IS 13 BP 4547 EP 4554 DI 10.1182/blood-2003-01-0291 PG 8 WC Hematology SC Hematology GA 751ZT UT WOS:000187122000054 PM 12933588 ER PT J AU Roschke, AV Tonon, G Gehlhaus, KS McTyre, N Bussey, KJ Lababidi, S Scudiero, DA Weinstein, JN Kirsch, IR AF Roschke, AV Tonon, G Gehlhaus, KS McTyre, N Bussey, KJ Lababidi, S Scudiero, DA Weinstein, JN Kirsch, IR TI Karyotypic complexity of the NCI-60 drug-screening panel SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; CANCER-CELL-LINES; IN-SITU HYBRIDIZATION; MOLECULAR CYTOGENETIC ANALYSIS; DOUBLE-STRAND BREAKS; CHROMOSOMAL INSTABILITY; TELOMERE DYSFUNCTION; SOLID TUMORS; SACCHAROMYCES-CEREVISIAE; OVARIAN ADENOCARCINOMA AB We used spectral karyotyping to provide a detailed analysis of karyotypic aberrations in the diverse group of cancer cell lines established by the National Cancer Institute for the purpose of anticancer drug discovery. Along with the karyotypic description of these cell lines we defined and studied karyotypic complexity and heterogeneity (metaphase-to-metaphase variations) based on three separate components of genomic anatomy: (a) ploidy; (b) numerical changes; and (c) structural rearrangements. A wide variation in these parameters was evident in these cell lines, and different association patterns between them were revealed. Analysis of the breakpoints and other specific features of chromosomal changes across the entire set of cell lines or within particular lineages pointed to a striking lability of centromeric regions that distinguishes the epithelial tumor cell lines. We have also found that balanced translocations are as frequent in absolute number within the cell lines derived from solid as from hematopoietic tumors. Important similarities were noticed between karyotypic changes in cancer cell lines and that seen in primary tumors. This dataset offers insights into the causes and consequences of the destabilizing events and chromosomal instability that may occur during tumor development and progression. It also provides a foundation for investigating associations between structural genome anatomy and cancer molecular markers and targets, gene expression, gene dosage, and resistance or sensitivity to tens of thousands of molecular compounds. C1 NCI, Genet Branch, Ctr Canc Res, Natl Naval Med Ctr, Bethesda, MD 20889 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20889 USA. NCI, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Kirsch, IR (reprint author), NCI, Genet Branch, Ctr Canc Res, Natl Naval Med Ctr, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 76 TC 186 Z9 192 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2003 VL 63 IS 24 BP 8634 EP 8647 PG 14 WC Oncology SC Oncology GA 757UR UT WOS:000187580300013 PM 14695175 ER PT J AU Silva, S Kovalchuk, AL Kim, JS Klein, G Janz, S AF Silva, S Kovalchuk, AL Kim, JS Klein, G Janz, S TI BCL2 accelerates inflammation-induced BALB/c plasmacytomas and promotes novel tumors with coexisting T(12;15) and T(6;15) translocations SO CANCER RESEARCH LA English DT Article ID PLASMA CELL NEOPLASIA; C-MYC EXPRESSION; CHROMOSOMAL TRANSLOCATIONS; TRANSGENIC MICE; B-CELLS; MOUSE PLASMACYTOMAS; MULTIPLE-MYELOMA; LYMPHOID-TISSUES; INDUCTION; APOPTOSIS AB Previous studies on peritoneal plasmacytomas (PCTs) in BALB/c (C) mice suggested that the enforced expression of the death repressor BCL2 in B cells might facilitate the malignant transformation of aberrant B cells containing Myc-activating T(12;15) translocations, generating an improved model of plasmacytomagenesis. To investigate this hypothesis, we backcrossed a human BCL2 transgene onto strain C and performed a PCT induction study with pristane in the newly generated C.BCL2 congenics. In specific pathogen-free-maintained C.BCL2 mice, PCT incidence (19 of 34, 56%) was 24 times higher than in specific pathogen-free-maintained C mice (1 of 44, 2.3%), and tumor onset (113 days) was half that of conventionally maintained C mice (220 days). BCL2 transgenic PCT harbored T(12;15) translocations (12 of 12 tumors) with an unusual clustering of translocation breakpoints in the near 5' flank of Myc (4 of 5 tumors, 80%). Five tumors contained coexisting T(12;15) and T(6;15) translocations (not observed in >300 karyotyped PCTs from conventionally maintained C mice). BCL2 transgenic C57BL/6 mice exclusively developed B lymphomas (11 of 20, 55%) that also contained T(12;15) translocations (11 of 11 cases) with breakpoints in the near 5' flank of Myc (five of five tumors). We conclude that BCL2 accelerates PCT with novel Myc-activating translocations independently of environmental antigen stimulation. Accelerated plasmacytomagenesis in strain C.BCL2 may be useful for designing and testing BCL2 inhibition strategies in human plasma cell tumors overexpressing BCL2, such as Waldenstrom's macroglobulinemia and multiple myeloma. C1 NCI, Genet Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Ctr Microbiol & Tumor Biol, Stockholm, Sweden. RP Janz, S (reprint author), NCI, Genet Lab, Ctr Canc Res, NIH, Bldg 37,Room 2B10, Bethesda, MD 20892 USA. NR 70 TC 22 Z9 26 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2003 VL 63 IS 24 BP 8656 EP 8663 PG 8 WC Oncology SC Oncology GA 757UR UT WOS:000187580300015 PM 14695177 ER PT J AU Chun, YS Lee, KH Choi, E Bae, SY Yeo, EJ Huang, LE Kim, MS Park, JW AF Chun, YS Lee, KH Choi, E Bae, SY Yeo, EJ Huang, LE Kim, MS Park, JW TI Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor l alpha isoform: Implications for tumor promotion SO CANCER RESEARCH LA English DT Article ID PAS DOMAIN PROTEIN; FACTOR 1-ALPHA; PROLYL HYDROXYLATION; NUCLEAR TRANSLOCATION; GENE-EXPRESSION; HIF-ALPHA; FACTOR-I; FACTOR-1-ALPHA; HIF-1-ALPHA; PATHWAY AB Hypoxia-inducible factor-1 (HIF-1), which is present at higher levels in human tumors, plays important roles in tumor promotion. It is composed of HIF-1alpha and HIF-1beta subunits and its activity depends on the amount of HIF-1alpha, which is tightly controlled by cellular oxygen tension. In addition to hypoxia, various nonhypoxic stimuli can stabilize HIF-1alpha in tumor cells, implying that both hypoxic and nonhypoxic stimuli contribute to the overexpression of HIF-1alpha in tumors. On the other hand, phorbol esters such as phorbol-12-myristate-13-acetate (PMA) are known to be potent tumor promoters. Here, we identified a novel HIF-1alpha isoform, which is regulated primarily by PMA. The variant mRNA lacks exon 11 and produces a 785-amino acid isoform (HIF-1alpha(785)) without altering the reading frame and therefore the COOH-terminal transcriptional activity. HIF- 1alpha(785) is induced markedly by PMA and heat shock, the latter of which is also known to induce HIF-1alpha. HIF-1alpha(785) escapes from lysine acetylation because of the loss of Lys(532) and was stabilized under normoxic conditions. Its expression was blocked by reducing agents and by a mitogen-activated protein/extracellular signal-regulated kinase-1 inhibitor and enhanced by hydrogen peroxide. In addition, HIF-1alpha(785). overexpression strikingly enhanced tumor growth in vivo. These results suggest that HIF-1alpha(785). is induced by PMA under normoxic conditions via a redox-dependent mitogen-activated protein/extracellular signal-regulated kinase-1 pathway and that it plays an important role in tumor promotion. C1 Seoul Natl Univ, Coll Med, Dept Pharmacol, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Human Genome Res Inst, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Park, JW (reprint author), Seoul Natl Univ, Coll Med, Dept Pharmacol, 28 Yongon Dong, Seoul 110799, South Korea. EM parkjw@plaza.snu.ac.kr RI Park, Jong-Wan/J-2758-2012; Chun, Yang Sook/J-2789-2012 NR 37 TC 44 Z9 45 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2003 VL 63 IS 24 BP 8700 EP 8707 PG 8 WC Oncology SC Oncology GA 757UR UT WOS:000187580300022 PM 14695184 ER PT J AU Elkin, M Cohen, I Zcharia, E Orgel, A Guatta-Rangini, Z Peretz, T Vlodavsky, I Kleinman, HK AF Elkin, M Cohen, I Zcharia, E Orgel, A Guatta-Rangini, Z Peretz, T Vlodavsky, I Kleinman, HK TI Regulation of heparanase gene expression by estrogen in breast cancer SO CANCER RESEARCH LA English DT Article ID MAMMALIAN HEPARANASE; BASEMENT-MEMBRANE; IN-VITRO; MOLECULAR-PROPERTIES; TUMOR ANGIOGENESIS; ENDOTHELIAL-CELLS; GROWTH-FACTORS; MAMMARY-GLAND; METASTASIS; PROMOTER AB Numerous epidemiological studies clearly suggest that estrogen is one of the main driving forces in breast tumorigenesis, but precise mechanisms of cancer promotion by estrogen remain poorly understood. Classically, tumorigenic effects of estrogen have been attributed to its ability to directly promote the proliferation of breast cancer cells. In addition to abnormal proliferation, interactions between tumor cells and surrounding stromal components (e.g., enzymatic remodeling and degradation of extracellular matrix) are critical for cancer progression, angiogenesis, and metastasis. We now report that in breast carcinomas, estrogen may promote these pathological tumor-stromal interactions through up-regulation of heparanase gene expression. Heparanase is an endoglycosidase degrading heparan sulfate, of the basement membrane and extracellular matrix. This cleavage affects tumor-stromal interaction, neovascularization, local invasion, and metastatic spread. However, little is known about transcriptional regulation of the heparanase gene. We identified four putative estrogen response elements in the heparanase promoter region and found that transcription of a luciferase reporter gene driven by the heparanase promoter was significantly increased in estrogen-receptor positive MCF-7 human breast carcinoma cells after estrogen treatment. Estrogen-induced heparanase mRNA transcription in estrogen receptor-positive, but not in estrogen receptor-negative, breast cancer cells, confirmed the promoter study data. The estrogen effects on heparanase mRNA expression levels were abolished in the presence of the pure antiestrogen ICI 182,780, indicating that the classic estrogen receptor pathway is involved in transcriptional activation of heparanase. In vivo, exposure to estrogen augmented levels of heparanase protein in MCF-7 cells embedded in Matrigel plugs and correlated with increased plug vascularization. Collectively, our data suggest a new molecular pathway through which estrogen, independent of its proliferative effect, may induce heparanase overexpression and, thus, promote tumor-stromal interactions, critical for breast carcinoma development and progression. C1 Technion, Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, IL-31096 Haifa, Israel. Natl Inst Dent & Craniofacial Res, Cell Biol Sect, NIH, Bethesda, MD USA. Hadassah Hebrew Univ Med Ctr, Dept Oncol, Jerusalem, Israel. RP Vlodavsky, I (reprint author), Technion, Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, POB 9649, IL-31096 Haifa, Israel. FU NCI NIH HHS [R21 CA87085] NR 44 TC 71 Z9 79 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2003 VL 63 IS 24 BP 8821 EP 8826 PG 6 WC Oncology SC Oncology GA 757UR UT WOS:000187580300036 PM 14695198 ER PT J AU Lee, J Elkahloun, AG Messina, SA Ferrari, N Xi, D Smith, CL Cooper, R Albert, PS Fine, HA AF Lee, J Elkahloun, AG Messina, SA Ferrari, N Xi, D Smith, CL Cooper, R Albert, PS Fine, HA TI Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: A potential antiglioma cellular vector SO CANCER RESEARCH LA English DT Article ID APOPTOSIS-INDUCING LIGAND; CENTRAL-NERVOUS-SYSTEM; IN-VITRO; MOLECULAR CLASSIFICATION; PROGENITOR CELLS; EXPRESSION; VIVO; NEURONS; BRAIN; PROLIFERATION AB We describe the in vitro isolation and expansion of cells capable of forming neurosphere-like aggregates from human adult bone marrow. Cells within these passaged spheroids can differentiate into astrocytes, specific neuronal subtypes, and oligodendrocytes and have gene expression profiles similar to human fetal brain-derived neural stem cells. Genetically modified neural-competent bone marrow-derived cells efficiently migrate toward distant sites of brain injury and tumor in vivo, where they differentiate and express therapeutic transgenes when transplanted into the brains of mice. These studies suggest that adult bone marrow may serve as a large reservoir for autologous neural stem-like cells for future therapeutic strategies. C1 NCI, Neurooncol Branch, Natl inst neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Microarray Unit, NIH, Bethesda, MD USA. Natl Inst Neurol Disorders & Stroke, Light Imaging Facil, Bethesda, MD USA. NCI, Biometr Res Branch, DCTD, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), Room 225,Bloch Bldg Bldg 82,9030 Old Georgetown R, Bethesda, MD 20892 USA. NR 50 TC 77 Z9 94 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2003 VL 63 IS 24 BP 8877 EP 8889 PG 13 WC Oncology SC Oncology GA 757UR UT WOS:000187580300043 PM 14695205 ER PT J AU Bisht, KS Bradbury, CM Mattson, D Kaushal, A Sowers, A Markovina, S Ortiz, KL Sieck, LK Isaacs, JS Brechbiel, MW Mitchell, JB Neckers, LM Gius, D AF Bisht, KS Bradbury, CM Mattson, D Kaushal, A Sowers, A Markovina, S Ortiz, KL Sieck, LK Isaacs, JS Brechbiel, MW Mitchell, JB Neckers, LM Gius, D TI Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; PAPILLOMAVIRUS TYPE-16 E7; IONIZING-RADIATION; INDUCED ACTIVATION; HEAT-SHOCK-PROTEIN-90 FUNCTION; INDUCED RADIOSENSITIZATION; NUCLEAR TRANSLOCATION; MOLECULAR CHAPERONES; CANCER-THERAPY; GROWTH ARREST AB Ansamycin antibiotics inhibit function of the heat shock protein (HSP) 90, causing selective degradation of several intracellular proteins regulating such processes as proliferation, cell cycle regulation, and prosurvival signaling cascades. HSP90 has been identified previously as a molecular target for anticancer agents, including ionizing radiation (IR). Therefore, we hypothesized that the ansamycin geldanamycin and its 17-allylamino17-demethoxy analog (17-AAG), which inhibit HSP90, would enhance tumor cell susceptibility to the cytotoxicity of IR. Treatment of two human cervical carcinoma cell lines (HeLa and SiHa) with geldanamycin and 17-AAG resulted in cytotoxicity and, when combined with IR, enhanced the radiation response, each effect with a temporal range from 6 to 48 It after drug exposure. In addition, mouse in vivo models using 17-AAG at clinically achievable concentrations yielded results that paralleled the in vitro radiosensitization studies of both single and fractioned courses of irradiation. The increase in IR-induced cell death appears to be attributable to a combination of both programmed and nonprogrammed cell death. We also measured total levels of several prosurvival and apoptotic signaling proteins. Akt1, extracellular signal-regulated kinase-1, Glut-1, HER-2/neu, Lyn, cAMP-dependent protein kinase, Raf-1, and vascular endothelial growth factor expression were down-regulated in 17-AAG-treated cells, identifying these factors as molecular markers and potential therapeutic targets. Finally, a series of immortalized and human papillomavirus-transformed cell lines were used to demonstrate that the radio-sensitizing effects of 17-AAG were limited to transformed cells, suggesting a possible differential cytotoxic effect. This work shows that altered HSP90 function induces significant tumor cytotoxicity and radiosensitization, suggesting a potential therapeutic utility. C1 NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Rockville, MD USA. RP NCI, Mol Radiat Oncol Sect, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bldg 10,Room B3B6,9000 R, Bethesda, MD 20892 USA. EM giusd@mail.nih.gov NR 61 TC 126 Z9 139 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2003 VL 63 IS 24 BP 8984 EP 8995 PG 12 WC Oncology SC Oncology GA 757UR UT WOS:000187580300055 PM 14695217 ER PT J AU Wang, G Tschoi, M Spolski, R Lou, YY Ozaki, K Feng, CG Kim, G Leonard, WJ Hwu, P AF Wang, G Tschoi, M Spolski, R Lou, YY Ozaki, K Feng, CG Kim, G Leonard, WJ Hwu, P TI In vivo antitumor activity of interleukin 21 mediated by natural killer cells SO CANCER RESEARCH LA English DT Article ID ESTABLISHED PULMONARY METASTASES; RECOMBINANT INTERLEUKIN-2; ADAPTIVE IMMUNITY; CYTOKINE RECEPTOR; PLASMID DNA; GAMMA CHAIN; IL-21; NK; RESPONSES; CANCER AB Immunotherapy with high-dose interleukin (IL) 2 has been shown to successfully treat tumors in animal models and cause dramatic tumor regressions in some patients with metastatic melanoma,renal cell carcinoma, and non-Hodgkin's lymphoma. However, toxicity associated with IL-2 administration has compromised its widespread use in the clinic. IL-21 is a more recently discovered cytokine produced by activated CD4(+) T cells that shares significant sequence homology to IL-2, IL-4, and IL-15. Because IL-21 and IL-2 and their receptors share significant sequence similarities and both cytokines can stimulate T and natural killer (NK) cells, we sought to study whether IL-21, like IL-2, exhibits antitumor effects in vivo. In this study, we treated established s.c. tumor in mice by systemically administering plasmid DNA encoding murine IL-21 using a hydrodynamics-based gene delivery technique. Administration of IL-21 plasmid DNA resulted in high levels of circulating IL-21 in vivo. Treatment of tumor-bearing mice with IL-21 plasmid DNA significantly inhibited the growth of B16 melanoma and MCA205 fibrosarcoma in a dose-dependent manner without significant toxicity and increased the survival rate, compared with mice treated with control plasmid DNA. In vivo depletion of either CD4(+) or CD8(+) T cells did not affect IL-21-mediated antitumor activity. However, depletion of NK cells completely abolished IL-21-induced tumor inhibition. Consistent with this, the antitumor activity of IL-21 seemed to be mediated through enhanced cytolytic activity of NK cells. Our study suggests that IL-21 has significant antitumor activity and may have therapeutic potentials as an antitumor agent in the clinic. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Wang, G (reprint author), Univ Texas, MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 430, Houston, TX 77030 USA. NR 28 TC 163 Z9 171 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2003 VL 63 IS 24 BP 9016 EP 9022 PG 7 WC Oncology SC Oncology GA 757UR UT WOS:000187580300058 PM 14695220 ER PT J AU Hayashi, SM Ton, TV Hong, HHL Irwin, RD Haseman, JK Devereux, TR Sills, RC AF Hayashi, SM Ton, TV Hong, HHL Irwin, RD Haseman, JK Devereux, TR Sills, RC TI Genetic alterations in the Catnb gene but not the H-ras gene in hepatocellular neoplasms and hepatoblastomas of B6C3F(1) mice following exposure to diethanolamine for 2 years SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE beta-catenin; molecular hepatocarcinogenesis; hepatoblastomas ID BETA-CATENIN MUTATIONS; MOUSE-LIVER TUMORS; LUNG-TUMORS; PROTOONCOGENE ACTIVATION; PROTEIN ACCUMULATION; SOMATIC MUTATIONS; HIGH-FREQUENCY; CARCINOMAS; OVEREXPRESSION; FORESTOMACH AB The present study characterized the immunohistochemical localization of beta-catenin protein in hepatocellular neoplasms and hepatoblastomas in B6C3F(1) mice exposed to diethanolamine (DEA) for 2 years and evaluated genetic alterations in the Catnb and H-ras genes which are known to play important roles in the pathogenesis of liver malignancies. Genomic DNA was isolated from paraffin sections of each liver tumor. Catnb exon 2 (corresponds to exon 3 in human) genetic alterations were identified in 18/18 (100%) hepatoblastomas from DEA exposed mice. Deletion mutations (15/18, 83%) were identified more frequently than point mutations (6/18, 33%) in hepatoblastomas. Eleven of 34 (32%) hepatocellular adenomas and carcinomas from DEA treated mice had mutations in exon 2 of the beta-catenin gene, while only 1 of 10 spontaneous neoplasms had a deletion mutation of codon 5-6. Common to all liver neoplasms (hepatocellular adenomas, carcinomas and hepatoblastomas) was membrane staining for the beta-catenin protein, while cytoplasmic and nuclear staining was observed only in hepatoblastomas. The lack of H-ras mutations in hepatocellular neoplasms and hepatoblastomas suggests that the ras signal transduction pathway is not involved in the development of liver tumors following DEA exposure which is different from that of spontaneous liver tumors that often contain H-ras mutations. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Gen Toxicol, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Sills, RC (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 39 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD DEC 15 PY 2003 VL 146 IS 3 BP 251 EP 261 DI 10.1016/j.cbi.2003.07.001 PG 11 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 753TF UT WOS:000187246100004 PM 14642737 ER PT J AU Alexander, HR Libutti, SK Pingpank, JF Steinberg, SM Bartlett, DL Helsabeck, C Beresneva, T AF Alexander, HR Libutti, SK Pingpank, JF Steinberg, SM Bartlett, DL Helsabeck, C Beresneva, T TI Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-NECROSIS-FACTOR; UVEAL MELANOMA; SURVIVAL; CANCER; INTERLEUKIN-2; EXPERIENCE; REGRESSION; THERAPY; CELL AB Purpose: Liver metastases are the sole or life-limiting component of disease in the majority of patients with ocular melanoma who recur. Because median survival after diagnosis of liver metastases is short and no satisfactory treatment options exist, we have conducted clinical trials evaluating isolated hepatic perfusion (IHP) for patients afflicted with this condition. Experimental Design: Twenty-nine patients (male: 14, female: 15; mean age, 49 years) with unresectable liver metastases from ocular melanoma were treated with a 60-min hyperthermic IHP using 1.5 mg/kg of melphalan (mean total dose 105 mg). Via laparotomy, perfusion inflow was established with a cannula in the gastroduodenal artery and outflow via a cannula positioned in an isolated segment of the retrohepatic inferior vena cava. Portal and infra-renal inferior vena cava blood flow was shunted externally to the axillary vein using a veno-veno bypass circuit. Patients were assessed for toxicity, radiographic response, and survival. Results: There was no treatment related mortality and transient grade 3/4 hepatic toxicity was observed in 19 patients (65%). Mean length of operation and hospital stay was 8.3 h and 10 days, respectively. There were 3 (10%) complete responses (duration: 12, 14+, 15 months) and 15 partial responses (52%; mean duration: 10 months). The initial site of disease progression included liver in 17 of 25 patients (68%) who recurred. At a median follow-up of 30.7 months the median actuarial progression-free and overall survivals were 8 and 12.1 months, respectively. Conclusions: IHP with melphalan alone results in significant regression of established liver metastases for patients with ocular melanoma. However, after IHP, disease progression is most commonly observed in the liver, and survival after disease progression is short. On the basis of a pattern of tumor progression predominantly in liver, continued clinical evaluation of hepatic directed therapy in this patient population is justified. C1 NCI, Surg Metab Sect, NIH, Surg Branch,Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Canc Res Ctr, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Metab Sect, NIH, Surg Branch,Ctr Canc Res, 10 Ctr Dr,Bldg 10,Room 2B07, Bethesda, MD 20892 USA. NR 26 TC 67 Z9 69 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2003 VL 9 IS 17 BP 6343 EP 6349 PG 7 WC Oncology SC Oncology GA 758QH UT WOS:000187661300006 PM 14695133 ER PT J AU Kawakami, M Kawakami, K Kasperbauer, JL Hinkley, LL Tsukuda, M Strome, SE Puri, RK AF Kawakami, M Kawakami, K Kasperbauer, JL Hinkley, LL Tsukuda, M Strome, SE Puri, RK TI Interleukin-13 receptor alpha 2 chain in human head and neck cancer serves as a unique diagnostic marker SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; IN-SITU HYBRIDIZATION; PSEUDOMONAS EXOTOXIN; CYTOTOXIN; PROTEIN; EXPRESSION; THERAPY; PATHWAY; MODEL; IL-13 AB Previous studies have demonstrated that approximately 30% of squamous cell carcinoma of the head and neck (SCCHN) cell lines express high levels of interleukin-13 receptor(s) (IL-13R). However, the incidence, expression level, and significance of IL-13R expression in human tumor specimens is not known. In addition, it is not known whether normal head and neck tissues express IL-13R. In this study, we evaluated the expression of IL-13R subunits (IL-13alpha1, IL-13Ralpha2, and IL-4Ralpha) in 337 surgically excised specimens of SCCHN and normal head and neck tissues. Specimens were obtained from 139 patients with SCCHN and 16 patients with benign tonsil disorders from two centers in the United States and Japan and evaluated with immunohistochemistry and in situ hybridization. Extensive analysis demonstrated that the majority of SCCHN tumors uniformly expressed low levels of IL-13Ralpha1 chain; however, 77% of the tumors expressed moderate to high levels of IL-4Ralpha, which forms a signaling complex with IL-13Ralpha1 chain. On the other hand, 33% of SCCHN tumors expressed moderate to high levels of IL-13Ralpha2 chain. Using tissue array from 99 patients, we observed that the expression levels of IL-13Ralpha2 and IL-4Ralpha were significantly higher in SCCHN than in normal head and neck tissues (P < 0.005). Detailed analysis of clinicopathological features demonstrated a positive statistically significant correlation between IL-13Ralpha2 expression and clinically advanced primary SCCHN tumor (T-4; Tumor-Node-Metastasis classification; P < 0.05). However, there was no correlation among IL-13R expression and sex, age of patients, stage of lymph node metastasis, squamous cell carcinoma grade, or allergic history. Taken together, this study suggests that IL-13R may be involved in SCCHN tumor progression, and 33% of IL-13Ralpha2-positive SCCHN cases may be targeted by IL-13 cytotoxin and IL-13R-targeted agent. C1 US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cell & Gene Therapies, Bethesda, MD 20892 USA. Mayo Clin, Dept Otolaryngol, Rochester, MN USA. Mayo Clin, Dept Head & Neck Surg, Rochester, MN USA. Yokohama City Univ, Sch Med, Dept Otolaryngol, Yokohama, Kanagawa 232, Japan. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cell & Gene Therapies, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. NR 24 TC 34 Z9 38 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2003 VL 9 IS 17 BP 6381 EP 6388 PG 8 WC Oncology SC Oncology GA 758QH UT WOS:000187661300011 PM 14695138 ER PT J AU Nasraway, SA Shorr, AF Kuter, DJ O'Grady, N Le, VH Cammarata, SK AF Nasraway, SA Shorr, AF Kuter, DJ O'Grady, N Le, VH Cammarata, SK TI Linezolid does not increase the risk of thrombocytopenia in patients with nosocomial pneumonia: Comparative analysis of linezolid and vancomycin use SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INTENSIVE-CARE-UNIT; DRUG-INDUCED THROMBOCYTOPENIA; CRITICALLY ILL PATIENTS; DOUBLE-BLIND; MULTICENTER; EXPERIENCE AB Reports from uncontrolled studies suggest that linezolid is associated with rates of thrombocytopenia higher than those reported in clinical studies. We assessed the risk of thrombocytopenia in 686 patients with nosocomial pneumonia who received linezolid or vancomycin for greater than or equal to 5 days in 2 randomized, double- blind studies and for whom follow- up platelet counts had been measured. New- onset thrombocytopenia ( platelet count of < 150 x 10(9) platelets/ L) occurred in 19 ( 6.4%) of 295 linezolid recipients and 22 ( 7.7%) of 285 vancomycin recipients with baseline platelet counts of &GE; 150 x 10(9) platelets/ L; severe thrombocytopenia (platelet count of < 50 x 10(9) platelets/ L) occurred in only 1 patient in each group. Platelet counts decreased to less than the baseline level in 4 ( 6.6%) of 61 linezolid recipients and 5 ( 11.1%) of 45 vancomycin recipients who had baseline counts of < 150 x 10(9) platelets/ L. No patient had a decrease to < 20 x 10(9) platelets/ L. There were no statistically significant differences between groups in these or any other platelet assessments. Clinically significant thrombocytopenia was uncommon in our analysis, and linezolid was not associated with a greater risk of thrombocytopenia in seriously ill patients than was vancomycin. C1 Tufts Univ, Tufts New England Med Ctr, Sch Med, Dept Surg,Div Surg Crit Care, Boston, MA 02111 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Massachusetts Gen Hosp Canc Ctr,Hematol Div, Boston, MA USA. Walter Reed Army Med Ctr, Pulm & Crit Care Med Serv, Washington, DC 20307 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. Pharmacia, Clin Biostat, Peapack, NJ USA. Pharmacia, Infect Dis Clin Res, Peapack, NJ USA. RP Nasraway, SA (reprint author), Tufts Univ, Tufts New England Med Ctr, Sch Med, Dept Surg,Div Surg Crit Care, 750 Washington St,NEMC Box 4630, Boston, MA 02111 USA. NR 23 TC 47 Z9 55 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 DEC 15 PY 2003 VL 37 IS 12 BP 1609 EP 1616 DI 10.1086/379327 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 749VJ UT WOS:000186949300015 PM 14689341 ER PT J AU Flanzer, DSW AF Flanzer, DSW TI Research in clinical epidemiology and services: Drug use and HIV in the United States SO CLINICAL INFECTIOUS DISEASES LA Spanish DT Meeting Abstract CT Meeting on Bloodborne and Sexually Transmitted Infections among Intravenous Drug Users and Their Partners in the Western Hemisphere CY DEC 17-19, 2001 CL BUENOS AIRES, ARGENTINA SP Ctr AIDS & Other Med Consequences Drug Abuse, NIDA, NIH, US Dept HHS, Pan Amer Hlth Org, WHO Americas, Reg Off C1 NIDA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2003 VL 37 SU 5 BP S473 EP S473 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 749VL UT WOS:000186949600032 ER PT J AU Flanzer, J AF Flanzer, J TI Health services research: Drug use and human immunodeficiency virus in the United States SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Meeting on Bloodborne and Sexually Transmitted Infections among Intravenous Drug Users and Their Partners in the Western Hemisphere CY DEC 17-19, 2001 CL BUENOS AIRES, ARGENTINA SP Ctr AIDS & Other Med Consequences Drug Abuse, NIDA, NIH, US Dept HHS, Pan Amer Hlth Org, WHO Americas, Reg Off ID METHADONE TREATMENT PRACTICES; ABUSE TREATMENT; TREATMENT OUTCOMES; COCAINE DEPENDENCE; SUBSTANCE USE; FOLLOW-UP; DATOS; ADOLESCENTS; DISORDERS; ORGANIZATIONS AB Major research findings show gaps in health services research on the prevalence and outcomes of patient- and organization-level human immunodeficiency virus (HIV) and drug abuse prevention and treatment services. The latest thrust of health services research on translational research issues includes informing and training practitioners about new, proven drug abuse treatment interventions; changing treatment organizations ( creating a climate for change and building a culture to sustain change); and financing new treatments. Findings defining the direct relationship between the quality of drug abuse treatment and the patients' program completion, the perception of the staff by the patient, feelings of self-empowerment and mitigation of patient and organizational readiness, the superiority of integrated care, and the primary reasons for delays in HIV-infected substance-using patients seeking care are included. More needs to be done to increase the participation of substance abuse programs in teaching about and implementing HIV prevention and developing means to modulate or eliminate barriers to the integration of HIV and substance abuse care. C1 NIDA, Serv Res Branch, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Flanzer, J (reprint author), NIDA, Serv Res Branch, Div Epidemiol Serv & Prevent Res, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. NR 33 TC 1 Z9 1 U1 1 U2 2 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 DEC 15 PY 2003 VL 37 SU 5 BP S439 EP S444 DI 10.1086/377563 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 749VL UT WOS:000186949600020 PM 14648461 ER PT J AU Francis, H AF Francis, H TI Sexually transmitted and blood-borne infections among drug users: Research at the National Institute on Drug Abuse in the United States SO CLINICAL INFECTIOUS DISEASES LA Spanish DT Meeting Abstract CT Meeting on Bloodborne and Sexually Transmitted Infections among Intravenous Drug Users and Their Partners in the Western Hemisphere CY DEC 17-19, 2001 CL BUENOS AIRES, ARGENTINA SP Ctr AIDS & Other Med Consequences Drug Abuse, NIDA, NIH, US Dept HHS, Pan Amer Hlth Org, WHO Americas, Reg Off C1 NIDA, Programa VIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2003 VL 37 SU 5 BP S474 EP S474 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 749VL UT WOS:000186949600033 ER PT J AU Khalsa, JH AF Khalsa, JH TI Research at the NIDa on the Medical and Health Consequences of Drug Abuse and Comorbid Infections SO CLINICAL INFECTIOUS DISEASES LA Spanish DT Meeting Abstract CT Meeting on Bloodborne and Sexually Transmitted Infections among Intravenous Drug Users and Their Partners in the Western Hemisphere CY DEC 17-19, 2001 CL BUENOS AIRES, ARGENTINA SP Ctr AIDS & Other Med Consequences Drug Abuse, NIDA, NIH, US Dept HHS, Pan Amer Hlth Org, WHO Americas, Reg Off C1 NIDA, Ctr SIDA & Otras Consecuencias Med Abuso Drogas C, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2003 VL 37 SU 5 BP S475 EP S475 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 749VL UT WOS:000186949600036 ER PT J AU Khalsa, JH Francis, H Mazin, R AF Khalsa, JH Francis, H Mazin, R TI Bloodborne and sexually transmitted infections in drug abusers in the United States, Latin America, the Caribbean, and Spain - Introduction SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material AB In the United States, similar to 1 million Americans are infected with human immunodeficiency virus (HIV), and several thousand new infections are reported each year. More than one-third of cases of acquired immunodeficiency syndrome ( AIDS) are associated with injection drug use. An estimated 1.8 million adults and children are currently living with HIV in Latin America and the Caribbean, and injection drug abuse remains a major factor in initial exposures to HIV in these parts of the world. Although only 3 cases of AIDS related to drug abuse have been reported in Bolivia, a country with a nascent epidemic, 119,000 cases of AIDS have been reported in Argentina and 122,000 in Brazil, with a significant number associated with injection drug use. Extensive epidemiological and clinical research has been conducted in the United States and elsewhere to determine the extent and nature of the problem and to design and develop interventions ( prevention and treatment) for drug abusers infected with HIV. The articles in this supplement present a current view of the nature and extent of the bloodborne and sexually transmitted infections in drug abusers and their partners in the Western Hemisphere. C1 NIDA, Ctr Aids & Other Med Consequences Drug Abuse, NIH, Bethesda, MD 20892 USA. Pan Amer Hlth Org, Reg AIDS Program, Washington, DC USA. RP Khalsa, JH (reprint author), NIDA, Ctr Aids & Other Med Consequences Drug Abuse, NIH, 6001 Execut Blvd,Rm 5198,MSC 9593, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 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 DEC 15 PY 2003 VL 37 SU 5 BP S331 EP S337 DI 10.1086/377543 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 749VL UT WOS:000186949600001 PM 14648442 ER PT J AU Isayama, F Froh, MR Bradford, BU McKim, SE Kadiiska, MB Connor, HD Mason, RP Koop, DR Wheeler, MD Arteel, GE AF Isayama, F Froh, MR Bradford, BU McKim, SE Kadiiska, MB Connor, HD Mason, RP Koop, DR Wheeler, MD Arteel, GE TI The CYP inhibitor 1-aminobenzotriazole does not prevent oxidative stress associated with alcohol-induced liver injury in rats and mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE electron spin-resonance; alcohol; 4-hydroxynonenal; liver disease; free radicals ID INTRAGASTRIC ETHANOL INFUSION; CYTOCHROME-P450 2E1; RADICAL FORMATION; ARACHIDONIC-ACID; KUPFFER CELLS; KAPPA-B; DISEASE; MECHANISM; OXIDASE; INVIVO AB Cytochrome P450 (CYP) 2E1 is induced by ethanol and is postulated to be a source of reactive oxygen species during alcoholic liver disease. However, there was no difference in liver pathology and radical formation between wild-type and CYP2E1 knockout mice fed ethanol. Other CYP isoforms may contribute these effects if CYP2E1 is inhibited or absent. The purpose of this study was, therefore, to determine if blocking most of the P450 isoforms with 1-aminobenzotriazole (ABT; 100 mg/kg i.g.), has any effect on liver damage and oxidative stress due to alcohol in rats and mice. Male C57BL/6 mice and Wistar rats were fed either high-fat control or ethanol-containing enteral diet for 4 weeks. ABT had a significant inhibitory effect on many P450 isoforms independent of concomitant alcohol administration. However, ABT did not protect against liver damage due to alcohol in either species. Indices of oxidative stress and inflammation were also similar in livers from vehicle-treated and ABT-treated animals fed ethanol. In summary, suppression of P450 activity with ABT had no apparent effect on oxidative stress caused by alcohol in both rats and mice. These data support the hypothesis that oxidative stress and liver damage can occur independently of CYP activities in both rats and mice during early alcohol-induced liver injury. (C) 2003 Elsevier Inc. C1 Univ Louisville, Hlth Sci Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Oregon Hlth Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. RP Arteel, GE (reprint author), Univ Louisville, Hlth Sci Ctr, Dept Pharmacol & Toxicol, Room 1306,Res Tower 500,S Preston St, Louisville, KY 40292 USA. FU NIAAA NIH HHS [AA08608] NR 55 TC 19 Z9 23 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD DEC 15 PY 2003 VL 35 IS 12 BP 1568 EP 1581 DI 10.1016/j.freeradbiomed.2003.09.007 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 754CG UT WOS:000187284700005 PM 14680680 ER PT J AU Ahmed, ZM Riazuddin, S Ahmad, J Bernstein, SL Guo, Y Sabar, MF Sieving, P Riazuddin, S Griffith, AJ Friedman, TB Belyantseva, IA Wilcox, ER AF Ahmed, ZM Riazuddin, S Ahmad, J Bernstein, SL Guo, Y Sabar, MF Sieving, P Riazuddin, S Griffith, AJ Friedman, TB Belyantseva, IA Wilcox, ER TI PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23 SO HUMAN MOLECULAR GENETICS LA English DT Article ID SYNDROME TYPE 1D; USHER-SYNDROME; MYOSIN VIIA; PHOTORECEPTOR CELLS; PROTOCADHERIN GENE; RECESSIVE DEAFNESS; HAIR-CELLS; INNER-EAR; MUTATIONS; CADHERIN AB Recessive splice site and nonsense mutations of PCDH15, encoding protocadherin 15, are known to cause deafness and retinitis pigmentosa in Usher syndrome type 1F (USH1F). Here we report that non-syndromic recessive hearing loss (DFNB23) is caused by missense mutations of PCDH15. This suggests a genotype-phenotype correlation in which hypomorphic alleles cause non-syndromic hearing loss, while more severe mutations of this gene result in USH1F. We localized protocadherin 15 to inner ear hair cell stereocilia, and to retinal photoreceptors by immunocytochemistry. Our results further strengthen the importance of protocadherin 15 in the morphogenesis and cohesion of stereocilia bundles and retinal photoreceptor cell maintenance or function. C1 Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD USA. Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, Mol Genet Lab, NIH, Rockville, MD USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, NIH, Rockville, MD USA. Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. Univ Maryland, Sch Med, Dept Ophthalmol, Baltimore, MD 21201 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Wilcox, ER (reprint author), 5 Res Court,2A-19, Rockville, MD 20850 USA. RI Ahmad, Jamil/D-4130-2009 FU NIDCD NIH HHS [Z01DC00035-06, Z01DC00039-06, Z01DC00064-02] NR 36 TC 150 Z9 153 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 15 PY 2003 VL 12 IS 24 BP 3215 EP 3223 DI 10.1093/hmg/ddg358 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 753GT UT WOS:000187224200002 PM 14570705 ER PT J AU Sunyaev, S Kondrashov, FA Bork, P Ramensky, V AF Sunyaev, S Kondrashov, FA Bork, P Ramensky, V TI Impact of selection, mutation rate and genetic drift on human genetic variation SO HUMAN MOLECULAR GENETICS LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; COMMON DISEASE GENES; CLASS-II REGION; HUMAN GENOME; NONSYNONYMOUS SUBSTITUTION; LINKAGE DISEQUILIBRIUM; SEQUENCE VARIATION; CANDIDATE GENES; RECOMBINATION; EVOLUTION AB The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed. C1 Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. European Mol Biol Lab, D-69117 Heidelberg, Germany. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Univ Calif Davis, Sect Evolut & Ecol, Davis, CA 95616 USA. Max Delbrueck Ctr Mol Med, D-13122 Berlin, Germany. VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. RP Sunyaev, S (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM ssunyaev@rics.bwh.harvard.edu RI Bork, Peer/F-1813-2013; Kondrashov, Fyodor Alexeevich/H-6331-2015 OI Bork, Peer/0000-0002-2627-833X; Kondrashov, Fyodor Alexeevich/0000-0001-8243-4694 NR 48 TC 14 Z9 17 U1 0 U2 6 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 DEC 15 PY 2003 VL 12 IS 24 BP 3325 EP 3330 DI 10.1093/hmg/ddg359 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 753GT UT WOS:000187224200013 PM 14570704 ER PT J AU Karthikeyan, G Santos, JH Graziewicz, MA Copeland, WC Isaya, G Van Houten, B Resnick, MA AF Karthikeyan, G Santos, JH Graziewicz, MA Copeland, WC Isaya, G Van Houten, B Resnick, MA TI Reduction in frataxin causes progressive accumulation of mitochondrial damage SO HUMAN MOLECULAR GENETICS LA English DT Article ID IRON-BINDING PROPERTIES; FRIEDREICH-ATAXIA; YEAST FRATAXIN; SACCHAROMYCES-CEREVISIAE; DNA-DAMAGE; OXIDATIVE DAMAGE; CLUSTER BIOSYNTHESIS; CALCIUM HOMEOSTASIS; ALZHEIMERS-DISEASE; GENE-EXPRESSION AB Frataxin protein controls iron availability in mitochondria and reduced levels lead to the human disease, Friedreich's ataxia (FRDA). The molecular aspects of disease progression are not well understood. We developed a highly regulatable promoter system for expressing frataxin in yeast to address the consequences of chronically reduced amounts of this protein. Shutting off the promoter resulted in changes normally associated with loss of frataxin including iron accumulation within the mitochondria and the induction of mitochondrial petite mutants. While there was considerable oxidative damage to mitochondrial proteins, the petites were likely due to accumulation of mitochondrial DNA lesions and subsequent DNA loss. Chronically reduced frataxin levels resulted in similar response patterns. Furthermore, nuclear DNA damage was detected in a rad52 mutant, deficient in double-strand break repair. We conclude that reduced frataxin levels, which is more representative of the disease state, results in considerable oxidative damage in both mitochondrial and nuclear DNA. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Mayo Clin & Mayo Fdn, Dept Pediat & Adolescent Med, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, NIH, Mail Drop D3-01,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NIA NIH HHS [AG15709] NR 67 TC 70 Z9 71 U1 0 U2 5 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 DEC 15 PY 2003 VL 12 IS 24 BP 3331 EP 3342 DI 10.1093/hmg/ddg349 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 753GT UT WOS:000187224200014 PM 14570713 ER PT J AU Baum, BJ Goldsmith, CM Kok, MR Lodde, BM van Mello, NM Voutetakis, A Wang, JH Yamano, S Zheng, CY AF Baum, BJ Goldsmith, CM Kok, MR Lodde, BM van Mello, NM Voutetakis, A Wang, JH Yamano, S Zheng, CY TI Advances in vector-mediated gene transfer SO IMMUNOLOGY LETTERS LA English DT Article DE viral vectors; adenovirus; adeno-associated virus; autoimmune diseases ID ADENOASSOCIATED VIRUS VECTORS; SEVERE COMBINED IMMUNODEFICIENCY; VIRAL IL-10 GENE; SALIVARY-GLANDS; IN-VIVO; ADENOVIRAL VECTOR; LOCAL-DELIVERY; THERAPY; EXPRESSION; SECRETION AB Clinical applications of gene transfer technology initially targeted the treatment of inherited monogenetic disorders and cancers refractory to conventional therapies. Today, gene transfer approaches are being developed for most tissues and for multiple disorders including those affecting quality of life. The focus herein is eventual application of gene transfer technology for the management of organ-directed autoimmunity. A specific example is presented: Sjogren's syndrome and localized salivary gland gene transfer. The status of relevant pre-clinical gene transfer studies is reviewed, with an emphasis on use of adenoviral and adeno-associated viral vectors. Current limitations of effective organ-directed gene transfer are also discussed. (C) 2003 Elsevier B.V. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, Bethesda, MD 20892 USA. Acad Med Ctr, Div Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, Bldg 10,Room 1N113,MSC-1190, Bethesda, MD 20892 USA. EM bbaum@dir.nider.nih.gov OI Yamano, Seiichi/0000-0003-2056-4359 NR 50 TC 21 Z9 25 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD DEC 15 PY 2003 VL 90 IS 2-3 BP 145 EP 149 DI 10.1016/j.imlet.2003.08.006 PG 5 WC Immunology SC Immunology GA 763YB UT WOS:000188127100012 PM 14687716 ER PT J AU Muthusamy, N Park, DJ Rho, HW Rhee, SG Subbarao, B AF Muthusamy, N Park, DJ Rho, HW Rhee, SG Subbarao, B TI Impaired antigen receptor induced calcium mobilization in a phospholipase C-gamma(1) deficient B cell line SO IMMUNOLOGY LETTERS LA English DT Article DE phospholipase C isozymes; B lymphocytes; antigen receptor; calcium signaling ID TYROSINE PHOSPHORYLATION; C ISOZYMES; ACTIVATION; LYMPHOCYTES; STIMULATION; HYDROLYSIS; RESIDUES; GROWTH; KINASE; GAMMA AB B lymphocytes express phospholipase C-gamma(1) (PLC-gamma(1)) and phospholipase C-gamma(2) (PLC-gamma(2)) isozymes. However, the relative importance of these two isozymes in B cell signaling is not known. We report here the identification and analysis of a B cell line deficient in PLC-gamma(1). Mature splenic B lymphocytes and a panel of cell lines representing pre-B, immature and mature B cell stages expressed phospholipase C-gamma (PLC-gamma), but not the beta or delta isoforms of phospholipase C (PLC). While all the tested B cell lines and primary splenic B cells expressed PLC-gamma(1) and PLC-gamma(2) isozymes, the L1.2 B cell line exclusively expressed PLC-gamma(2), but not PLC-gamma(1), isozyme. The PLC-gamma(1) deficient L1.2 B cells expressed levels of surface IgM comparable to that of PLC-gamma(1) positive 70Z/3 B cell line. However, stimulation through the antigen receptor induced Ca++ response in 70Z/3, but not L1.2 B cells, suggesting a requirement for PLC-gamma(1) in antigen receptor induced Ca++ signaling in these cells. The possible use for L1.2 cells in testing the regulation of PLC-gamma(1) and PLC-gamma(2) dependent calcium mobilization in B lymphocytes is discussed. (C) 2003 Elsevier B.V. All rights reserved. C1 Ohio State Univ, Columbus Childrens Res Inst, Dept Pediat Mol Virol Immunol & Med Genet & Vet B, Ctr Mol & Human Genet, Columbus, OH 43205 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Kentucky, Dept Microbiol & Immunol, Lexington, KY 40536 USA. Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. RP Muthusamy, N (reprint author), Ohio State Univ, Columbus Childrens Res Inst, Dept Pediat Mol Virol Immunol & Med Genet & Vet B, Ctr Mol & Human Genet, Room W410,700 Childrens Dr, Columbus, OH 43205 USA. EM rmuthusa@chi.osu.edu RI Muthusamy, Natarajan/A-6915-2009 NR 21 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD DEC 15 PY 2003 VL 90 IS 2-3 BP 203 EP 207 DI 10.1016/j.imlet.2003.09.010 PG 5 WC Immunology SC Immunology GA 763YB UT WOS:000188127100022 PM 14687726 ER PT J AU Tien, PC Cole, SR Williams, CM Li, R Justman, JE Cohen, MH Young, M Rubin, N Augenbraun, M Grunfeld, C AF Tien, Phyllis C. Cole, Stephen R. Williams, Carolyn Masters Li, Rui Justman, Jessica E. Cohen, Mardge H. Young, Mary Rubin, Nancy Augenbraun, Michael Grunfeld, Carl TI Incidence of Lipoatrophy and Lipohypertrophy in the Women's Interagency HIV Study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE fat distribution; HIV; lipodystrophy; women AB Objective: To estimate the incidence of lipoatrophy and lipohypertrophy among HIV-infected and HIV-uninfected women from the Women's Interagency HIV Study. Design: Eight hundred fifteen women with semiannual data on self-report of bidirectional change in body fat, anthropometric measurements, weight, and bioelectric impedance analysis were included in a 30-month incidence analysis. Methods: Lipoatrophy and lipohypertrophy in both peripheral (arms, legs, and buttocks) and central (waist, chest, and upper back) sites were defined by self-report of either a decrease or an increase in a body fat region over the previous 6 months that was confirmed by a corresponding change in anthropometric measurement. Results: Weight and total body fat increased in HIV-uninfected women but remained stable in HIV-infected women over 30 months. Among HIV-infected women, the incidence of peripheral (relative hazard, 2.1; 95% confidence interval [CI], 1.4-3.3) and central (relative hazard, 1.9; 95% CI, 1.2-2.8) lipoatrophy was about double that among HIV-uninfected women, after adjustment for age and race. The incidence of peripheral lipohypertrophy appeared lower among HIV-infected women than among HIV-uninfected women (relative hazard, 0.8; 95% CI, 0.6-1.1), while the incidence of central lipohypertrophy did not differ by HIV status. Of HIV-infected women with 2 of 4 lipodystrophy outcomes, most (81%) had combined peripheral and central lipoatrophy or combined peripheral and central lipohypertrophy. Only 14% of these women had both peripheral lipoatrophy and central lipohypertrophy Conclusions: These prospective data suggest that lipoatrophy, affecting both peripheral and central sites, predominates in HIV-infected women. The simultaneous occurrence of peripheral lipoatrophy and central lipohypertrophy was uncommon. C1 [Tien, Phyllis C.] VAMC, Metab Sect, San Francisco, CA 94121 USA. [Tien, Phyllis C.; Grunfeld, Carl] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Cole, Stephen R.; Li, Rui] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Williams, Carolyn Masters] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Justman, Jessica E.] Bronx Lebanon Hosp Ctr, Dept Med, Bronx, NY 10457 USA. [Cohen, Mardge H.] Cook Cty Hosp, Dept Med, Chicago, IL 60612 USA. [Young, Mary] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Rubin, Nancy] Univ So Calif, Dept Med, Los Angeles, CA USA. [Augenbraun, Michael] SUNY Hlth Sci Ctr, Dept Med, Brooklyn, NY 11203 USA. RP Tien, PC (reprint author), VAMC, Metab Sect, 111F,4150 Clement St, San Francisco, CA 94121 USA. EM ptien@medicine.ucsf.edu FU National Cancer Institute; National Institute of Child Health & Human Development; National Institute on Drug Abuse; National Institute of Dental and Craniofacial Research; Agency for Health Care Policy and Research; Centers for Disease Control and Prevention [U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632, U01-AI-34993, U01-AI-42590, M01-RR00071, M01-RR00083] FX The WIHS is funded by the National Institute of Allergy and Infectious Diseases, with supplemental funding from the National Cancer Institute, the National Institute of Child Health & Human Development, the National Institute on Drug Abuse, the National Institute of Dental and Craniofacial Research, the Agency for Health Care Policy and Research, and the Centers for Disease Control and Prevention ( U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632 [NICHD], U01-AI-34993, U01-AI-42590, M01-RR00071, and M01-RR00083). NR 26 TC 73 Z9 74 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2003 VL 34 IS 5 BP 461 EP 466 DI 10.1097/00126334-200312150-00003 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V93OL UT WOS:000206324300003 PM 14657755 ER PT J AU Shetty, AK Coovadia, HM Mirochnick, MM Maldonado, Y Mofenson, LM Eshleman, SH Fleming, T Emel, L George, K Katzenstein, DA Wells, J Maponga, CC Mwatha, A Jones, SA Karim, SSA Bassett, MT AF Shetty, Avinash K. Coovadia, Hoosen M. Mirochnick, Mark M. Maldonado, Yvonne Mofenson, Lynne M. Eshleman, Susan H. Fleming, Thomas Emel, Lynda George, Kathy Katzenstein, David A. Wells, Jennifer Maponga, Charles C. Mwatha, Anthony Jones, Samuel Adeniyi Karim, Salim S. Abdool Bassett, Mary T. CA HIVNET 023 Study Team TI Safety and Trough Concentrations of Nevirapine Prophylaxis Given Daily, Twice Weekly, or Weekly in Breast-Feeding Infants From Birth to 6 Months SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE clinical trial; HIV-1; infant; nevirapine; pregnancy; prophylaxis; safety AB Despite the success of antiretroviral prophylaxis in reducing mother-to-child HIV-1 transmission, postpartum transmission through breast milk remains a problem. Antiretroviral administration to the infant during the period of breast-feeding could protect against postnatal transmission. An open-label phase 1/2 study was designed to assess the safety and trough concentrations of nevirapine (NVP) given once weekly (OW), twice weekly (TW), or once daily (OD) to HIV-exposed breast-feeding infants for 24 weeks. Following maternal dosing with 200 mg NVP orally at onset of labor, breast-feeding infants were randomized within 48 hours of birth to 1 of 3 regimens: arm 1, NVP given OW (4 mg/kg from birth to 14 days, up arrow to 8 mg/kg from 15 days to 24 weeks), arm 2, NVP given TW(4 mg/kg from birth to 14 days, up arrow to 8 mg/kg from 15 days to 24 weeks), and arm 3, NVP given OD (2 mg/kg from birth to 14 days, up arrow to 4 mg/kg from 15 days to 24 weeks). Trough NVP concentrations and clinical and laboratory abnormalities were monitored. Of the 75 infants randomized (26 to OW, 25 to TW, and 24 to OD dosing), 63 completed the 32-week follow-up visit. No severe skin, hepatic, or renal toxicity related to NVP was observed. Neutropenia occurred in 8 infants. Trough NVP levels were lower than the therapeutic target (100 ng/mL) in 48 of 75 (64.0%) samples from infants in the OW arm, 3 of 65 (4.6%) samples in the TW arm, and 0 of 72 samples in the OD arm. Median (range) trough NVP concentrations were 64 ng/mL (range: < 25-1519 ng/mL) with OW dosing; 459 (range: < 25-1386 ng/mL) with TW dosing; and 1348 (range: 108-4843 ng/ml) with OD dosing. Our data indicate that NVP prophylaxis for 6 months was safe and well tolerated in infants. OD NVP dosing resulted in all infants with trough concentration greater than the therapeutic target and maintenance of high drug concentrations. A phase 3 study is planned to assess the efficacy of OD infant NVP regimen to prevent breast-feeding HIV-1 transmission. C1 [Shetty, Avinash K.; Maldonado, Yvonne] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Katzenstein, David A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Shetty, Avinash K.; Wells, Jennifer; Maponga, Charles C.; Bassett, Mary T.] Zimbabwe AIDS Prevent Project, Harare, Zimbabwe. [Shetty, Avinash K.; Wells, Jennifer; Maponga, Charles C.; Bassett, Mary T.] Univ Zimbabwe, Sch Med, Harare, Zimbabwe. [Coovadia, Hoosen M.; Karim, Salim S. Abdool] Univ KwaZulu Natal, Dept Pediat & Child Hlth, ZA-4001 Durban, South Africa. [Mirochnick, Mark M.] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Mofenson, Lynne M.] Natl Inst Child Hlth & Dev, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. [Eshleman, Susan H.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Fleming, Thomas; Emel, Lynda; Mwatha, Anthony] Fred Hutchinson Canc Res Ctr, HIV NET Stat Ctr, Seattle, WA 98104 USA. [Fleming, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [George, Kathy] Family Hlth Int, Durham, NC USA. [Jones, Samuel Adeniyi] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. RP Shetty, AK (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27157 USA. EM avishetty@pol.net RI Abdool Karim, Salim Safurdeen/N-5947-2013; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; Mofenson, Lynne/0000-0002-2818-9808 FU HIV Network for Prevention Trials (HIVNET); US National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Department of Health and Human Services (DHHS); HIV Prevention Trials Network; National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Mental Health; HIVNET; Division of AIDS; NIAID/NIH; Boehringer Ingelheim Pharmaceuticals FX Supported by the HIV Network for Prevention Trials (HIVNET) and sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services (DHHS). In addition, this work was supported by the HIV Prevention Trials Network and sponsored by the NIAID, National Institute of Child Health and Human Development, National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research of the NIH/DHHS. This trial was sponsored by the HIVNET, Division of AIDS, NIAID/NIH. Pharmaceutical support provided by Boehringer Ingelheim Pharmaceuticals. NR 37 TC 35 Z9 35 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2003 VL 34 IS 5 BP 482 EP 490 DI 10.1097/00126334-200312150-00006 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V93OL UT WOS:000206324300006 PM 14657758 ER PT J AU Lambert, JS Harris, DR Stiehm, ER Moye, J Fowler, MG Meyer, WA Bethel, J Mofenson, LM AF Lambert, John S. Harris, D. Robert Stiehm, E. Richard Moye, John, Jr. Fowler, Mary Glenn Meyer, William A., III Bethel, James Mofenson, Lynne M. TI Performance Characteristics of HIV-1 Culture and HIV-1 DNA and RNA Amplification Assays for Early Diagnosis of Perinatal HIV-1 Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE infant diagnosis; HIV-1 quantitative RNA; HIV-1 DNA PCR; HIV-1 culture AB A plasma HIV-1 RNA amplification assay (RNA assay), a quantitative peripheral blood mononuclear cell (PBMC) microculture (culture), and a PBMC HIV-1 DNA amplification assay (DNA assay) were compared for diagnosis of HIV-1 infection in infants receiving zidovudine in Pediatric AIDS Clinical Trials Group protocol 185; assays were performed for all 24 infected and 100 uninfected infants. HIV-1 infection was defined as >= 2 positive cultures or positive antibody to HIV-1 at >= 18 months. Cultures were performed at birth and 6 and 24 weeks of age; DNA and RNA assays were performed on cryopreserved specimens. The sensitivity of culture and DNA and RNA assays at birth was 20.8%, 10.5%, and 26.7%, respectively. At older ages, sensitivity typically exceeded 80%, remaining highest for the RNA assay (> 85%). Assay specificity was > 99%. Positive predictive values exceeded 93% for each assay at each age; negative predictive values were highest (> 90%) for the RNA assay. At birth (P < 0.005) and age 6 weeks (P < 0.001), a significantly larger proportion of infected infants were identified by means of the RNA assay than by the other assays. The diagnostic performance of the RNA assay matched or exceeded that of culture and the DNA assay. Given that RNA assays require less blood volume and yield rapid results, our study adds to existing data suggesting that RNA assays may be used for early diagnosis of HIV-1 infection in infants. C1 [Lambert, John S.] Inst Child Hlth, Dept Epidemiol & Publ Hlth, London WC1N 1EH, England. [Lambert, John S.] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Harris, D. Robert; Bethel, James] WESTAT Corp, Rockville, MD 20850 USA. [Stiehm, E. Richard] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Moye, John, Jr.; Mofenson, Lynne M.] NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. [Fowler, Mary Glenn] Ctr Dis Control & Prevent, Atlanta, GA USA. [Meyer, William A., III] Quest Diagnost Inc, Baltimore, MD USA. RP Lambert, JS (reprint author), Inst Child Hlth, Dept Epidemiol & Publ Hlth, 30 Guilford St, London WC1N 1EH, England. EM lambert@umbi.umd.edu OI Mofenson, Lynne/0000-0002-2818-9808; moye, john/0000-0001-9976-8586 FU NIAID NIH HHS [AI-27565, AI-27550]; NICHD NIH HHS [HD-33162] NR 30 TC 49 Z9 51 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2003 VL 34 IS 5 BP 512 EP 519 DI 10.1097/00126334-200312150-00011 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V93OL UT WOS:000206324300011 PM 14657763 ER PT J AU Li, WJ Danielson, KG Alexander, PG Tuan, RS AF Li, WJ Danielson, KG Alexander, PG Tuan, RS TI Biological response of chondrocytes cultured in three-dimensional nanofibrous poly(epsilon-caprolactone) scaffolds SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE cartilage tissue engineering; electrospinning; nanofiber; poly(epsilon-caprolactone); chondrocyte redifferentiation ID IN-VITRO; CARTILAGINOUS TISSUE; DIFFERENTIATED CELLS; ARTICULAR-CARTILAGE; GROWTH-FACTORS; COLLAGEN; REDIFFERENTIATION; EXPRESSION; DEPOSITION; ADHESION AB Nanofibrous materials, by virtue of their morphological similarities to natural extracellular matrix, have been considered as candidate scaffolds for cell delivery in tissue-engineering applications. In this study, we have evaluated a novel, three-dimensional, nanofibrous poly(epsilon-caprolactone) (PCL) scaffold composed of electrospun nanofibers for its ability to maintain chondrocytes in a mature functional state. Fetal bovine chondrocytes (FBCs), maintained in vitro between passages 2 to 6, were seeded onto three-dimensional biodegradable PCL nanofibrous scaffolds or as monolayers on standard tissue culture polystyrene (TCPS) as a control substrate. Gene expression analysis by reverse transcription-polymerase chain reaction showed that chondrocytes seeded on the nanofibrous scaffold and maintained in serum-free medium supplemented with ITS+, ascorbate, and dexamethasone continuously maintained their chondrocytic phenotype by expressing cartilage-specific extracellular matrix genes, including collagen types II and IX, aggrecan, and cartilage oligomeric matrix protein. Specifically, expression of the collagen type IIB splice variant transcript, which is indicative of the mature chondrocyte phenotype, was up-regulated. FBCs exhibited either a spindle or round shape on the nanofibrous scaffolds, in contrast to a flat, well-spread morphology seen in monolayer cultures on TCPS. Organized actin stress fibers were only observed in the cytoplasm of cells cultured on TCPS. Histologically, nanofibrous cultures maintained in the supplemented serum-free medium produced more sulfated proteoglycan-rich, cartilaginous matrix than monolayer cultures. In addition to promoting phenotypic differentiation, the nanofibrous scaffold also supported cellular proliferation as evidenced by a 21-fold increase in cell growth over 21 days when the cultures were maintained in serum-containing medium. These results indicate that the biological activities of FBCs are crucially dependent on the architecture of the extracellular scaffolds as well as the composition of the culture medium, and that nanofibrous PCL acts as a biologically preferred scaffold/substrate for proliferation and maintenance of the chondrocytic phenotype. We propose that the PCL nanofibrous structure may be a suitable candidate scaffold for cartilage tissue engineering. (C) 2003 Wiley Periodicals, Inc. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Cell & Tissue Engn Grad Program, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1503,MSC8022, Bethesda, MD 20892 USA. RI Li, Wan-Ju/A-7002-2008 NR 42 TC 352 Z9 371 U1 15 U2 100 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9304 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD DEC 15 PY 2003 VL 67A IS 4 BP 1105 EP 1114 DI 10.1002/jbm.a.10101 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 748TT UT WOS:000186877700005 PM 14624495 ER PT J AU Kroeze, WK Sheffler, DJ Roth, BL AF Kroeze, WK Sheffler, DJ Roth, BL TI G-protein-coupled receptors at a glance SO JOURNAL OF CELL SCIENCE LA English DT Article ID ARRESTIN-INDEPENDENT INTERNALIZATION; SEROTONIN RECEPTORS; HUMAN GENOME; AGONIST; ENDOCYTOSIS; DISRUPTION; ACTIVATION; SEQUENCE; NETWORKS C1 Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening,Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening,Dept Neurosci, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening,Dept Psychiat, Cleveland, OH 44106 USA. RP Roth, BL (reprint author), Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening,Dept Biochem, Cleveland, OH 44106 USA. RI Roth, Bryan/F-3928-2010 NR 25 TC 159 Z9 165 U1 3 U2 18 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD DEC 15 PY 2003 VL 116 IS 24 BP 4867 EP 4869 DI 10.1242/jcs.00902 PG 3 WC Cell Biology SC Cell Biology GA 755GV UT WOS:000187395900001 PM 14625380 ER PT J AU Dagdug, L Berezhkovskii, AM Shvartsman, SY Weiss, GH AF Dagdug, L Berezhkovskii, AM Shvartsman, SY Weiss, GH TI Equilibration in two chambers connected by a capillary SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID NETWORKS; NANOTUBES; CHANNEL AB A problem common to biophysics, chemical engineering, physical chemistry, and physiology relates to a description of the kinetics of particle transport between two or more chambers. In this paper we analyze the case of two chambers connected by a cylindrical capillary. We derive general solutions for the Laplace transforms of the relaxation functions describing the equilibration of particles between the two chambers and the capillary. These solutions show how the relaxation functions depend on geometric parameters (volumes of the two chambers, the length and radius of the capillary) as well as diffusion coefficients in the three compartments. The general solutions are used to analyze the reduction to single-exponential kinetics which describes equilibration of the particles when the capillary is not too long. When all of the diffusion constants are equal we derive simple expressions for the average relaxation times. Brownian dynamics simulations were run to check the accuracy of approximations used to derive the results. We found excellent agreement between the theoretical predictions and numerical results. (C) 2003 American Institute of Physics. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. Karpov Inst Phys Chem, Moscow 103064, Russia. RP Dagdug, L (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 21 Z9 22 U1 0 U2 4 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 DEC 15 PY 2003 VL 119 IS 23 BP 12473 EP 12478 DI 10.1063/1.1626639 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 750AW UT WOS:000186970000047 ER PT J AU Earle, CC Emanuel, EJ AF Earle, CC Emanuel, EJ TI Patterns of care studies: Creating "An environment of watchful concern" SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID QUALITY C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Earle, CC (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 12 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 15 PY 2003 VL 21 IS 24 BP 4479 EP 4480 DI 10.1200/JCO.2003.09.979 PG 2 WC Oncology SC Oncology GA 755VN UT WOS:000187432300004 PM 14597747 ER PT J AU Feldman, AL Libutti, SK Pingpank, JF Bartlett, DL Beresnev, TH Mavroukakis, SM Steinberg, SM Liewehr, DJ Kleiner, DE Alexander, HR AF Feldman, AL Libutti, SK Pingpank, JF Bartlett, DL Beresnev, TH Mavroukakis, SM Steinberg, SM Liewehr, DJ Kleiner, DE Alexander, HR TI Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SYSTEMIC THIOSULFATE PROTECTION; LONG-TERM SURVIVAL; P53 MUTATIONS; CISPLATIN; P27(KIP1); PERFUSION; IMMUNOREACTIVITY; PROLIFERATIONS; EXPERIENCE; THERAPY AB Purpose: Malignant mesothelioma (MM) arising in the peritoneal cavity is a rare neoplasm characterized by peritoneal progression and for which there are limited therapeutic options. We evaluated the peritoneal progression-free and overall survival (PFS and OS, respectively) for patients with peritoneal MM after surgical resection and regional chemotherapy. Patients and Methods: Forty-nine patients (28 males, 21 females; median age, 47 years; range, 16 to 76 years) with MM underwent laparotomy, tumor resection, continuous hyperthermic peritoneal perfusion with cisplatin (median dose 250 mg/m(2)), and a single postoperative intraperitoneal dwell of fluorouracil and paclitaxel (n = 35) on protocols approved by the Institutional Review Board. Standard techniques for actuarial analyses of potential prognostic variables (Kaplan-Meier method with two-tailed log-rank test and Cox proportional hazards model) were performed. Results: At a median potential follow-up of 28.3 months, median actuarial PFS is 17 months and actuarial OS is 92 months. Factors associated with improved PFS and OS by the Cox proportional hazards model were a history of previous debulking surgery, absence of deep tissue invasion, minimal residual disease after surgical resection (OS only), and age younger than 60 years (OS only). Conclusion: Surgical resection and regional chemotherapy for MM results in durable PFS and OS. Favorable outcome is associated with age, tumor biology (selection of patients with a history of previous debulking), lack of invasive tumor growth, and minimal residual disease after tumor resection. (C) 2003 by American Society of Clinical Oncology. C1 NCI, Surg Metab Sect, Surg Branch,Lab Pathol, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Reg Canc Ctr, NIH, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Metab Sect, Surg Branch,Lab Pathol, Ctr Canc Res,NIH, 10 Ctr Dr,10-2B07, Bethesda, MD 20892 USA. RI Feldman, Andrew/D-5028-2012; OI Kleiner, David/0000-0003-3442-4453 NR 45 TC 185 Z9 197 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 15 PY 2003 VL 21 IS 24 BP 4560 EP 4567 DI 10.1200/JCO.2003.04.150 PG 8 WC Oncology SC Oncology GA 755VN UT WOS:000187432300017 PM 14673042 ER PT J AU Skotheim, RI Kallioniemi, A Bjerkhagen, B Mertens, F Brekke, HR Monni, O Mousses, S Mandahl, N Saeter, G Nesland, JM Smeland, S Kallioniemi, OP Lothe, RA AF Skotheim, RI Kallioniemi, A Bjerkhagen, B Mertens, F Brekke, HR Monni, O Mousses, S Mandahl, N Saeter, G Nesland, JM Smeland, S Kallioniemi, OP Lothe, RA TI Topoisomerase-II alpha is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; NEUROFIBROMATOSIS TYPE-1 GENE; SOFT-TISSUE SARCOMAS; BREAST-CANCER; CELL-LINES; EXPRESSION; MUTATIONS; DELETIONS; TUMORIGENESIS; INACTIVATION AB Purpose: To identify target genes of clinical significance for patients with malignant peripheral-nerve sheath tumor (MPNST), an aggressive cancer for which no consensus therapy exists. Materials and Methods: Biopsies and clinical data from 51 patients with MPNST were included in this study. Based on our previous research implicating chromosome arm 17q amplification in MPNST, we performed gene expression analyses of 14 MPNSTs using chromosome 17-specific cDNA microarrays. Copy numbers of selected gene probes and centromere probes were then determined by interphase fluorescence in situ hybridization in 16 MPNSTs. Finally, we generated a tissue microarray containing 79 samples from 44 MPNSTs, on which in situ protein expressions of candidate genes were examined and related to clinical end points. Results: Among several deregulated genes found by cDNA microarray analyses, topoisomerase IIalpha (TOP2A) was the most overexpressed gene in MPNSTs compared with benign neurofibromas. Excess copies of the TOP2A were also seen at the DNA level in 10 of 16 cases, and high expression of the TOP2A protein was seen in 83% of the tumors on the tissue microarray. The TOP2A-expressing tumors were associated with poor cancer-specific survival and presence of metastases. Conclusion: We have identified TOP2A as a target gene in MPNST, using a focused gene expression profiling followed by a DNA copy number evaluation and clinical validation of the encoded protein using a tissue microarray. This study is the first to suggest that TOP2A expression may be a predictive factor for adverse outcome in MPNST. (C) 2003 by American Society of Clinical Oncology. C1 Norwegian Radium Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. Norwegian Radium Hosp, Inst Canc Res, Dept Pathol, N-0310 Oslo, Norway. Norwegian Radium Hosp, Dept Oncol, N-0310 Oslo, Norway. Univ Oslo, N-0316 Oslo, Norway. Univ Tampere, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. Biomedicum, Biochip Ctr, Helsinki, Finland. VTT Tech Res Ctr Finland, Turku, Finland. Turku Univ, Turku, Finland. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden. RP Lothe, RA (reprint author), Norwegian Radium Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Mertens, Fredrik/0000-0002-6278-5232 NR 45 TC 35 Z9 35 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 15 PY 2003 VL 21 IS 24 BP 4586 EP 4591 DI 10.1200/JCO.2003.07.067 PG 6 WC Oncology SC Oncology GA 755VN UT WOS:000187432300021 PM 14673046 ER PT J AU Chen, WJ Jin, WW Hardegen, N Lei, KJ Li, L Marinos, N McGrady, G Wahl, SM AF Chen, WJ Jin, WW Hardegen, N Lei, KJ Li, L Marinos, N McGrady, G Wahl, SM TI Conversion of peripheral CD4(+)CD25(-) naive T cells to CD4(+)CD25(+) regulatory T cells by TGF-beta induction of transcription factor Foxp3 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE anergy; IL-10; OVA TCR transgenic; house dust mite; asthma ID GROWTH-FACTOR-BETA; IMMUNOLOGICAL SELF-TOLERANCE; ANTIGEN 4; ALLERGIC-ASTHMA; IN-VITRO; DISRUPTION; CTLA-4; MOUSE; IMMUNOSUPPRESSION; PROLIFERATION AB CD4(+)CD25(+) regulatory T cells (T-reg) are instrumental in the maintenance of immunological tolerance. One critical question is whether T-reg can only be generated in the thymus or can differentiate from peripheral CD4(+)CD25(-) naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4(+)CD25(-) T cells into anergic/suppressor cells that are CD25(+), CD45RB(-/low) and intracellular CTLA-4(+) can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor beta (TGF-beta). Although transcription factor Foxp3 has been shown recently to be associated with the development of T-reg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-beta induced Foxp3 gene expression in TCR-challenged CD4(+)CD25(-) naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-beta and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-beta-converted transgenic CD4(+)CD25(+) suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4(+) T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-beta-induced suppressor T cells prevented house dust mite-induced allergic pathogenesis in lungs. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 40 TC 2607 Z9 2766 U1 28 U2 177 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 DEC 15 PY 2003 VL 198 IS 12 BP 1875 EP 1886 DI 10.1084/jem.20030152 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 756CZ UT WOS:000187449400012 PM 14676299 ER PT J AU Wooldridge, L Hutchinson, SL Choi, EM Lissina, A Jones, E Mirza, F Dunbar, PR Price, DA Cerundolo, V Sewell, AK AF Wooldridge, L Hutchinson, SL Choi, EM Lissina, A Jones, E Mirza, F Dunbar, PR Price, DA Cerundolo, V Sewell, AK TI Anti-CD8 antibodies can inhibit or enhance Peptide-MHC class I (pMHCI) multimer binding: This is paralleled by their effects on CTL activation and occurs in the absence of an interaction between pMHCI and CD8 on the cell surface SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; CYTOTOXIC T-LYMPHOCYTES; ALPHA-3 DOMAIN; SIGNAL-TRANSDUCTION; CORECEPTOR FUNCTION; CRYSTAL-STRUCTURE; PERIPHERAL-BLOOD; RECEPTOR-BINDING; TRANSGENIC MICE; MEDIATED LYSIS AB Cytotoxic T lymphocytes recognize short peptides presented in association with MHC class I (MHCI) molecules on the surface of target cells. The Ag specificity of T lymphocytes is conferred by the TCR, but invariable regions of the peptide-MHCI (pMHCI) molecule also interact with the cell surface glycoprotein CD8. The distinct binding sites for CD8 and the TCR allow pMHCI to be bound simultaneously by both molecules. Even before it was established that the TCR recognized pMHCI, it was shown that CTL exhibit clonal heterogeneity in their ability to activate in the presence of anti-CD8 Abs. These Ab-based studies have since been interpreted in the context of the interaction between pMHCI and CD8 and have recently been extended to show that anti-CD8 Ab can affect the cell surface binding of multimerized pMHCI Ags. In this study, we examine the role of CDS further using point-mutated pMHCI Ag and show that anti-CD8 Abs can either enhance or inhibit the activation of CTL and the stable cell surface binding of multimerized pMHCI, regardless of whether there is a pMHCI/CD8 interaction. We further demonstrate that multimerized pMHCI Ag can recruit CD8 in the absence of a pMHCI/CD8 interaction and that anti-CD8 Abs can generate an intracellular activation signal resulting in CTL effector function. These results question many previous assumptions as to how anti-CD8 Abs must function and indicate that CD8 has multiple roles in CTL activation that are not necessarily dependent on an interaction with pMHCI. C1 T Cell Modulat Grp, Oxford, England. John Radcliffe Hosp, Weatherall Inst Mol Med, Nuffield Dept Med, Oxford OX3 9DU, England. John Radcliffe Hosp, Weatherall Inst Mol Med, Tumor Immunol Unit, Oxford OX3 9DU, England. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sewell, AK (reprint author), Univ Oxford, Nuffield Dept Med, Peter Medawar Bldg Pathogen Res,S Pk Rd, Oxford OX1 3SY, England. RI Dunbar, Rod/C-2570-2012; Price, David/C-7876-2013; OI Dunbar, Rod/0000-0001-9626-2600; Price, David/0000-0001-9416-2737; Cerundolo, Vincenzo/0000-0003-0040-3793 NR 55 TC 37 Z9 37 U1 1 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 DEC 15 PY 2003 VL 171 IS 12 BP 6650 EP 6660 PG 11 WC Immunology SC Immunology GA 753JF UT WOS:000187227700046 PM 14662868 ER PT J AU Babu, S Nutman, TB AF Babu, S Nutman, TB TI Proinflammatory cytokines dominate the early immune response to filarial parasites SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN LYMPHATIC FILARIASIS; BRUGIA-MALAYI; ONCHOCERCA-VOLVULUS; WOLBACHIA BACTERIA; T-CELLS; EXPERIMENTAL-INFECTION; PROTECTIVE IMMUNITY; TH2 RESPONSES; BALB/C MICE; LOA LOA AB Although the early human immune response to the infective-stage larvae (L3) of Brugia malayi has not been well-characterized in vivo (because of the inability to determine the precise time of infection), the consensus has been that it must involve a predominant Th2 environment. We have set up an in vitro system to study this early immune response by culturing PBMC from unexposed individuals with live L3 of B. malayi. After 24 h of culture, T cell responses were examined by flow cytometry and by quantitative real-time RT-PCR for multiple cytokines. T cells were activated early following exposure to L3 as indicated by up-regulation of surface markers CD69 and CD71. The frequency of T cells expressing proinflammatory Th1 cytokines (IFN-gamma, TNF-alpha, GM-CSF, IL-1alpha, and IL-8) but not Th2 cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13) was significantly increased in response to L3. This T cell response occurred in both the CD4 and CD8 T cell compartment and was restricted to the effector/memory pool (CD45RO(+)). This T cell response was not due to LPS activity from the parasite or from its endosymbiont, Wolbachia; moreover, it required the presence of APC as well as direct contact with live L3. Real-time RT-PCR analysis of multiple cytokines in the T cells confirmed the increased expression of proinflammatory Th1 cytokines. Up-regulation of these cytokines suggests that the primary immune response to the live infective stage of the parasite is not predominantly Th2 in nature but rather dominated by a proinflammatory response. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-126, Bethesda, MD 20892 USA. NR 39 TC 44 Z9 45 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2003 VL 171 IS 12 BP 6723 EP 6732 PG 10 WC Immunology SC Immunology GA 753JF UT WOS:000187227700054 PM 14662876 ER PT J AU Cui, XL Rouhani, FN Hawari, F Levine, SJ AF Cui, XL Rouhani, FN Hawari, F Levine, SJ TI Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN MYELOMONOCYTIC CELLS; INTERLEUKIN-1 RECEPTOR; MESSENGER-RNA; RAPID RELEASE; IFN-GAMMA; EXPRESSION; ANTAGONIST; CLONING; CORTICOSTEROIDS; IL-1-BETA AB Proteolytic cleavage of the extracellular domain of the type II IL-1 decoy receptor (IL-1RII) generates soluble IL-1-binding proteins that prevent excessive bioactivity by binding free IL-1. In this study we report that an aminopeptidase, aminopeptidase regulator of TNFR1 shedding (ARTS-1), is required for IL-1RII shedding. Coimmunoprecipitation experiments demonstrate an association between endogenous membrane-associated ARTS-1 and a 47-kDa IL-IRII, consistent with ectodomain cleavage of the membrane-bound receptor. A direct correlation exists between ARTS-1 protein expression and IL-1RII shedding, as cell lines overexpressing ARTS-1 have increased IL-1RII shedding and decreased membrane-associated IL-1RII. Basal IL-1RII shedding is absent from ARTS-1 knockout cell lines, demonstrating that ARTS-1 is required for constitutive 1L-1RII shedding. Similarly, PMA-mediated 1L-1RII shedding is almost entirely ARTS-1-dependent. ARTS-1 expression also enhances ionomycin-induced IL-1RII shedding. ARTS-1 did not alter levels of membrane-associated IL-1RI or IL-1R antagonist release from ARTS-1 cell lines, which suggests that the ability of ARTS-1 to promote shedding of IL-1R family members may be specific for IL-1RII Further, increased IL-1RII shedding by ARTS-1-overexpressing cells attenuates the biological activity of IL-1beta. We conclude that the ability of ARTS-1 to enhance IL-1RII shedding represents a new mechanism by which IL-1-induced cellular events can be modulated. As ARTS-1 also promotes the shedding of the structurally unrelated 55-kDa, type I TNF receptor and the IL-6R, we propose that ARTS-1 may play an important role in regulating innate immune and inflammatory responses by increasing cytokine receptor shedding. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. NR 41 TC 118 Z9 122 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2003 VL 171 IS 12 BP 6814 EP 6819 PG 6 WC Immunology SC Immunology GA 753JF UT WOS:000187227700065 PM 14662887 ER PT J AU Hengel, RL Kovacs, JA AF Hengel, RL Kovacs, JA TI Surrogate markers of immune function in human immunodeficiency virus-infected patients: What are they surrogates for? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; RESTORATION; SUPPRESSION; DISEASE C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. Georgetown Univ, Washington, DC USA. RP Hengel, RL (reprint author), NIAID, Immunoregulat Lab, NIH, Rm 11B05,Bldg 10-MSC 1880,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rhengel@nih.gov NR 11 TC 4 Z9 4 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2003 VL 188 IS 12 BP 1791 EP 1793 DI 10.1086/379901 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 762QB UT WOS:000187992700001 PM 14673756 ER PT J AU Lederman, HM Williams, PL Wu, JW Evans, TG Cohn, SE McCutchan, JA Koletar, SL Hafner, R Connick, E Valentine, FT McElrath, MJ Roberts, NJ Currier, JS AF Lederman, HM Williams, PL Wu, JW Evans, TG Cohn, SE McCutchan, JA Koletar, SL Hafner, R Connick, E Valentine, FT McElrath, MJ Roberts, NJ Currier, JS CA AIDS Clinical Trials Grp 889 Study TI Incomplete immune reconstitution after initiation of highly active antiretroviral therapy in human immunodeficiency virus-infected patients with severe CD4(+) cell depletion SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID AVIUM COMPLEX PROPHYLAXIS; PLACEBO-CONTROLLED TRIAL; CYTOKINE PRODUCTION; HIV-1-INFECTED PATIENTS; HIV-1 INFECTION; DOUBLE-BLIND; TETANUS; VACCINE; IMMUNOGENICITY; RESTORATION AB Immune function was observed for 144 weeks in 643 human immunodeficiency virus (HIV)-infected subjects who (1) had nadir CD4(+) cell counts of <50 cells/mm(3), followed by a sustained increase to &GE;100 cells/mm(3) after the initiation of HAART, and (2) were enrolled in a randomized trial of continued azithromycin prophylaxis versus withdrawal for prevention of Mycobacterium avium complex disease. The median CD4(+) cell count was 226 cells/mm(3) at entry and 358 cells/mm(3) at week 144. Anergy (80.2% of patients) and lack of lymphoproliferative response to tetanus toxoid (TT; 73%) after immunization and impaired antibody responses after receipt of hepatitis A (54%) and TT (86%) vaccines were considered to be evidence of impaired immune reconstitution. Receipt of azithromycin did not have an effect on CD4(+) cell count but was associated with higher rates of delayed-type hypersensitivity responses to TT (25% of subjects who received azithromycin vs. 15% of those who did not; P =.009) and mumps skin test antigen (29% vs. 17%; P =.001). Although the subjects had only partial responses to immune function testing, the rate of opportunistic infections was very low, and none of the tests was predictive of risk. C1 Johns Hopkins Univ, Sch Med, Eudowood Div Pediat Allergy & Immunol, Baltimore, MD USA. NIAID, Treatment Res Program, Div AIDS, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Univ Rochester, Med Ctr, Infect Dis Unit, Rochester, NY 14627 USA. NYU, Sch Med, New York, NY USA. Univ Calif San Diego, Sch Med, Div Infect Dis, San Diego, CA 92103 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. Ohio State Univ, Div Infect Dis, Columbus, OH 43210 USA. Univ Colorado, Hlth Sci Ctr, Div Infect Dis, Denver, CO USA. Univ Washington, Sch Med, Seattle, WA USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. RP Lederman, HM (reprint author), Johns Hopkins Univ Hosp, Div Pediat Allergy & Immunol, CMSC 1102, Baltimore, MD 21287 USA. EM hlederm1@jhem.jhmi.edu FU NCRR NIH HHS [5M01 RR00044, RR00046, RR00051, RR00052]; NIAID NIH HHS [5U01 AI39156-03, 1 U01 AI46370-03, 5U01 AI27666, 5U01 AI27673-140, 5U01 AI32782, 5U01 AI39156-04, 5U01 AI39156-05, 5U01 AI39156-06, AI25868, AI258799, AI25924, AI2760-17, AI27660, AI27664, AI27668, AI32770, AI38858, AI50410, P30 AI27742, U01 AI25915, U01 AI27658, U01 AI27665, U01 AI38855, UO1 AI27659] NR 36 TC 71 Z9 73 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2003 VL 188 IS 12 BP 1794 EP 1803 DI 10.1086/379900 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 762QB UT WOS:000187992700002 PM 14673757 ER PT J AU Jacobson, JM Lederman, MM Spritzler, J Valdez, H Tebas, P Skowron, G Wang, R Jackson, JB Fox, L Landay, A Gilbert, MJ O'Neil, D Bancroft, L Al-Harthi, L Jacobson, MA Merigan, TC Glesby, MJ AF Jacobson, JM Lederman, MM Spritzler, J Valdez, H Tebas, P Skowron, G Wang, R Jackson, JB Fox, L Landay, A Gilbert, MJ O'Neil, D Bancroft, L Al-Harthi, L Jacobson, MA Merigan, TC Glesby, MJ CA Natl Inst Allergy Infect Dis AIDS TI Granulocyte-macrophage colony-stimulating factor induces modest increases in plasma human immunodeficiency virus (HIV) type 1 RNA levels and CD4(+) lymphocyte counts in patients with uncontrolled HIV infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PLACEBO-CONTROLLED TRIAL; NECROSIS-FACTOR-ALPHA; ANTIRETROVIRAL THERAPY; EXPRESSION; AIDS; INTERLEUKIN-1; RITONAVIR; CCR5 AB Background. Studies have reported that plasma human immunodeficiency virus type I (HIV-1) RNA levels and CD4(+) lymphocyte counts in HIV-infected patients improved after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). Methods. In AIDS Clinical Trials Group Protocol 5041, 116 patients were enrolled in a double-blind, randomized, placebo-controlled clinical trial of 16 weeks of 250 mug of GM-CSF administered subcutaneously 3 times/week, followed by open-label treatment for an additional 32 weeks. Patients had stable baseline plasma HIV-1 RNA levels of greater than or equal to 1500 copies/mL and received constant antiretroviral regimens through at least the first 16 weeks of the study. Results. After 16 weeks, the GM-CSF group tended to have greater, though clinically insignificant, increases in plasma HIV-1 RNA levels, compared with the placebo group (median change, +0.048 vs. -0.103 log copies/mL; P =.036, in a post hoc analysis). There were trends toward progressive modest increases in CD4+ lymphocyte counts with GM-CSF treatment at 16 weeks (median change, +14 vs. -6 cells/mm(3); p =.06) and beyond. Conclusions. GM-CSF does not have an antiviral effect in patients with ongoing HIV replication but may increase CD4+ lymphocyte counts. C1 Beth Israel Med Ctr, Dept Med, New York, NY 10003 USA. Albert Einstein Coll Med, New York, NY USA. Cornell Univ, Weill Med Coll, Dept Med, New York, NY USA. Frontier Sci Technol & Res Fdn, Data Management Ctr, Amherst, NY USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Roger Williams Med Ctr, Dept Med, Providence, RI USA. Brown Univ, Providence, RI 02912 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. AIDS Clin Trials Grp Operat Ctr, Rockville, MD USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Rush Med Coll, Dept Pathol, Chicago, IL 60612 USA. Immunex Corp, Seattle, WA USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. RP Jacobson, JM (reprint author), Beth Israel Med Ctr, Dept Med, 1st Ave & 16th St 19BH14, New York, NY 10003 USA. EM jjacobson@chpnet.org RI Tebas, Pablo/A-7061-2008 FU NCRR NIH HHS [RR-00865]; NIAID NIH HHS [1U01 AI-46370, 5U01 AI-32782, 5U01 AI-38855, 5U01 AI-39156, AI-25879, AI-25903, AI-25924, AI-27660, AI-28691, AI-36219, AI-38855, AI-38858, U01 AI-25859-17] NR 24 TC 10 Z9 12 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2003 VL 188 IS 12 BP 1804 EP 1814 DI 10.1086/379899 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 762QB UT WOS:000187992700003 PM 14673758 ER PT J AU Banks, DJ Porcella, SF Barbian, KD Martin, JM Musser, JM AF Banks, DJ Porcella, SF Barbian, KD Martin, JM Musser, JM TI Structure and distribution of an unusual chimeric genetic element encoding macrolide resistance in phylogenetically diverse clones of group A Streptococcus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID FALCIPARUM PROTEIN MESA; GRAM-POSITIVE BACTERIA; GENOME SEQUENCE; ERYTHROMYCIN RESISTANCE; PLASMODIUM-FALCIPARUM; INFECTED ERYTHROCYTE; SURFACE-PROTEINS; ESCHERICHIA-COLI; UNITED-STATES; M3 STRAIN AB The resistance of group A Streptococcus(GAS) to macrolide antibiotics is now a worldwide problem. Preliminary sequencing of the genome of an erythromycin-resistant serotype M6 clone that was responsible for a pharyngitis outbreak in I Pittsburgh, Pennsylvania, was conducted to determine the structure of the genetic element containing the mefA gene, which encodes a macrolide efflux protein. The mefA gene is associated with a 58.8-kb chimeric genetic element composed of a transposon inserted into a prophage. This element also encodes a putative extracellular protein with a cell-wall anchoring Motif (LPKTG) located at the carboxyterminus. The mefA element was present in phylogenetically diverse GAS strains isolated throughout the United States. Culture supernatants, prepared after mitomycin C treatment, of a strain representing the outbreak clone contained mefA element DNA in a DNAse-resistant form. Together, these data provide new information about the molecular genetic basis of macrolide resistance and dissemination in GAS strains. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Dept Pediat,Div Allergy Immunol & Infect Dis, Pittsburgh, PA USA. RP Musser, JM (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jmusser@niaid.nih.gov NR 73 TC 62 Z9 66 U1 1 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2003 VL 188 IS 12 BP 1898 EP 1908 DI 10.1086/379897 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 762QB UT WOS:000187992700016 PM 14673771 ER PT J AU Dishon, M Taitelbaum, H Weiss, GH AF Dishon, M Taitelbaum, H Weiss, GH TI Effects of the scattering coefficient on width estimates in a two-layer tissue SO JOURNAL OF MODERN OPTICS LA English DT Article ID PHOTON MIGRATION; DIFFUSION; MEDIA; MODEL; LIGHT; MEDICINE; LAYER AB We pose the problem of estimating the width of the upper layer of a two-stratum medium using data from reflectance measurements made at the interface separating the medium from its surroundings. The lower stratum is assumed to be infinite. In this analysis both the scattering and the absorption coefficients are allowed to differ, but are assumed to be known. We also suggest a simple way to include effects of noise into the analysis. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Bar Ilan Univ, Dept Phys, Ramat Gan, Israel. RP Dishon, M (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. NR 26 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0950-0340 J9 J MOD OPTIC JI J. Mod. Opt. PD DEC 15 PY 2003 VL 50 IS 18 BP 2727 EP 2740 DI 10.1080/0950034031000096712 PG 14 WC Optics SC Optics GA 750ZZ UT WOS:000187029500003 ER PT J AU Anokhin, AP Heath, AC Myers, E Ralano, A Wood, S AF Anokhin, AP Heath, AC Myers, E Ralano, A Wood, S TI Genetic influences on prepulse inhibition of startle reflex in humans SO NEUROSCIENCE LETTERS LA English DT Article DE startle reflex; prepulse inhibition; sensorimotor gating; twins; genetics; heritability ID MODULATION; DISORDERS; DEFICITS; TWINS; RAT AB Prepulse inhibition (PPI) is a suppression of the startle reflex that occurs when an intense startling stimulus is preceded by a weaker 'prepulse' stimulus. PPI deficits have been implicated in the biological bases of schizophrenia and some other neuropsychiatric disorders and proposed as a possible biological marker (endophenotype) for genetic studies. However, little is known about the genetic determination of PPI in humans. We examined acoustic eye-blink startle reflex and PPI in 142 young female twins (40 monozygotic and 31 dizygotic pairs) and conducted a biometrical genetic analysis using structural equation modeling. PPI showed significant heritability suggesting that over 50% of PPI variance in this sample can be attributed to genetic factors. Baseline startle magnitude showed higher heritability (about 70%). (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63108 USA. Binghamton Univ, Dept Psychol, Binghamton, NY USA. NIMH, MIB, Sect Neuroimaging Mood & Anxiety Disorders, Mood & Anxiety Disorders Program,NIH, Bethesda, MD USA. RP Anokhin, AP (reprint author), Washington Univ, Sch Med, Dept Psychiat, 18 s Kingshighway,Suite 2T-U, St Louis, MO 63108 USA. RI Anokhin, Andrey/A-5008-2013 FU NIAAA NIH HHS [5P50 AA11998]; NIDA NIH HHS [DA00421] NR 21 TC 87 Z9 89 U1 1 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 15 PY 2003 VL 353 IS 1 BP 45 EP 48 DI 10.1016/j.neulet.2003.09.014 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 747NM UT WOS:000186810700012 PM 14642434 ER PT J AU Gollust, SE Thompson, RE Gooding, HC Biesecker, BB AF Gollust, SE Thompson, RE Gooding, HC Biesecker, BB TI Living with achondroplasia: attitudes towards population screening and correlation with quality of life SO PRENATAL DIAGNOSIS LA English DT Article DE achondroplasia; prenatal testing; population screening; quality of life ID PRENATAL-DIAGNOSIS; SELECTIVE ABORTION; BIPOLAR DISORDER; KNOWLEDGE; PERCEPTIONS; DISABILITY; MUTATIONS; RELATIVES; GENETICS; FAMILIES AB Objectives Since the discovery of the gene that causes achondroplasia, population-wide prenatal screening for this condition has become a possibility. This study sought to assess attitudes toward screening for achondroplasia and correlation with quality of life in a population of individuals affected with achondroplasia and first-degree relatives. Methods Surveys were collected from 189 individuals affected with achondroplasia and 136 average-statured first-degree relatives. Results While 87% of all respondents would support the use of prenatal screening by affected parents at risk of having a fetus with the homozygous, lethal form of achondroplasia, 29% would support general population prenatal screening for achondroplasia. Attitudes supporting general population screening were more likely to be held by those people with less education, who were affected with achondroplasia, who supported abortion, and who believed that achondroplasia is a serious condition without any accompanying advantages (p < 0.01). Those respondents who felt positively toward offering the prenatal test for individuals at risk for homozygous achondroplasia were more likely to have lower mean quality of life scores and to support abortion in general (p < 0.05). Conclusion These data suggest that opinions about prenatal screening are heterogeneous within this study population and are related to individuals' experiences and perceptions of the condition. Future research is needed to assess attitudes toward population screening and quality of life in communities of individuals affected with genetic conditions, both to support policy decisions and to inform the education and counseling provided in the prenatal setting. Copyright (C) 2003 John Wiley Sons, Ltd. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. RP Biesecker, BB (reprint author), 10 Ctr Dr,Bldg 10,Room 10C101, Bethesda, MD 20892 USA. NR 31 TC 18 Z9 18 U1 3 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD DEC 15 PY 2003 VL 23 IS 12 BP 1003 EP 1008 DI 10.1002/pd.743 PG 6 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 755QD UT WOS:000187420000009 PM 14663838 ER PT J AU Oz, M Zhang, L Rotondo, A Sun, H Morales, M AF Oz, M Zhang, L Rotondo, A Sun, H Morales, M TI Direct activation by dopamine of recombinant human 5-HT1A receptors: Comparison with human 5-HT2C and 5-HT3 receptors SO SYNAPSE LA English DT Article DE recombinant human 5-HT1A receptors; dopamine ID VENTRAL TEGMENTAL AREA; XENOPUS-OOCYTES; RAT-BRAIN; NEUROBLASTOMA-CELLS; SEROTONIN; CHANNELS; SCHIZOPHRENIA; BINDING; NEURONS AB The effects of dopamine (DA) on the function of human 5-HT1A receptors expressed in Xenopus oocytes and CHO-K1 cells were investigated. In addition, the effect of DA on the activation of three different types of human 5-HT receptors (5-HT1A, 5-HT2C, and 5-HT3) were studied comparatively in Xenopus oocyte expression system. Application of 5-HT or DA in oocytes coexpressing 5-HT1A receptors and G-protein-activated inwardly rectifying potassium channels (GIRK1) induced inward currents with respective EC50 values of 4.2 nM and 11.2 muM. Maximal responses induced by DA were 85 +/- 4% of maximal 5-HT currents and DA responses were blocked by the specific 5-HT1A antagonist, WAY-100635 (50 nM). In CHO-K1 cells expressing 5-HT1A receptors, 5-HT and DA inhibited the specific binding of selective antagonist [H-3]-8-OH-DPAT with IC50 values of 10.2 nM and 1.4 muM, and both 5-HT and DA inhibited the forskolin-induced accumulation of cAMP. In oocytes expressing 5-HT2C receptors, 5-HT and DA induced inward currents with respective EC50 values of 6.2 nM and 67.7 muM. Magnitudes of maximal DA induced currents were 42 +/- 3% of maximal 5-HT responses and blocked by the 5-HT2 antagonist, piperazine (1 muM). In oocytes expressing 5-HT3 receptors, 5-HT and DA induced fast inward currents with respective EC50 values of 2.1 muM and 266.3 muM. Maximal DA induced currents were 37 +/- 3% of maximal 5-HT responses and blocked the specific 5-HT3 antagonist LY-278584 (0.1 muM). Comparison of the potencies and efficacies of 5-HT and DA indicated that the relative potency of DA increased in the order of 5-HT3 > 5-HT1A > 5-HT2C, and relative efficacy increased in the order of 5-HT1A > 5-HT2C > 5-HT3. These results suggest that although DA activates different subtypes of human 5-HT receptors directly, the potency and efficacy of the binding site varies significantly among different receptors. Published 2003 Wiley-Liss, Inc.(dagger) C1 Natl Inst Drug Abuse, IRP, Cellular Neurobiol Sect, DHHS,Cellular Neurobiol Branch,NIH, Baltimore, MD 21224 USA. NIAAA, Lab Mol & Cellular Neurobiol, Rockville, MD 20852 USA. Univ Pisa, Dept Psychiat, Pisa, Italy. Instramural Res Program, DHHS, NIDA, Cellular Neurophysiol Sect,NIH, Baltimore, MD USA. RP Oz, M (reprint author), Natl Inst Drug Abuse, IRP, Cellular Neurobiol Sect, DHHS,Cellular Neurobiol Branch,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Oz, Murat/E-2148-2012 NR 33 TC 12 Z9 12 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 0887-4476 J9 SYNAPSE JI Synapse PD DEC 15 PY 2003 VL 50 IS 4 BP 303 EP 313 DI 10.1002/syn.10273 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 739ZF UT WOS:000186375900005 PM 14556235 ER PT J AU Erickson, KL Gustafson, KR Milanowski, DJ Pannell, LK Klose, JR Boyd, MR AF Erickson, KL Gustafson, KR Milanowski, DJ Pannell, LK Klose, JR Boyd, MR TI Myriastramides A-C, new modified cyclic peptides from the Philippines marine sponge Myriastra clavosa SO TETRAHEDRON LA English DT Article DE Myriastra clavosa; myriastramide A-C; marine sponge; cyclic peptide ID HEXAPEPTIDES; MACROLIDES AB Chemical investigation of the Philippines marine sponge Myriastra clavosa has resulted in the isolation of three new cyclic octapeptides, myriastramides A (1), B (2), and C (3). The structures of compounds 1-3 were assigned based on extensive NMR spectroscopic analyses and a series of degradation and derivatization studies. (C) 2003 Elsevier Ltd. All rights reserved. C1 NCI, Ctr Canc Res, Mol Targets Dev Program, Ft Detrick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. SAIC Frederick Inc, NCI Frederick, Analyt Chem Lab, Ft Detrick, MD 21702 USA. Univ S Alabama, Coll Med, USA Canc Res Inst, Mobile, AL 36688 USA. RP Gustafson, KR (reprint author), NCI, Ctr Canc Res, Mol Targets Dev Program, Bldg 1052,Rm 121, Ft Detrick, MD 21702 USA. EM manuscripts@mail.ncifcrf.gov NR 18 TC 11 Z9 11 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD DEC 15 PY 2003 VL 59 IS 51 BP 10231 EP 10238 DI 10.1016/j.tet.2003.10.060 PG 8 WC Chemistry, Organic SC Chemistry GA 750TA UT WOS:000187013100013 ER PT J AU Brunssen, SH Morgan, DL Parham, FM Harry, GJ AF Brunssen, SH Morgan, DL Parham, FM Harry, GJ TI Carbon monoxide neurotoxicity: transient inhibition of avoidance response and delayed microglia reaction in the absence of neuronal death SO TOXICOLOGY LA English DT Article DE carbon monoxide; avoidance-aversion; microglia; carboxyhemoglobin ID BLOOD CARBOXYHEMOGLOBIN; NEUROLOGIC SEQUELAE; HALF-LIFE; BRAIN; EXPOSURE; RATS; INTOXICATION; ANXIETY; DAMAGE; MICE AB Carbon monoxide exposure produces neurobehavioral effects associated with the level of carboxyhemoglobin (COHb) in the blood. A threshold has been proposed of approximately 35% COHb for the manifestation of disruption in neurobehavioral tasks. The effects of CO exposure producing 30-40% carboxyhemoglobin (COHb) levels in young adult male Fischer 344 rats were examined with regard to clinical signs of toxicity, performance on a previously learned avoidance procedure, and neuronal and glia histopathology. High levels of exposure (4000 ppm) for 15 min were imposed on either a background blood COHb level of 5% produced by a 2 h exposure to 50 ppm CO or a control background from conditioned-air exposure. Upon removal from the nose-only inhalation holder, signs of mild lethargy and decreased activity were evident for 2 min for conditioned-air controls and 50 ppm CO exposure groups and 3-4 min following 4000 ppm CO. Performance on a two-way shuttle box active avoidance task showed no differences between 50 ppm CO rats and conditioned-air controls while the 4000 ppm, CO exposed groups showed a significant decrease in avoidance and escape responses. Histological examination showed no evidence of delayed neuronal death or astrocyte reactivity in the hippocampus or cerebellum; however, a distinct focal staining of reactive microglia in both regions was evident in animals exposed to 4000 ppm CO. While 50 ppm CO (5% COHb) alone produced no disruption in avoidance performance, microglia staining in the cerebellum was significantly increased over conditioned-air controls. This regional and focal response of microglia suggests the need for further study regarding such subtle cellular changes and their relationship with COHb levels. Published by Elsevier Ireland Ltd. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC 27709 USA. RP Morgan, DL (reprint author), NIEHS, Mol Toxicol Lab, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 50 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD DEC 15 PY 2003 VL 194 IS 1-2 BP 51 EP 63 DI 10.1016/j.tox.2003.08.003 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 750TE UT WOS:000187013500005 PM 14636696 ER PT J AU Andric, NL Andric, SA Zoric, SN Kostic, TS Stojilkovic, SS Kovacevic, RZ AF Andric, NL Andric, SA Zoric, SN Kostic, TS Stojilkovic, SS Kovacevic, RZ TI Parallelism and dissociation in the actions of an Aroclor 1260-based transformer fluid on testicular androgenesis and antioxidant enzymes SO TOXICOLOGY LA English DT Article DE polychlorinated biphenyls; pyralene; testosterone; catalase; glutathione; transferase; glutathione peroxidase ID POLYCHLORINATED BIPHENYL; LIPID-PEROXIDATION; RAT TESTIS; OXIDATIVE STRESS; HEPATIC GLUTATHIONE; CHRONIC EXPOSURE; SPERM FUNCTION; ADULT RATS; STEROIDOGENESIS; INDUCTION AB The mechanism by which Aroclors and other polychlorinated biphenyls (PCBs) inhibit testicular androgenesis in vivo and in vitro has not been characterized. Here we studied in adult rats the effects of intratesticular (itt), intraperitoneal (ip) and by gavage (po) administration of Pyralene, an Aroclor 1260-based transformer fluid, on testicular androgenesis and oxidative status in androgen-producing interstitial cells and liver. Pyralene markedly decreased in vitro agonist stimulated androgenesis 24 h after bilateral itt-injection (25 mug/testis), 24 h and 96 It after single ip-injection (10 and 50 mg/kg body weight), and 96 h after po-administration (7 x 10 mg and 7 x 50 mg/kg body weight daily). Inhibited androgenesis was accompanied by changes in the activity of antioxidant enzymes (AOEs) in interstitial cells after local itt-treatment and occasionally after systemic Pyralene application. Among changes in the activity, glutathione peroxidase and catalase reflected relatively well the toxicity of Pyralene in these cells. In liver, glutathione-S-transferase (GST) and glutathione peroxidase activities were enhanced after po-treatment and total glutathione (tGSH) content and lipid peroxidation (LP) were enhanced after ip-administration. These results indicate that Pyralene inhibits androgenesis independently of the method of its administration. The results also suggest that changes in the oxidative status in testicular milieu are not critical for Pyralene-induced inhibition of androgenesis. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Fac Sci, Dept Biol & Ecol, YU-21000 Novi Sad, Serbia And Mont, Yugoslavia. RP Stojilkovic, SS (reprint author), NICHD, Endocrinol & Reprod Res Branch, NIH, Room 6A-36,Bldg 49,49 Convent Dr, Bethesda, MD 20892 USA. NR 44 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD DEC 15 PY 2003 VL 194 IS 1-2 BP 65 EP 75 DI 10.1016/j.tox.2003.08.002 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 750TE UT WOS:000187013500006 PM 14636697 ER PT J AU Geisbert, TW Hensley, LE Jahrling, PB Larsen, T Geisbert, JB Paragas, J Young, HA Fredeking, TM Rote, WE Vlasuk, GP AF Geisbert, TW Hensley, LE Jahrling, PB Larsen, T Geisbert, JB Paragas, J Young, HA Fredeking, TM Rote, WE Vlasuk, GP TI Treatment of Ebola virus infection with a recombinant inhibitor of factor Vila/tissue factor: a study in rhesus monkeys SO LANCET LA English DT Article ID ANTICOAGULANT PROTEIN C2; DISSEMINATED INTRAVASCULAR COAGULATION; TISSUE FACTOR/FACTOR-VIIA; FACTOR VIIA/TISSUE FACTOR; FACTOR PATHWAY; IN-VITRO; ACTIVATION; MECHANISMS; RELEASE; COMPLEX AB Background Infection with the Ebola virus induces overexpression of the procoagulant tissue factor in primate monocytes and macrophages, suggesting that inhibition of the tissue-factor pathway could ameliorate the effects of Ebola haemorrhagic fever. Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with Ebola virus. Methods We used a rhesus macaque model of Ebola haemorrhagic fever, which produces near 100% mortality. We administered recombinant nematode anticoagulant protein c2 (rNAPc2), a potent inhibitor of tissue factor-initiated blood coagulation, to the macaques either 10 min (n=6) or 24 h (n=3) after a high-dose lethal injection of Ebola virus. Three animals served as untreated Ebola virus-positive controls. Historical controls were also used in some analyses. Findings Both treatment regimens prolonged survival time, with a 33% survival rate in each treatment group. Survivors are still alive and healthy after 9 months. All but one of the 17 controls died. The mean survival for the six rNAPc2-treated macaques that died was 11.7 days compared with 8.3 days for untreated controls (p=0.0184). rNAPc2 attenuated the coagulation response as evidenced by modulation of various important coagulation factors, including plasma D dimers, which were reduced in nearly all treated animals; less prominent fibrin deposits and intravascular thromboemboli were observed in tissues of some animals that succumbed to Ebola virus. Furthermore, rNAPc2 attenuated the proinflammatory response with lower plasma concentrations of interleukin 6 and monocyte chemoattractant protein-1 (MCP-1) noted in the treated than in the untreated macaques. Interpretation Post-exposure protection with rNAPc2 against Ebola virus in primates provides a new foundation for therapeutic regimens that target the disease process rather than viral replication. C1 USA, Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Div Pathol, Ft Detrick, MD 21702 USA. NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, FCRDC, Frederick, MD USA. Antibody Syst, Hurst, TX USA. Corvas Int, San Diego, CA USA. RP Geisbert, TW (reprint author), USA, Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. NR 20 TC 204 Z9 222 U1 1 U2 26 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD DEC 13 PY 2003 VL 362 IS 9400 BP 1953 EP 1958 DI 10.1016/S0140-6736(03)15012-X PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 753BC UT WOS:000187210700006 PM 14683653 ER PT J AU Covitz, PA Hartel, F Schaefer, C De Coronado, S Fragoso, G Sahni, H Gustafson, S Buetow, KH AF Covitz, PA Hartel, F Schaefer, C De Coronado, S Fragoso, G Sahni, H Gustafson, S Buetow, KH TI caCORE: A common infrastructure for cancer informatics SO BIOINFORMATICS LA English DT Article ID GENOME-ANATOMY-PROJECT; REPRESENTATION AB Motivation:Sites with substantive bioinformatics operations are challenged to build data processing and delivery infrastructure that provides reliable access and enables data integration. Locally generated data must be processed and stored such that relationships to external data sources can be presented. Consistency and comparability across data sets requires annotation with controlled vocabularies and, further, metadata standards for data representation. Programmatic access to the processed data should be supported to ensure the maximum possible value is extracted. Confronted with these challenges at the National Cancer Institute Center for Bioinformatics, we decided to develop a robust infrastructure for data management and integration that supports advanced biomedical applications. Results: We have developed an interconnected set of software and services called caCORE. Enterprise Vocabulary Services (EVS) provide controlled vocabulary, dictionary and thesaurus services. The Cancer Data Standards Repository (caDSR) provides a metadata registry for common data elements. Cancer Bioinformatics Infrastructure Objects (caBIO) implements an object-oriented model of the biomedical domain and provides Java, Simple Object Access Protocol and HTTP-XML application programming interfaces. caCORE has been used to develop scientific applications that bring together data from distinct genomic and clinical science sources. C1 NCI, Ctr Bioinformat, NIH, US Dept HHS, Rockville, MD 20852 USA. RP Covitz, PA (reprint author), NCI, Ctr Bioinformat, NIH, US Dept HHS, 6 Execut Blvd,Suite 403, Rockville, MD 20852 USA. NR 17 TC 83 Z9 88 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 DEC 12 PY 2003 VL 19 IS 18 BP 2404 EP 2412 DI 10.1093/bioinformatics/btg335 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 753DX UT WOS:000187217700009 PM 14668224 ER PT J AU Wright, GW Simon, RM AF Wright, GW Simon, RM TI A random variance model for detection of differential gene expression in small microarray experiments SO BIOINFORMATICS LA English DT Article AB Motivation: Microarray techniques provide a valuable way of characterizing the molecular nature of disease. Unfortunately expense and limited specimen availability often lead to studies with small sample sizes. This makes accurate estimation of variability difficult, since variance estimates made on a gene by gene basis will have few degrees of freedom, and the assumption that all genes share equal variance is unlikely to be true. Results: We propose a model by which the within gene variances are drawn from an inverse gamma distribution, whose parameters are estimated across all genes. This results in a test statistic that is a minor variation of those used in standard linear models. We demonstrate that the model assumptions are valid on experimental data, and that the model has more power than standard tests to pick up large changes in expression, while not increasing the rate of false positives. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Wright, GW (reprint author), NCI, Biometr Res Branch, 6130 Execut Blvd,MSC 7434, Bethesda, MD 20892 USA. NR 8 TC 439 Z9 449 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 12 PY 2003 VL 19 IS 18 BP 2448 EP 2455 DI 10.1093/bioinformatics/btg345 PG 8 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 753DX UT WOS:000187217700015 PM 14668230 ER PT J AU Dimitrov, DS AF Dimitrov, DS TI The secret life of ACE2 as a receptor for the SARS virus SO CELL LA English DT Editorial Material ID FUNCTIONAL-CHARACTERIZATION; CORONAVIRUS AB The membrane-associated carboxypeptidase angiotensin-converting enzyme 2 (ACE2) is an essential regulator of heart function. Now, Li at al. identify and characterize an unexpected second function of ACE2 as a partner of the SARS-CoV spike glycoprotein in mediating virus entry and cell fusion. C1 NIH, NCI Frederick, CCR, LECB,Human Immunovirol & Computat Biol Grp, Ft Detrick, MD 21702 USA. RP Dimitrov, DS (reprint author), NIH, NCI Frederick, CCR, LECB,Human Immunovirol & Computat Biol Grp, Ft Detrick, MD 21702 USA. NR 8 TC 46 Z9 51 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD DEC 12 PY 2003 VL 115 IS 6 BP 652 EP 653 DI 10.1016/S0092-8674(03)00976-0 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 755AR UT WOS:000187366100005 PM 14675530 ER PT J AU Iavarone, C Catania, A Marinissen, MJ Visconti, R Acunzo, M Tarantino, C Carlomagno, MS Bruni, CB Gutkind, JS Chiariello, M AF Iavarone, C Catania, A Marinissen, MJ Visconti, R Acunzo, M Tarantino, C Carlomagno, MS Bruni, CB Gutkind, JS Chiariello, M TI The platelet-derived growth factor controls c-myc expression through a JNK- and AP-1-dependent signaling pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; N-TERMINAL KINASE; JUN NH2-TERMINAL KINASE; KAPPA-B; CELLULAR-TRANSFORMATION; TRANSCRIPTION; JNK; SURVIVAL; PDGF; GENE AB Pro-inflammatory cytokines, environmental stresses, as well as receptor tyrosine kinases regulate the activity of JNK. In turn, JNK phosphorylates Jun members of the AP-1 family of transcription factors, thereby controlling processes as different as cell growth, differentiation, and apoptosis. Still, very few targets of the JNK-Jun pathway have been identified. Here we show that JNK is required for the induction of c-myc expression by PDGF. Furthermore, we identify a phylogenetically conserved AP-1-responsive element in the promoter of the c-myc proto-oncogene that recruits in vivo the c-Jun and JunD AP-1 family members and controls the PDGF-dependent transactivation of the c-myc promoter. These findings suggest the existence of a novel biochemical route linking tyrosine kinase receptors, such as those for PDGF, and c-myc expression through JNK activation of AP-1 transcription factors. They also provide a novel potential mechanism by which both JNK and Jun proteins may exert either their proliferative or apoptotic potential by stimulating the expression of the c-myc proto-oncogene. C1 CNR, Ist Endocrinol & Oncol Sperimentale, I-80131 Naples, Italy. Univ Naples Federico II, Dipartimento Biol & Patol Cellulare & Mol, I-80131 Naples, Italy. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Chiariello, M (reprint author), CNR, Ist Endocrinol & Oncol Sperimentale, Via Pansini 5, I-80131 Naples, Italy. RI Gutkind, J. Silvio/A-1053-2009; Visconti, Roberta/C-5299-2009; Chiariello, Mario/O-3642-2014; OI Chiariello, Mario/0000-0001-8434-5177; Tarantino, Carolina/0000-0003-2470-3803 NR 37 TC 36 Z9 37 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 DEC 12 PY 2003 VL 278 IS 50 BP 50024 EP 50030 DI 10.1074/jbc.M308617200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 751LH UT WOS:000187068200045 PM 14523011 ER PT J AU Makarova, A Mikhailenko, I Bugge, TH List, K Lawrence, DA Strickland, DK AF Makarova, A Mikhailenko, I Bugge, TH List, K Lawrence, DA Strickland, DK TI The low density lipoprotein receptor-related protein modulates protease activity in the brain by mediating the cellular internalization of both neuroserpin and neuroserpin-tissue-type plasminogen activator complexes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LONG-TERM POTENTIATION; ALPHA-2-MACROGLOBULIN RECEPTOR; VLDL RECEPTOR; MICE LACKING; INCLUSION-BODIES; LIGAND-BINDING; IN-VITRO; INHIBITOR; NEURONS; GENE AB Proteases contribute to a variety of processes in the brain; consequently, their activity is carefully regulated by protease inhibitors, such as neuroserpin. This inhibitor is thought to be secreted by axons at synaptic regions where it controls tissue-type plasminogen activator (tPA) activity. Mechanisms regulating neuroserpin are not known, and the current studies were undertaken to define the cellular pathways involved in neuroserpin catabolism. We found that both active neuroserpin and neuroserpin . tPA complexes were internalized by mouse cortical cultures and embryonic fibroblasts in a process mediated by the low density lipoprotein receptor-related protein (LRP). Surprisingly, despite the fact that active neuroserpin is internalized by LRP, this form of the molecule does not directly bind to LRP on its own, indicating the requirement of a cofactor for neuroserpin internalization. Our studies ruled out the possibility that endogenously produced plasminogen activators (i.e. tPA and urokinase-type plasminogen activator) are responsible for the LRP-mediated internalization of active neuroserpin, but could not rule out the possibility that another cell-associated proteases capable of binding active neuroserpin functions in this capacity. In summary, neuroserpin levels appear to be carefully regulated by LRP and an unidentified cofactor, and this pathway may be critical for maintaining the balance between proteases and inhibitors. C1 Amer Red Cross, Jerome H Holland Lab, Dept Vasc Biol, Rockville, MD 20855 USA. George Washington Univ, Med Ctr, Inst Biomed Sci, Washington, DC 20037 USA. NIDCR, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Strickland, DK (reprint author), Amer Red Cross, Jerome H Holland Lab, Dept Vasc Biol, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. FU NHLBI NIH HHS [HL-55747, HL-55374, HL50784, HL54710] NR 48 TC 43 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 DEC 12 PY 2003 VL 278 IS 50 BP 50250 EP 50258 DI 10.1074/jbc.M309150200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 751LH UT WOS:000187068200073 PM 14522960 ER PT J AU Kokoska, RJ McCulloch, SD Kunkel, TA AF Kokoska, RJ McCulloch, SD Kunkel, TA TI The efficiency and specificity of apurinic/apyrimidinic site bypass by human DNA polymerase eta and Sulfolobus solfataricus Dpo4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APURINIC APYRIMIDINIC SITES; PRONE LESION BYPASS; ERROR-PRONE; XERODERMA-PIGMENTOSUM; Y-FAMILY; THYMINE DIMER; ABASIC SITE; POL-ETA; A-RULE; FIDELITY AB One of the most common DNA lesions arising in cells is an apurinic/ apyrimidinic ( AP) site resulting from base loss. Although a template strand AP site impedes DNA synthesis, translesion synthesis ( TLS) DNA polymerases can bypass an AP site. Because this bypass is expected to be highly mutagenic because of loss of base coding potential, here we quantify the efficiency and the specificity of AP site bypass by two Y family TLS enzymes, Sulfolobus solfataricus DNA polymerase 4 ( Dpo4) and human DNA polymerase eta ( Pol eta). During a single cycle of processive DNA synthesis, Dpo4 and Pol eta bypass synthetic AP sites with 13 - 30 and 10 - 13%, respectively, of the bypass efficiency for undamaged bases in the same sequence contexts. These efficiencies are higher than for the A family, exonuclease- deficient Klenow fragment of Escherichia coli DNA polymerase I. We then determined AP site bypass specificity for complete bypass, requiring insertion or misalignment at the AP site followed by multiple incorporations using the aberrant primer templates. Although Dpo4, Pol eta, and Klenow polymerase have different fidelity when copying undamaged DNA, bypass of AP sites lacking A or G by all three polymerases is nearly 100% mutagenic. The majority ( 70 - 80%) of bypass events made by all three polymerases are insertion of dAMP opposite the AP site. Single base deletion errors comprise 10 - 25% of bypass events, with other base insertions observed at lower rates. Given that mammalian cells contain five polymerases implicated in TLS, and given that a large number of AP sites are generated per mammalian cell per day, even moderately efficient AP site bypass could be a source of substitution and frameshift mutagenesis in vivo. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 43 TC 90 Z9 91 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 DEC 12 PY 2003 VL 278 IS 50 BP 50537 EP 50545 DI 10.1074/jbc.M308515200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 751LH UT WOS:000187068200107 PM 14523013 ER PT J AU Selmane, T Schofield, MJ Nayak, S Du, CW Hsieh, P AF Selmane, T Schofield, MJ Nayak, S Du, CW Hsieh, P TI Formation of a DNA mismatch repair complex mediated by ATP SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA repair; mismatch repair; MutS; MutL; mutagenesis ID NEGATIVE MUTATOR MUTATIONS; ESCHERICHIA-COLI MUTS; HETERODUPLEX DNA; HMUTS-ALPHA; CRYSTAL-STRUCTURE; SLIDING CLAMP; TRANSLOCATION MECHANISM; MOLECULAR-MECHANISMS; YEAST MSH2-MSH6; PROTEIN MUTS AB The mismatch repair proteins, MutS and MutL, interact in a DNA mismatch and ATP-dependent manner to activate downstream events in repair. Here, we assess the role of ATP binding and hydrolysis in mismatch recognition by MutS and the formation of a ternary complex involving MutS and MutL bound to a mismatched DNA. We show that ATP reduces the affinity of MutS for mismatched DNA and that the modulation of DNA binding affinity by nucleoticle is even more pronounced for MutS E694A, a protein that binds ATP but is defective for ATP hydrolysis. Despite the ATP hydrolysis defect, E694A, like WT MutS, undergoes rapid, ATP-dependent dissociation from a DNA mismatch. Furthermore, MutS E694A retains the ability to interact with Mutl, on mismatched DNA. The recruitment of MutL to a mismatched DNA by MutS is also observed for two mutant MutL proteins, E29A, defective for ATP hydrolysis, and R266A, defective for DNA binding. These results suggest that ATP binding in the absence of hydrolysis is sufficient to trigger formation of a MutS sliding clamp. However, recruitment of MutL results in the formation of a dynamic ternary complex that we propose is the intermediate that signals subsequent repair steps requiring ATP hydrolysis. Published by Elsevier Ltd. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Hsieh, P (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NR 45 TC 48 Z9 48 U1 0 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 DEC 12 PY 2003 VL 334 IS 5 BP 949 EP 965 DI 10.1016/j.jmb.2003.10.010 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 752GP UT WOS:000187153000009 PM 14643659 ER PT J AU Schofield, DJ Purcell, RH Nguyen, HT Emerson, SU AF Schofield, DJ Purcell, RH Nguyen, HT Emerson, SU TI Monoclonal antibodies that neutralize HEV recognize an antigenic site at the carboxyterminus of an ORF2 protein vaccine SO VACCINE LA English DT Article DE Hepatitis E virus; phage display; neutralization site ID HEPATITIS-E VIRUS; RECOMBINANT VACCINE; CAPSID PROTEIN; PHAGE DISPLAY; INSECT CELLS; IDENTIFICATION; LIBRARIES; SEROREACTIVITY; IMMUNIZATION; REPERTOIRE AB In order to obtain monoclonal antibodies that might have prophylactic applications and to understand better the immune response to hepatitis E virus (HEV), we used phage display to isolate chimpanzee antibodies to HEV. The panning antigen was an two open reading frame (ORF2) recombinant protein that elicits a broadly protective immune response in vaccinated monkeys. Two major antigenic sites were identified on the ORF2 protein: one site was not accessible on the surface of infectious virions but the other site was accessible to antibodies and was recognized specifically by antibodies that neutralize the virus. Published by Elsevier Ltd. C1 NIAID, Lab Infect Dis, Hepatitis Viruses & Mol Hepatitis Sect, NIH, Bethesda, MD 20892 USA. RP Emerson, SU (reprint author), NIAID, Lab Infect Dis, Hepatitis Viruses & Mol Hepatitis Sect, NIH, Bethesda, MD 20892 USA. NR 28 TC 35 Z9 37 U1 2 U2 4 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 DEC 12 PY 2003 VL 22 IS 2 BP 257 EP 267 DI 10.1016/j.vaccine.2003.07.008 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 754WL UT WOS:000187355600014 PM 14615154 ER PT J AU Robbins, GK De Gruttola, V Shafer, RW Smeaton, LM Snyder, SW Pettinelli, C Dube, MP Fischl, MA Pollard, RB Delapenha, R Gedeon, L van der Horst, C Murphy, RL Becker, MI D'Aquila, RT Vella, S Merigan, TC Hirsch, MS Nokta, M Johnson, V Morse, G Putnam, B Klebert, M Martinez, A Chiesi, A Tomino, C Deeks, S Testa, M Nevin, T Levin, J French, V Fennell, O Stevens, M Grosso, R Dusak, B Hodder, S Squibb, M Brothers, C Tolson, J Leavitt, R Manion, D Ruiz, N Morrisey, K Quart, B Jennings, C Dascomb, S Cooper, M Murphy, M Blakelock, K Doolan, A AF Robbins, GK De Gruttola, V Shafer, RW Smeaton, LM Snyder, SW Pettinelli, C Dube, MP Fischl, MA Pollard, RB Delapenha, R Gedeon, L van der Horst, C Murphy, RL Becker, MI D'Aquila, RT Vella, S Merigan, TC Hirsch, MS Nokta, M Johnson, V Morse, G Putnam, B Klebert, M Martinez, A Chiesi, A Tomino, C Deeks, S Testa, M Nevin, T Levin, J French, V Fennell, O Stevens, M Grosso, R Dusak, B Hodder, S Squibb, M Brothers, C Tolson, J Leavitt, R Manion, D Ruiz, N Morrisey, K Quart, B Jennings, C Dascomb, S Cooper, M Murphy, M Blakelock, K Doolan, A CA AIDS Clin Trials Group 384 Team TI Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CLINICAL-TRIALS; SUPPRESSION; ZIDOVUDINE; LAMIVUDINE; INDINAVIR AB BACKGROUND: The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. METHODS: This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen. RESULTS: A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. CONCLUSIONS: The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study. C1 Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. Social & Sci Syst, Silver Spring, MD USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Indianapolis, IN USA. Univ Miami, Sch Med, Miami, FL USA. Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. Howard Univ, Washington, DC 20059 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. Northwestern Univ, Chicago, IL 60611 USA. Agouron Pharmaceut, La Jolla, CA USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Ist Super Sanita, I-00161 Rome, Italy. RP Robbins, GK (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, 55 Fruit St, Boston, MA 02114 USA. RI Robbins, Gregory/F-7988-2011; Vella, Stefano/D-4912-2015; OI Vella, Stefano/0000-0003-2347-5984; Murphy, Robert/0000-0003-3936-2052 FU NCRR NIH HHS [M01 RR005096, M01 RR000044, M01 RR000052, M01 RR000070, RR00044, RR00052, RR00070, RR05096]; NIAID NIH HHS [AI38855, AI38858, R01 AI046148, U01 AI038855, U01 AI038858] NR 16 TC 249 Z9 258 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 11 PY 2003 VL 349 IS 24 BP 2293 EP 2303 DI 10.1056/NEJMoa030264 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 752AX UT WOS:000187125000005 PM 14668455 ER PT J AU Shafer, RW Smeaton, LM Robbins, GK De Gruttola, V Snyder, SW D'Aquila, RT Johnson, VA Morse, GD Nokta, MA Martinez, AI Gripshover, BM Kaul, P Haubrich, R Swingle, M McCarty, SD Vella, S Hirsch, MS Merigan, TC Fischl, M Pollard, R Dube, M Pettinelli, C Delapenha, R Putnam, B Klebert, M Testa, M Chiesi, A Tomino, C Deeks, S Nevin, T Levin, J French, V Fennell, O Stevens, M Grosso, R Dusak, B Hodder, S Tolson, J Brothers, C Leavitt, R Manion, D Ruiz, N Morrisey, K Becker, M Quart, B Jennings, C Gedeon, L Dascomb, S Cooper, M Murphy, M Blakelock, K Doolan, A AF Shafer, RW Smeaton, LM Robbins, GK De Gruttola, V Snyder, SW D'Aquila, RT Johnson, VA Morse, GD Nokta, MA Martinez, AI Gripshover, BM Kaul, P Haubrich, R Swingle, M McCarty, SD Vella, S Hirsch, MS Merigan, TC Fischl, M Pollard, R Dube, M Pettinelli, C Delapenha, R Putnam, B Klebert, M Testa, M Chiesi, A Tomino, C Deeks, S Nevin, T Levin, J French, V Fennell, O Stevens, M Grosso, R Dusak, B Hodder, S Tolson, J Brothers, C Leavitt, R Manion, D Ruiz, N Morrisey, K Becker, M Quart, B Jennings, C Gedeon, L Dascomb, S Cooper, M Murphy, M Blakelock, K Doolan, A CA AIDS Clin Trials Grp 384 Team TI Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; VIROLOGICAL FAILURE; REVERSE-TRANSCRIPTASE; CLINICAL-TRIALS; RESISTANCE; NUCLEOSIDE; ZIDOVUDINE; LAMIVUDINE; EFAVIRENZ; INHIBITOR AB BACKGROUND: It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS: In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir. RESULTS: A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21). CONCLUSIONS: There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice. C1 Stanford Univ, Med Ctr, Stanford, CA 94305 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Social & Sci Syst, Silver Spring, MD USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. Univ Alabama, Sch Med, Birmingham, AL USA. SUNY Buffalo, Buffalo, NY 14260 USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Univ Calif San Diego, San Diego, CA 92103 USA. Bristol Myers Squibb Co, Plainsboro, NJ USA. GlaxoSmithKline, Res Triangle Pk, NC USA. Ist Super Sanita, I-00161 Rome, Italy. RP Robbins, GK (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, 55 Fruit St, Boston, MA 02114 USA. RI Robbins, Gregory/F-7988-2011; Vella, Stefano/D-4912-2015 OI Vella, Stefano/0000-0003-2347-5984 FU NCRR NIH HHS [M01 RR000044, M01 RR000052, M01 RR000070, M01 RR005096, RR00044, RR00052, RR00070, RR05096]; NIAID NIH HHS [AI38855, AI38858, R01 AI046148, U01 AI038855, U01 AI038858] NR 20 TC 167 Z9 173 U1 0 U2 6 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 DEC 11 PY 2003 VL 349 IS 24 BP 2304 EP 2315 DI 10.1056/NEJMoa030265 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 752AX UT WOS:000187125000006 PM 14668456 ER PT J AU Kolodgie, FD Gold, HK Burke, AP Fowler, DR Kruth, HS Weber, DK Farb, A Guerrero, LJ Hayase, M Kutys, R Narula, J Finn, AV Virmani, R AF Kolodgie, FD Gold, HK Burke, AP Fowler, DR Kruth, HS Weber, DK Farb, A Guerrero, LJ Hayase, M Kutys, R Narula, J Finn, AV Virmani, R TI Intraplaque hemorrhage and progression of coronary atheroma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RED-BLOOD-CELLS; LOW-DENSITY-LIPOPROTEIN; ATHEROSCLEROTIC LESIONS; PLAQUE MORPHOLOGY; CHOLESTEROL; ERYTHROCYTES; MEMBRANE; RECEPTOR; DISEASE; HYPERCHOLESTEROLEMIA AB BACKGROUND: Intraplaque hemorrhage is common in advanced coronary atherosclerotic lesions. The relation between hemorrhage and the vulnerability of plaque to disruption may involve the accumulation of free cholesterol from erythrocyte membranes. METHODS: We stained multiple coronary lesions from 24 randomly selected patients who had died suddenly of coronary causes with an antibody against glycophorin A (a protein specific to erythrocytes that facilitates anion exchange) and Mallory's stain for iron (hemosiderin), markers of previous intraplaque hemorrhage. Coronary lesions were classified as lesions with pathologic intimal thickening, fibrous-cap atheromas with cores in an early or late stage of necrosis, or thin-cap fibrous atheromas (vulnerable plaques). The arterial response to plaque hemorrhage was further defined in a rabbit model of atherosclerosis. RESULTS: Only traces of glycophorin A and iron were found in lesions with pathologic intimal thickening or fibrous-cap atheromas with cores in an early stage of necrosis. In contrast, fibroatheromas with cores in a late stage of necrosis or thin caps had a marked increase in glycophorin A in regions of cholesterol clefts surrounded by iron deposits. Larger amounts of both glycophorin A and iron were associated with larger necrotic cores and greater macrophage infiltration. Rabbit lesions with induced intramural hemorrhage consistently showed cholesterol crystals with erythrocyte fragments, foam cells, and iron deposits. In contrast, control lesions from the same animals had a marked reduction in macrophages and lipid content. CONCLUSIONS: By contributing to the deposition of free cholesterol, macrophage infiltration, and enlargement of the necrotic core, the accumulation of erythrocyte membranes within an atherosclerotic plaque may represent a potent atherogenic stimulus. These factors may increase the risk of plaque destabilization. C1 Armed Forces Inst Pathol, Dept Cardiovasc Pathol, Washington, DC 20306 USA. Massachusetts Gen Hosp, Dept Internal Med, Cardiac Unit, Boston, MA 02114 USA. Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA. NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. RP Virmani, R (reprint author), Armed Forces Inst Pathol, Dept Cardiovasc Pathol, Bldg 54,Rm 2005,6825 16th St, Washington, DC 20306 USA. FU NHLBI NIH HHS [R01 HL61799-02] NR 40 TC 723 Z9 772 U1 4 U2 24 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 DEC 11 PY 2003 VL 349 IS 24 BP 2316 EP 2325 DI 10.1056/NEJMoa035655 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 752AX UT WOS:000187125000007 PM 14668457 ER PT J AU Becker, KG Hosack, DA Dennis, G Lempicki, RA Bright, TJ Cheadle, C Engel, J AF Becker, KG Hosack, DA Dennis, G Lempicki, RA Bright, TJ Cheadle, C Engel, J TI PubMatrix: a tool for multiplex literature mining SO BMC BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION; PATTERNS AB Background: Molecular experiments using multiplex strategies such as cDNA microarrays or proteomic approaches generate large datasets requiring biological interpretation. Text based data mining tools have recently been developed to query large biological datasets of this type of data. PubMatrix is a web-based tool that allows simple text based mining of the NCBI literature search service PubMed using any two lists of keywords terms, resulting in a frequency matrix of term co-occurrence. Results: For example, a simple term selection procedure allows automatic pair-wise comparisons of approximately 1-100 search terms versus approximately 1-10 modifier terms, resulting in up to 1,000 pair wise comparisons. The matrix table of pair-wise comparisons can then be surveyed, queried individually, and archived. Lists of keywords can include any terms currently capable of being searched in PubMed. In the context of cDNA microarray studies, this may be used for the annotation of gene lists from clusters of genes that are expressed coordinately. An associated PubMatrix public archive provides previous searches using common useful lists of keyword terms. Conclusions: In this way, lists of terms, such as gene names, or functional assignments can be assigned genetic, biological, or clinical relevance in a rapid flexible systematic fashion. http://pubmatrix.grc.nia.nih.gov/. C1 NIH, Gene Express & Genom Unit, Baltimore, MD USA. NIA, NCTS, NIH, Baltimore, MD 21224 USA. SAIC Frederich Inc, Lab Immunopathogenesis & Bioinformat, Frederick, MD USA. RP Becker, KG (reprint author), NIH, Gene Express & Genom Unit, Baltimore, MD USA. EM beckerk@grc.nia.nih.gov; DHosack@niaid.nih.gov; GDennis@niaid.nih.gov; RLempicki@niaid.nih.gov; bright1@umbc.edu; Cheadlec@mail.nih.gov; engelj@grc.nia.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Becker, Kevin/0000-0002-6794-6656 NR 12 TC 101 Z9 105 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 10 PY 2003 VL 4 AR 61 DI 10.1186/1471-2105-4-61 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 765ZR UT WOS:000188321400001 PM 14667255 ER PT J AU Arndt, MAE Krauss, J Schwarzenbacher, R Vu, BK Greene, S Rybak, SM AF Arndt, MAE Krauss, J Schwarzenbacher, R Vu, BK Greene, S Rybak, SM TI Generation of a highly stable, internalizing anti-CD22 single-chain Fv fragment for targeting non-Hodgkin's lymphoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ScFv; antibody stability; LL2; non-Hodgkin's lymphoma; CD22; internalization ID B-CELL LYMPHOMA; MONOCLONAL-ANTIBODY; OVERLAP EXTENSION; VARIABLE DOMAINS; FLOW-CYTOMETRY; LL2; STABILITY; PROTEIN; RADIOIMMUNOTHERAPY; CONSTRUCTION AB The generation of a single chain Fv (scFv) fragment derived from the anti-CD22 monoclonal antibody LL2 resulted in a molecule with good antigen binding but very poor stability properties, thus hampering its clinical applicability. Here we report on the construction of an engineered LL2 scFv fragment by rational mutagenesis. The contribution of uncommon wild-type sequence residues for providing stability to the conserved common core structure of immunoglobulins was examined. Aided by computer homology modeling, 3 destabilizing residues within the core of the wild-type V-H domain were identified. Owing to the conserved nature of the buried core structure, mutagenesis of these sites to respective consensus residues markedly stabilized the molecule but did not influence its antigen binding properties: the engineered scFv MJ-7 exhibited exceptional biophysical stability with a half-life not reached after 6 days of incubation in human serum at 37degreesC, while fully retaining the epitope specificity of the monoclonal antibody, and antigen binding affinity of the wild-type scFv. Furthermore, both the monoclonal antibody LL2 and the engineered scFv fragment became fully internalized after only 30 min of incubation at 37degreesC with CD22(+) tumor cells. These properties predict scFv MJ-7 could become a novel powerful tool to selectively deliver cytotoxic agents to malignant CD22(+) cells. (C) 2003 Wiley-Liss, Inc. C1 NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Burnham Inst, La Jolla, CA 92037 USA. NCI, SAIC Frederick, Frederick, MD 21702 USA. RP Rybak, SM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Bldg 320,Room 9, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 46 TC 17 Z9 17 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 10 PY 2003 VL 107 IS 5 BP 822 EP 829 DI 10.1002/ijc.11451 PG 8 WC Oncology SC Oncology GA 740ZE UT WOS:000186432500020 PM 14566834 ER PT J AU Ding, HM Han, CH Gibson-D'Ambrosio, R Steele, VE D'Ambrosio, SM AF Ding, HM Han, CH Gibson-D'Ambrosio, R Steele, VE D'Ambrosio, SM TI Piroxicam selectively inhibits the growth of premalignant and malignant human oral cell lines by limiting their progression through the S phase and reducing the levels of cyclins and AP-1 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE piroxicam; oral cancer; S phase; cyclins; cyclin-dependent kinase; AP-1 ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CYCLOOXYGENASE-2 EXPRESSION; ADENOCARCINOMA CELLS; SQUAMOUS CARCINOMA; DEPENDENT KINASES; CANCER CELLS; IN-VITRO; PROLIFERATION; APOPTOSIS; HEAD AB Studies have shown that nonsteroidal anti inflammatory drugs (NSAIDs) reduce the risk of and mortality from a variety of cancers. Although cyclooxygenase (COX)-dependent and -independent pathways may be involved, the mechanisms responsible for these effects remain unknown. In our study, we found that piroxicam inhibited cell growth in premalignant and malignant, but not normal, human oral epithelial cell lines in a concentration- and time-dependent manner. After 6 days of exposure, the concentration that inhibited growth by 50% was 181 and 211 muM for premalignant and malignant cells, respectively. Piroxicam did not induce apoptosis. The growth inhibitory effect was COX and PGE(2) independent. Adding PGE(2) or infecting cells with a COX-1 transgene did not abrogate piroxicam-induced growth inhibition. After treatment of the premalignant and malignant cell lines with piroxicam, cells accumulated in the S phase of the cell cycle. Upon removal of piroxicam, cells entered the G(2) phase. The S phase block was accompanied by a reduction in the protein levels of cyclin A, cyclin 131, cyclin D1, cdc2, PCNA and the c-jun AP-1 component. Therefore, piroxicam may exert its growth inhibitory effects selectively on the premalignant and malignant human oral epithelial cells lines via signaling pathways regulating the progression of cells through the S phase of the cell cycle. (C) 2003 Wiley-Liss, Inc. C1 Ohio State Univ, Dept Radiol, Columbus, OH 43210 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Ohio State Univ, Dept Pharmacol, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP D'Ambrosio, SM (reprint author), 400 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [N01-CN-05105]; NIDCR NIH HHS [P01-DE12704] NR 54 TC 22 Z9 22 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 10 PY 2003 VL 107 IS 5 BP 830 EP 836 DI 10.1002/ijc.11499 PG 7 WC Oncology SC Oncology GA 740ZE UT WOS:000186432500021 PM 14566835 ER PT J AU Travis, LB Boice, JD Travis, WD AF Travis, LB Boice, JD Travis, WD TI Second primary cancers after thymoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID NEOPLASMS; THYMECTOMY; MALIGNANCY; INFANCY; RISK C1 NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20852 USA. Int Epidemiol Inst, Rockville, MD USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Armed Forces Inst Pathol, Dept Pulm & Mediatinal Pathol, Washington, DC 20306 USA. RP Travis, LB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, EPS 7086,MS 7238, Rockville, MD 20852 USA. NR 16 TC 9 Z9 9 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 10 PY 2003 VL 107 IS 5 BP 868 EP 870 DI 10.1002/ijc.11480 PG 3 WC Oncology SC Oncology GA 740ZE UT WOS:000186432500027 PM 14566841 ER PT J AU Lieberman, DA Prindiville, S Weiss, DG Willett, W AF Lieberman, DA Prindiville, S Weiss, DG Willett, W CA VA Cooperative Study Grp 380 TI Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID FECAL-OCCULT-BLOOD; MALE HEALTH-PROFESSIONALS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLORECTAL-CANCER; PHYSICAL-ACTIVITY; ASPIRIN USE; LARGE-BOWEL; SCREENING SIGMOIDOSCOPY; SERUM-CHOLESTEROL; CIGARETTE-SMOKING AB Context Knowledge of risk factors for colorectal neoplasia could inform risk reduction strategies for asymptomatic individuals. Few studies have evaluated risk factors for advanced colorectal neoplasia in asymptomatic individuals, compared risk factors between persons with and without polyps, or included most purported risk factors in a multivariate analysis. Objective To determine risk factors associated with advanced colorectal neoplasia in a cohort of asymptomatic persons with complete colonoscopy. Design, Setting, and Participants Prospective, cross-sectional study of 3121 asymptomatic patients aged 50 to 75 years from 13 Veterans Affairs medical centers conducted between February 1994 and January 1997. All participants had complete colonoscopy to determine the prevalence of advanced neoplasia, defined as an adenoma that was 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. Variables examined included history of first-degree relative with colorectal cancer, prior cholecystectomy, serum cholesterol level, physical activity, smoking, alcohol use, and dietary factors. Main Outcome Measures An age-adjusted analysis was performed for each variable to calculate the odds ratios (ORs) and 95% confidence intervals (CIS) associated with having advanced neoplasia compared with having no polyps. We developed a multivariate logistic regression model to identify the most informative risk factors. A secondary analysis examined risk factors for having hyperplastic polyps compared with having no polyps and compared with having advanced neoplasia. Results Three hundred twenty-nine participants had advanced neoplasia and 1441 had no polyps. In multivariate analyses, we found positive associations for history of a first-degree relative with colorectal cancer (OR, 1.66; 95% Cl, 1.16-2.35), current-smoking (OR, 1.85; 95% Cl, 1.33-2.58), and current moderate to heavy alcohol use (OR, 1.02; 95% Cl, 1.01 -1.03). Inverse associations were found for cereal fiber intake (OR, 0.95; 95% Cl, 0.91-0.99), vitamin D intake (OR, 0.94; 95% Cl, 0.90-0.99), and use of nonsteroidal anti-inflammatory drugs (NSAIDs) (OR, 0.66; 95% Cl, 0.48-0.91). In the univariate analysis, the inverse association was found with cereal fiber intake greater than 4.2 g/d, vitamin D intake greater than 645 IU/d, and daily use of NSAIDs. Marginal factors included physical activity, daily multivitamin use, and intake of calcium and fat derived from red meat. No association was found for body mass index, prior cholecystectomy, or serum cholesterol level. Three hundred ninety-one patients had hyperplastic polyps as the worst lesion found at colonoscopy. Risk variables were similar to those for patients with no polyps, except that past and current smoking were associated with an increased risk of hyperplastic polyps. Conclusions Our data endorse several important risk factors for advanced colonic neoplasia and provide a rationale for prudent risk reduction strategies. Further study is needed to determine if lifestyle changes can moderate the risk of colorectal cancer. C1 Dept Vet Affairs Med Ctr, Portland, OR USA. NCI, Bethesda, MD 20892 USA. Dept Vet Affairs Med Ctr, Perry Point, MD USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Lieberman, DA (reprint author), Portland VA Med Ctr, Div Gastroenterol, P3-GI,POB 1034, Portland, OR 97207 USA. FU NCI NIH HHS [K07CA75159] NR 57 TC 258 Z9 264 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 10 PY 2003 VL 290 IS 22 BP 2959 EP 2967 DI 10.1001/jama.290.22.2959 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 751WH UT WOS:000187112700027 PM 14665657 ER PT J AU Volkow, ND Wang, GJ Ma, YM Fowler, JS Zhu, W Maynard, L Telang, F Vaska, P Ding, YS Wong, C Swanson, JM AF Volkow, ND Wang, GJ Ma, YM Fowler, JS Zhu, W Maynard, L Telang, F Vaska, P Ding, YS Wong, C Swanson, JM TI Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers SO JOURNAL OF NEUROSCIENCE LA English DT Article DE imaging; cerebellum; FDG; addiction; context; dopamine; reinforcement; conditioned responses ID POSITRON-EMISSION-TOMOGRAPHY; GLUCOSE-UTILIZATION; BASAL GANGLIA; DOPAMINE CONCENTRATIONS; THREO-METHYLPHENIDATE; CEREBELLAR VERMIS; PRIMATE; REWARD; HUMANS; CORTEX AB The reinforcing effects of drugs of abuse result from the complex interaction between pharmacological effects and conditioned responses. Here we evaluate how expectation affects the response to the stimulant drug methylphenidate in 25 cocaine abusers. The effects of methylphenidate (0.5 mg/kg, i.v.) on brain glucose metabolism ( measured by [F-18] deoxyglucose - positron emission tomography) and on its reinforcing effects (self-reports of drug effects) were evaluated in four conditions: ( 1) expecting placebo and receiving placebo; ( 2) expecting placebo and receiving methylphenidate; ( 3) expecting methylphenidate and receiving methylphenidate; ( 4) expecting methylphenidate and receiving placebo. Methylphenidate increased brain glucose metabolism, and the largest changes were in cerebellum, occipital cortex, and thalamus. The increases in metabolism were similar to 50% larger when methylphenidate was expected than when it was not, and these differences were significant in cerebellum ( vermis) and thalamus. In contrast, unexpected methylphenidate induced greater increases in left lateral orbitofrontal cortex than when it was expected. Methylphenidate-induced increases in self-reports of "high" were also similar to 50% greater when subjects expected to receive it than when they did not and were significantly correlated with the metabolic increases in thalamus but not in cerebellum. These findings provide evidence that expectation amplifies the effects of methylphenidate in brain and its reinforcing effects. They also suggest that the thalamus, a region involved with conditioned responses, may mediate the enhancement of the reinforcing effects of methylphenidate by expectation and that the orbitofrontal cortex mediates the response to unexpected reinforcement. The enhanced cerebellar activation with expectation may reflect conditioned responses that are not linked to conscious responses. C1 Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. SUNY Stony Brook, Dept Appl Math, Stony Brook, NY 11794 USA. Univ Calif Irvine, Child Dev Ctr, Irvine, CA 92612 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5274, Rockville, MD 20853 USA. FU NIDA NIH HHS [DA 7092-01, DA00280] NR 50 TC 178 Z9 180 U1 2 U2 15 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 DEC 10 PY 2003 VL 23 IS 36 BP 11461 EP 11468 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 753LL UT WOS:000187232800021 PM 14673011 ER PT J AU Kasprzak, KS Sunderman, FW Salnikow, K AF Kasprzak, Kazimierz S. Sunderman, F. William, Jr. Salnikow, Konstantin TI Nickel carcinogenesis SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE Nickel carcinogenesis; Epigenetic toxicity; Genotoxicity; Histones; Hypoxia; Oxidative damage AB Human exposure to highly nickel-polluted environments, such as those associated with nickel refining, electroplating, and welding, has the potential to produce a variety of pathologic effects. Among them are skin allergies, lung fibrosis, and cancer of the respiratory tract. The exact mechanisms of nickel-induced carcinogenesis are not known and have been the subject of numerous epidemiologic and experimental investigations. These mechanisms are likely to involve genetic and epigenetic routes. The present review provides evidence for the genotoxic and mutagenic activity of Ni(II) particularly at high doses. Such doses are best delivered into the cells by phagocytosis of sparingly soluble nickel-containing dust particles. Ni(II) genotoxicity may be aggravated through the generation of DNA-damaging reactive oxygen species (ROS) and the inhibition of DNA repair by this metal. Broad spectrum of epigenetic effects of nickel includes alteration in gene expression resulting from DNA hypermethylation and histone hypoacetylation, as well as activation or silencing of certain genes and transcription factors, especially those involved in cellular response to hypoxia. The investigations of the pathogenic effects of nickel greatly benefit from the understanding of the chemical basis of Ni(II) interactions with intracellular targets/ligands and oxidants. Many pathogenic effects of nickel are due to the interference with the metabolism of essential metals such as Fe(II), Mn(II), Ca(II), Zn(II), or Mg(II). Research in this field allows for identification of putative Ni(II) targets relevant to carcinogenesis and prediction of pathogenic effects caused by exposure to nickel. Ultimately, the investigations of nickel carcinogenesis should be aimed at the development of treatments that would inhibit or prevent Ni(II) interactions with critical target molecules and ions, Fe(II) in particular, and thus avert the respiratory tract cancer and other adverse health effects in nickel workers. (C) 2003 Elsevier B.V. All rights reserved. C1 [Kasprzak, Kazimierz S.; Salnikow, Konstantin] NCI, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. [Sunderman, F. William, Jr.] Univ Vermont, Dept Pathol, Coll Med, Burlington, VT 05401 USA. RP Kasprzak, KS (reprint author), NCI, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. EM kasprkaz@mail.ncifcrf.gov NR 313 TC 339 Z9 369 U1 6 U2 60 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD DEC 10 PY 2003 VL 533 IS 1-2 SI SI BP 67 EP 97 DI 10.1016/j.mrfmmm.2003.08.021 PG 31 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA V18WB UT WOS:000208033800004 PM 14643413 ER PT J AU Waalkes, MP AF Waalkes, Michael P. TI Cadmium carcinogenesis SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE Cadmium; Carcinogenesis; Humans; Rodents; Mechanisms AB Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis. (C) 2003 Elsevier B.V. All rights reserved. C1 Natl Inst Environm Hlth Sci, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27706 USA. RP Waalkes, MP (reprint author), Natl Inst Environm Hlth Sci, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, 111 Alexander Dr,POB 12233,Mail Drop F0-09, Res Triangle Pk, NC 27706 USA. EM waalkes@niehs.nih.gov NR 77 TC 457 Z9 499 U1 10 U2 73 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD DEC 10 PY 2003 VL 533 IS 1-2 SI SI BP 107 EP 120 DI 10.1016/j.mrfmmm.2003.07.011 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA V18WB UT WOS:000208033800006 PM 14643415 ER PT J AU Dimitrov, AS Rawat, SS Jiang, S Blumenthal, R AF Dimitrov, AS Rawat, SS Jiang, S Blumenthal, R TI Role of the fusion peptide and membrane-proximal dornain in HIV-I envelope glycoprotein-mediated membrane fusion SO BIOCHEMISTRY LA English DT Article ID CELL-CELL FUSION; VIRUS TYPE-1 GP41; INFLUENZA HEMAGGLUTININ; ATOMIC-STRUCTURE; VIRAL MEMBRANE; CO-RECEPTORS; ENTRY; CD4; ECTODOMAIN; DOMAIN AB The N-terminal fusion peptide and the interfacial sequence preceding the transmembrane anchor of HIV-1 gp41 are required for viral fusion. Studies with synthetic peptides indicated that these regions function by destabilizing membranes, which is regarded as a crucial step in the membrane fusion reaction. However, it is not clear whether membrane destabilization is induced by these sequences in the intact gp41. We address this question by examining fusion and destabilization of membranes expressing HIV-1(IIIB) wild-type Env and two mutant Envs. (1) A Glu residue at position 2 of the gp41 fusion peptide is substituted for Va1 (V2E) to produce one Mutant. (2) Residues 665-682 in the membrane-proximal domain are deleted to form the other. The process of membrane destabilization was monitored by the influx of Sytox, an impermeant fluorescent dye, into the Env-expressing cells following the interaction with CD4-CXCR4 complexes, and fusion was monitored by observing dye transfer between Env-expressing cells and appropriate target cells. We also monitored the conformational changes in the Envs following their interactions with CD4 and CXCR4 by immunofluorescence using an anti-gp41 mAb that reacts with the six-helix bundle. In contrast to the wild type, both Env mutants did not mediate cell fusion. The V2E Env did not mediate membrane destabilization. However, the Env with an unmodified fusion peptide but with a deletion of residues 665-682 in the membrane-proximal domain did mediate membrane destabilization. The wild type and both mutant Envs undergo conformational changes detected by the anti-gp41 six-helix bundle mAbs. Our results Suggest that in intact HIV-1 Env the membrane-proximal domain is not required for membrane perturbations, but rather enables the bending of gp41 that is required for viral and target membranes to come together. Moreover, the observation that the Delta665-683 Env self-inserts its fusion peptide but does not cause fusion suggests that self-insertion of the fusion peptide is not Sufficient for HIV-1 Env-mediated fusion. C1 Natl Canc Inst, Canc Res Ctr, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. New York Blood Ctr, Lab Viral Immunol, Lindsley F Kimball Res Inst, New York, NY 10021 USA. RP Blumenthal, R (reprint author), Natl Canc Inst, Canc Res Ctr, Lab Expt & Computat Biol, NIH, POB B,Bldg 469,Rm 216A,Miller Dr, Frederick, MD 21702 USA. RI Jiang, Shibo/L-4500-2014 NR 52 TC 46 Z9 48 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 DEC 9 PY 2003 VL 42 IS 48 BP 14150 EP 14158 DI 10.1021/bi035154g PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 750JC UT WOS:000186986700008 PM 14640682 ER PT J AU Dick, AJ Guttman, MA Raman, VK Peters, DC Pessanha, BSS Hill, JM Smith, S Scott, G McVeigh, ER Lederman, RJ AF Dick, AJ Guttman, MA Raman, VK Peters, DC Pessanha, BSS Hill, JM Smith, S Scott, G McVeigh, ER Lederman, RJ TI Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in swine SO CIRCULATION LA English DT Article DE magnetic resonance imaging; cells; drugs; myocardial infarction; catheterization ID INTERVENTIONAL MRI; INJECTION; CATHETERS; PLACEMENT; GUIDANCE; CLOSURE; MODEL; WIRES AB Background-The local environment of delivered mesenchymal stem cells (MSCs) may affect their ultimate phenotype. MR fluoroscopy has the potential to guide intramyocardial MSC injection to desirable targets, such as the border between infarcted and normal tissue. We tested the ability to (1) identify infarcts, (2) navigate injection catheters to preselected targets, (3) inject safely even into fresh infarcts, and (4) confirm injection success immediately. Methods and Results-A 1.5-T MRI scanner was customized for interventional use, with rapid imaging, independent color highlighting of catheter channels, multiple-slice 3D rendering, catheter-only viewing mode, and infarct-enhanced imaging. MRI receiver coils were incorporated into guiding catheters and injection needles. These devices were tested for heating and used for targeted MSC delivery. In infarcted pigs, myocardium was targeted by MR fluoroscopy. Infarct-enhanced imaging included both saturation preparation MRI after intravenous gadolinium and wall motion. Porcine MSCs were MRI-labeled with iron-fluorescent particles. Catheter navigation and multiple cell injections were performed entirely with MR fluoroscopy at 8 frames/s with 1.7X3.3X8-mm voxels. Infarct-enhanced MR fluoroscopy permitted excellent delineation of infarct borders. All injections were safely and successfully delivered to their preselected targets, including infarct borders. Iron-fluorescent particle-labeled MSCs were readily visible on delivery in vivo and post mortem. Conclusions-Precise targeted delivery of potentially regenerative cellular treatments to recent myocardial infarction borders is feasible with an MR catheter delivery system. MR fluoroscopy permits visualization of catheter navigation, myocardial function, infarct borders, and labeled cells after injection. C1 NHLBI, Cardiovasc Branch, Clin Res Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Boston Sci Corp, Plymouth, MN USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc Branch, Clin Res Program, Div Intramural Res,NIH, Bldg 10,Room 2C713, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL004608-08] NR 24 TC 134 Z9 148 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 9 PY 2003 VL 108 IS 23 BP 2899 EP 2904 DI 10.1161/01.CIR.0000095790.28368.F9 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 751MD UT WOS:000187070100026 PM 14656911 ER PT J AU Breitner, JCS Costa, PT AF Breitner, JCS Costa, PT TI "At my wits' end" - Neuroticism and dementia SO NEUROLOGY LA English DT Editorial Material ID DISEASE; BRAIN C1 Univ Washington, Ctr Geriatr Res Educ & Clin, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Univ Washington, Div Geriatr Psychiat, Seattle, WA 98195 USA. NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Breitner, JCS (reprint author), Univ Washington, Ctr Geriatr Res Educ & Clin, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. OI Costa, Paul/0000-0003-4375-1712 FU NIA NIH HHS [AG-11380, AG-15477] NR 11 TC 2 Z9 2 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 DEC 9 PY 2003 VL 61 IS 11 BP 1468 EP 1469 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 751MG UT WOS:000187070400002 PM 14663023 ER PT J AU Boroojerdi, B Cohen, LG Hallett, M AF Boroojerdi, B Cohen, LG Hallett, M TI Effects of botulinum toxin on motor system excitability in patients with writer's cramp SO NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; CORTICAL INHIBITION; HUMAN-BRAIN; DYSTONIA; MUSCLES; RESPONSES; CORTEX AB Objective: To investigate botulinum toxin ( BTX) effects on central and peripheral motor excitability in writer's cramp. Methods: Using transcranial magnetic stimulation over the motor cortex and brainstem and peripheral electrical stimulation, the authors investigated measures of motor cortical and peripheral motor excitability on the affected and unaffected side before and 2 to 4 weeks after BTX A injection into the affected muscles in six patients with writer's cramp. The following motor excitability measures were studied: resting and active motor threshold, cortical silent period, intracortical inhibition and facilitation using the double- pulse technique, recruitment curves, motor evoked potentials following magnetic brainstem stimulation, and maximum M- response amplitude following supramaximal peripheral nerve stimulation. Results: BTX injection improved function and reduced the M response. No other measures of motor system excitability showed significant changes following BTX injection, and there was no difference in these measures between sides. Conclusions: BTX A effects on motor system excitability seem to be based mainly on its peripheral mechanisms of action. There was no difference in the motor system excitability between the clinically affected and unaffected sides in this group of patients. C1 Univ Klinikum, Neurol Klin, D-52074 Aachen, Germany. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Boroojerdi, B (reprint author), Univ Klinikum, Neurol Klin, Pauwelsstr 30, D-52074 Aachen, Germany. NR 24 TC 24 Z9 24 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 DEC 9 PY 2003 VL 61 IS 11 BP 1546 EP 1550 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 751MG UT WOS:000187070400019 PM 14663040 ER PT J AU Vortmeyer, AO Weil, RJ Zhuang, ZP AF Vortmeyer, AO Weil, RJ Zhuang, ZP TI Proteomic applications for differential diagnosis of histologically identical tumors SO NEUROLOGY LA English DT Editorial Material ID HIPPEL-LINDAU-DISEASE; RENAL-CELL CARCINOMA; CEREBELLAR HEMANGIOBLASTOMA; METASTASIS C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Weil, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Rm 5D37, Bethesda, MD 20892 USA. EM weilr@ninds.nih.gov NR 7 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 9 PY 2003 VL 61 IS 11 BP 1626 EP 1627 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 751MG UT WOS:000187070400041 PM 14663062 ER PT J AU Wang, H Yang, Y Schofield, MJ Du, CW Fridman, Y Lee, SD Larson, ED Drummond, JT Alani, E Hsieh, P Erie, DA AF Wang, H Yang, Y Schofield, MJ Du, CW Fridman, Y Lee, SD Larson, ED Drummond, JT Alani, E Hsieh, P Erie, DA TI DNA bending and unbending by MutS govern mismatch recognition and specificity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ATOMIC-FORCE MICROSCOPY; REPAIR PROTEIN MUTS; SACCHAROMYCES-CEREVISIAE; TRANSLOCATION MECHANISM; NONSPECIFIC COMPLEXES; REPLICATION FIDELITY; BASE COMPOSITION; ATP HYDROLYSIS; HETERODUPLEX; VISUALIZATION AB DNA mismatch repair is central to the maintenance of genomic stability. It is initiated by the recognition of base-base mismatches and insertion/deletion loops by the family of MutS proteins. Subsequently, ATP induces a unique conformational change in the MutS-mismatch complex but not in the MutS-homoduplex complex that sets off the cascade of events that leads to repair. To gain insight into the mechanism by which MutS discriminates between mismatch and homoduplex DNA, we have examined the conformations of specific and nonspecific MutS-DNA complexes by using atomic force microscopy. Interestingly, MutS-DNA complexes exhibit a single population of conformations, in which the DNA is bent at homoduplex sites, but two populations of conformations, bent and unbent, at mismatch sites. These results suggest that the specific recognition complex is one in which the DNA is unbent. Combining our results with existing biochemical and crystallographic data leads us to propose that MutS: (i) binds to DNA nonspecifically and bends it in search of a mismatch; (ii) on specific recognition of a mismatch, undergoes a conformational change to an initial recognition complex in which the DNA is kinked, with interactions similar to those in the published crystal structures; and (iii) finally undergoes a further conformational change to the ultimate recognition complex in which the DNA is unbent. Our results provide a structural explanation for the long-standing question of how MutS achieves mismatch repair specificity. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Univ N Carolina, Curriculum Appl & Mat Sci, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. RP Erie, DA (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RI Wang, Hong/F-3164-2014 OI Wang, Hong/0000-0003-0165-3559 FU NIGMS NIH HHS [R01 GM053085] NR 51 TC 117 Z9 117 U1 2 U2 16 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 DEC 9 PY 2003 VL 100 IS 25 BP 14822 EP 14827 DI 10.1073/pnas.2433654100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200041 PM 14634210 ER PT J AU Bliskovsky, V Ramsay, ES Scott, J DuBois, W Shi, W Zhang, SL Qian, XL Lowy, DR Mock, BA AF Bliskovsky, V Ramsay, ES Scott, J DuBois, W Shi, W Zhang, SL Qian, XL Lowy, DR Mock, BA TI Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID P70 S6 KINASE; SERINE PHOSPHORYLATION; SIGNALING PATHWAY; MAMMALIAN PROTEIN; BINDING LECTIN; CELL-GROWTH; IN-VIVO; TARGET; MTOR; TRANSLATION AB Susceptibility to mouse plasmacytomagenesis is a complex genetic trait controlled by several Pctr loci (Pctr1, Pctr2, etc). Congenic strain analysis narrowed the genetic interval surrounding the Pctr2 locus, and genes identified in the interval were sequenced from susceptible BALB/c and resistant DBA/2 mice. Frap (FKBP12 rapamycin-associated protein, mTOR, RAFT) was the only gene differing in amino acid sequence between alleles that correlated with strain sensitivity to tumor development. The in vitro kinase activity of the BALB/c FRAP allele was lower than the DBA/2 allele; phosphorylation of p53 and PHAS1/4EBP1 (properties of heat and acid stability/eukaryotic initiation factor 4E-binding protein) and autophosphorylation of FRAP were less efficient with the BALB/c allele. FRAP also suppressed transformation of NIH 3T3 cells by ras, with DBA/2 FRAP being more efficient than BALB/c FRAP. Rapamycin, a specific inhibitor of FRAP, did not inhibit growth of plasmacytoma cell lines. These studies identify Frap as a candidate tumor suppressor gene, in contrast to many reports that hide focus cl on its prooncogenic properties. Frap may be similar to Tgfb and EN in exerting both positive and negative growth-regulatory signals, depending on the timing, pathway, or tumor system involved. The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors. Pctr2 joins Pctr1 in possessing alleles that modify susceptibility to plasmacytomagenesis by encoding differences in efficiency. of function (efficiency alleles), rather than all-or-none, gain-of-function, or loss-of-function alleles. By analogy, human cancer may also result from the combined effects of several inefficient alleles. C1 NCI, Genet Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mock, BA (reprint author), NCI, Genet Lab, Canc Res Ctr, NIH, Bldg 37,Room 3146A, Bethesda, MD 20892 USA. NR 57 TC 19 Z9 19 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 DEC 9 PY 2003 VL 100 IS 25 BP 14982 EP 14987 DI 10.1073/pnas.2431627100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200069 PM 14634209 ER PT J AU Storici, F Durham, CL Gordenin, DA Resnick, MA AF Storici, F Durham, CL Gordenin, DA Resnick, MA TI Chromosomal site-specific double-strand breaks are efficiently targeted for repair by oligonucleotides in yeast SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; GENE DISRUPTION; MITOTIC RECOMBINATION; ADENOASSOCIATED VIRUS; DNA-REPLICATION; CELLS; ENDONUCLEASE; ENDS; TRANSFORMATION AB The repair of chromosomal double-strand breaks (DSBs) can be accomplished through homologous recombination in most organisms. We report here that exogenous oligonucleotides can efficiently target for repair a single DSB induced in a chromosome of yeast. The efficiency of recombinational targeting leading to a desired DNA change can be as high as 20% of cells. The DSB was generated either by a regulatable I-Scel endonuclease just before transformation or appeared spontaneously at the site of a long inverted repeat composed of human AN sequences. The approach used features of our previously described delitto perfetto system for selecting transformants with integrative recombinant oligonucleotides. The DSB repair mediated by pairs of complementary integrative recombinant oligonucleotides was efficient for targeting to homologous sequences that were close to or distant from the DSB and in the presence of a competing homologous chromosome in diploid cells. We also demonstrate that a DSB can strongly stimulate recombination with single-stranded DNA, without strand bias. These findings expand current models of DSB repair. In addition, we establish a high-throughput system for rapid genome-wide modification with oligonucleotides. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. OI Gordenin, Dmitry/0000-0002-8399-1836 NR 40 TC 99 Z9 99 U1 2 U2 16 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 DEC 9 PY 2003 VL 100 IS 25 BP 14994 EP 14999 DI 10.1073/pnas.2036296100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200071 PM 14630945 ER PT J AU Mavilio, D Benjamin, J Daucher, M Lombardo, G Kottilil, S Planta, MA Marcenaro, E Bottino, C Moretta, L Moretta, A Fauci, AS AF Mavilio, D Benjamin, J Daucher, M Lombardo, G Kottilil, S Planta, MA Marcenaro, E Bottino, C Moretta, L Moretta, A Fauci, AS TI Natural killer cells in HIV-1 infection: Dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; IMMUNODEFICIENCY-VIRUS; NK-CELLS; VIRAL LOAD; CHEMOKINES; EXPRESSION; INDIVIDUALS; PATHOGENESIS; IMMUNITY AB Natural killer (NK) cells play a central role in host defense against various pathogens. Functional defects of NK cells in HIV-1 infection as a direct effect of abnormal expression or function of inhibitory NK receptors (iNKRs), activating natural cytotoxicity receptors (NCRs), and NKG2D have not yet been described. This study demonstrates an expansion of the functionally defective CD56(-)/CD16(+) population of NK cells in viremic versus aviremic patients. We also demonstrate that in HIV-infected viremic patients, expression of iNKRs was well conserved and that in most cases, there was a trend toward increased expression on NK cells as compared with healthy donors. It was also demonstrated that the major activating NK receptors, with the exception of NKG2D, were significantly down-regulated. In contrast, the expression of iNKRs and activating receptors in HIV-infected individuals whose viremia was suppressed to below detectable levels by highly active antiretroviral therapy for 2 years or longer was comparable to that of healthy donors. Functional tests confirmed that the abnormal expression of the activating receptors and of iNKRs was associated with a markedly impaired NK cytolytic function. This phenomenon is not attributed to a direct HIV-1 infection of INK cells; thus, this study may provide insight into the mechanisms of impaired host defenses in HIV-1 viremic patients. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20814 USA. Univ Genoa, Dipartimento Med Sperimentale, I-16132 Genoa, Italy. Ist Giannina Gaslini, I-16147 Genoa, Italy. Ctr Eccellenza Ric Biomed, I-16132 Genoa, Italy. RP Mavilio, D (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Room 6A08A,MSC 1576, Bethesda, MD 20814 USA. OI Mavilio, Domenico/0000-0001-6147-0952 NR 33 TC 212 Z9 220 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 9 PY 2003 VL 100 IS 25 BP 15011 EP 15016 DI 10.1073/pnas.2336091100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200074 PM 14645713 ER PT J AU Chen, Y Ruetzler, C Pandipati, S Spatz, M McCarron, RM Becker, K Hallenbeck, JM AF Chen, Y Ruetzler, C Pandipati, S Spatz, M McCarron, RM Becker, K Hallenbeck, JM TI Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; ORAL TOLERANCE; ARTERY OCCLUSION; AUTOIMMUNE ENCEPHALOMYELITIS; T-CELLS; STROKE; RATS; INFLAMMATION; RESPONSES; SUPPRESSION AB We have demonstrated that induction of mucosal tolerance to E-selectin, a cytokine-inducible adhesion molecule restricted to activating blood vessels, prevents ischemic and hemorrhagic stroke in spontaneously hypertensive, genetically stroke-prone (SHR-SP) rats. We now examine whether mucosal tolerance to E-selectin has protective effects in ischemic brain damage after permanent middle cerebral artery occlusion (MCAO) in SHR-SP rats and whether these effects are related to generation of regulatory T cells. Rats were exposed to intranasal administration of E-selectin every other day for 10 days (single tolerization group) or on two tolerization schedules separated by 11 days (booster tolerization group). Control groups received PBS on corresponding schedules. MCAO was performed 48 h after the last dose of E-selectin or PBS. There were 45.8% and 37.9% (P < 0.05) decreases of infarction volume in the E-selectin booster group compared with the PBS group at 6 and 48 h, respectively. Single tolerization with E-selectin had only a slight trend toward a decrease in infarction volume (6.3%). CD8-positive cells were decreased in brains of E-selectin booster animals (46.6%, P < 0.01) compared with controls; splenocyte-culture supernatant levels of IL-10 were increased (59.3%, P < 0.05) in E-selectin booster animals. A decrease of infarction volume (34%, P < 0.05) was also observed in SHR-SP rats subjected to MCAO after adoptive transfer of splenocytes from E-selectin-tolerized compared with PBS-tolerized donors. The results indicate that, in addition to preventing stroke, mucosal tolerance to E-selectin is cytoprotective. Thus, immunomodulation targeted to activated blood vessel segments can both reduce stroke occurrence and attenuate brain damage if a stroke supervenes. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. USN, Med Res Ctr, Resuscitat Med Dept, Silver Spring, MD 20910 USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. NR 47 TC 66 Z9 72 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 DEC 9 PY 2003 VL 100 IS 25 BP 15107 EP 15112 DI 10.1073/pnas.2436538100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200090 PM 14645708 ER PT J AU Nishimura, Y Igarashi, T Haigwood, NL Sadjadpour, R Donau, OK Buckler, C Plishka, RJ Buckler-White, A Martin, MA AF Nishimura, Y Igarashi, T Haigwood, NL Sadjadpour, R Donau, OK Buckler, C Plishka, RJ Buckler-White, A Martin, MA TI Transfer of neutralizing IgG to macaques 6 h but not 24 h after SHIV infection confers sterilizing protection: Implications for HIV-1 vaccine development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MEMORY B-CELLS; ENVELOPE GLYCOPROTEIN TRIMERS; T-LYMPHOCYTE RESPONSE; LIVED PLASMA-CELLS; PBL-SCID MICE; RHESUS-MONKEYS; IMMUNOLOGICAL MEMORY; TYPE-1 INFECTION; ANTIBODY-RESPONSES AB Passive transfer of high-titered antiviral neutralizing IgG, known to confer sterilizing immunity in pig-tailed monkeys, has been used to determine how soon after virus exposure neutralizing antibodies (NAbs) must be present to block a simian immunodeficiency virus (SIV)/HIV chimeric virus infection. Sterilizing protection was achieved in three of four macaques receiving neutralizing IgG 6 h after intravenous SIV/HIV chimeric virus inoculation as monitored by PCR analyses of and attempted virus isolations from plasma, peripheral blood mononuclear, cell, and lymph node specimens. In the fourth animal, the production of progeny virus was suppressed for >4 weeks. A delay in transferring NAbs until 24 h after virus challenge resulted in infection in two of two monkeys. These results suggest that even if a vaccine capable of eliciting broadly reactive NAbs against primary HIV-1 were at hand, the Abs generated must remain at, or rapidly achieve, high levels within a relatively short period after exposure to virus to prevent the establishment of a primate lentivirus infection. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. Seattle Biomed Res Inst, Viral Vaccines Program, Seattle, WA 98109 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 315, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI27577] NR 59 TC 92 Z9 97 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 DEC 9 PY 2003 VL 100 IS 25 BP 15131 EP 15136 DI 10.1073/pnas.2436476100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200094 PM 14627745 ER PT J AU Varthakavi, V Smith, RM Bour, SP Strebel, K Spearman, P AF Varthakavi, V Smith, RM Bour, SP Strebel, K Spearman, P TI Viral protein U counteracts a human host cell restriction that inhibits HIV-1 particle production SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VPU PROTEIN; HIGH-TITER; DIVERGENT RETROVIRUSES; ENVELOPE GLYCOPROTEIN; HELPER-FREE; RELEASE; CCR5; GENE; DEGRADATION AB Human cells resist viral infections by a variety of mechanisms. Viruses must overcome host cell restrictions to successfully reproduce their genetic material. Here, we identify a host restriction to viral replication that acts at the stage of particle assembly. Viral protein U (Vpu) is an HIV-1 accessory protein that enhances particle assembly and release in most human cells, but not in simian cells. By using human-simian cell heterokaryons, we show that the inhibition of assembly in human cells is dominant. Vpu overcomes the block to assembly in human cells and in human-simian heterokaryons. The HIV-1 vpu gene may have evolved to counteract an assembly restriction that is present in human cells. C1 Vanderbilt Univ, Pediat ID, Dept Pediat, Sch Med, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Spearman, P (reprint author), Vanderbilt Univ, Pediat ID, Dept Pediat, Sch Med, D-7235 MCN, Nashville, TN 37232 USA. FU NIAID NIH HHS [AI52007, R01 AI058828, AI47985, R01 AI040338, R01 AI052007, R01 AI40338, T32 AI007474, T32 AI07474, U01 AI047985] NR 31 TC 129 Z9 138 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 DEC 9 PY 2003 VL 100 IS 25 BP 15154 EP 15159 DI 10.1073/pnas.2433165100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200098 PM 14657387 ER PT J AU Knight, DC Nguyen, HT Bandettini, PA AF Knight, DC Nguyen, HT Bandettini, PA TI Expression of conditional fear with and without awareness SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SKIN-CONDUCTANCE RESPONSES; COGNITIVE NEUROSCIENCE; FUNCTIONAL MRI; BRAIN SYSTEMS; STIMULI; PERCEPTION; MEMORY; DISSOCIATION; HIPPOCAMPUS; ACQUISITION AB Conditional responding during simple Pavlovian conditioning is often characterized as a form of implicit memory. The extent to which this type of associative learning is independent of awareness is an issue of continuing debate. Previous studies have demonstrated conditioning in the absence of awareness. However, their results have been questioned based on methodological concerns with postexperimental questionnaires. In the present study, skin conductance response (SCR) and unconditioned stimulus (UCS) expectancy were measured concurrently as participants were exposed to a differential delay fear conditioning procedure in which one tone (CS+) predicted a loud white noise, whereas a second tone (CS-) was presented alone. UCS predictability was varied on a trial-by-trial basis by presenting conditioned stimuli (CSs) at volumes just above or below the perceptual threshold. Differential UCS expectancy (awareness) was observed only on perceived trials, whereas differential SCR developed on both perceived and unperceived trials. Although perceived stimuli elicited larger SCRs, the magnitude of conditioning, indexed by differential conditioned response expression (conditioned SCR to CS+ minus the SCR to CS-), was not influenced by stimulus perception. These data indicate that conditional fear can be expressed when individuals are unaware of fear-eliciting stimuli and suggest that the degree of conditioning is independent of awareness during differential Pavlovian fear conditioning. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Knight, DC (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NR 40 TC 62 Z9 63 U1 2 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 9 PY 2003 VL 100 IS 25 BP 15280 EP 15283 DI 10.1073/pnas.2535780100 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 753JA UT WOS:000187227200120 PM 14657356 ER PT J AU Aparicio, IM Garcia-Marin, LJ Andreolotti, AG Bodega, G Jensen, RT Bragado, MJ AF Aparicio, IM Garcia-Marin, LJ Andreolotti, AG Bodega, G Jensen, RT Bragado, MJ TI Hepatocyte growth factor activates several transduction pathways in rat pancreatic acini SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE pancreatic acini; hepatocyte growth factor; PI3-kinase; ERK1/2; PTP1D; amylase secretion ID FACTOR SCATTER FACTOR; TYROSINE KINASE RECEPTOR; C-DEPENDENT MECHANISM; GTP-BINDING PROTEIN; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOLIPASE C-GAMMA-1; MET PROTOONCOGENE; MET/HGF RECEPTOR; CELLS; EXPRESSION AB The receptor of hepatocyte growth factor (HGF), c-met induces different physiological responses in several cell types. Little is known about the role of HGF in exocrine pancreas. However, abnormal HGF signaling has been strongly implicated in pancreatic tumorigenesis and association of HGF with pancreatitis has been demonstrated. We have studied the presence of c-met and activation of their intracellular pathways associated in rat pancreatic acini in comparison with cholecystokinin (CCK) and epidermal growth factor (EGF). C-met expression in rat exocrine pancreas was identified by immunohistochemistry and immunoprecipitation followed by Western analysis. Tyrosine phosphorylation of c-met is strongly stimulated as well as kinase pathways leading to ERK1/2 cascade. HGF, but not CCK or EGF, selectively caused a consistent increase in the amount of p85 regulatory subunit of P13-K present in anti-phosphotyrosine immunoprecipitates. Downstream of P13-K, HGF increased Ser473 phosphorylation of Akt selectively, as CCK or EGF did not affect it. HGF selectively stimulated tyrosine phosphorylation of phosphatase PTP1D. HGF failed to promote the well-known CCK effects in pancreatic acini such as amylase secretion and intracellular calcium mobilization. Although HGF shares activation of ERK1/2 with CCK, we demonstrate that it promotes the selective activation of intracellular pathways not regulated by CCK or EGF. Our results suggest that HGF is an in vivo stimulus of pancreatic acini and provide novel insight into the transduction pathways and effects of c-met/HGF in normal pancreatic acinar cells. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Extremadura, Fac Vet, Dept Fisiol, Caceres 10071, Spain. Univ Alcala de Henares, Dept Biol Celular & Genet, Madrid, Spain. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Extremadura, Dept Bioquim Biol Mol & Genet, Caceres 10071, Spain. RP Garcia-Marin, LJ (reprint author), Univ Extremadura, Fac Vet, Dept Fisiol, Avda Univ S-N, Caceres 10071, Spain. RI Garcia-Marin, Luis /L-4680-2014; Aparicio, Ines Maria/L-5775-2014; Bragado, Maria/L-6988-2014 OI Garcia-Marin, Luis /0000-0002-1795-7381; Bragado, Maria/0000-0001-7770-0775 NR 33 TC 17 Z9 18 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD DEC 7 PY 2003 VL 1643 IS 1-3 BP 37 EP 46 DI 10.1016/j.bbamcr.2003.08.007 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 754ZF UT WOS:000187362800005 PM 14654226 ER PT J AU Ho, NC AF Ho, NC TI Adults with congenital heart disease SO LANCET LA English DT Letter C1 NICHHD, NIH, Bethesda, MD 20814 USA. Johns Hopkins Med Inst, Bethesda, MD 20814 USA. RP Ho, NC (reprint author), NICHHD, NIH, Bethesda, MD 20814 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD DEC 6 PY 2003 VL 362 IS 9399 BP 1942 EP 1942 DI 10.1016/S0140-6736(03)14987-2 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 750RN UT WOS:000187011600046 PM 14667772 ER PT J AU Stadtman, ER AF Stadtman, ER TI Enzymology is basic to an understanding of intermediary metabolism SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Editorial Material ID PROTEINS C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2140,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 5 PY 2003 VL 312 IS 1 BP 41 EP 43 DI 10.1016/j.bbrc.2003.09.178 PG 3 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 749KR UT WOS:000186919500006 PM 14630014 ER PT J AU Samanta, TB Das, N Das, M Marik, R AF Samanta, TB Das, N Das, M Marik, R TI Mechanism of impairment of cytochrome P450-dependent metabolism in hamster liver during leishmaniasis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE leishmaniasis; cytochrome P450 impairment; nitric oxide; mediator ID P450 SUPERFAMILY; ENZYMES; NOMENCLATURE; MICROSOMES; INFECTION; GENES AB The mechanism of impairment of cytochrome P450 (P450)-dependent metabolism in hamster liver during leishmaniasis is reported. A significant decrease in the level of P450 was observed on the 20th day of infection when the parasite load in the liver was maximum. The decrease in P450 level was accompanied by a significant increase in the level of marker enzymes of liver and degeneration of liver tissue. The impairment was isozyme-specific and concomitant with the induction of nitric oxide synthase. The results of in vitro experiments with generated nitric oxide and with scavengers demonstrated that the impairment is mediated by NO. Treatment of the infected animals with a combination therapy showed reduction in parasite load, reversal of P450 impairment, and recovery of liver enzymes and tissue close to normal. (C) 2003 Elsevier Inc. All rights reserved. C1 Bose Inst, Dept Microbiol, Kolkata 700054, India. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Samanta, TB (reprint author), Bose Inst, Dept Microbiol, Kolkata 700054, India. NR 21 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 5 PY 2003 VL 312 IS 1 BP 75 EP 79 DI 10.1016/j.bbrc.2003.09.227 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 749KR UT WOS:000186919500013 PM 14630021 ER PT J AU Stadtman, TC AF Stadtman, TC TI Gunny's enthusiastic role as faculty advisor for fledgling microbiologists at Cornell SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Editorial Material ID FORMATE DEHYDROGENASE; SELENOCYSTEINE; SELENIUM C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2120,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 5 PY 2003 VL 312 IS 1 BP 161 EP 162 DI 10.1016/j.bbrc.2003.10.082 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 749KR UT WOS:000186919500027 ER PT J AU Tsibris, JCM Maas, S Segars, JH Nicosia, SV Enkemann, SA O'Brien, WF Spellacy, WN AF Tsibris, JCM Maas, S Segars, JH Nicosia, SV Enkemann, SA O'Brien, WF Spellacy, WN TI New potential regulators of uterine leiomyomata from DNA arrays: the ionotropic glutamate receptor GluR2 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE AMPA receptors; arrays; glutamate receptors; leiomyoma; myometrium; neovascularization; uterine neoplasms ID SMOOTH-MUSCLE-CELLS; GROWTH-FACTOR; TUMOR-GROWTH; PDZ DOMAINS; BODY-SIZE; MYOMETRIUM; CHANNELS; RNA; ANGIOGENESIS; ANTAGONISTS AB In the post-Genome era, new concepts emerge about the growth regulation of uterine leiomyomata. Screening of leiomyoma and myometrial tissues with DNA arrays revealed numerous genes up-regulated in leiomyomata that were not known to be expressed in the human uterus. GluR2, a subunit of a ligand-gated cation channel, is up-regulated in leiomyomata relative to myometrium by 15-to 30-fold at the protein and mRNA level and is localized in endothelial cells. GluR2 pre-mRNA in leiomyoma and myometrial tissues is nearly 100% edited at the Q/R site, indicative of low Ca2+ permeability of the ion channels. In spontaneous leiomyomata in women or leiomyomata induced in the guinea pig model, there is a likely synergism linking increased production of estradiol and all-trans retinoic acid with up-regulation of nuclear receptor PPARgamma and RXRalpha proteins to support tumor growth. GluR2 might be coupled to this synergism directly or via interleukin-17B, kinesin KIF5 or related genes also up-regulated in leiomyomata. GluR antagonists should be tested as inhibitors of leiomyoma growth. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ S Florida, Coll Med, Dept Obstet & Gynecol, Tampa, FL 33606 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ S Florida, Dept Pathol, Tampa, FL 33606 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. RP Tsibris, JCM (reprint author), Univ S Florida, Coll Med, Dept Obstet & Gynecol, 4 Columbia Dr,Room 524, Tampa, FL 33606 USA. NR 42 TC 15 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 5 PY 2003 VL 312 IS 1 BP 249 EP 254 DI 10.1016/j.bbrc.2003.09.189 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 749KR UT WOS:000186919500043 PM 14630051 ER PT J AU Mocellin, S Rossi, CR Nitti, D Lise, M Marincola, FM AF Mocellin, S Rossi, CR Nitti, D Lise, M Marincola, FM TI Dissecting tumor responsiveness to immunotherapy: the experience of peptide-based melanoma vaccines SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE anticancer immune response; melanoma; peptide; vaccine; immunotherapy ID CYTOTOXIC T-LYMPHOCYTES; DOSE RECOMBINANT INTERLEUKIN-2; COLONY-STIMULATING FACTOR; RENAL-CELL CARCINOMA; PHASE-I TRIAL; MHC CLASS-I; METASTATIC MELANOMA; DENDRITIC CELLS; IMMUNE-RESPONSE; MULTIPEPTIDE VACCINE AB Recent years have witnessed important breakthroughs in our understanding of tumor immunology. A variety of immunotherapeutic strategies has shown that immune manipulation can induce the regression of established cancer in humans. The identification of the genes encoding tumor-associated antigens (TAA) and the development of means for immunizing against these antigens have opened new avenues for the development of an effective anticancer immumotherapy. However, an efficient immune response against tumor requires an intricate cross-talk between cancer and immune system cells, which is still poorly understood. Only when the molecular basis underlying tumor susceptibility to an immune response is deciphered could new therapeutic strategies be designed to fit biologically defined mechanisms of cancer immune rejection. In this article, we address some of the critical issues that have been identified in cancer immunotherapy, in part from our own studies on immune therapies in melanoma patients treated with peptide-based vaccination regimens. This is not meant to be a comprehensive overview of the immunological phenomena accompanying cancer patient vaccination but rather emphasizes some emergent findings, puzzling controversies and unanswered questions that characterize this complex field of oncology. In addition to reviewing the main immunological concepts underlying peptide-based vaccination, we also review the available data regarding naturally occurring and therapeutically induced anticancer immune response, both at the peripheral and intratumoral level. The hypothesized role of innate immunity in predetermining tumor responsiveness to immumotherapeutic manipulation is also discussed. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Padua, Dipartimento Oncol & Chirurg, Clin Chirurg Gen 2, I-35128 Padua, Italy. NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Mocellin, S (reprint author), Univ Padua, Dipartimento Oncol & Chirurg, Clin Chirurg Gen 2, Via Giustiniani 2, I-35128 Padua, Italy. RI Rossi, Carlo Riccardo/A-7685-2010 OI Rossi, Carlo Riccardo/0000-0001-7875-5655 NR 109 TC 27 Z9 28 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD DEC 5 PY 2003 VL 1653 IS 2 BP 61 EP 71 DI 10.1016/S0304-419X(03)00032-5 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 750JJ UT WOS:000186987300002 PM 14643925 ER PT J AU Ren, H Honse, Y Peoples, RW AF Ren, H Honse, Y Peoples, RW TI A site of alcohol action in the fourth membrane-associated domain of the N-methyl-D-aspartate receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED ION CURRENT; CYCLIC-GMP PRODUCTION; ETHANOL INHIBITION; HIPPOCAMPAL-NEURONS; XENOPUS OOCYTES; INDUCED NORADRENALINE; GENERAL-ANESTHETICS; H-3 NOREPINEPHRINE; GABA(A) RECEPTORS; GLYCINE RECEPTORS AB The N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptor is an important mediator of the behavioral effects of ethanol in the central nervous system. Although ethanol is known to inhibit NMDA receptors by influencing ion-channel gating, its molecular site of action and the mechanism underlying this effect have not been established. We have previously identified a conserved methionine residue in the fourth membrane-associated domain of the NMDA receptor NR2A subunit (Met(823)) that influences desensitization and gating of the ion channel. Here we report that this residue plays an important role in mediating the effect of ethanol on the NMDA receptor. Ethanol IC50 values among functional substitution mutants at this position varied over the range similar to 130-225 mM. There was a weak correlation between ethanol IC50 and mean open time of NR2A( Met823) mutants that was dependent on inclusion of the value for the tryptophan mutant. In the absence of this value, there was no trend toward a correlation among the remaining mutants. Desensitization appeared to influence the action of ethanol, because ethanol IC50 of the mutants was correlated with the steady-state to peak current ratio. With the exception of tryptophan, ethanol sensitivity was significantly related to the molecular volume and hydrophobicity of the substituent. The relation between ethanol sensitivity and the molecular volume and hydrophobicity at this position suggests that this residue interacts with or forms part of a site of ethanol action and that the presence of a tryptophan residue in this site disrupts its ability to interact with ethanol. C1 NIAAA, Unit Cellular Neuropharmacol, Mol & Cellular Neurobiol Lab, Bethesda, MD 20892 USA. RP Peoples, RW (reprint author), Marquette Univ, Dept Biomed Sci, POB 1881, Milwaukee, WI 53201 USA. NR 38 TC 46 Z9 47 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 DEC 5 PY 2003 VL 278 IS 49 BP 48815 EP 48820 DI 10.1074/jbc.M302097200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 747WL UT WOS:000186829000038 PM 14506267 ER PT J AU Davis, MI Ronesi, J Lovinger, DM AF Davis, MI Ronesi, J Lovinger, DM TI A predominant role for inhibition of the adenylate cyclase/protein kinase A pathway in ERK activation by cannabinoid receptor 1 in N1E-115 neuroblastoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAS-DEPENDENT ACTIVATION; SIGNAL-REGULATED KINASE; GROWTH-FACTOR RECEPTOR; PROTEIN-KINASE; MAP KINASE; HIPPOCAMPAL-NEURONS; POSITIVE REGULATOR; CB2 RECEPTORS; CYCLIC-AMP; IN-VIVO AB Cannabinoids activate several members of the mitogen-activated protein kinase superfamily including p44 and p42 extracellular signal-regulated kinase (ERK). We used N1E-115 neuroblastoma cells and the cannabinoid receptor agonist WIN 55,212-2 (WIN) to examine the signal transduction pathways leading to the activation of ERK. ERK phosphorylation ( activation) was measured by Western blot. The EC50 for stimulation of ERK phosphorylation was 10 nM, and this effect was blocked by pertussis toxin and the CB1 ( cannabinoid) receptor antagonist SR141716A. The MEK inhibitors PD 98059 and U0126 blocked ERK phosphorylation, as did the adenylate cyclase activator forskolin. The phosphatidylinositol (PI) 3-kinase inhibitor LY 294002 and the Src kinase inhibitor PP2 partially occluded the response but also decreased basal levels of phospho-ERK. The PI 3-kinase and Src pathways are known to promote cell survival in many systems; therefore, MTT (1-(4,5-dimethylthiazol-2-yl)- 3,5-diphenylformazan) conversion was used to examine the effects of these inhibitors on cellular viability. LY 294002 decreased the number of viable cells after 18 h of treatment; therefore, the inhibition of ERK by this inhibitor is probably because of cytotoxicity. Forskolin blocked ERK phosphorylation with an EC50 of < 3 μM, and the protein kinase A (PKA) inhibitor H-89 enhanced ERK phosphorylation. c-Raf phosphorylation at an inhibitory PKA-regulated site (Ser(259)) was also reduced by WIN. This is probably due to constitutive phosphatase activity because WIN did not directly stimulate PP1 or PP2A activity when measured using 6,8-difluoro-4-methylumbelliferyl phosphate as a fluorogenic substrate. These data implicate the inhibition of PKA as the predominant pathway for ERK activation by CB1 receptors in N1E-115 cells. PI 3-kinase and Src appear to contribute to ERK activation by maintaining activation of kinases, which prime the pathway and maintain cellular viability. C1 NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, Bethesda, MD 20892 USA. RP Davis, MI (reprint author), NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, 12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. RI Davis, Margaret/F-4165-2010; OI Davis, Margaret/0000-0002-0489-8351 NR 45 TC 49 Z9 57 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 DEC 5 PY 2003 VL 278 IS 49 BP 48973 EP 48980 DI 10.1074/jbc.M305697200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 747WL UT WOS:000186829000058 PM 14517212 ER PT J AU Zhu, PP Patterson, A Lavoie, B Stadler, J Shoeb, M Patel, R Blackstone, C AF Zhu, PP Patterson, A Lavoie, B Stadler, J Shoeb, M Patel, R Blackstone, C TI Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOMINANT OPTIC ATROPHY; GTP-BINDING PROTEIN; TORSION DYSTONIA; DYNAMIN; MUTATION; CLASSIFICATION; INTERACTS; GTPASES; DISEASE; NEURONS AB Hereditary spastic paraplegias comprise a group of clinically heterogeneous syndromes characterized by lower extremity spasticity and weakness, with distal axonal degeneration in the long ascending and descending tracts of the spinal cord. The early onset hereditary spastic paraplegia SPG3A is caused by mutations in the atlastin/human guanylate-binding protein-3 gene (renamed here atlastin-1), which codes for a 64-kDa member of the dynamin/Mx/guanylate-binding protein superfamily of large GTPases. The atlastin-1 protein is localized predominantly in brain, where it is enriched in pyramidal neurons in the cerebral cortex and hippocampus. In cultured cortical neurons, atlastin-1 colocalized most prominently with markers of the Golgi apparatus, and immunogold electron microscopy revealed a predominant localization of atlastin-1 to the cis-Golgi. Yeast two-hybrid analyses and co-immunoprecipitation studies demonstrated that atlastin-1 can self-associate, and gel-exclusion chromatography and chemical cross-linking studies indicated that atlastin-1 exists as an oligomer in vivo, most likely a tetramer. Membrane fractionation and protease protection assays revealed that atlastin-1 is an integral membrane protein with two predicted transmembrane domains; both the N-terminal GTP-binding and C-terminal domains are exposed to the cytoplasm. Together, these findings indicate that the SPG3A protein atlastin-1 is a multimeric integral membrane GTPase that may be involved in Golgi membrane dynamics or vesicle trafficking. C1 NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. George Washington Univ, NIH, Grad Partnerships Program Genet, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), NINDS, Cellular Neurol Unit, NIH, Bldg 36,Rm 5W21,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 NR 42 TC 91 Z9 102 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 DEC 5 PY 2003 VL 278 IS 49 BP 49063 EP 49071 DI 10.1074/jbc.M306702200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 747WL UT WOS:000186829000068 PM 14506257 ER PT J AU Paciga, M McCudden, CR Londos, C DiMattia, GE Wagner, GF AF Paciga, M McCudden, CR Londos, C DiMattia, GE Wagner, GF TI Targeting of big stanniocalcin and its receptor to lipid storage droplets of ovarian steroidogenic cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HORMONE-SENSITIVE LIPASE; BENZODIAZEPINE RECEPTOR; GROWTH-FACTOR; LEYDIG-CELLS; PERILIPIN; MOUSE; EXPRESSION; METABOLISM; PROTEIN; BINDING AB Stanniocalcin (STC) is a large polypeptide hormone that is widely distributed in tissues such as kidney, adrenal, and ovary. In most tissues, STC exists as a 50-kDa homodimer (STC50). The ovaries produce a higher molecular weight variant ( big STC) in androgen-producing theca cell and interstitial cell compartments. Luteal cells, which do not express the STC gene, nonetheless contain high levels of STC protein, suggesting they are targeted by and sequester big STC through a receptor-mediated process. Recently, an STC . alkaline phosphatase fusion protein was used to characterize mitochondrial targeting and sequestration of STC50 and its receptor in liver and kidney. The main objective of the present study was to characterize big STC and its receptor in mammalian ovary and determine whether the ovarian STC variant was similarly targeted to luteal cell mitochondria. By in situ ligand binding, we identified large numbers of STC receptors on corpus luteal cells. However, a more detailed analysis of sub-cellular fractions revealed that both STC and its receptor were not preferentially targeted to mitochondria but instead to cholesterol/lipid storage droplets, which was more indicative of a role in steroidogenesis. Functional studies revealed that additions of big STC had concentration-dependent inhibitory effects on both basal and stimulated progesterone output by primary cultured luteal cells. Furthermore, STC receptor levels were upregulated in luteal cells in response to protein kinase A activation. Taken together, these findings indicate that theca cell-derived big STC is targeted to the cholesterol/ lipid storage droplets of luteal cells to regulate steroidogenesis. This constitutes the first reported description of polypeptide hormone and receptor targeting to cholesterol/ lipid droplets and the first biological role for the big STC variant. C1 Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5C1, Canada. Univ Western Ontario, Dept Biol, London, ON N6A 5B7, Canada. NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. London Reg Canc Ctr, Dept Biochem, London, ON N6A 4L6, Canada. London Reg Canc Ctr, Dept Oncol, London, ON N6A 4L6, Canada. London Reg Canc Ctr, Dept Obstet Gynecol, London, ON N6A 4L6, Canada. RP Wagner, GF (reprint author), Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5C1, Canada. NR 31 TC 38 Z9 40 U1 1 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 DEC 5 PY 2003 VL 278 IS 49 BP 49549 EP 49554 DI 10.1074/jbc.M307302200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 747WL UT WOS:000186829000125 PM 14512426 ER PT J AU Gustafson, RA Moolchan, ET Barnes, A Levine, B Huestis, MA AF Gustafson, RA Moolchan, ET Barnes, A Levine, B Huestis, MA TI Validated method for the simultaneous determination of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC and 11-nor-9-carboxy-THC in human plasma using solid phase extraction and gas chromatography-mass spectrometry with positive chemical ionization SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Delta(9)-tetrahydrocannabinol; 11-hydroxy-Delta(9)-tetrahydrocannabinol; 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol ID GC-MS; MAJOR METABOLITES; FOOD-PRODUCTS; CANNABINOIDS; URINE; BLOOD; TETRAHYDROCANNABINOL; MARIJUANA; MECONIUM; 11-NOR-9-CARBOXY-DELTA(9)-TETRAHYDROCANNABINOL AB A fully validated, highly sensitive and specific method for the extraction and quantification of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinoI (THCCOOH) in plasma is presented. This method incorporates Escherichia coli beta-glucuronidase hydrolysis to cleave glucuronic acid moieties to capture total analyte concentrations, and simultaneous solid phase extraction (SPE) of the three analytes in a single eluant with separation and quantification on a bench-top positive chemical ionization (PCI) gas chromatography-mass spectrometry (GC-MS) in the selected ion monitoring (SIM) mode. Quantitation was achieved by the addition of deuterated analogues for each analyte as internal standards (IS). Limits of quantitation (LOQ) were 0.5, 0.5 and 1.0 for THC, 11-OH-THC and THCCOOH, respectively, with linearity ranging up to 50 ng/ml for THC and 11-OH-THC, and 100 ng/ml for THCCOOH. Absolute recoveries ranged from 67.3 to 83.5% for all three analytes. Intra-assay accuracy and precision ranged from 1.2 to 12.2 and 1.4 to 4.7%, respectively. Inter-assay accuracy and precision ranged from 1.4 to 12.2 and 3.1 to 7.3%, respectively. This method was used to analyze plasma samples collected from individuals participating in a controlled oral THC administration study. Statistically significant (P less than or equal to 0.05) increases of 40% for 11-OH-THC and 42% for THCCOOH concentrations were found between hydrolyzed and non-hydrolyzed results. This method will be utilized in ongoing controlled cannabinoid administration studies and may be a useful analytical procedure for the fields of forensic toxicology and cannabinoid pharmacology. (C) 2003 Elsevier B.V. All rights reserved. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 32 TC 50 Z9 53 U1 4 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD DEC 5 PY 2003 VL 798 IS 1 BP 145 EP 154 DI 10.1016/j.jchromb.2003.09.022 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 748CN UT WOS:000186844800018 PM 14630369 ER PT J AU Yamada, M Basile, AS Fedorova, I Zhang, WL Duttaroy, A Cui, YH Lamping, KG Faraci, FM Deng, CX Wess, J AF Yamada, M Basile, AS Fedorova, I Zhang, WL Duttaroy, A Cui, YH Lamping, KG Faraci, FM Deng, CX Wess, J TI Novel insights into M-5 muscarinic acetylcholine receptor function by the use of gene targeting technology SO LIFE SCIENCES LA English DT Article; Proceedings Paper CT 4th International Symposium on Receptor Mechanisms, Signal Transduction and Drug Effects CY MAY 22-24, 2003 CL FUKUI, JAPAN DE acetylcholine; blood vessels; dopamine release; drug addiction; morphine analgesia; morphine reward; morphine withdrawal; muscarinic receptors; naloxone; vasodilation ID VENTRAL TEGMENTAL AREA; NITRIC-OXIDE SYNTHASE; CEREBRAL BLOOD-FLOW; RAT-BRAIN; CHOLINERGIC STIMULATION; CORTICAL MICROVESSELS; DOPAMINE RELEASE; MESSENGER-RNA; NEURONS; EXPRESSION AB Until recently, little was known about the possible physiological functions of the M-5 muscarinic acetylcholine receptor subtype, the last member of the muscarinic receptor family (M-1-M-5) to be cloned. To learn more about the potential physiological roles of this receptor subtype, we generated and analyzed M-5 receptor-deficient mice (M5 -/- mice). Strikingly, acetylcholine, a potent dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5 -/- mice, suggesting that endothelial M-5 receptors mediate this activity in wild-type mice. This effect was specific for cerebral blood vessels, since acetylcholine-mediated dilation of extracerebral arteries remained fully intact in M5 -/- mice. In addition, in vitro neurotransmitter release experiments indicated that M-5 receptors located on dopaminergic nerve terminals play a role in facilitating muscarinic agonist-induced dopamine release in the striatum, consistent with the observation that the dopaminergic neurons innervating the striatum almost exclusively express the M-5 receptor subtype. We also found that the rewarding effects of morphine, the prototypical opiate analgesic, were substantially reduced in M5 -/- mice, as measured in the conditioned place preference paradigm. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M5 -/- mice. It is likely that these behavioral deficits are caused by the lack of mesolimbic M-5 receptors, activation of which is known to stimulate dopamine release in the nucleus accumbens. These results convincingly demonstrate that the M-5 muscarinic receptor is involved in modulating several important pharmacological and behavioral functions. These findings may lead to novel therapeutic strategies for the treatment of drug addiction and certain cerebrovascular disorders. (C) 2003 Elsevier Inc. All rights reserved. C1 NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. NIDDKD, Neurosci Grp, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ Iowa, Dept Internal Med, Ctr Cardiovasc, Iowa City, IA 52242 USA. Univ Iowa, Dept Pharmacol, Ctr Cardiovasc, Iowa City, IA 52242 USA. Vet Adm Med Ctr, Iowa City, IA 52242 USA. NIDDKD, Biochem & Metab Lab, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, 8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 39 TC 42 Z9 45 U1 1 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 DEC 5 PY 2003 VL 74 IS 2-3 BP 345 EP 353 DI 10.1016/j.lfs.2003.09.022 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 744WV UT WOS:000186656600025 PM 14607263 ER PT J AU Princler, GL Julias, JG Hughes, SH Derse, D AF Princler, GL Julias, JG Hughes, SH Derse, D TI Roles of viral and cellular proteins in the expression of alternatively spliced HTLV-1 pX mRNAs SO VIROLOGY LA English DT Article ID VIRUS TYPE-I; READING FRAME-I; CYTOTOXIC T-LYMPHOCYTES; TYPE-1 P12(I) PROTEIN; VACUOLAR H+-ATPASE; LEUKEMIA-VIRUS; BOVINE PAPILLOMAVIRUS; NUCLEAR FACTOR; SILENCER ELEMENT/; VIVO PRODUCTION AB The human T cell leukemia virus type 1 (HTLV-1) genome contains a cluster of at least five open reading frames (ORFs) near the 3' terminus within the pX region. The pX ORFs are encoded by mono- or bicistronic mRNAs that are generated by alternative splicing. The various pX mRNAs result from skipping of the internal exon (2-exon versus 3-exon isofoms) or from the utilization of alternative splice acceptor sites in the terminal exon. The Rex and Tax proteins, encoded by ORFs X-III and X-IV, have been studied intensively and are encoded by the most abundant of the alternative 3-exon mRNAs. The protein products of the other pX ORFs have not been detected in HTLV-1-infected cell lines and the levels of the corresponding mRNAs have not been accurately established. We have used real-time RT-PCR with splice-site specific primers to accurately measure the levels of individual pX mRNA species in chronically infected T cell lines. We have asked whether virus regulatory proteins or ectopic expression of cellular factors influence pX mRNA splicing in cells that were transfected with HTLV-1 provirus clones. In chronically infected cell lines, the pX-tax/rex mRNA was present at 500- to 2500-fold higher levels than the pX-tax-orfII mRNA and at approximately 1000-fold higher levels than pX-rex-orfI mRNA. Chronically infected cell lines that contain numerous defective proviruses expressed 2-exon forms of pX mRNAs at significantly higher levels compared to cell lines that contain a single full-length provirus. Cells transfected with provirus expression plasmids expressed similar relative amounts of 3-exon pX mRNAs but lower levels of 2-exon mRNA forms compared to cells containing a single, full-length provirus. The pX mRNA expression patterns were nearly identical in cells transfected with wild-type, Tax-minus, or Rex-minus proviruses. Cotransfection of cells with HTLV-1 provirus in combination with SF2/ASF expression plasmid resulted in a relative increase in pX-tax/rex mRNA compared to pX-tax-orfII and pX-rex-orfI mRNAs, but did not affect exon skipping. Ectopic expression of hnRNP A1 did not affect pX splice site utilization, but increased exon skipping, as the level of pX-p21rex mRNA was increased by almost 10-fold. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Derse, D (reprint author), NCI, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. NR 55 TC 34 Z9 34 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 DEC 5 PY 2003 VL 317 IS 1 BP 136 EP 145 DI 10.1016/j.virol.2003.09.010 PG 10 WC Virology SC Virology GA 755UX UT WOS:000187430800013 PM 14675632 ER PT J AU Waheed, AA AF Waheed, AA TI Citation rate unrelated to journals' impact factors SO NATURE LA English DT Letter C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Waheed, AA (reprint author), NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NR 1 TC 2 Z9 3 U1 1 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 DEC 4 PY 2003 VL 426 IS 6966 BP 495 EP 495 DI 10.1038/426495c PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 749TE UT WOS:000186944300016 PM 14654813 ER PT J AU Lippincott-Schwartz, J Liu, W AF Lippincott-Schwartz, J Liu, W TI Membrane trafficking - Coat control by curvature SO NATURE LA English DT Editorial Material ID PROTEIN; VESICLES; COPI; HYDROLYSIS; TRANSPORT; DYNAMICS; GTP C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NR 12 TC 16 Z9 16 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 4 PY 2003 VL 426 IS 6966 BP 507 EP 508 DI 10.1038/426507a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 749TE UT WOS:000186944300022 PM 14654824 ER PT J AU Morris, CM O'Brien, KK Gibson, AM Hardy, JA Singleton, AB AF Morris, CM O'Brien, KK Gibson, AM Hardy, JA Singleton, AB TI Polymorphism in the human DJ-1 gene is not associated with sporadic dementia with Lewy bodies or Parkinson's disease SO NEUROSCIENCE LETTERS LA English DT Article DE Parkinson's disease; Lewy body; DJ-1; apolipoprotein E ID DIAGNOSIS; MUTATIONS AB Genetic analysis of early onset Parkinson's disease (PD) has indicated that the mutation DJ-1 gene is one cause of autosomal recessive PD. Its role in the development of late onset PD and other Lewy body associated disorders such as dementia with Lewy bodies (DLB) is however unknown. We have therefore determined the influence of a common polymorphism in the DJ-1 gene that shows strong linkage disequilibrium with other DJ-1 polymorphisms, in late onset PD and DLB. No alteration in the frequency of the intron I deletion allele was seen in PD or DLB, nor were DJ-1 genotypes altered by disease. Stratification of the cases according to the apolipoprotein E epsilon4 allele additionally failed to show any significant association. The DJ-1 gene does not appear to be a significant risk factor for late onset Lewy body disease in this population. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Newcastle Gen Hosp, Inst Hlth Elderly, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Morris, CM (reprint author), Newcastle Gen Hosp, Inst Hlth Elderly, MRC Bldg,Westgate Rd, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI O'Brien, Kirsty/0000-0002-0240-1292 NR 14 TC 14 Z9 18 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 4 PY 2003 VL 352 IS 2 BP 151 EP 153 DI 10.1016/S0304-3940(03)01030-9 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 745GF UT WOS:000186680400019 PM 14625045 ER PT J AU Pickhardt, PJ Choi, JR Hwang, I Butler, JA Puckett, ML Hildebrandt, HA Wong, RK Nugent, PA Mysliwiec, PA Schindler, WR AF Pickhardt, PJ Choi, JR Hwang, I Butler, JA Puckett, ML Hildebrandt, HA Wong, RK Nugent, PA Mysliwiec, PA Schindler, WR TI Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CT COLONOGRAPHY; PERFORMANCE-CHARACTERISTICS; POLYPS; CANCER; MULTICENTER; SIZE AB BACKGROUND: We evaluated the performance characteristics of computed tomographic (CT) virtual colonoscopy for the detection of colorectal neoplasia in an average-risk screening population. METHODS: A total of 1233 asymptomatic adults (mean age, 57.8 years) underwent same-day virtual and optical colonoscopy. Radiologists used the three-dimensional endoluminal display for the initial detection of polyps on CT virtual colonoscopy. For the initial examination of each colonic segment, the colonoscopists were unaware of the findings on virtual colonoscopy, which were revealed to them before any subsequent reexamination. The sensitivity and specificity of virtual colonoscopy and the sensitivity of optical colonoscopy were calculated with the use of the findings of the final, unblinded optical colonoscopy as the reference standard. RESULTS: The sensitivity of virtual colonoscopy for adenomatous polyps was 93.8 percent for polyps at least 10 mm in diameter, 93.9 percent for polyps at least 8 mm in diameter, and 88.7 percent for polyps at least 6 mm in diameter. The sensitivity of optical colonoscopy for adenomatous polyps was 87.5 percent, 91.5 percent, and 92.3 percent for the three sizes of polyps, respectively. The specificity of virtual colonoscopy for adenomatous polyps was 96.0 percent for polyps at least 10 mm in diameter, 92.2 percent for polyps at least 8 mm in diameter, and 79.6 percent for polyps at least 6 mm in diameter. Two polyps were malignant; both were detected on virtual colonoscopy, and one of them was missed on optical colonoscopy before the results on virtual colonoscopy were revealed. CONCLUSIONS: CT virtual colonoscopy with the use of a three-dimensional approach is an accurate screening method for the detection of colorectal neoplasia in asymptomatic average-risk adults and compares favorably with optical colonoscopy in terms of the detection of clinically relevant lesions. C1 Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD USA. Natl Naval Med Res Inst, Dept Gastroenterol, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Radiol, Bethesda, MD 20814 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Dept Radiol, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Dept Gastroenterol, Washington, DC 20307 USA. Natl Naval Med Res Inst, Dept Radiol, San Diego, CA USA. Natl Naval Med Res Inst, Dept Gastroenterol, San Diego, CA USA. RP Pickhardt, PJ (reprint author), Univ Wisconsin, Sch Med, Dept Radiol, E3-311 Clin Sci Ctr,600 Highland Ave, Madison, WI 53792 USA. EM ppickhardt@mail.radiology.wisc.edu NR 33 TC 1215 Z9 1247 U1 1 U2 21 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 DEC 4 PY 2003 VL 349 IS 23 BP 2191 EP 2200 DI 10.1056/NEJMoa031618 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 749LH UT WOS:000186921700005 PM 14657426 ER PT J AU Drazen, JM Ingelfinger, JR AF Drazen, JM Ingelfinger, JR TI Grants, politics, and the NIH SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NHLBI, Advisory Council, Bethesda, MD 20892 USA. RP Drazen, JM (reprint author), NHLBI, Advisory Council, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 10 Z9 10 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 4 PY 2003 VL 349 IS 23 BP 2259 EP 2261 DI 10.1056/NEJMe038192 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 749LH UT WOS:000186921700014 PM 14657434 ER PT J AU Iha, H Kibler, KV Yedavalli, VRK Peloponese, JM Haller, K Miyazato, A Kasai, T Jeang, KT AF Iha, H Kibler, KV Yedavalli, VRK Peloponese, JM Haller, K Miyazato, A Kasai, T Jeang, KT TI Segregation of NF-kappa B activation through NEMO/IKK gamma by Tax and TNF alpha: implications for stimulus-specific interruption of oncogenic signaling SO ONCOGENE LA English DT Article DE Tax; HTLV-I; adult T-cell leukemia; NEMO/IKK gamma; TNF alpha; NF-kappa B; oncogenic transformation ID T-CELL LEUKEMIA; VIRUS TYPE-1 TAX; SEVERE LIVER DEGENERATION; IKK-GAMMA; KINASE COMPLEX; DEFICIENT MICE; INCONTINENTIA PIGMENTI; MEDIATED ACTIVATION; SPINDLE CHECKPOINT; REGULATORY SUBUNIT AB Nuclear factor-kappaB essential modulator (NEMO), also called IKKgamma, has been proposed as a 'universal' adaptor of the I-kappaB kinase (IKK) complex for stimuli such as proinflammatory cytokines, microbes, and the HTLV-I Tax oncoprotein. Currently, it remains unclear whether the many signals that activate NF-kappaB through NEMO converge identically or differently. We have adopted two approaches to answer this question. First, we generated and targeted intracellularly three NEMO-specific monoclonal antibodies (mAbs). These mAbs produced two distinct intracellular NF-kappaB inhibition profiles segregating TNFalpha from Tax activation. Second, using NEMO knockout mouse fibroblasts and 10 NEMO mutants, we found that different regions function in trans either to complement or to inhibit dominantly TNFalpha, IL-1beta, or Tax activation of NF-kappaB. For instance, NEMO (1-245 amino acids) supported Tax-mediated NF-kappaB activation, but did not serve TNFalpha- or IL-1beta signaling. Altogether, our findings indicate that while NEMO 'universally' adapts numerous NF-kappaB activators, it may do so through separable domains. We provide the first evidence that selective targeting of NEMO can abrogate oncogenic Tax signaling without affecting signals used for normal cellular metabolism. C1 NIAID, Mol Microbiol Lab, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008; OI Iha, Hidekatsu/0000-0002-0999-5636 NR 67 TC 51 Z9 51 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 DEC 4 PY 2003 VL 22 IS 55 BP 8912 EP 8923 DI 10.1038/sj.onc.1207058 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 750GD UT WOS:000186982200012 PM 14654787 ER PT J AU Aglipay, JA Lee, SW Okada, S Fujiuchi, N Ohtsuka, T Kwak, JC Wang, Y Johnstone, RW Deng, CX Qin, J Ouchi, T AF Aglipay, JA Lee, SW Okada, S Fujiuchi, N Ohtsuka, T Kwak, JC Wang, Y Johnstone, RW Deng, CX Qin, J Ouchi, T TI A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway SO ONCOGENE LA English DT Article DE BRCA1; IFI16; p53; apoptosis ID DNA-DAMAGE; CELL-CYCLE; BRCA1; P53; PHOSPHORYLATION; TRANSCRIPTION; CANCER; BREAST; DOMAIN; CHECKPOINT AB We identified IFI16 as a BRCA1-associated protein involved in p53-mediated apoptosis. IFI16 contains the Pyrin/PAAD/DAPIN domain, commonly found in cell death-associated proteins. BRCA1 (aa 502-802) interacted with the IFI16 Pyrin domain (aa 1-130). We found that IFI16 was localized in the nucleoplasm and nucleoli. Clear nucleolar IFI16 localization was not observed in HCC1937 BRCA1 mutant cells, but reintroduction of wild-type BRCA1 restored IFI16 nuclear relocalization following IR (ionizing radiation). Coexpression of IFI16 and BRCA1 enhanced DNA damage-induced apoptosis in mouse embryonic fibroblasts from BRCA1 mutant mice expressing wild-type p53, although mutant IFI16 deficient in binding to BRCA1 did not induce apoptosis. Furthermore, tetracycline-induced IFI16 collaborated in inducing apoptosis when adenovirus p53 was expressed in DNA-damaged p53-deficient EJ cells. These results indicate a BRCA1-IFI16 role in p53-mediated transmission of DNA damage signals and apoptosis. C1 NYU, Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, New York, NY 10029 USA. Beth Israel Deaconess Med Ctr, Canc Biol Program, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Peter MacCallum Canc Inst, Trescowthick Res Labs, Melbourne, Vic, Australia. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Ouchi, T (reprint author), NYU, Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, Box 1130,1 Gustave L Levy Pl, New York, NY 10029 USA. RI deng, chuxia/N-6713-2016 FU NCI NIH HHS [CA90631, CA78356, CA79892, CA80058, CA84199] NR 35 TC 78 Z9 83 U1 5 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 4 PY 2003 VL 22 IS 55 BP 8931 EP 8938 DI 10.1038/sj.onc.1207057 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 750GD UT WOS:000186982200014 PM 14654789 ER PT J AU Prabakaran, P Umadevi, B Panneerselvam, P Muthiah, PT Bocelli, G Righi, L AF Prabakaran, P Umadevi, B Panneerselvam, P Muthiah, PT Bocelli, G Righi, L TI Conformational pseudo-polymorphism and hydrogen bonding: benzthiazide anhydrate and monohydrate, an antihypertensive drug SO CRYSTENGCOMM LA English DT Article ID CARBONIC-ANHYDRASE; CH/PI INTERACTION; DATABASE; SOLIDS AB Crystal structures of benzthiazide [6-chloro-3-[[(phenylmethyl) thio] ethyl]4H-1,2,4-benzthiadiazine-7-sulfonamide-1,1, dioxide] in its anhydrate and monohydrate forms reveal, respectively, a J-like folded as well as extended type conformations that have critical torsional flexibility along the C-C-S-C bonds and novel H-bonded sulfonamide motifs. C1 Bharathidasan Univ, Dept Chem, Tiruchchirappalli 620024, India. CNR, IMEM, I-43100 Parma, Italy. RP Muthiah, PT (reprint author), NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RI Ponraj, Prabakaran/D-6325-2011; Righi, Lara/L-6232-2015 OI Righi, Lara/0000-0001-9372-5438 NR 18 TC 7 Z9 7 U1 0 U2 6 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1466-8033 J9 CRYSTENGCOMM JI Crystengcomm PD DEC 3 PY 2003 VL 5 BP 487 EP 489 DI 10.1039/b312815f PG 3 WC Chemistry, Multidisciplinary; Crystallography SC Chemistry; Crystallography GA 750WB UT WOS:000187020500001 ER PT J AU Venstrom, JM McBride, MA Rother, KI Hirshberg, B Orchard, TJ Harlan, DM AF Venstrom, JM McBride, MA Rother, KI Hirshberg, B Orchard, TJ Harlan, DM TI Survival after pancreas transplantation in patients with diabetes and preserved kidney function SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; COMPLICATIONS; MELLITUS; RECIPIENTS; REGISTRY; PROGNOSIS; MORTALITY; IMPACT; ONSET; ERA AB Context Solitary pancreas transplantation (ie, pancreas alone or pancreas-after-kidney) for diabetes mellitus remains controversial due to procedure-associated morbidity/ mortality, toxicity of immunosuppression, expense, and unproven effects on the secondary complications of diabetes. Whether transplantation offers a survival advantage over conventional therapies for diabetes is unknown. Objective To determine the association between solitary pancreas transplantation and survival in patients with diabetes and preserved kidney function. Design, Setting, and Patients Retrospective observational cohort study conducted at 124 transplant centers in the United States, in 11572 patients with diabetes mellitus on the waiting list for pancreas transplantation (pancreas alone, pancreas-after-kidney, or simultaneous pancreas-kidney) at the United Network for Organ Sharing/ Organ Procurement and Transplantation Network between January 1, 1995, and December 31, 2000. All patients receiving a multiorgan (other than simultaneous pancreas-kidney) transplant were excluded, as were those listed for solitary pancreas transplantation who had a serum creatinine level greater than 2 mg/dL (176.8 mumol/L) at time of listing, or who ultimately received a simultaneous pancreas-kidney transplant. Main Outcome Measure All-cause mortality Within 4 years following transplantation (or within a comparable time on the waiting list for the group not undergoing transplantation). Results Overall relative risk of all-cause mortality for transplant recipients (compared with patients awaiting the same procedure) over 4 years of follow-up was 1.57 (95% confidence interval [CI], 0.98-2.53; P=.06) for pancreas transplant alone, 1.42 (95% Cl, 1.03-1.94; P=.03) for pancreas-after-kidney transplant, and 0.43 (95% Cl, 0.39-0.48) for simultaneous pancreas-kidney transplant. Transplant patient 1 - and 4-year survival rates were 96.5% and 85.2% for pancreas transplant alone, respectively, and 95.3% and 84.5% for pancreas-after-kidney transplant, while 1 - and 4-year survival rates for patients on the waiting list were 97.6% and 92.1% for pancreas transplant alone, respectively, and 97.1% and 88.1% for pancreas-after-kidney transplant. Conclusion From 1995-2000, survival for those with diabetes and preserved kidney function and receiving a solitary pancreas transplant was significantly worse compared with the survival of waiting-list patients receiving conventional therapy. C1 NIDDKD, Transplantat & Autoimmun Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. United Network Organ Sharing, Richmond, VA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Harlan, DM (reprint author), NIDDKD, Transplantat & Autoimmun Branch, NIH, US Dept HHS, 10 Ctr Dr,Bldg 10,Room 8N307, Bethesda, MD 20892 USA. OI orchard, trevor/0000-0001-9552-3215 FU PHS HHS [231-00-0115] NR 25 TC 178 Z9 185 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 3 PY 2003 VL 290 IS 21 BP 2817 EP 2823 DI 10.1001/jama.290.21.2817 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 748QP UT WOS:000186872800023 PM 14657065 ER PT J AU Weber, HA Zart, MK Hodges, AE Molloy, HM O'Brien, BM Moody, LA Clark, AP Harris, RK Overstreet, D Smith, CS AF Weber, HA Zart, MK Hodges, AE Molloy, HM O'Brien, BM Moody, LA Clark, AP Harris, RK Overstreet, D Smith, CS TI Chemical comparison of goldenseal (Hydrastis canadensis L.) root powder from three commercial suppliers SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE goldenseal; Hydrastis canadensis L.; alkaloids; palmatine; berberine; hydrastine; canadine; HPLC; GC-MS; LC-MS ID MEDICINAL-PLANTS; BERBERINE; ACID AB The characterization of herbal materials is a significant challenge to analytical chemists, Goldenseal (Hydrastis canadensis L.), which has been chosen for toxicity evaluation by NIEHS, is among the top 15 herbal supplements currently on the market and contains a complex mixture of indigenous components ranging from carbohydrates and amino acids to isoquinoline alkaloids. One key component of herbal supplement production is botanical authentication, which is also recommended prior to initiation of efficacy or toxicological studies. To evaluate material available to consumers, goldenseal root powder was obtained from three commercial suppliers and a strategy was developed for characterization and comparison that included Soxhlet extraction, HPLC, GC-MS, and LC-MS analyses. HPLC was used to determine the weight percentages of the goldenseal alkaloids berberine, hydrastine, and canadine in the various extract residues. Palmatine, an isoquinoline alkaloid native to Coptis spp. and other common goldenseal adulterants, was also quantitated using HPLC. GC-MS was used to identify non-alkaloid constituents in goldenseal root powder, whereas LC-MS was used to identify alkaloid components. After review of the characterization data, it was determined that alkaloid content was the best biomarker for goldenseal. A 20-min ambient extraction method for the determination of alkaloid content was also developed and used to analyze the commercial material. All three lots of purchased material contained goldenseal alkaloids hydrastinine, berberastine, tetrahydroberberastine, canadaline, berberine, hydrastine, and canadine. Material from a single supplier also contained palmatine, coptisine, and jatrorrhizine, thus indicating that the material was not pure goldenseal. Comparative data for three commercial sources of goldenseal root powder are presented. C1 Midwest Res Inst, Kansas City, MO 64110 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Weber, HA (reprint author), Midwest Res Inst, 425 Volker Blvd, Kansas City, MO 64110 USA. FU NIEHS NIH HHS [N01-ES-05457, N01-ES-55385] NR 19 TC 40 Z9 43 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD DEC 3 PY 2003 VL 51 IS 25 BP 7352 EP 7358 DI 10.1021/jf034339r PG 7 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 748VB UT WOS:000186880800022 PM 14640583 ER PT J AU Beggs, JM Plenz, D AF Beggs, JM Plenz, D TI Neuronal avalanches in neocortical circuits SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cortex; organotypic culture; branching process; self-organized criticality; multielectrode array; power law ID SELF-ORGANIZED CRITICALITY; CORTICAL-NEURONS; SYNCHRONOUS SPIKING; NEURAL-NETWORKS; IN-VITRO; PROPAGATION; CULTURES; CORTEX; OSCILLATIONS; BEHAVIOR AB Networks of living neurons exhibit diverse patterns of activity, including oscillations, synchrony, and waves. Recent work in physics has shown yet another mode of activity in systems composed of many nonlinear units interacting locally. For example, avalanches, earthquakes, and forest fires all propagate in systems organized into a critical state in which event sizes show no characteristic scale and are described by power laws. We hypothesized that a similar mode of activity with complex emergent properties could exist in networks of cortical neurons. We investigated this issue in mature organotypic cultures and acute slices of rat cortex by recording spontaneous local field potentials continuously using a 60 channel multielectrode array. Here, we show that propagation of spontaneous activity in cortical networks is described by equations that govern avalanches. As predicted by theory for a critical branching process, the propagation obeys a power law with an exponent of -3/2 for event sizes, with a branching parameter close to the critical value of 1. Simulations show that a branching parameter at this value optimizes information transmission in feedforward networks, while preventing runaway network excitation. Our findings suggest that "neuronal avalanches" may be a generic property of cortical networks, and represent a mode of activity that differs profoundly from oscillatory, synchronized, or wave-like network states. In the critical state, the network may satisfy the competing demands of information transmission and network stability. C1 NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Plenz, D (reprint author), NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bldg 36,Room 2D-26,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 54 TC 700 Z9 707 U1 6 U2 65 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 DEC 3 PY 2003 VL 23 IS 35 BP 11167 EP 11177 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 753JP UT WOS:000187228500021 PM 14657176 ER PT J AU Petersen, JD Chen, XB Vinade, L Dosemeci, A Lisman, JE Reese, TS AF Petersen, JD Chen, XB Vinade, L Dosemeci, A Lisman, JE Reese, TS TI Distribution of postsynaptic density (PSD)-95 and Ca2+/calmodulin-dependent protein kinase II at the PSD SO JOURNAL OF NEUROSCIENCE LA English DT Article DE postsynaptic density; CaMKII; PSD; PSD-95; electron microscopy; tomography ID LONG-TERM POTENTIATION; NMDA RECEPTOR; GLUTAMATE RECEPTORS; DENDRITIC SPINES; AMPA RECEPTORS; DOMAIN INTERACTION; RAT HIPPOCAMPUS; MOLECULAR-BASIS; SYNAPSES; CAMKII AB Postsynaptic densities (PSDs) contain proteins that regulate synaptic transmission. We determined the positions of calcium/calmodulin-dependent protein kinase II (CaMKII) and PSD-95 within the three-dimensional structure of isolated PSDs using immunogold labeling, rotary shadowing, and electron microscopic tomography. The results show that all PSDs contain a central mesh immediately underlying the postsynaptic membrane. Label for PSD-95 is found on both the cytoplasmic and cleft sides of this mesh, averaging 12 nm from the cleft side. All PSDs label for PSD-95. The properties of CaMKII labeling are quite different. Label is virtually absent on the cleft sides of PSDs, but can be heavy on the cytoplasmic side at a mean distance of 25 nm from the cleft. In tomograms, CaMKII holoenzymes can be visualized directly, appearing as labeled, tower-like structures reflecting the 20 nm diameter of the holoenzyme. These towers protrude from the cytoplasmic side of the central mesh. There appears to be a local organization of CaMKII, as judged by fact that the nearest-neighbor distances are nearly invariant over a wide range of labeling density for CaMKII. The average density of CaMKII holoenzymes is highly variable, ranging from zero to values approaching a tightly packed state. This variability is significantly higher than that for PSD-95 and is consistent with an information storage role for CaMKII. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20854 USA. Marine Biol Lab, Program Mol Physiol, Woods Hole, MA 02543 USA. Brandeis Univ, Volen Ctr Complex Syst, Waltham, MA 02454 USA. RP Reese, TS (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Room 2A-19, Bethesda, MD 20854 USA. EM tsr@codon.nih.gov OI Petersen, Jennifer/0000-0003-1107-8535 FU NINDS NIH HHS [R01 NS-27337, R01 NS-35083] NR 47 TC 116 Z9 122 U1 1 U2 12 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 DEC 3 PY 2003 VL 23 IS 35 BP 11270 EP 11278 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 753JP UT WOS:000187228500031 PM 14657186 ER PT J AU Kopelovich, L Crowell, JA Fay, JR AF Kopelovich, L Crowell, JA Fay, JR TI The epigenome as a target for cancer chemoprevention SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID CPG-ISLAND METHYLATION; ABERRANT PROMOTER METHYLATION; HISTONE DEACETYLASE INHIBITION; ACID RECEPTOR-BETA-2 GENE; TUMOR-SUPPRESSOR GENE; HUMAN COLON-CANCER; BREAST-CANCER; DNA METHYLATION; COLORECTAL-CANCER; ULCERATIVE-COLITIS AB Epigenetic events, a key driving force in the development of cancer, are alterations in gene expression without changes in the DNA coding sequence that are heritable through cell division. Such changes occur throughout all stages of tumorigenesis, including the early phases, and are increasingly recognized as major mechanisms involved in silencing tumor suppressor genes. Epigenetic changes can be reversed by the use of small molecules and, thus, such changes are promising targets for cancer chemopreventive drug development. This review examines the basis for targeting the epigenome as a prevention strategy, focusing on understanding the epigenetic changes that occur before the development of frank malignancy, when chemopreventive intervention will have the maximal impact. C1 NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. CCS Associates, Mountain View, CA USA. RP Kopelovich, L (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, NIH, 6130 Execut Plaza N,Rm 2117, Bethesda, MD 20892 USA. NR 119 TC 94 Z9 97 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 3 PY 2003 VL 95 IS 23 BP 1747 EP 1757 DI 10.1093/jnci/dig109 PG 11 WC Oncology SC Oncology GA 751RL UT WOS:000187080700008 PM 14652236 ER PT J AU Buxton, DB Lee, SC Wickline, SA Ferrari, M AF Buxton, DB Lee, SC Wickline, SA Ferrari, M CA Natl Heart Lung Blood Inst Nanotec TI Recommendations of the National Heart, Lung, and Blood Institute Nanotechnology Working Group SO CIRCULATION LA English DT Article DE nanotechnology; cardiovascular diseases; lung; blood diseases; sleep ID NANOMECHANICAL CANTILEVER ARRAY; SELF-ASSEMBLED MONOLAYERS; SMOOTH-MUSCLE CELLS; CONTRAST AGENT; IN-VIVO; DRUG-DELIVERY; DENDRIMER; NANOPARTICLES; MOLECULES; SURFACES AB Recent rapid advances in nanotechnology and nanoscience offer a wealth of new opportunities for diagnosis and therapy of cardiovascular, pulmonary, and hematologic diseases and sleep disorders. To review the challenges and opportunities offered by these nascent fields, the National Heart, Lung, and Blood Institute convened a Working Group on Nanotechnology. Working Group participants discussed the various aspects of nanotechnology and its applications to heart, lung, blood, and sleep (HLBS) diseases. This report summarizes their discussions according to scientific opportunities, perceived needs and barriers, specific disease examples, and recommendations on facilitating research in the field. An overarching recommendation of the Working Group was to focus on translational applications of nanotechnology to solve clinical problems. The Working Group recommended the creation of multidisciplinary research centers capable of developing applications of nanotechnology and nanoscience to HLBS research and medicine. Centers would also disseminate technology, materials, and resources and train new investigators. Individual investigators outside these centers should be encouraged to conduct research on the application of nanotechnology to biological and clinical problems. Pilot programs and developmental research are needed to attract new investigators and to stimulate creative, high-impact research. Finally, encouragement of small businesses to develop nanotechnology-based approaches to clinical problems was considered important. C1 NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Ohio State Univ, Ctr Biomed Engn, Columbus, OH 43210 USA. Washington Univ, Sch Med, St Louis, MO USA. RP Buxton, DB (reprint author), 6701 Rockledge Dr, Bethesda, MD 20892 USA. RI Lee, Stephen/C-2394-2011; OI Buxton, Denis/0000-0003-3077-6435 NR 32 TC 34 Z9 37 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 2 PY 2003 VL 108 IS 22 BP 2737 EP 2742 DI 10.1161/01.CIR.0000096493.93058.E8 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 748ZQ UT WOS:000186894500003 PM 14656908 ER PT J AU Yeong, FM Hombauer, H Wendt, KS Hirota, T Mudrak, I Mechtler, K Loregger, T Marchler-Bauer, A Tanaka, K Peters, JM Ogris, E AF Yeong, FM Hombauer, H Wendt, KS Hirota, T Mudrak, I Mechtler, K Loregger, T Marchler-Bauer, A Tanaka, K Peters, JM Ogris, E TI Identification of a subunit of a novel kleisin-beta/SMC complex as a potential substrate of protein phosphatase 2A SO CURRENT BIOLOGY LA English DT Article ID MITOTIC CHROMOSOME ARCHITECTURE; MAP KINASE PATHWAY; REGULATORY SUBUNIT; REPEAT PROTEINS; TUMOR-ANTIGEN; CONDENSIN; MITOSIS; DROSOPHILA; RESOLUTION; MEIOSIS AB Protein phosphatase 2A (PP2A) holoenzymes consist of a catalytic C subunit, a scaffolding A subunit, and one of several regulatory B subunits that recruit the AC dimer to substrates [1, 2]. PP2A is required for chromosome segregation [3-6], but PP2A's substrates in this process remain unknown. To identify PP2A substrates, we carried out a two-hybrid screen with the regulatory B/PR55 subunit. We isolated a human homolog of C. elegans HCP6, a protein distantly related to the condensin subunit hCAP-D2, and we named this homolog hHCP-6. Both C. elegans HCP-6 and condensin are required for chromosome organization and segregation [7-11]. HCP-6 binding partners are unknown, whereas condensin is composed of the structural maintenance of chromosomes proteins SMC2 and SMC4 and of three non-SMC subunits [12]. Here we show that hHCP-6 becomes phosphorylated during mitosis and that its dephosphorylation by PP2A in vitro depends on B/PR55, suggesting that hHCP-6 is a B/PR55-specific substrate of PP2A. Unlike condensin, hHCP-6 is localized in the nucleus in interphase, but similar to condensin, hHCP-6 associates with chromosomes during mitosis. hHCP-6 is part of a complex that contains SMC2, SMC4, kleisin-beta, and the previously uncharacterized HEAT repeat protein FLJ20311. hHCP-6 is therefore part of a condensin-related complex that associates with chromosomes in mitosis and may be regulated by PP2A. C1 Univ Vienna, Vienna Bioctr, Div Mol Biol, Inst Med Biochem, A-1030 Vienna, Austria. Res Inst Mol Pathol, A-1030 Vienna, Austria. NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Ogris, E (reprint author), Univ Vienna, Vienna Bioctr, Div Mol Biol, Inst Med Biochem, Dr Bohr Gasse 9, A-1030 Vienna, Austria. RI Marchler-Bauer, Aron/A-9681-2009; yeong, foong/J-7832-2012; OI yeong, foong/0000-0002-5641-6588; Marchler-Bauer, Aron/0000-0003-1516-0712; Mechtler, Karl/0000-0002-3392-9946 NR 30 TC 60 Z9 63 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD DEC 2 PY 2003 VL 13 IS 23 BP 2058 EP 2064 DI 10.1016/j.cub.2003.10.032 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 750NG UT WOS:000187002200023 PM 14653995 ER PT J AU Elgin, SCR Grewal, SIS AF Elgin, SCR Grewal, SIS TI Heterochromatin: silence is golden SO CURRENT BIOLOGY LA English DT Article ID MECHANISMS; RNA C1 Washington Univ, Dept Biol, St Louis, MO 63130 USA. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Elgin, SCR (reprint author), Washington Univ, Dept Biol, 1 Brookings Dr,CB-1229, St Louis, MO 63130 USA. NR 14 TC 113 Z9 115 U1 4 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD DEC 2 PY 2003 VL 13 IS 23 BP R895 EP R898 DI 10.1016/j.cub.2003.11.006 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 750NG UT WOS:000187002200006 PM 14654010 ER PT J AU Brady, RO AF Brady, RO TI Gaucher and Fabry diseases: from understanding pathophysiology to rational therapies SO ACTA PAEDIATRICA LA English DT Article; Proceedings Paper CT 3rd International Symposium on Lysosomal Storage Diseases CY MAY, 2003 CL SANTIAGO DE COMPOSTELA, SPAIN DE enzyme replacement therapy; Fabry disease; Gaucher disease; gene therapy; lysosomal storage disease ID INHERITED ENZYME DEFICIENCY; MANNOSE-TERMINAL GLUCOCEREBROSIDASE; REPLACEMENT THERAPY; ALPHA-GALACTOSIDASE; GLOBOTRIAOSYLCERAMIDE STORAGE; PURIFIED GLUCOCEREBROSIDASE; N-BUTYLDEOXYNOJIRIMYCIN; GENE-TRANSFER; CELLS; MICE AB Over the past 40 years there has been remarkable development in our understanding of the pathophysiology of lysosomal storage disorders. This review describes the research carried out on the sphingolipid storage disorders from the first demonstration of the underlying metabolic abnormality in Gaucher disease to the development of enzyme replacement therapy for Gaucher and Fabry diseases. Initial developments in gene therapy are also described. Conclusion: The introduction of enzyme replacement therapy has provided a lifeline for patients with Gaucher or Fabry disease. It is anticipated that future developments, including gene therapy, will provide additional therapeutic options. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. EM BradyR@ninds.nih.gov NR 46 TC 13 Z9 14 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD DEC PY 2003 VL 92 SU 443 BP 19 EP 24 DI 10.1080/08035320310000401 PG 6 WC Pediatrics SC Pediatrics GA 762VV UT WOS:000188003600005 PM 14989461 ER PT J AU Zhang, M Sun, M Dwyer, NK Comly, ME Patel, SC Sundaram, R Hanover, JA Blanchette-Mackie, EJ AF Zhang, M Sun, M Dwyer, NK Comly, ME Patel, SC Sundaram, R Hanover, JA Blanchette-Mackie, EJ TI Differential trafficking of the Niemann-Pick C1 and 2 proteins highlights distinct roles in late endocytic lipid trafficking SO ACTA PAEDIATRICA LA English DT Article; Proceedings Paper CT 3rd International Symposium on Lysosomal Storage Diseases CY MAY, 2003 CL SANTIAGO DE COMPOSTELA, SPAIN DE Niemann-Pick type C; NPC1 protein; NPC2 protein; cholesterol trafficking; glycolipid trafficking ID DISEASE TYPE-C; CONDENSED COMPLEXES; CHOLESTEROL; FIBROBLASTS; GANGLIOSIDES; TRANSPORT; STORAGE; RAFTS; HE-1; ACCUMULATION AB The cellular location of Niemann - Pick C2 protein (NPC2) in cultured human fibroblasts and Chinese hamster ovary cells was examined immunocytochemically and in living cells by expression of a functional red fluorescent protein chimeric analogue. Results: NPC2 is present in the lysosomes of both cholesterol-depleted and - replenished cells, unlike Niemann - Pick C1 protein (NPC1) which is recruited to late endosomes only upon uptake of low-density lipoprotein. With mobilization of cholesterol from lysosomes, immunocytochemical detection of NPC2 in lysosomes is greatly diminished, whereas NPC1 remains in the late endosomal compartment. We found a partial overlap in the trafficking and organellar sites of accumulation of NPC2 and NPC1. In living cells, NPC2 traffics with NPC1 in late endosomal tubules. However, in contrast to NPC1, which remains either in late endosomal vesicles and tubules or at the peripheries of cholesterol-laden lysosomes, NPC2 moves into the central core of lysosomes. Glycolipid analysis reveals that, in contrast to null mutant NPC1 cells, which accumulate G(M2) ganglioside only at the plasma membrane, with no endocytic storage, absence of NPC2 protein in null mutant NPC2 cells does not block internalization of GM2 into endocytic vesicles. This difference in the cellular distribution of GM2 in NPC1 and NPC2 null mutants is the first report of a variation in the phenotypic expression of these genotypically distinct lesions. Conclusion: We speculate that while NPC1 may play a major role in the sorting of glycolipids as well as cholesterol within the late endosomes, NPC2 primarily plays a role in the egress of cholesterol and, potentially, glycolipids from lysosomes. These proteins appear not to be integrated into a tightly bound biological complex, but rather represent separate functional entities that complement each other. C1 NIDDKD, Lipid Cell Biol Sect, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, Cell Biochem Sect, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. New England Biomed Res Ctr, Newington, CT USA. VA Connecticut Healthcare Syst, Newington, CT USA. RP Blanchette-Mackie, EJ (reprint author), NIDDKD, Lipid Cell Biol Sect, NIH, Bldg 8,Room 427,8 Ctr Dr,MSC 0851, Bethesda, MD 20892 USA. EM joanbm@bdg8.niddk.nih.gov NR 33 TC 26 Z9 28 U1 1 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD DEC PY 2003 VL 92 SU 443 BP 63 EP 73 DI 10.1080/08035320310021958 PG 11 WC Pediatrics SC Pediatrics GA 762VV UT WOS:000188003600014 PM 14989468 ER PT J AU Litten, RZ Fertig, J AF Litten, RZ Fertig, J TI Self-report and biochemical measures of alcohol consumption SO ADDICTION LA English DT Editorial Material C1 NIAAA, Div Treatment & Recovery Res, Bethesda, MD USA. 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