FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Tanaka, Y Kurbanov, F Vargas, V Esteban, JI Yuen, MF Lai, CL Kramvis, A Kew, MC Alter, HJ Mizokami, M AF Tanaka, Y Kurbanov, F Vargas, V Esteban, JI Yuen, MF Lai, CL Kramvis, A Kew, MC Alter, HJ Mizokami, M TI Molecular tracing of the global hepatitis C virus epidemic predicts regional patterns of hepatocellular carcinoma mortality SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 Nagoya City Univ, Grad Sch Med Sci, Nagoya, Aichi 467, Japan. Univ Vall Hebron, Gen Hosp, Barcelona, Spain. Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. Univ Witwatersrand, Parktown, South Africa. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RI Lai, Ching Lung/C-4298-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 434A EP 434A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301145 ER PT J AU Brown, KE Mathahs, M Broadhurst, K Coleman, M Ridnour, L Spitz, D AF Brown, KE Mathahs, M Broadhurst, K Coleman, M Ridnour, L Spitz, D TI Chronic iron overload is associated with increased telomerase activity in rodent liver: A role for altered thiol redox state? SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 Univ Iowa, Iowa City, IA USA. Iowa City Vet Affairs Med Ctr, Iowa City, IA USA. Iowa City Vet AAdm Med Ctr, Iowa City, IA USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 456A EP 456A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301200 ER PT J AU Gomez-Quiroz, LE Factor, VM Conner, EA Thorgeirsson, SS AF Gomez-Quiroz, LE Factor, VM Conner, EA Thorgeirsson, SS TI HGF protects mouse hepatocytes from JO2-induced apoptosis by a mechanism dependent on the AKT pathway and NF-KB activation SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Gomez-Quiroz, Luis/L-8415-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 499A EP 499A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301312 ER PT J AU Wakabayashi, Y Dutt, P Lippincott-Schwartz, J Arias, IM AF Wakabayashi, Y Dutt, P Lippincott-Schwartz, J Arias, IM TI Bile canalicular formation requires RAB11A and myosin VB in WIF-B9 hepatic cells SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis ID APICAL DOMAIN; MEMBRANE; GOLGI C1 Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. NIH, CBMB, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 504A EP 504A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301327 ER PT J AU Martin, J Piguet, AC Schmidt, K Lee, JS Thorgeirsson, S Dufour, JF AF Martin, J Piguet, AC Schmidt, K Lee, JS Thorgeirsson, S Dufour, JF TI Hint2, a mitochondrial candidate tumor supressor downregulated in a subclass of human hepatoicellular carcinoma SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 Univ Bern, Bern, Switzerland. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 519A EP 519A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301365 ER PT J AU Kaposi-Novak, P AF Kaposi-Novak, P TI Identification HGF/c-met signaling regulated gene expression profiles in primary mouse hepatocytes SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 523A EP 523A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301375 ER PT J AU Farci, P Meunier, JC Strazzera, R Farci, S Cao, D Casadei, AM Quinti, I Vegnente, A Coiana, A Bukh, J Purcell, RH Tovo, PA AF Farci, P Meunier, JC Strazzera, R Farci, S Cao, D Casadei, AM Quinti, I Vegnente, A Coiana, A Bukh, J Purcell, RH Tovo, PA TI Neutralizing antibodies to HCV in prospectively followed children with perinatally acquired hepatitis C virus infection. SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 Univ Cagliari, Cagliari, Italy. NIH, Bethesda, MD 20892 USA. Univ Roma La Sapienza, Rome, Italy. Univ Naples Federico II, Naples, Italy. Univ Turin, Turin, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 543A EP 543A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301422 ER PT J AU Bonkovsky, HL Di Bisceglie, AM Morishima, C Chung, RT Everson, GT Ghany, MG Hoofnagle, JH Lindsay, KL Hoefs, JC Lee, WM Lok, AS Shiffman, ML Wright, EC AF Bonkovsky, HL Di Bisceglie, AM Morishima, C Chung, RT Everson, GT Ghany, MG Hoofnagle, JH Lindsay, KL Hoefs, JC Lee, WM Lok, AS Shiffman, ML Wright, EC TI Iron and HFE gene mutations in advanced chronic hepatitis C (CHC): Results from the lead-in phase of the HALT-C trial SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 Univ Connecticut, Ctr Hlth, Farmington, CT USA. St Louis Univ, St Louis, MO 63103 USA. Univ Washington, Seattle, WA 98195 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Colorado, Ctr Hlth Sci, Denver, CO USA. NIDDKD, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA 90089 USA. Univ Calif Irvine, Irvine, CA USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. Virginia Commonwealth Univ, Hlth Syst, Richmond, VA USA. New England Res Inst, Watertown, MA 02172 USA. RI Lok, Anna /B-8292-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 548A EP 548A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480301435 ER PT J AU Gao, B Sun, R Kulkarni, S Jaruga, B Radaeva, S AF Gao, B Sun, R Kulkarni, S Jaruga, B Radaeva, S TI STAT1 plays an important role in TLR3 ligand suppression of liver regeneration and is inversely correlated with hepatocyte proliferation in HCV infection SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 569A EP 569A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480302007 ER PT J AU Ghany, M Lutchman, G Kleiner, D Borg, B Heller, T Feld, J Loomba, R Park, Y Liang, TJ Hoofnagle, J AF Ghany, M Lutchman, G Kleiner, D Borg, B Heller, T Feld, J Loomba, R Park, Y Liang, TJ Hoofnagle, J TI Lamivudine and adefovir versus adefovir alone for HBeAg-positive chronic hepatitis B. SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 5 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 591A EP 592A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480302063 ER PT J AU Siegmund, SV Harvey-White, J Kunos, G Dinh, T Piomelli, D Schwabe, R AF Siegmund, SV Harvey-White, J Kunos, G Dinh, T Piomelli, D Schwabe, R TI The endocannabinoid 2-arachidonoyl glycerol is elevated during hepatic fibrogenesis in vivo and induces cell death in primary hepatic stellate cells through an ROS-dependent mechanism SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 Columbia Univ, Coll Phys & Surg, New York, NY USA. NIAAA, NIH, Bethesda, MD USA. Univ Calif Irvine, Irvine, CA 92717 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 599A EP 600A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480302083 ER PT J AU Sunman, JA Zeldin, DC Rippe, RA Hawke, RL AF Sunman, JA Zeldin, DC Rippe, RA Hawke, RL TI Role of cytochrome P450 epoxygenases in arachidonic acid-induced oxidative stress and cell death in primary mouse hepatocytes. SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 Univ N Carolina, Chapel Hill, NC USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 640A EP 640A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480302187 ER PT J AU Huang, Y Sapp, R Blatt, L Murthy, K Liang, TJ AF Huang, Y Sapp, R Blatt, L Murthy, K Liang, TJ TI Analysis of responses to alpha and gamma interferons in hepatitis C virus infected chimpanzees SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD 20892 USA. InterMune Inc, Brisbane, Qld, Australia. SW Fdn Biomed Res, San Antonio, TX 78284 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 660A EP 660A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480302237 ER PT J AU Lutchman, GA Neumann, A Ghany, M Heller, T Borg, B Feld, JJ Loomba, R Park, Y Liang, TJ Hoofnagle, J AF Lutchman, GA Neumann, A Ghany, M Heller, T Borg, B Feld, JJ Loomba, R Park, Y Liang, TJ Hoofnagle, J TI Early viral kinetics in patients with chronic hepatitis C and end stage renal disease during therapy with peginterferon alfa-2a SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 666A EP 667A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480302253 ER PT J AU Borg, BB Neumann, AU Ghany, M Heller, T Kleiner, DE Lutchman, GA Feld, J Loomba, R Park, Y Rivera, E Liang, TJ Hoofnagle, JH AF Borg, BB Neumann, AU Ghany, M Heller, T Kleiner, DE Lutchman, GA Feld, J Loomba, R Park, Y Rivera, E Liang, TJ Hoofnagle, JH TI Trial of low dose peginterferon alfa-2a and ribavirin for patients with chronic hepatitis C infected with genotypes 2 or 3. SO HEPATOLOGY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 11-15, 2005 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 NIDDK, NIH, Bethesda, MD USA. NCI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 SU 1 BP 702A EP 702A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 972VC UT WOS:000232480302335 ER PT J AU Ghany, MG Doo, E AF Ghany, MG Doo, E TI Assessment of liver fibrosis: Palpate, poke or pulse? SO HEPATOLOGY LA English DT Editorial Material ID CHRONIC HEPATITIS-C; TRANSIENT ELASTOGRAPHY; SAMPLING VARIABILITY; BIOPSY; PROGRESSION; CIRRHOSIS; IDENTIFICATION; CLASSIFICATION; POLYMORPHISMS; INFECTION C1 NIDDK, Liver Dis Res Branch, NIH, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Res Branch, NIH, Div Digest Dis & Nutr, 10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov NR 24 TC 17 Z9 27 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 BP 759 EP 761 DI 10.1002/hep.20913 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 970XB UT WOS:000232344600003 PM 16175617 ER PT J AU Simmonds, P Bukh, J Combet, C Deleage, G Enomoto, N Feinstone, S Halfon, P Inchauspe, G Kuiken, C Maertens, G Mizokami, M Murphy, DG Okamoto, H Pawlotsky, JM Penin, FO Sablon, E Tadasu, SI Stuyver, L Thiel, HJ Viazov, S Weiner, A Widell, A AF Simmonds, P Bukh, J Combet, C Deleage, G Enomoto, N Feinstone, S Halfon, P Inchauspe, G Kuiken, C Maertens, G Mizokami, M Murphy, DG Okamoto, H Pawlotsky, JM Penin, FO Sablon, E Tadasu, SI Stuyver, L Thiel, HJ Viazov, S Weiner, A Widell, A TI Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes SO HEPATOLOGY LA English DT Article ID ENTIRE NUCLEOTIDE-SEQUENCE; COMPLETE CODING SEQUENCE; FULL-LENGTH SEQUENCE; MAJOR GENETIC GROUPS; LINE PROBE ASSAY; BLOOD-DONORS; PHYLOGENETIC ANALYSIS; PREDOMINANT GENOTYPE; ADDITIONAL SUBTYPES; VIRAL GENOTYPES AB International standardization and coordination of the nomenclature of variants of hepatitis C virus (HCV) is increasingly needed as more is discovered about the scale of HCV-related liver disease and important biological and antigenic differences that exist between variants. A group of scientists expert in the field of HCV genetic variability, and those involved in development of HCV sequence databases, the Hepatitis Virus Database (Japan), euHCVdb (France), and Los Alamos (United States), met to re-examine the status of HCV genotype nomenclature, resolve conflicting genotype or subtype names among described variants of HCV, and draw up revised criteria for the assignment of new genotypes as they are discovered in the future. A comprehensive listing of all currently classified variants of HCV incorporates a number of agreed genotype and subtype name reassignments to create consistency in nomenclature. The paper also contains consensus proposals for the classification of new variants into genotypes and subtypes, which recognizes and incorporates new knowledge of HCV genetic diversity and epidemiology. A proposal was made that HCV variants be classified into 6 genotypes (representing the 6 genetic groups defined by phylogenetic analysis). Subtype name assignment will be either confirmed or provisional, depending on the availability of complete or partial nucleotide sequence data, or remain unassigned where fewer than 3 examples of a new subtype have been described. In conclusion, these proposals provide the framework by which the HCV databases store and provide access to data on HCV, which will internationally coordinate the assignment-of-new genotypes and subtypes in the future. C1 Univ Edinburgh, Ctr Infect Dis, Edinburgh EH9 1QH, Midlothian, Scotland. NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. BioSci Lyon Gerland, Inst Biol & Chin Prot, Pole Bioinformat Lyon, Lyon, France. Univ Yamanashi, Dept Internal Med 1, Yamanashi, Japan. US FDA, Div Viral Prod, Lab Hepatitis Viruses, Bethesda, MD 20014 USA. Lab Alphabio, Marseille, France. CNRS, BioMerieux, Immunotherapie Malad Infect Chron, Lyon, France. Los Alamos Natl Lab, Theoret Biol & Biophys Grp, Los Alamos, NM USA. Innogenet NV, Ghent, Belgium. Nagoya City Univ, Grad Sch Med Sci, Dept Clin Mol Informat Med, Nagoya, Aichi 467, Japan. Inst Natl Sante Publ Quebec, Lab Sante Publ Quebec, Quebec City, PQ, Canada. Jichi Med Sch, Dept Infect & Immun, Div Virol, Minami Kawachi, Tochigi, Japan. Univ Paris, Hop Henri Mondor, INSERM, Dept Virol,U635, Creteil, France. Virco BVBA, Mechelen, Belgium. Univ Giessen, Inst Virol, D-6300 Giessen, Germany. Essen Univ Hosp, Inst Virol, Essen, Germany. Chiron Corp, Emeryville, CA 94608 USA. Lund Univ, Malmo Univ Hosp, Dept Med Microbiol, Malmo, Sweden. RP Simmonds, P (reprint author), Univ Edinburgh, Ctr Infect Dis, Edinburgh EH9 1QH, Midlothian, Scotland. EM Peter.Simmonds@ed.ac.uk RI PENIN, Francois/A-7315-2008; DELEAGE, Gilbert/F-7163-2010; Okamoto, Hiroaki/H-4371-2011 OI Okamoto, Hiroaki/0000-0003-0827-0964 NR 96 TC 939 Z9 1016 U1 9 U2 48 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2005 VL 42 IS 4 BP 962 EP 973 DI 10.1002/hep.20819 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 970XB UT WOS:000232344600025 PM 16149085 ER PT J AU Eagle, ARR Hanson, RL Jiang, WP Han, XL Matters, GL Imperatore, G Knowler, WC Bond, JS AF Eagle, ARR Hanson, RL Jiang, WP Han, XL Matters, GL Imperatore, G Knowler, WC Bond, JS TI Meprin beta metalloprotease gene polymorphisms associated with diabetic nephropathy in the Pima Indians SO HUMAN GENETICS LA English DT Article ID HYDROLASE HUMAN MEPRIN; LINKAGE DISEQUILIBRIUM; QUANTITATIVE TRAITS; PAIR ANALYSIS; CELL-SURFACE; CANCER-CELLS; KIDNEY; SUBUNITS; DISEASE; MOUSE AB There is evidence that susceptibility to diabetic nephropathy has a significant genetic component. This investigation tested the hypothesis that variations in the structural or regulatory regions of the MEP1B gene are related to susceptibility to diabetic nephropathy in the Pima Indian population. The structure of the human MEP1B gene on chromosome 18 was determined by polymerase chain reaction (PCR) amplification. Samples from 154 diabetic individuals were analyzed for polymorphisms. These individuals belonged to 65 sibships with at least one sibling pair discordant for diabetic nephropathy. Approximately half of the individuals had diabetic nephropathy. Of the 154 samples, there were 91 discordant sibling pairs. Sequencing revealed 19 single nucleotide polymorphisms (SNPs) in the MEP1B gene. SNPs 1-5 were in the 5' region upstream of the start site for transcription; SNPs 6, 7, 9, 11-15, 17, and 19 were within introns; SNPs 8, 10, 16, and 18 were in exons 4, 9, 12, and 14. SNP 18 was the only one that results in an amino acid change (proline to leucine in the cytoplasmic tall). No overall associations were found for individual SNPs. Within-family association tests found significant results for SNPs 1, 3, 4, 5, 6, 9, 11, 18, and 19 such that the more common allele was more frequently observed in those with nephropathy than in their unaffected siblings. The present study demonstrates significant within family association for SNPs in MEP1B gene with diabetic nephropathy. These results could be explained by functional effects of one or more of these SNPs or by linkage disequilibrium with a nearby functional locus. C1 Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. NIDDKD, NIH, Phoenix, AZ 85014 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. R&D Syst Inc, Minneapolis, MN 55413 USA. CDC, NCCDPHP, Div Diabet Translat, Atlanta, GA 30341 USA. RP Bond, JS (reprint author), Penn State Univ, Coll Med, Dept Biochem & Mol Biol, H171, Hershey, PA 17033 USA. EM jbond@psu.edu RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 52 TC 21 Z9 21 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2005 VL 118 IS 1 BP 12 EP 22 DI 10.1007/s00439-005-0019-7 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 984WM UT WOS:000233338100002 ER PT J AU Makishima, T Rodriguez, CI Robertson, NG Morton, CC Stewart, CL Griffith, AJ AF Makishima, T Rodriguez, CI Robertson, NG Morton, CC Stewart, CL Griffith, AJ TI Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder SO HUMAN GENETICS LA English DT Article DE COCH; cochlin; DFNA9; deafness; hearing loss ID INNER-EAR; MENIERES-DISEASE; SENSORINEURAL DEAFNESS; EXTRACELLULAR-MATRIX; VESTIBULAR DISORDER; LCCL DOMAIN; MUTATION; GENE; DYSFUNCTION; IDENTIFICATION AB Dominant progressive hearing loss and vestibular dysfunction DFNA9 is caused by mutations of the human COCH gene. COCH encodes cochlin, a highly abundant secreted protein of unknown function in the inner ear. Cochlin has an N-terminal LCCL domain followed by two vWA domains, and all known DFNA9 mutations are either missense substitutions or an amino acid deletion in the LCCL domain. Here, we have characterized the auditory phenotype associated with a genomic deletion of mouse Coch downstream of the LCCL domain. Homozygous Coch(-/-) mice express no detectable cochlin in the inner ear. Auditory brainstem responses to click and pure-tone stimuli (8, 16, 32 kHz) were indistinguishable among wild type and homozygous Coch(-/-) mice. A Coch-LacZ Delta neo reporter allele detected Coch mRNA expression in nonsensory epithelial and stromal regions of the cochlea and vestibular labyrinth. These data provide functional evidence that DFNA9 is probably not caused by COCH haploinsufficiency, but via a dominant negative or gain-of-function effect, in nonsensory regions of the inner ear. C1 Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, NIH, Rockville, MD 20850 USA. RP Stewart, CL (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. EM stewartc@ncifcrf.gov; griffita@nidcd.nih.gov RI Rodriguez, Clara/E-4835-2012; Rodriguez, Clara/E-5402-2012 FU Intramural NIH HHS; NIDCD NIH HHS [DC03402, Z01-DC-000060-03] NR 26 TC 17 Z9 18 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2005 VL 118 IS 1 BP 29 EP 34 DI 10.1007/s00439-005-0001-4 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 984WM UT WOS:000233338100004 PM 16078052 ER PT J AU Kantor, L Harding, HP Ron, D Schiffmann, R Kaneski, CR Kimball, SR Elroy-Stein, O AF Kantor, L Harding, HP Ron, D Schiffmann, R Kaneski, CR Kimball, SR Elroy-Stein, O TI Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients SO HUMAN GENETICS LA English DT Article DE eIF2B; leukodystrophy; CACH/VWM syndrome; stress; ATF4; translation ID CENTRAL-NERVOUS-SYSTEM; INITIATION-FACTOR 2B; VANISHING WHITE-MATTER; NUCLEOTIDE EXCHANGE FACTOR; UNFOLDED PROTEIN RESPONSE; TRANSLATION INITIATION; ENDOPLASMIC-RETICULUM; CHILDHOOD ATAXIA; FACTOR EIF2-ALPHA; MAMMALIAN-CELLS AB Childhood ataxia with central nervous system hypomyelination (CACH), also called vanishing white matter (VWM) leukoencephalopathy, is a fatal genetic disease caused by mutations in eukaryotic initiation factor 2B (eIF2B) genes. The five subunits eIF2B factor is critical for translation initiation under normal conditions and regulates protein synthesis in response to cellular stresses. Primary fibroblasts from CACH/VWM patients and normal individuals were used to measure basal eIF2B activity as well as global protein synthesis and ATF4 induction in response to stress in the endoplasmic reticulum. We show that although the cells expressing mutant eIF2B genes respond normally to stress conditions by reduced global translation rates, they exhibit significantly greater increase in ATF4 induction compared to normal controls despite equal levels of stress and activity of the upstream eIF2 alpha kinase. This heightened stress response observed in primary fibroblasts that suffer from minor loss of basal eIF2B activity may be employed as an initial screening tool for CACH/VWM leukodystrophy. C1 Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res Immunol, IL-69978 Tel Aviv, Israel. NYU, Sch Med, Dept Med & Cell Biol, Skirball Inst Biomol Med, New York, NY USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA USA. RP Elroy-Stein, O (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res Immunol, IL-69978 Tel Aviv, Israel. EM ornaes@tauex.tau.ac.il OI Kaneski, Christine/0000-0003-1453-2502; Ron, David/0000-0002-3014-5636 FU NIDDK NIH HHS [DK15658, DK47119]; NIEHS NIH HHS [ES08681] NR 40 TC 40 Z9 43 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2005 VL 118 IS 1 BP 99 EP 106 DI 10.1007/s00439-005-0024-x PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 984WM UT WOS:000233338100014 PM 16041584 ER PT J AU Fornage, M Lee, CR Doris, PA Bray, MS Heiss, G Zeldin, DC Boerwinkle, E AF Fornage, M Lee, CR Doris, PA Bray, MS Heiss, G Zeldin, DC Boerwinkle, E TI The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke SO HUMAN MOLECULAR GENETICS LA English DT Article ID LINKAGE DISEQUILIBRIUM; ATHEROSCLEROSIS RISK; HUMAN GENOME; POLYMORPHISMS; MUTATION; CALCIFICATION; HAPLOTYPES; ACID; CYTOCHROME-P450; POPULATIONS AB Stroke is the leading cause of severe disability and the third leading cause of death, accounting for one of every 15 deaths in the USA. We investigated the association of polymorphisms in the soluble epoxide hydrolase gene (EPHX2) with incident ischemic stroke in African-Americans and Whites. Twelve single nucleotide polymorphisms (SNPs) spanning EPHX2 were genotyped in a case-cohort sample of 1336 participants from the Atherosclerosis Risk in Communities (ARIC) study. In each racial group, Cox proportional hazard models were constructed to assess the relationship between incident ischemic stroke and EPHX2 polymorphisms. A score test method was used to investigate the association of common haplotypes of the gene with risk of ischemic stroke. In African-Americans, two common EPHX2 haplotypes with significant and opposing relationships to ischemic stroke risk were identified. In Whites, two common haplotypes showed suggestive indication of an association with ischemic stroke risk but, as in African-Americans, these relationships were in opposite direction. These findings suggest that multiple variants exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence; some associated with a higher incidence and others with a lower incidence. C1 Univ Texas, Hlth Sci Ctr, Inst Mol Med & Prevent Human Dis, Houston, TX 77030 USA. Univ N Carolina, Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, Houston, TX 77030 USA. RP Fornage, M (reprint author), Univ Texas, Hlth Sci Ctr, Inst Mol Med & Prevent Human Dis, 2121 W Holcombe Blvd, Houston, TX 77030 USA. EM myriam.fornage@uth.tmc.edu OI Lee, Craig/0000-0003-3595-5301 FU NHLBI NIH HHS [N01HC55022, N01HC55019, N01-HC-55021, N01-HC-55018, N01-HC-55015, N01HC55016, N01HC55018, N01HC55015, N01-HC-55020, N01HC55021, N01-HC-55019, N01-HC-55016, N01HC55020, R01 HL069126, N01-HC-55022, HL69126]; NIEHS NIH HHS [F32 ES012856-01, ES012856, F32 ES012856-03, F32 ES012856-02, F32 ES012856]; NINDS NIH HHS [NS41466, R01 NS041466] NR 47 TC 57 Z9 58 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2005 VL 14 IS 19 BP 2829 EP 2837 DI 10.1093/hmg/ddi315 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 965AV UT WOS:000231923000006 PM 16115816 ER PT J AU Savage, SA Stewart, BJ Eckert, A Kiley, M Liao, JS Chanock, SJ AF Savage, SA Stewart, BJ Eckert, A Kiley, M Liao, JS Chanock, SJ TI Genetic variation, nucleotide diversity, and linkage disequilibrium in seven telomere stability genes suggest that these genes may be under constraint SO HUMAN MUTATION LA English DT Article DE telomere; SNP; nucleotide diversity ID APLASTIC-ANEMIA; HUMAN GENOME; HAPLOTYPE RECONSTRUCTION; STATISTICAL-METHOD; DNA POLYMORPHISM; FISSION YEAST; END; EVOLUTION; PROTEIN; LENGTH AB To maintain chromosomal integrity and to protect the ends of chromosomes against recognition as damaged DNA, end-to-end fusion, or recombination, a coordinated set of genes is required to stabilize the telomere. We surveyed common genetic variation in seven genes that are vital to telomere stability (TERT, POT1, TNKS, TERF1, TINF2, TERF2, and TERF2IP) and validated single nucleotide polymorphisms (SNPs) in four different ethnic groups (n = 118 total). Overall, our data show limited degrees of nucleotide diversity in comparison with data from other gene families. We observed that these genes are highly conserved in sequence between species, and that for nearly all of the coding SNPs the most common allele is ancestral (i.e., it is observed in primate sequences). Our findings support the hypothesis that genetic variation in a pathway that is critical for telomere stability may be under constraint. These data establish a foundation for further investigation of these genes in population-genetics, evolution, and disease,association studies. C1 NCI, Pediat Oncol Branch, Sect Genom Variat, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, NCI, Bethesda, MD USA. NCI FCRDC, SAIC, Intramural Res Support Program, Frederick, MD USA. RP Savage, SA (reprint author), NCI, Pediat Oncol Branch, Sect Genom Variat, Ctr Canc Res, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Intramural NIH HHS NR 63 TC 34 Z9 36 U1 2 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD OCT PY 2005 VL 26 IS 4 BP 343 EP 350 DI 10.1002/humu.20226 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 966IY UT WOS:000232014500009 PM 16110488 ER PT J AU Lloyd-Jones, DM Sutton-Tyrrell, K Patel, AS Matthews, KA Pasternak, RC Everson-Rose, SA Scuteri, A Chae, CU AF Lloyd-Jones, DM Sutton-Tyrrell, K Patel, AS Matthews, KA Pasternak, RC Everson-Rose, SA Scuteri, A Chae, CU TI Ethnic variation in hypertension among premenopausal and perimenopausal women - Study of women's health across the nation SO HYPERTENSION LA English DT Article DE blood pressure; ethnicity; antihypertensive agents ID BODY-MASS INDEX; NUTRITION EXAMINATION SURVEY; NORMAL BLOOD-PRESSURE; WAIST-HIP RATIO; RISK-FACTORS; CIRCUMFERENCE; PREVALENCE; ADULTS; POPULATION; PREVENTION AB Data are sparse regarding hypertension prevalence, treatment, and control among some ethnic groups of American women. Furthermore, the effects of ethnicity on hypertension, independent of other factors that vary with ethnicity, are poorly understood. We examined the prevalence of hypertension (defined as systolic >= 140 or diastolic >= 90 mm Hg or receiving treatment), treatment, and control (to < 140/< 90 mm Hg) in a multiethnic study of premenopausal and perimenopausal women. Stepwise multivariable logistic regression was used to select covariates associated with hypertension. Among 3292 women, 46.9% were white, 28.3% were black, 8.7% were Hispanic, 7.6% were Chinese, and 8.5% were Japanese. Among these 5 ethnic groups, respectively, there was substantial variation in prevalence of normal blood pressure levels (<120/<80 mm Hg; 59.9%, 35.4%, 16.8%, 67.2%, and 63.7%) and hypertension (14.5%, 38.1%, 27.6%, 12.8%, and 11.0%). After multivariable adjustment, hypertension prevalence was 2 to 3 X higher among black and Hispanic women but similar among Chinese and Japanese women compared with white women. Among hypertensive participants, prevalence of anti hypertensive treatment was highest among blacks (58.9%) and whites (55.2%) and lowest among Chinese (34.4%). Prevalence of control to goal blood pressure levels was highest among whites (43.0%) and Japanese (38.7%) and markedly lower among Hispanic women (11.4%). Compared with whites, black and Hispanic women have significantly higher prevalence of hypertension independent of other factors, whereas Chinese and Japanese women have similar prevalence. Treatment and control rates vary considerably across ethnicities. Greater efforts must be made to improve hypertension awareness, treatment, and control in all middle-aged women, particularly those in ethnic minority groups. C1 Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. NIH, Bethesda, MD 20892 USA. RP Lloyd-Jones, DM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM dlj@northwestern.edu RI Lloyd-Jones, Donald/C-5899-2009 NR 25 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2005 VL 46 IS 4 BP 689 EP 695 DI 10.1161/01.HYP.0000182659.03194.db PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 973YR UT WOS:000232559000012 PM 16144985 ER PT J AU Schweda, F Segerer, F Castrop, H Schnermann, J Kurtz, A AF Schweda, F Segerer, F Castrop, H Schnermann, J Kurtz, A TI Blood pressure-dependent inhibition of renin secretion requires A1 adenosine receptors SO HYPERTENSION LA English DT Article DE kidney; phenylephrine; prostaglandins ID RENOVASCULAR HYPERTENSION; TUBULOGLOMERULAR FEEDBACK; GENE-EXPRESSION; JUXTAGLOMERULAR CELLS; PLASMA-RENIN; MICE LACKING; MACULA DENSA; RAT-KIDNEY; CLIP RATS; RELEASE AB Renal perfusion pressure (RPP) regulates renin release with a reduction of RPP stimulating and an elevation inhibitin renin secretion. The precise sensing and effector mechanisms by which changes in arterial pressure are linked to the exocytosis of renin are not well-defined. The present experiments were designed to study the potential role of adenosine as a mediator of this renal baroreceptor mechanism. In isolated perfused mouse kidneys a stepwise reduction of RPP from 90 rum Hg to 65 and 40 mm Hg stimulated renin secretion rates (RSR) 1.4-fold and 3.6-fold, whereas stepwise elevations of RPP from 90 mm Hg to 115 and 140mm Hg suppressed RSR to 64% or 40% of baseline. Inactivation of A1 adenosine receptors by either pharmacological blockade (DPCPX 1 mu mol/L) or genetic deletion (A1AR(-/-) mice) did not modify the stimulation of renin release by a low RPP, but completely prevented the suppression of renin secretion by higher perfusion pressures. In vivo, the induction of arterial hypertension by either acute (single subcutaneous injection) or chronic (osmotic minipump for 72 hours) application of phenylephrine significantly reduced plasma renin concentration (PRC) in wild-type mice to approximate to 40% of control, whereas it did not significantly affect PRC in A1AR(-/-) mice. Together these data demonstrate that A1 adenosine receptors are indispensable for the inhibition of renin secretion by an increase in blood pressure, suggesting that formation and action of adenosine is responsible for baroreceptor-mediated inhibition of renin release. In contrast, the stimulation of the renin system by a low blood pressure appears to follow different pathways. C1 Univ Regensburg, Inst Physiol, D-93040 Regensburg, Germany. NIDDK, NIH, Bethesda, MD USA. RP Schweda, F (reprint author), Univ Regensburg, Inst Physiol, D-93040 Regensburg, Germany. EM frank.schweda@klinik.uni-regensburg.de NR 32 TC 33 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2005 VL 46 IS 4 BP 780 EP 786 DI 10.1161/01.HYP.0000183963.07801.65 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 973YR UT WOS:000232559000026 PM 16172432 ER PT J AU Goldstein, DS Holmes, C Sharabi, Y AF Goldstein, DS Holmes, C Sharabi, Y TI Sympathetic noradrenergic denervation in Parkinson disease SO HYPERTENSION LA English DT Meeting Abstract CT 59th Annual Fall Conference and Scientific Sessions of the Council-for-High-Blood-Pressure-Research CY SEP 21-24, 2005 CL Washington, DC SP Council High Blood Pressure Res 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 19106-3261 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2005 VL 46 IS 4 BP 815 EP 815 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 973YR UT WOS:000232559000044 ER PT J AU Awumey, EM Hill, SK Kunos, G Diz, DI Salem, W Bukoski, RD AF Awumey, EM Hill, SK Kunos, G Diz, DI Salem, W Bukoski, RD TI Ionized calcium, in the physiological range, induces the release and metabolism of anandamide and 2-arachidonyl glycerol in isolated mesenteric artery arcade SO HYPERTENSION LA English DT Meeting Abstract CT 59th Annual Fall Conference and Scientific Sessions of the Council-for-High-Blood-Pressure-Research CY SEP 21-24, 2005 CL Washington, DC SP Council High Blood Pressure Res C1 N Carolina Cent Univ, Durham, NC USA. NIAAA, NIH, Bethesda, MD USA. Wake Forest Univ, 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 19106-3261 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2005 VL 46 IS 4 BP 833 EP 833 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 973YR UT WOS:000232559000138 ER PT J AU Morris, RG Hoorn, EJ Knepper, MA AF Morris, RG Hoorn, EJ Knepper, MA TI Hypokalemia in thiazide-sensitive Na-Cl cotransporter knockout mice SO HYPERTENSION LA English DT Meeting Abstract CT 59th Annual Fall Conference and Scientific Sessions of the Council-for-High-Blood-Pressure-Research CY SEP 21-24, 2005 CL Washington, DC SP Council High Blood Pressure Res C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2005 VL 46 IS 4 BP 860 EP 860 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 973YR UT WOS:000232559000278 ER PT J AU Kawada, N Solis, G Connors, S Kawada, JT AF Kawada, N Solis, G Connors, S Kawada, JT TI Cyclooxygenase-1 deficient mice are salt-sensitive due to enhanced catecholamine production SO HYPERTENSION LA English DT Meeting Abstract CT 59th Annual Fall Conference and Scientific Sessions of the Council-for-High-Blood-Pressure-Research CY SEP 21-24, 2005 CL Washington, DC SP Council High Blood Pressure Res C1 Georgetown Univ, Washington, DC USA. Osaka Univ, Suita, Osaka, Japan. NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2005 VL 46 IS 4 BP 862 EP 862 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 973YR UT WOS:000232559000290 ER PT J AU McGuire, HL Vollmer, W Appel, L Cooper, L Elmer, P AF McGuire, HL Vollmer, W Appel, L Cooper, L Elmer, P TI Weight loss reduces urine albumin excretion SO HYPERTENSION LA English DT Meeting Abstract CT 59th Annual Fall Conference and Scientific Sessions of the Council-for-High-Blood-Pressure-Research CY SEP 21-24, 2005 CL Washington, DC SP Council High Blood Pressure Res C1 Duke Univ, Med Ctr, Durham, NC USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Johns Hopkins Med Ctr, Baltimore, MD 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 19106-3261 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2005 VL 46 IS 4 BP 864 EP 864 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 973YR UT WOS:000232559000298 ER PT J AU Wang, SM Chen, J AF Wang, SM Chen, J TI A performance study of the iterative ADI-FDTD method SO IEEE TRANSACTIONS ON ANTENNAS AND PROPAGATION LA English DT Article DE alternating-direction implicit finite-difference time-domain; (ADI-FDTD) method; convergence; Crank-Nicolson (CN) scheme; iterative method ID TIME-DOMAIN METHOD AB The performance of the iterative alternating-direction implicit finite-difference time-domain (ADI-FDTD) method is studied. By interpreting the ADI-FDTD method as an iterative solver for the Crank-Nicolson scheme, we present analytical results of its convergence rate. Numerical examples further to demonstrate the performance of different variants of the iterative ADI-FDTD method. C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. RP Wang, SM (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM james.wang@ieec.org NR 16 TC 3 Z9 3 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-926X J9 IEEE T ANTENN PROPAG JI IEEE Trans. Antennas Propag. PD OCT PY 2005 VL 53 IS 10 BP 3413 EP 3417 DI 10.1109/TAP.2005.856386 PG 5 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA 973CV UT WOS:000232501400042 ER PT J AU Li, W Kim, MG Gourley, TS McCarthy, BP Sant'Angelo, DB Chang, CH AF Li, W Kim, MG Gourley, TS McCarthy, BP Sant'Angelo, DB Chang, CH TI An alternate pathway for CD4 T cell development: Thymocyte-expressed MHC class II selects a distinct T cell population SO IMMUNITY LA English DT Article ID BARE LYMPHOCYTE SYNDROME; BONE-MARROW-TRANSPLANTATION; BLOOD CD34(+) CELLS; POSITIVE SELECTION; IN-VITRO; ANTIGEN PRESENTATION; HEMATOPOIETIC-CELLS; THYMIC ENVIRONMENT; PROGENITOR CELLS; DENDRITIC CELLS AB Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical thymic epithelial cell are necessary for positive selection, as demonstrated in mouse models. Clinical data, however, show that hematopoietic stem cells reconstitute CD4 T cells in patients devoid of MHC class II. Additionally, CD4 T cells generated from human stem cells in immunocompromised mice were restricted to human, but not mouse, MHC class II. These studies suggest an alternative pathway for CD4 T cell development that does not normally exist in mice. MHC class II is expressed on developing human thymocytes, indicating a possible role of MHC II on thymocytes for CD4 T cell generation. Therefore, we created mice in which MHC class II is expressed only on T lineage cells. Remarkably, the CD4 compartment in such mice is efficiently reconstituted with unique specificity, demonstrating a novel thymocyte-driven pathway of CD4 T cell selection. C1 Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. NIAID, Thym Mol Dev Unit, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. Mem Sloan Kettering Canc Ctr, Lab T Cell Immunobiol, Program Immunol, New York, NY 10021 USA. RP Chang, CH (reprint author), Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. EM chechang@iupui.edu FU NIAID NIH HHS [AI45811] NR 56 TC 78 Z9 78 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT PY 2005 VL 23 IS 4 BP 375 EP 386 DI 10.1016/j.immuni.2005.09.002 PG 12 WC Immunology SC Immunology GA 980EC UT WOS:000232995800006 PM 16226503 ER PT J AU Banerjee, D Liou, HC Sen, R AF Banerjee, D Liou, HC Sen, R TI c-ReI-dependent priming of naive T cells by inflammatory cytokines SO IMMUNITY LA English DT Article ID NF-KAPPA-B; NUCLEAR EXPORT SIGNAL; IN-VIVO; LYMPHOCYTE-PROLIFERATION; COSTIMULATORY MOLECULES; TRANSCRIPTION FACTORS; INDEPENDENT PATHWAYS; ADAPTIVE IMMUNITY; GENE-EXPRESSION; 3RD SIGNAL AB The intrinsic refractoriness of naive T cells for cytokine production is counteracted by cells of the innate immune system. Upon sensing danger via Toll-like receptors, these cells upregulate T cell costimulatory molecules and secrete cytokines that enhance T cell activation. We show that cytokine-mediated priming of naive T cells requires the NF-kappa B family member c-Rel. In resting naive cells c-Rel is associated primarily with I kappa B beta, an inhibitory molecule that is not effectively degraded by TCR signals. Exposure of T cells to proinflammatory cytokines, TNF-alpha and IL-1 beta, shifts c-Rel to I kappa B alpha-associated complexes that are readily targeted by the TCR. As a consequence, IL-2 and IFN-gamma mRNA are produced more quickly, and at higher levels, in cytokine-primed T cells. This mechanism does not operate in effector T cells where cytokine gene expression is c-Rel-independent. We propose that c-Rel plays a crucial role as a target of innate signals in T cells. C1 NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. Brandeis Univ, Rosenstiel Res Ctr, Waltham, MA 02454 USA. Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. Cornell Univ, Weill Sch Med, Dept Immunol, New York, NY 10021 USA. RP Sen, R (reprint author), NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. EM rs465z@nih.gov FU Intramural NIH HHS; NIAID NIH HHS [AI41035] NR 62 TC 39 Z9 41 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT PY 2005 VL 23 IS 4 BP 445 EP 458 DI 10.1016/j.immuni.2005.09.012 PG 14 WC Immunology SC Immunology GA 980EC UT WOS:000232995800012 PM 16226509 ER PT J AU Yewdell, JW AF Yewdell, JW TI The seven dirty little secrets of major histocompatibility complex class I antigen processing SO IMMUNOLOGICAL REVIEWS LA English DT Review ID MHC-CLASS-I; TOXIC LYMPHOCYTES-T; HEAT-SHOCK PROTEINS; NONINFECTIOUS INFLUENZA-VIRUS; NEWLY SYNTHESIZED PROTEINS; NF-KAPPA-B; ENDOPLASMIC-RETICULUM; CROSS-PRESENTATION; DENDRITIC CELLS; PROTEASOMAL DEGRADATION AB Every field has its dirty little secrets (DLSs): assumptions based on flimsy evidence, findings that directly contradict prevailing models or so beg comprehension that they cannot even seed reasonable alternative hypotheses. Although our natural tendency is to hug these DLSs, they should be exposed, for it is these gaps in our understanding that point to the path to enlightenment. Here, I discuss some of the DLSs of major histocompatibility complex class I antigen processing. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, 4 Ctr Dr,Bldg 4,Rm211, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 77 TC 55 Z9 56 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD OCT PY 2005 VL 207 BP 8 EP 18 PG 11 WC Immunology SC Immunology GA 966UR UT WOS:000232048300002 PM 16181323 ER PT J AU Carlson, JH Porcella, SF McClarty, G Caldwell, HD AF Carlson, JH Porcella, SF McClarty, G Caldwell, HD TI Comparative genomic analysis of Chlamydia trachomatis oculotropic and genitotropic strains SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-MEMBRANE PROTEIN; AUTOTRANSPORTER PROTEINS; INTRACELLULAR PATHOGEN; MONOCLONAL-ANTIBODIES; TRYPTOPHAN SYNTHASE; INFECTED HUMANS; CD8(+) CTLS; IN-VITRO; T-CELLS; SEQUENCE AB Chlamydia trachomatis infection is an important cause of preventable blindness and sexually transmitted disease (STD) in humans. C trachomatis exists as multiple serovariants that exhibit distinct organotropism for the eye or urogenital tract. We previously reported tissue-tropic correlations with the presence or absence of a functional tryptophan synthase and a putative GTPase-inactivating domain of the chlamydial toxin gene. This suggested that these genes may be the primary factors responsible for chlamydial disease organotropism. To test this hypothesis, the genome of an oculotropic trachoma isolate (A/HAR-13) was sequenced and compared to the genome of a genitotropic (D/UW-3) isolate. Remarkably, the genomes share 99.6% identity, supporting the conclusion that a functional tryptophan synthase enzyme and toxin might be the principal virulence factors underlying disease organotropism. Tarp (translocated actin-recruiting phosphoprotein) was identified to have variable numbers of repeat units within the N and C portions of the protein. A correlation exists between lymphogranuloma venereum serovars and the number of N-terminal repeats. Single-nucleotide polymorphism (SNP) analysis between the two genomes highlighted the minimal genetic variation. A disproportionate number of SNPs were observed within some members of the polymorphic membrane protein (pmp) autotransporter gene family that corresponded to predicted T-cell epitopes that bind HLA class I and II alleles. These results implicate Pmps as novel immune targets, which could advance future chlamydial vaccine strategies. Lastly, a novel target for PCR diagnostics was discovered that can discriminate between ocular and genital strains. This discovery will enhance epidemiological investigations in nations where both trachoma and chlamydial STD are endemic. C1 NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0W3, Canada. RP Caldwell, HD (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM hcaldwell@niaid.nih.gov NR 48 TC 144 Z9 387 U1 3 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2005 VL 73 IS 10 BP 6407 EP 6418 DI 10.1128/IAI.73.10.6407-6418.2005 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 967JN UT WOS:000232087600022 PM 16177312 ER PT J AU Bertholet, S Debrabant, A Afrin, F Caler, E Mendez, S Tabbara, KS Belkaid, Y Sacks, DL AF Bertholet, S Debrabant, A Afrin, F Caler, E Mendez, S Tabbara, KS Belkaid, Y Sacks, DL TI Antigen requirements for efficient priming of CD8(+) T cells by Leishmania major-infected dendritic cells SO INFECTION AND IMMUNITY LA English DT Article ID CUTANEOUS LEISHMANIASIS; CROSS-PRESENTATION; GAMMA-INTERFERON; TRYPANOSOMA-CRUZI; IN-VIVO; IMMUNITY; MACROPHAGES; MICE; RESPONSES; PATHWAY AB CD4(+) and CD8(+) T-cell responses have been shown to be critical for the development and maintenance of acquired resistance to infections with the protozoan parasite Leishmania major. Monitoring the development of immunodominant or clonally restricted T-cell subsets in response to infection has been difficult, however, due to the paucity of known epitopes. We have analyzed the potential of L. major transgenic parasites, expressing the model antigen ovalbumin (OVA), to be presented by antigen-presenting cells to OVA-specific OT-II CD4(+) or OT-I CD8(+) T cells. Truncated OVA was expressed in L. major as part of a secreted or nonsecreted chimeric protein with L. donovani 3' nucleotidase (NT-OVA). Dendritic cells (DC) but not macrophages infected with L. major that secreted NT-OVA could prime OT-I T cells to proliferate and release gamma interferon. A diminished T-cell response was observed when DC were infected with parasites expressing nonsecreted NT-OVA or with heat-killed parasites. Inoculation of mice with transgenic parasites elicited the proliferation of adoptively transferred OT-I T cells and their recruitment to the site of infection in the skin. Together, these results demonstrate the possibility of targeting heterologous antigens to specific cellular compartments in L. major and suggest that proteins secreted or released by L. major in infected DC are a major source of peptides for the generation of parasite-specific CD8(+) T cells. The ability of L. major transgenic parasites to activate OT-I CD8(+) T cells in vivo will permit the analysis of parasite-driven T-cell expansion, differentiation, and recruitment at the clonal level. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. US FDA, CBER, OBRR, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20892 USA. RP Sacks, DL (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. EM dsacks@nih.gov NR 44 TC 33 Z9 33 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2005 VL 73 IS 10 BP 6620 EP 6628 DI 10.1128/IAI.73.10.6620-6628.2005 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 967JN UT WOS:000232087600048 PM 16177338 ER PT J AU Porcella, SF Raffel, SJ Anderson, DE Gilk, SD Bono, JL Schrumpf, ME Schwan, TG AF Porcella, SF Raffel, SJ Anderson, DE Gilk, SD Bono, JL Schrumpf, ME Schwan, TG TI Variable tick protein in two genomic groups of the relapsing fever spirochete Borrelia hermsii in western North America SO INFECTION AND IMMUNITY LA English DT Article ID OUTER SURFACE PROTEIN; LYME-DISEASE SPIROCHETE; WHITE-FOOTED MICE; PEROMYSCUS-LEUCOPUS; MAJOR PROTEINS; MONOCLONAL-ANTIBODY; CIRCULAR PLASMIDS; SEQUENCE-ANALYSIS; OSPC GENE; C OSPC AB Borrelia hermsii is the primary cause of tick-borne relapsing fever in North America. When its tick vector, Ornithodoros hermsi, acquires these spirochetes from the blood of an infected mammal, the bacteria switch their outer surface from one of,many bloodstream variable major proteins (Vmps) to a unique protein, Vtp (Vsp33). Vtp may be critical for successful tick transmission of B. hermsii; however, the gene encoding this protein has been described previously in only one isolate. Here we identified and sequenced the vtp gene in 31 isolates of B. hermsii collected over 40 years from localities throughout much of its known geographic distribution. Seven major Vtp types were found. Little or no sequence variation existed within types, but between them significant variation was observed,, similar to the pattern of diversity described for the outer surface protein C (OspC) gene in Lyme disease spirochetes. The pattern of sequence relatedness among the Vtp types was incongruent in two branches compared to two genomic groups identified among the isolates by multilocus sequence typing of the 16S rRNA,flaB, gyrB, and glpQ genes. Therefore, both horizontal transfer and recombination within and between the two genomic, groups were responsible for some of the variation observed in the vtp gene. O. hermsi ticks were capable of transmitting spirochetes in the newly identified genomic group. Therefore, given the longevity of the tick vector and persistent infection of spirochetes in ticks, these arthropods rather than mammals may be the likely host where the exchange of spirochetal DNA occurs. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Hamilton, MT 59840 USA. Sacred Heart Med Ctr, Spokane, WA USA. RP Schwan, TG (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, 903 S 4th St, Hamilton, MT 59840 USA. EM tom_schwan@nih.gov NR 91 TC 41 Z9 41 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2005 VL 73 IS 10 BP 6647 EP 6658 DI 10.1128/IAI.73.10.6647-6658.2005 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 967JN UT WOS:000232087600051 PM 16177341 ER PT J AU Knodler, LA Bestor, A Ma, CX Hansen-Wester, I Hensel, M Vallance, BA Steele-Mortimer, O AF Knodler, LA Bestor, A Ma, CX Hansen-Wester, I Hensel, M Vallance, BA Steele-Mortimer, O TI Cloning vectors and fluorescent proteins can significantly inhibit Salmonella enterica virulence in both epithelial cells and macrophages: Implications for bacterial pathogenesis studies SO INFECTION AND IMMUNITY LA English DT Article ID PATHOGENICITY ISLAND 2; GENE-EXPRESSION; FLOW-CYTOMETRY; III SECRETION; HOST-CELLS; IN-VIVO; INTRACELLULAR SURVIVAL; SEROVAR TYPHIMURIUM; DENDRITIC CELLS; CONSTRUCTION AB Plasmid vectors and fluorescent protein reporter systems are commonly used in the study of bacterial pathogenesis. Here we show that they can impair the ability of Salmonella enterica serovar Typhimurium to productively infect either cultured mammalian cells or mice. This has significant implications for studies that rely on these systems. C1 NIAID, Lab Intracellular Parasites, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. British Columbia Childrens Hosp, Div Gastroenterol, Vancouver, BC V6H 3V4, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Erlangen Nurnberg, Inst Klin Mikrobiol Immunol & Hyg, Erlangen, Germany. RP Steele-Mortimer, O (reprint author), NIAID, Lab Intracellular Parasites, NIH, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM omortimer@niaid.nih.gov OI Vallance, Bruce/0000-0003-1345-6747 NR 32 TC 36 Z9 37 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2005 VL 73 IS 10 BP 7027 EP 7031 DI 10.1128/IAI.73.10.7027-7031.2005 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 967JN UT WOS:000232087600096 PM 16177386 ER PT J AU Klein, KS Thompson, D Scheidt, PC Overpeck, MD Gross, LA AF Klein, KS Thompson, D Scheidt, PC Overpeck, MD Gross, LA CA HBSC Int Investigators TI Factors associated with bicycle helmet use among young adolescents in a multinational sample SO INJURY PREVENTION LA English DT Article ID SAFETY HELMETS; CHILDREN; LEGISLATION; VALIDITY; BEHAVIOR; BARRIERS; LAWS AB Objective: To determine factors associated with variation in bicycle helmet use by youth of different industrialized countries. Design: A multinational cross sectional nationally representative survey of health behaviors including symptoms, risk taking, school setting, and family context. Setting: School based survey of 26 countries. Subjects: School students, ages 11, 13, and 15 years totaling 112 843. Outcome measures: Reported frequency of bicycle helmet use among bicycle riders. Results: Reported helmet use varied greatly by country from 39.2% to 1.9%, with 12 countries reporting less than 10% of the bicycle riders as frequent helmet users and 14 countries more than 10%. Reported helmet use was highest at 11 years and decreased as children's age increased. Use was positively associated with other healthy behaviors, with parental involvement, and with per capita gross domestic product of the country. It is negatively associated with risk taking behaviors. Countries reported to have interventions promoting helmet use, exemplified by helmet giveaway programmes, had greater frequency of reported helmet use than those without programmes. Conclusions: Bicycle helmet use among young adolescents varies greatly between countries; however, helmet use does not reach 50% in any country. Age is the most significant individual factor associated with helmet for helmet using countries. The observation that some helmet promotion programmes are reported for countries with relatively higher student helmet use and no programmes reported for the lowest helmet use countries, suggests the possibility of a relation and the need for objective evaluation of programme effectiveness. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Maryland Med Res Inst, Baltimore, MD USA. Macro Int Inc, Calverton, MD USA. Maternal & Child Hlth Bur, Hlth Resources & Serv Adm, Rockville, MD USA. RP Scheidt, PC (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. EM Scheidtp@nih.gov FU NICHD NIH HHS [N01-HD-3272]; PHS HHS [283-91-005] NR 32 TC 18 Z9 18 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1353-8047 J9 INJURY PREV JI Inj. Prev. PD OCT PY 2005 VL 11 IS 5 BP 288 EP 293 DI 10.1136/ip.2004.007013 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 970EZ UT WOS:000232289300009 PM 16203837 ER PT J AU Francischetti, IMB Pham, VM Mans, BJ Andersen, JF Mather, TN Lane, RS Ribeiro, JMC AF Francischetti, IMB Pham, VM Mans, BJ Andersen, JF Mather, TN Lane, RS Ribeiro, JMC TI The transcriptome of the salivary glands of the female western black-legged tick Ixodes pacificus (Acari : Ixodidae) SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Ixodes pacificus; sialome; tick; blood-feeding; Kunitz inhibitor; Lyme disease; vascular biology; ixolaris; vector biology; transcriptome; proteome ID FACTOR PATHWAY INHIBITOR; PLATELET-AGGREGATION INHIBITOR; HEPARIN-BINDING EXOSITE; GLYCOPROTEIN-IIB-IIIA; LYME-DISEASE; FACTOR-XA; 3-DIMENSIONAL STRUCTURE; CAENORHABDITIS-ELEGANS; BLOOD-COAGULATION; ARTHROPOD SALIVA AB Sequencing of an Ixodes pacificus salivary gland cDNA library yielded 1068 sequences with an average undetermined nucleotide of 1.9% and an average length of 487 base pairs. Assembly of the expressed sequence tags yielded 557 contigs, 138 of which appear to code for secreted peptides or proteins based on translation of a putative signal peptide. Based on the BLASTX similarity of these contigs to 66 matches of Rodes scapularis peptide sequences, only 58% sequence identity was found, indicating a rapid divergence of salivary proteins as observed previously for mosquito and triatomine bug salivary proteins. Here we report 106 mostly full-length sequences that clustered in 16 different families: Basic-tail proteins rich in lysine in the carboxy-terminal, Kunitz-containing proteins (monolaris, ixolaris and penthalaris families), proline-rich peptides, 5-, 9.4- and 18.7-kDa proteins of unknown functions, in addition to metalloproteases (class PIII-like) similar to reprolysins. We also have found a family of disintegrins, named ixodegrins that display homology to variabilin, a GPIIb/IIIa antagonist from the tick Dermacentor variabilis. In addition, we describe peptides (here named ixostatins) that display remarkable similarities to the cysteine-rich domain of ADAMST-4 (aggrecanase). Many molecules were assigned in the lipocalin family (histamine-binding proteins); others appear to be involved in oxidant metabolism, and still others were similar to ixodid proteins such as the anticomplement ISAC. We also identified for the first time a neuropeptide-like protein (nlp-31) with GGY repeats that may have antimicrobial activity. In addition, 16 novel proteins without significant similarities to other tick proteins and 37 housekeeping proteins that may be useful for phylogenetic studies are described. Some of these proteins may be useful for studying vascular biology or the immune system, for vaccine development, or as immunoreagents to detect prior exposure to ticks. Electronic version of the manuscript can be found at http://www.ncbi.nlm.nih.gov/projects/omes/. Published by Elsevier Ltd. C1 NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA. RP Francischetti, IMB (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Rockville, MD 20892 USA. EM ifrancischetti@niaid.nih.gov OI Mans, Ben/0000-0002-0177-0029; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z99 AI999999, Z01 AI000810-11] NR 62 TC 98 Z9 98 U1 4 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD OCT PY 2005 VL 35 IS 10 BP 1142 EP 1161 DI 10.1016/j.ibmb.2005.05.007 PG 20 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 959AP UT WOS:000231489600007 PM 16102420 ER PT J AU Brown, EE Whitby, D Vitale, F Fei, PC Del Carpio, C Marshall, V Alberg, AJ Serraino, D Messina, A Gafa, L Goedert, JJ AF Brown, EE Whitby, D Vitale, F Fei, PC Del Carpio, C Marshall, V Alberg, AJ Serraino, D Messina, A Gafa, L Goedert, JJ CA Classical Kaposi Sarcoma Working TI Correlates of human herpesvirus-8 DNA detection among adults in Italy without Kaposi sarcoma SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE HHV8; Kaposi sarcoma herpesvirus; KSHV; viral DNA; viral load ID KIDNEY-TRANSPLANT RECIPIENTS; HUMAN-HERPESVIRUS TYPE-8; MOTHER-TO-CHILD; SEXUAL TRANSMISSION; GENERAL-POPULATION; RISK-FACTORS; HOMOSEXUAL-MEN; LYTIC ANTIGENS; BLOOD-DONORS; INFECTION AB Background The presence of Human Herpesvirus-8 (HHV8) DNA is predictive of Kaposi sarcoma (KS) among patients with HIV-associated or iatrogenic immunosuppression. However, correlates of HHV8-DNA detection in the general population remain undefined. Methods We assessed correlates of HHV8-DNA detection among Italian adults without KS who had antibodies against HHV8-latent nuclear antigen by immunofluorescence assay. HHV8-K6 DNA sequences were detected in peripheral blood mononuclear cells using TaqMan PCR. Results Of the 158 subjects 26 (16.5%) had detectable HHV8-DNA [median copies/million cells, 53; (13-2128)]. Adjusted for age, sex, and laboratory, HHV8-DNA was detected more frequently in participants with > 7 total residents in the childhood home [OR = 3.7 (1.5-9.1)], > 2 younger siblings [OR = 2.6 (1.1-6.5)], and current cardiovascular [OR = 3.6 (1.3-9.7)] or renal [OR = 3.1 (1.2-8.0)] disease. Excluding the participants using immune modulating drugs, HHV8-DNA was more frequent among those with low red blood cells (RBC) [< 4.5 10(6)/mu l; OR = 5.3 (1.7-16.2)], slightly elevated mean corpuscular volume [> 92 mu m(3)/red cell; OR = 2.8 (1.0-7.8)], and mild thrombocytopenia [< 151 K/mu l; OR = 5.6 (1.9-16.3)]. Conclusions Presence of HHV8-DNA in elderly Italians is associated with childhood crowding, low RBCs, and platelets, perhaps indicating roles for early infection and chronic inflammation. These risk factors are the first to be reported for non-immunosuppressed HHV8-seropositive adults. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Rockville, MD 20852 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NCI Frederick, SAIC Frederick, AIDS Vaccine Program, Viral Epidemiol Sect, Frederick, MD USA. Univ Palermo, Dipartimento Igiene & Microbiol Giusepe DAlessand, Palermo, Italy. San Gallicano Hosp, Rome, Italy. Osped Bambini Brescia, ARNAS Serv Anal Chim Clin, Palermo, Italy. IRCCS, Ist Nazl Malattie Infett L Spallanzani, Dept Epidemiol, Rome, Italy. Catania Univ, Dept Biomed Sci, Catania, Italy. Lega Italiana Lotta Contro & Tumori, Ragusa, Italy. Fdn G Pascale, Ist Tumori Napoli, Unita Operat Epidemiol, Naples, Italy. Ist Super Sanita, Epidemiol & Biostat Lab, I-00161 Rome, Italy. Ist Dermatopat Immacolata, Rome, Italy. Res Triangle Inst, Rockville, MD USA. NCI, Viral Epidemiol Branch, Rockville, MD USA. RP Brown, EE (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, 6120 Execut Blvd,EPS 8005 MSC 7248, Rockville, MD 20852 USA. EM brownbe@mail.nih.gov OI Crispo, Anna/0000-0002-8455-3328; Tramuto, Fabio/0000-0003-0108-4608; Serraino, Diego/0000-0003-0565-8920; Piselli, Pierluca/0000-0002-7342-0263 FU NCI NIH HHS [CA-09314-23, N01-CO-12400, N02-CP-91027] NR 56 TC 13 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2005 VL 34 IS 5 BP 1110 EP 1117 DI 10.1093/ije/dyi131 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 974MB UT WOS:000232594600028 PM 16043440 ER PT J AU Chen, JC AF Chen, JC TI Senescence of hematopoietic stem cells and bone marrow failure SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE hematopoietic stem cells; bone marrow failure; senescence; telomerase ID ACQUIRED APLASTIC-ANEMIA; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; TELOMERE LENGTH; SERIAL TRANSPLANTATION; IN-VIVO; MYELODYSPLASTIC SYNDROME; LIFELONG HEMATOPOIESIS; DYSKERATOSIS-CONGENITA; REPOPULATING ABILITY; IRRADIATED MICE AB Functional failure in hematopoietic stem cells (HSCs) may bring fatal consequences because HSCs are the ultimate source of mature blood cells, which need continuous replenishment. One potential cause of HSC dysfunction is senescence, in which HSCs and progenitor cells enter a state of proliferative arrest. HSC senescence is genetically regulated and one particular regulator is the telomerase gene. Mutations in the telomerase gene complex have been found in patients with bone marrow failure syndromes. During a normal lifetime, HSC clones function over the long term and may not show any functional loss under normal circumstances. However, pathologic environments may limit HSC proliferation, accelerate HSC turnover, and shorten the functional life of HSCs, leading to HSC clonal exhaustion and senescence. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, JC (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC Room 3-5132,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov NR 75 TC 10 Z9 12 U1 1 U2 2 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD OCT PY 2005 VL 82 IS 3 BP 190 EP 195 DI 10.1523/IJH97.05094 PG 6 WC Hematology SC Hematology GA 980EF UT WOS:000232996100004 PM 16207589 ER PT J AU Engeli, S Feldpausch, M Gorzelniak, K Janke, J Batkai, S Pacher, P Sharma, AM Luft, FC Jordan, J AF Engeli, S Feldpausch, M Gorzelniak, K Janke, J Batkai, S Pacher, P Sharma, AM Luft, FC Jordan, J TI Activation of the peripheral endocannabinoid system in human obesity SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Meeting Abstract CT 4th International Symposium on Obesity and Hypertension CY OCT 27-29, 2005 CL Berlin, GERMANY C1 Franz Volhard Clin Res Ctr, Berlin, Germany. NIAAA, Physiol Lab, Bethesda, MD USA. McMaster Univ, Hamilton Gen Hosp, Toronto, ON, Canada. RI Batkai, Sandor/G-3889-2010; Batkai, Sandor/H-7983-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD OCT PY 2005 VL 29 SU 3 BP S3 EP S3 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 991HO UT WOS:000233803400010 ER PT J AU Li-Ning-T, E Ronchetti, R Torres-Cabala, C Merino, MJ AF Li-Ning-T, E Ronchetti, R Torres-Cabala, C Merino, MJ TI Role of chromogenic in situ hybridization (CISH (TM)) in the evaluation of HER2 status in breast carcinoma: Comparison with immunohistochemistry and FISH SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE chromogenic in situ hybridization (CISH (TM)); fluorescence in situ hybridization (FISH); immunohistochemistry; breast carcinoma; HER2; ERBB2 ID HER-2/NEU GENE AMPLIFICATION; ARCHIVAL TISSUE SAMPLES; TRASTUZUMAB THERAPY; PROTEIN EXPRESSION; COPY NUMBER; CANCER; FLUORESCENCE; ONCOGENE; OVEREXPRESSION; ERBB-2 AB We report Our experience with Chromogenic in Situ Hybridization (CISH (TM)) for the evaluation of HER2 amplification on 55 cases of formalin-fixed, paraffin-embedded invasive breast carcinomas of different histology. All the results were corrected for chromosome 17 aneusomy and compared with immunohistochemistry (IHC); a subset of cases was compared to FISH. Thirty-one of 32 cases in which FISH and CISH (TM) were performed yielded the same results. CISH (TM) and IHC showed a good concordance in the 0/1+ and 3+ category, while a poor agreement with weakly protein overexpression was confirmed. Chromosome 17 analysis was necessary in cases with a low number of HER2 gene copies. CISH (TM) is a useful tool to evaluate breast cancer HER2 status that can be easily implemented in a laboratory of surgical pathology. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, NIH, 9000 Rockville Pike,Bldg 10,Room 2N212, Bethesda, MD 20892 USA. NR 41 TC 19 Z9 21 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD OCT PY 2005 VL 13 IS 4 BP 343 EP 351 DI 10.1177/106689690501300406 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 981XT UT WOS:000233122000006 PM 16273190 ER PT J AU Zhang, XM Chen, BY Ng, AHL Tanner, JA Tay, D So, KF Rachel, RA Copeland, NG Jenkins, NA Huang, JD AF Zhang, XM Chen, BY Ng, AHL Tanner, JA Tay, D So, KF Rachel, RA Copeland, NG Jenkins, NA Huang, JD TI Transgenic mice expressing Cre-recombinase specifically in retinal rod bipolar neurons SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CEREBELLAR PURKINJE-CELLS; MAMMALIAN RETINA; SYNAPTIC COMPETITION; ESCHERICHIA-COLI; MOUSE; DIFFERENTIATION; DNA; CHROMOSOME; PIGMENTOSA; PROTEIN AB PURPOSE. To establish a transgenic mouse line that expresses Cre-recombinase in retinal rod bipolar cells for the generation of rod bipolar cell-specific knockout mutants. METHODS. The IRES-Cre-cDNA fragment was inserted into a 173-kb bacterial artificial chromosome (BAC) carrying the intact Pcp2 gene, by using red-mediated recombineering. Transgenic mice were generated with the modified BAC and identified. The Cre-transgenic mice were crossed with ROSA26 and Z/EG reporter mice to detect Cre-recombinase activity. RESULTS. X-gal staining showed that strong Cre-recombinase activities were present in retinal inner nuclear layers and cerebellar Purkinje cells. Double staining with an anti-GFP antibody and an anti-PKC alpha antibody ( specific for retinal rod bipolar cells) revealed that Cre-recombinase activity localized exclusively to the rod bipolar cells in the retina. CONCLUSIONS. A mouse BAC-Pcp2-IRES-Cre transgenic line that expresses Cre-recombinase in retinal rod bipolar neurons has been established. Because mutations in some ubiquitously expressed genes may result in retinal degenerative diseases, the mouse strain BAC-Pcp2-IRES-Cre will be a useful new tool for investigating the effects of retinal rod bipolar cell-specific gene inactivation. C1 Univ Hong Kong, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. Univ Hong Kong, Dept Anat, Hong Kong, Hong Kong, Peoples R China. NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Huang, JD (reprint author), Univ Hong Kong, Dept Biochem, Fac Med Bldg,21 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China. EM jdhuang@hkucc.hku.hk RI Huang, Jiandong/C-4277-2009; So, Kwok Fai/C-4399-2009; Tanner, Julian/C-4412-2009 OI Tanner, Julian/0000-0002-5459-1526 NR 30 TC 9 Z9 10 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2005 VL 46 IS 10 BP 3515 EP 3520 DI 10.1167/iovs.04-1201 PG 6 WC Ophthalmology SC Ophthalmology GA 967TA UT WOS:000232112900009 PM 16186328 ER PT J AU Karabekian, Z Lytton, SD Silver, PB Sergeev, YV Schneck, JP Caspi, RR AF Karabekian, Z Lytton, SD Silver, PB Sergeev, YV Schneck, JP Caspi, RR TI Antigen/MHC class II/Ig dimers for study of uveitogenic T cells: IRBP p161-180 presented by both IA and IE molecules SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CLASS-II TETRAMERS; HUMAN S-ANTIGEN; DETERMINANT RECOGNITION; AUTOIMMUNE ARTHRITIS; SELF-ANTIGENS; RESPONSES; PEPTIDES; COMPLEX; UVEITIS; INDUCTION AB PURPOSE. Detection and modulation of effector T cells specific to immunodominant epitopes is a central issue in autoimmune diseases. Experimental autoimmune uveitis is a model for human autoimmune uveitis, induced in B10. RIII mice with interphotoreceptor retinoid binding protein or with its immunodominant epitope encoded by residues 161-180. METHODS. The authors generated a dimer composed of p161-180 fused in frame to IA(r) and mouse IgG1, and studied its effects on a CD4(+) uveitogenic T-cell line specific to p161-180 and on a T-cell clone derived from that line. RESULTS. Immunofluorescent staining of the T-cell line with the peptide/IA(r)/Ig dimer revealed that about 90% of the cells bound the reagent, and 10% did not. The T-cell clone failed to bind the reagent. Consistent with this, the line proliferated when stimulated with the reagent plus anti-CD28, and the clone did not. Conversely, after being incubated with the reagent without CD28 cross-linking, the line showed decreased proliferation on subsequent stimulatory exposure to p161-180, whereas the clone was unaffected. Antigen-specific proliferation of splenocytes from B10. RIII mice primed with p161-180 was inhibited by anti-IA as well as anti-IE antibodies; proliferation of the T-cell line was inhibited strongly by anti-IA and poorly by anti-IE, and the clone showed the opposite pattern. Finally, the line, but not the clone, proliferated to p161-180 presented on a B-cell lymphoma expressing IA(r) as its only restriction element. CONCLUSIONS. Uveitogenic T cells can be detected as well as functionally modulated with their cognate peptide-class II reagent, suggesting the potential of such reagents for diagnostic and therapeutic use in uveitic disease; p161-180 can be presented by IA(r) as well as IEr major histocompatibility complex (MHC) class II molecules. The possibility that the same immunodominant fragment might be presented by more than one class II molecule should be taken into account when diagnostic or clinical use of peptide-MHC reagents is considered. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Genet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr 10-10N222, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Lytton, Simon/0000-0001-5617-4139; Caspi, Rachel/0000-0002-7140-7671 FU Intramural NIH HHS NR 31 TC 12 Z9 12 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2005 VL 46 IS 10 BP 3769 EP 3776 DI 10.1167/iovs.05-0187 PG 8 WC Ophthalmology SC Ophthalmology GA 967TA UT WOS:000232112900042 PM 16186361 ER PT J AU Rohrer, B Lohr, HR Humphries, P Redmond, TM Seeliger, MW Crouch, RK AF Rohrer, B Lohr, HR Humphries, P Redmond, TM Seeliger, MW Crouch, RK TI Cone opsin mislocalization in Rpe65(-/-) mice: A defect that can be corrected by 11-cis retinal SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID LEBER CONGENITAL AMAUROSIS; ROD PHOTORECEPTORS; RETINITIS-PIGMENTOSA; AGGRESOME FORMATION; VISUAL-PIGMENT; GENE-THERAPY; MOUSE MODEL; RHODOPSIN; PROTEIN; IDENTIFICATION AB PURPOSE. In retinal degenerative diseases, rod photoreceptors typically deteriorate more rapidly than cone photoreceptors. In the Rpe65(-/-) mouse, a model for Leber's congenital amaurosis, cones degenerate much more rapidly than rods. In this model, the retinoid processing pathway in the retinal pigment epithelium is disrupted, and 11-cis retinal is not generated. This study was designed to investigate the feasibility of restoring functional cones with exogenous 11-cis retinal. METHODS. Rpe65(-/-)::Rho(-/-) mice were used to remove any interference of rods and compared with wild-type (wt) mice. Pups were injected intraperitoneally with 11-cis retinal, starting at postnatal day (P) 10, and were maintained in complete darkness. At P25, cone function was assessed with photopic single-flash and flicker ERGs. Cone survival was determined immunohistochemically with cone-specific antibodies, and cone opsin levels were obtained by quantitative RT-PCR. RESULTS. At P25, cone density and transcript levels of cone opsins were drastically reduced, but a minute cone electroretinogram was detected, indicating that the cones were functional. Confocal microscopy revealed that the cone opsins were mislocalized, suggesting that their transport to the outer segments was impaired. Intraperitoneal administrations of 11-cis retinal before P25 led to increased transport of cone opsins to the outer segments and preserved cones anatomically and functionally. CONCLUSIONS. The results suggest that the ligand is required during cone opsin synthesis for successful opsin trafficking and that without 11-cis retinal, cones may degenerate because of opsin mislocalization. These results may have important consequences for the treatment of cone dystrophies. C1 Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Trinity Coll Dublin, Dept Genet, Ocular Genet Unit, Dublin, Ireland. NEI, NIH, Bethesda, MD 20892 USA. Univ Tubingen, Dept Ophthalmol 2, Retinal Electrodiagnost Res Grp, Tubingen, Germany. RP Rohrer, B (reprint author), Med Univ S Carolina, Dept Ophthalmol, 167 Ashley Ave,Room 511, Charleston, SC 29425 USA. EM rohrer@musc.edu OI Redmond, T. Michael/0000-0002-1813-5291 FU NEI NIH HHS [EY04939, EY13520, EY14793] NR 39 TC 87 Z9 87 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2005 VL 46 IS 10 BP 3876 EP 3882 DI 10.1167/iovs.050533 PG 7 WC Ophthalmology SC Ophthalmology GA 967TA UT WOS:000232112900058 PM 16186377 ER PT J AU Honda, T Tamura, G Endoh, Y Nishizuka, S Kawata, S Motoyama, T AF Honda, T Tamura, G Endoh, Y Nishizuka, S Kawata, S Motoyama, T TI Expression of tumor suppressor and tumor-related proteins in differentiated carcinoma, undifferentiated carcinoma with tubular component and pure undifferentiated carcinoma of the stomach SO JAPANESE JOURNAL OF CLINICAL ONCOLOGY LA English DT Article DE gastric cancer; tissue microarray; immunohistochemistry ID NONNEOPLASTIC GASTRIC EPITHELIA; HMLH1 PROMOTER HYPERMETHYLATION; TISSUE MICROARRAYS; MICROSATELLITE INSTABILITY; METHYLATION STATUS; C-ERBB-2 PROTEIN; GENE PROMOTER; CANCER; ADENOCARCINOMA; P16 AB Background: The recent development of tissue microarray (TMA) technology allows high-throughput protein expression profiling of cancer tissues by immunohistochemistry. We attempted to clarify the derivation of undifferentiated-type gastric carcinoma with tubular component by using TMA. Methods: We constructed a TMA system composed of six paraffin blocks in which 274 samples of formalin-fixed gastric carcinoma tissue from 274 patients were embedded. Using this system, we performed immunohistochemical stains for five tumor suppressor and tumor-related proteins, i.e. p53, p16, hMLH1, c-erbB-2 and carcinoembryonic antigen (CEA). The 274 gastric carcinomas were histopathologically divided into the following three groups according to the degree of differentiation: differentiated-type (D-type), undifferentiated-type with tubular component (UT-type) and pure undifferentiated-type (UP-type). Immunohistochemical results were then compared with histological types. Results: The percentages of abnormal expression of each protein in D-type, UT-type and UP-type carcinomas were as follows: 27% (38/143), 17% (17/98) and 15% (5/33) for p53; 27% (39/143), 19% (19/98) and 18% (6/33) for p16; 38% (54/143), 44% (43/98) and 24% (8/33) for hMLH1; 15% (22/143), 5% (5/98) and 0% (0/33) for c-erbB-2; and 22% (31/143), 35% (34/98) and 70% (23/33) for CEA. UP-type carcinomas exhibited the lowest frequencies of abnormal expression for p53, p16, hMLH1 and c-erbB-2, but the highest frequencies for CEA. UT-type carcinomas generally showed intermediate frequencies between those of D-type and UP-type carcinomas. Differences between D-type and UP-type for c-erbB-2 (P < 0.05) and CEA (P < 0.001) were significant, as were differences between D-type and UT-type for c-erbB-2 (P < 0.05) and CEA (P < 0.05), and differences between UT-type and UP-type for hMLH1 (P < 0.05) and CEA (P < 0.001). Conclusions: These findings reveal that gastric carcinomas have distinct expression profiles for tumor suppressor and tumor-related proteins depending on histological types, and support the hypothesis that UT-type carcinomas are derived not only from D-type but also from UP-type carcinomas. We also found significant differences between abnormal protein expression and other clinicopathological parameters such as gender, age and status of tumor and nodes. C1 Yamagata Univ, Sch Med, Dept Pathol, Yamagata 99023, Japan. Yamagata Univ, Sch Med, Dept Gastroenterol, Yamagata 99023, Japan. Tsubame Rosai Hosp, Div Pathol, Niigata, Japan. NCI, Mol Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Tamura, G (reprint author), 2-2-2 Iida Nishi, Yamagata 9909585, Japan. EM gtamura@med.id.yamagata-u.ac.jp NR 38 TC 13 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0368-2811 J9 JPN J CLIN ONCOL JI Jpn. J. Clin. Oncol. PD OCT PY 2005 VL 35 IS 10 BP 580 EP 586 DI 10.1093/jjco/hyi166 PG 7 WC Oncology SC Oncology GA 980VH UT WOS:000233045800003 PM 16254038 ER PT J AU Marsh, AP Rejeski, WJ Hutton, SL Brown, CL Ip, E Guralnik, JM AF Marsh, AP Rejeski, WJ Hutton, SL Brown, CL Ip, E Guralnik, JM TI Development of a lateral mobility task to identify individuals at risk for mobility disability and functional decline SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Article DE aging; balance; physical function ID OLDER-ADULTS; OBSERVATIONAL ARTHRITIS; KNEE PAIN; SENIORS OASIS; BALANCE; PEOPLE; FALLS; RELIABILITY; STABILITY; STRENGTH AB Lateral mobility is integral to many activities of daily living involving transfer from one position to another. The objective of this study was to develop and evaluate the validity and test-retest reliability of a lateral-mobility (LATMOB) task for older adults. Measurements of lateral mobility, balance, and strength and self-reported and performance-based physical functioning were obtained in 63 women and 77 men >= 50 years of age. The LATMOB task was significantly correlated with age, knee-extensor strength, grip strength, functional reach, and one-leg-stance time. Test-retest reliability of the task was excellent. The LATMOB task was highly correlated with the car task. Balance was significantly correlated with time to get into and out of a car and performance on the LATMOB task. The LATMOB task was significantly correlated with the Short Physical Performance Battery score. The LATMOB task is valid and reliable, but additional work is needed to assess its sensitivity to change and predictive validity. C1 Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Biostat Sect, Winston Salem, NC 27157 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Marsh, AP (reprint author), Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. RI Agaliotis, Maria/G-5334-2012 FU NIA NIH HHS [P30-AG-021332-01]; PHS HHS [263-MA-214599] NR 36 TC 6 Z9 6 U1 3 U2 3 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD OCT PY 2005 VL 13 IS 4 BP 363 EP 381 PG 19 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 972IF UT WOS:000232446800001 PM 16301751 ER PT J AU Pate, AD Hamilton, RG Ashley, PJ Zeldin, DC Halsey, JF AF Pate, AD Hamilton, RG Ashley, PJ Zeldin, DC Halsey, JF TI Proficiency testing of allergen measurements in residential dust SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE allergens; ELISA; quality control samples; residential dust ID MITE ALLERGEN; ASTHMA; EXPOSURE; CHILDREN; DESIGN AB Background: Analyses of household dust for allergens are more common with increased efforts to reduce and control asthma. Currently, no laboratory accreditation or quality assurance program specific to household dust allergen analyses exists. Moreover, there is an absence of peer-reviewed data on within-laboratory and between-laboratory variability that is achievable for these analyses. Objectives: The purpose of this study was to characterize the levels of intralaboratory and interlaboratory variability in analyses of allergen concentrations in residential dust and to investigate the utility of quality control samples for monitoring laboratory performance. Methods: Aliquots from homogeneous batches of dust and dust extracts were provided to 8 commercial, academic, and municipal laboratories to be analyzed for as many as 6 allergens (Der p 1, Der 11, Fel d 1, Can f 1, Bla g 1, Mus to 1) by using ELISA techniques. Results: Coefficients of variation on the estimated geometric means from the analytical results ranged between 61% and 93%. In most cases, between-laboratory variability was the dominant component of total variability. In spite of this between-laboratory variability, reasonable agreement was observed between the means of allergen levels in the reference laboratory characterizations and the estimated geometric means from the model fitting of results across participating laboratories. Conclusion: The results from this study indicate that, in most cases, participating laboratories could measure the concentrations of allergens by using ELISA procedures with a level of accuracy and precision that may be acceptable in many situations. C1 Battelle Mem Inst, Columbus, OH 43201 USA. Johns Hopkins Univ, Sch Med, Dermatol Allergy & Clin Immunol Reference Lab, Baltimore, MD 21218 USA. US Dept Housing & Urban Dev, Off Healthy Homes & Lead Hazard Control, Washington, DC USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. IBT Reference Lab, Lenexa, KS USA. RP Pate, AD (reprint author), 505 King Ave, Columbus, OH 43201 USA. EM patea@battelle.org FU Intramural NIH HHS NR 13 TC 12 Z9 12 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2005 VL 116 IS 4 BP 844 EP 850 DI 10.1016/j.jaci.2005.06.016 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 017IF UT WOS:000235686600019 PM 16210059 ER PT J AU Kim, I Wtsadik, A Choo, RE Jones, HE Huestis, MA AF Kim, I Wtsadik, A Choo, RE Jones, HE Huestis, MA TI Usefulness of salivary trans-3 '-hydroxycotinine concentration and trans-3 '-hydroxycotinine/cotinine ratio as biomarkers of cigarette smoke in pregnant women SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; SOLID-PHASE EXTRACTION; COTININE LEVELS; TRANSDERMAL NICOTINE; MASS-SPECTROMETRY; METABOLISM; EXPOSURE; PHARMACOKINETICS; PLASMA; MARKER C1 NIDA, Chem & Drug Metab Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Bayview Med Ctr, Ctr Addict & Pregnancy, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nidi.nih.gov FU NIDA NIH HHS [DA12403] NR 32 TC 11 Z9 11 U1 0 U2 4 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2005 VL 29 IS 7 BP 689 EP 695 PG 7 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 976XE UT WOS:000232766100017 PM 16419402 ER PT J AU Majdalani, N Heck, M Stout, V Gottesman, S AF Majdalani, N Heck, M Stout, V Gottesman, S TI Role of RcsF in signaling to the Rcs phosphorelay pathway in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CAPSULAR POLYSACCHARIDE SYNTHESIS; HIS-ASP PHOSPHORELAY; COLANIC ACID; TRANSDUCTION SYSTEM; 2-COMPONENT SYSTEM; SENSOR KINASE; K-12; EXPRESSION; GENE; REGULATOR AB The rcs phosphorelay pathway components were originally identified as regulators of capsule synthesis. In addition to the transmembrane sensor kinase RcsC, the RcsA coregulator, and the response regulator RcsB, two new components have been characterized, RcsD and RcsF. RcsD, the product of the yojN gene, now renamed rcsD, acts as a phosphorelay between RcsC and RcsB. Transcription of genes for capsule synthesis (cps) requires both RcsA and RcsB; transcription of other promoters, including that for the small RNA RprA, requires only RcsB. RcsF was described as an alternative sensor kinase for RcsB. We have examined the role of RcsF in the activation of both the rprA and cps promoters. We find that a number of signals that lead to activation of the phosphorelay require both RcsF and RcsC; epistasis experiments place RcsF upstream of RcsC. The RcsF sequence is characteristic of lipoproteins, consistent with a role in sensing cell surface perturbation and transmitting this signal to RcsC. Activation of RcsF does not require increased transcription of the gene, suggesting that modification of the RcsF protein may act as an activating signal. Signals from RcsC require RcsD to activate RcsB. Sequencing of an rcsC allele, rcsC137, that leads to high-level constitutive expression of both cps and rprA suggests that the response regulator domain of RcsC plays a role in negatively regulating the kinase activity of RcsC. The phosphorelay and the variation in the activation mechanism (dependent upon or independent of RcsA) provide multiple steps for modulating the output from this system. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, 9000 Rockville Pike,Bldg 37,Rm 5132, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU Intramural NIH HHS NR 45 TC 80 Z9 84 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2005 VL 187 IS 19 BP 6770 EP 6778 DI 10.1128/JB.187.19.6770-6778.2005 PG 9 WC Microbiology SC Microbiology GA 968FM UT WOS:000232147300020 PM 16166540 ER PT J AU Kuban, W Banach-Orlowska, M Bialoskorska, M Lipowska, A Schaaper, RM Jonczyk, P Fijalkowska, IJ AF Kuban, W Banach-Orlowska, M Bialoskorska, M Lipowska, A Schaaper, RM Jonczyk, P Fijalkowska, IJ TI Mutator phenotype resulting from DNA polymerase IV overproduction in Escherichia coli: Preferential mutagenesis on the lagging strand SO JOURNAL OF BACTERIOLOGY LA English DT Article ID III HOLOENZYME; ADAPTIVE MUTATION; POL-IV; REPLICATION FIDELITY; GENE-EXPRESSION; COPY-NUMBER; SPECIFICITY; RESISTANCE; SELECTION; SUBUNITS AB We investigated the mutator effect resulting from overproduction of Escherichia coli DNA polymerase IV. Using lac mutational targets in the two possible orientations on the chromosome, we observed preferential mutagenesis during lagging strand synthesis. The mutator activity likely results from extension of mismatches produced by polymerase III holoenzyme. C1 Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Fijalkowska, IJ (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Pawinskiego 5A, PL-02106 Warsaw, Poland. EM iwonaf@ibb.waw.pl RI Fijalkowska, Iwona/I-7796-2016 NR 38 TC 27 Z9 27 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2005 VL 187 IS 19 BP 6862 EP 6866 DI 10.1128/JB.187.19.6862-6866.2005 PG 5 WC Microbiology SC Microbiology GA 968FM UT WOS:000232147300032 PM 16166552 ER PT J AU Masse, E Vanderpool, CK Gottesman, S AF Masse, E Vanderpool, CK Gottesman, S TI Effect of RyhB small RNA on global iron use in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID FE-S CLUSTER; MESSENGER-RNA; CRYSTAL-STRUCTURE; GENES; EXPRESSION; BINDING; HOMEOSTASIS; FUR; IDENTIFICATION; METABOLISM AB RyhB is a noncoding RNA regulated by the Fur repressor. It has previously been shown to cause the rapid degradation of a number of mRNAs that encode proteins that utilize iron. Here we examine the effect of ectopic RyhB production on global gene expression by microarray analysis. Many of the previously identified targets were found, as well as other mRNAs encoding iron-binding proteins, bringing the total number of regulated operons to at least 18, encoding 56 genes. The two major operons involved in Fe-S cluster assembly showed different behavior; the isc operon appears to be a direct target of RyhB action, while the suf operon does not. This is consistent with previous findings suggesting that the suf genes but not the isc genes are important for Fe-S cluster synthesis under iron-limiting conditions, presumably for essential iron-binding proteins. In addition, we observed repression of Fur-regulated genes upon RyhB expression, interpreted as due to intracellular iron sparing resulting from reduced synthesis of iron-binding proteins. Our results demonstrate the broad effects of a single noncoding RNA on iron homeostasis. C1 Univ Sherbrooke, Dept Biochim, Sherbrooke, PQ J1H 5N4, Canada. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Masse, E (reprint author), Univ Sherbrooke, Dept Biochim, 3001 12e Ave, Sherbrooke, PQ J1H 5N4, Canada. EM eric.masse@usherbrooke.ca NR 48 TC 275 Z9 288 U1 7 U2 19 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2005 VL 187 IS 20 BP 6962 EP 6971 DI 10.1128/JB.187.20.6962-6971.2005 PG 10 WC Microbiology SC Microbiology GA 973FY UT WOS:000232509500013 PM 16199566 ER PT J AU Kim, MS Bae, SH Yun, SH Lee, HJ Ji, SC Lee, JH Srivastava, P Lee, SH Chae, H Lee, Y Choi, BS Chattoraj, DK Lim, HM AF Kim, MS Bae, SH Yun, SH Lee, HJ Ji, SC Lee, JH Srivastava, P Lee, SH Chae, H Lee, Y Choi, BS Chattoraj, DK Lim, HM TI Cnu, a novel oriC-binding protein of Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID HISTONE-LIKE PROTEIN; H-NS; REPLICATION ORIGIN; DNA-REPLICATION; IN-VIVO; EXPRESSION; GENE; INITIATION; HHA; CHROMOSOME AB We have found, using a newly developed genetic method, a protein (named Cnu, for oriC-binding nucleoid-associated) that binds to a specific 26-base-pair sequence (named cnb) in the origin of replication of Escherichia coli, oriC. Cnu is composed of 71 amino acids (8.4 kDa) and shows extensive amino acid identity to a group of proteins belonging to the Hha/YmoA family. Con was previously discovered as a protein that, like Hha, complexes with H-NS in vitro. Our in vivo and in vitro assays confirm the results and further suggest that the complex formation with H-NS is involved in Cnu/Hha binding to cnb. Unlike the hns mutants, elimination of either the cnu or hha gene did not disturb the growth rate, origin content, and synchrony of DNA replication initiation of the mutants compared to the wild-type cells. However, the cnu hha double mutant was moderately reduced in origin content. The Cnu/Hha complex with H-NS thus could play a role in optimal activity of oriC. C1 Chungnam Natl Univ, Dept Biol, Sch Biol Sci & Biotechnol, Taejon 305764, South Korea. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Korea Adv Inst Sci & Technol, Dept Chem, Taejon 305701, South Korea. RP Lim, HM (reprint author), Chungnam Natl Univ, Dept Biol, Sch Biol Sci & Biotechnol, Taejon 305764, South Korea. EM hmlim@cnu.ac.kr RI Choi, Byong-Seok/C-1937-2011; Lee, Younghoon/C-1991-2011; Ji, Sang Chun/C-5383-2012; OI Lee, Seol-Hoon/0000-0002-6381-4760 NR 38 TC 14 Z9 15 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2005 VL 187 IS 20 BP 6998 EP 7008 DI 10.1128/JB.187.20.6998-7008.2005 PG 11 WC Microbiology SC Microbiology GA 973FY UT WOS:000232509500017 PM 16199570 ER PT J AU Mueller, GA Kirby, TW DeRose, EF Li, DW Schaaper, RM London, RE AF Mueller, GA Kirby, TW DeRose, EF Li, DW Schaaper, RM London, RE TI Nuclear magnetic resonance solution structure of the Escherichia coli DNA polymerase III theta subunit SO JOURNAL OF BACTERIOLOGY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; SIDE-CHAIN RESONANCES; SEQUENTIAL ASSIGNMENT; LARGER PROTEINS; EPSILON-SUBUNIT; STRUCTURE VALIDATION; C-13 MAGNETIZATION; NMR-SPECTROSCOPY; BACKBONE AMIDE; SPECTRA AB The catalytic core of Escherichia coli DNA polymerase III holoenzyme contains three subunits: alpha, epsilon, and theta. The alpha subunit contains the polymerase, and the E subunit contains the exonucleolytic proofreading function. The small (8-kDa) theta subunit binds only to E. Its function is not well understood, although it was shown to exert a small stabilizing effect on the E proofreading function. In order to help elucidate its function, we undertook a determination of its solution structure. In aqueous solution, theta yielded poor-quality nuclear magnetic resonance spectra, presumably due to conformational exchange and/or protein aggregation. Based on our recently determined structure of the theta homolog from bacteriophage P1, named HOT, we constructed a homology model of theta. This model suggested that the unfavorable behavior of theta might arise from exposed hydrophobic residues, particularly toward the end of alpha-helix 3. In gel filtration studies, theta elutes later than expected, indicating that aggregation is potentially responsible for these problems. To address this issue, we recorded H-1-N-15 heteronuclear single quantum correlation (HSQC) spectra in water-alcohol mixed solvents and observed substantially improved dispersion and uniformity of peak intensities, facilitating a structural determination under these conditions. The structure of theta in 60/40 (vol/vol) water-methanol is similar to that of HOT but differs significantly from a previously reported theta structure. The new theta structure is expected to provide additional insight into its physiological role and its effect on the E proofreading subunit. C1 NIEHS, Lab Struct Biol, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Lab Struct Biol, MR-01,111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov FU Intramural NIH HHS NR 53 TC 14 Z9 14 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2005 VL 187 IS 20 BP 7081 EP 7089 DI 10.1128/JB.187.20.7081-7089.2005 PG 9 WC Microbiology SC Microbiology GA 973FY UT WOS:000232509500026 PM 16199579 ER PT J AU Tang, C Iwahara, J Clore, G AF Tang, C Iwahara, J Clore, G TI Accurate determination of leucine and valine side-chain conformations using U-[N-15/C-13/H-2]/[H-1-(methine/methyl)-Leu/Val] isotope labeling, NOE pattern recognition, and methine C gamma-H gamma/C beta-H beta residual dipolar couplings: application to the 34-kDa enzyme IIA (Chitobiose) SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE isotope labeling; Leu and Val conformation; NMR; NOE; residual dipolar couplings; solution structure ID NMR STRUCTURE REFINEMENT; PHOSPHOTRANSFERASE SYSTEM; 3-DIMENSIONAL STRUCTURES; ORIENTED MACROMOLECULES; H-2-LABELED PROTEINS; DEUTERATED PROTEINS; CROSS-VALIDATION; C-13; DYNAMICS; N-15 AB An isotope labeling scheme is described in which specific protonation of methine and methyl protons of leucine and valine is obtained on a N-15/C-13 labeled background with uniform deuteration of all other non-exchangeable protons. The presence of a protonated methine group has little effect on the favorable relaxation properties of the methyl protons of Leu and Val. This labeling scheme permits the rotameric state of leucine side-chains to be readily determined by simple inspection of the pattern of H gamma(i)-H-N(i) and H gamma(i)-H-N(i+1) NOEs in a 3D N-15-separated NOE spectrum free of complications arising from spectral overlap and spin-diffusion. In addition, one-bond residual dipolar couplings for the methine C-13-H-1 bond vectors of Leu and Val can be accurately determined from an intensity J-modulated constant-time HCCH-COSY experiment and used to accurately orient the side-chains of Leu and Val. Incorporation of these data into structure refinement improves the accuracy with which the conformations of Leu and Val side-chains can be established. This is important to ensure optimal packing both within the protein core and at intermolecular interfaces. The impact of the method on protein structure determination is illustrated by application to enzyme IIA(Chitobiose), a 34 kDa homotrimeric phosphotransferase protein. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5 BI 301, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 53 TC 12 Z9 12 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD OCT PY 2005 VL 33 IS 2 BP 105 EP 121 DI 10.1007/s10858-005-1206-5 PG 17 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 979EY UT WOS:000232926400003 PM 16258829 ER PT J AU Wei, H Juhasz, O Li, JL Tarasova, YS Boheler, KR AF Wei, H Juhasz, O Li, JL Tarasova, YS Boheler, KR TI Embryonic stem cells and cardiomyocyte differentiation: phenotypic and molecular analyses SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Review DE embryonic stem cells; mouse; human; cardiomyocytes; differentiation ID FREE CULTURE-SYSTEM; CARDIAC MYOCYTES; VENTRICULAR CARDIOMYOCYTES; POTENTIAL APPLICATIONS; FUNCTIONAL-PROPERTIES; HUMAN BLASTOCYSTS; MOUSE EMBRYOS; SELF-RENEWAL; IN-VITRO; CARDIOGENESIS AB Embryonic stem (ES) cell lines, derived from the inner cell mass (ICM) of blastocyst-stage embryos, are pluripotent and have a virtually unlimited capacity for self-renewal and differentiation into all cell types of an embryo-proper. Both human and mouse ES cell lines are the subject of intensive investigation for potential applications in developmental biology and medicine. ES cells from both sources differentiate in vitro into cells of ecto-, endo- and meso-dermal lineages, and robust cardiomyogenic differentiation is readily observed in spontaneously differentiating ES cells when cultured under appropriate conditions. Molecular, cellular and physiologic analyses demonstrate that ES cell-derived cardiomyocytes are functionally viable and that these cell derivatives exhibit characteristics typical of heart cells in early stages of cardiac development. Because terminal heart failure is characterized by a significant loss of cardiomyocytes, the use of human ES cell-derived progeny represents one possible source for cell transplantation therapies. With these issues in mind, this review will focus on the differentiation of pluripotent embryonic stem cells into cardiomyocytes as a developmental model, and the possible use of ES cell-derived cardiomyocytes as source of donor cells. C1 NIA, NIH, GRC, LCS, Baltimore, MD 21224 USA. RP Boheler, KR (reprint author), NIA, NIH, GRC, LCS, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bohelerk@grc.nia.nih.gov FU Intramural NIH HHS NR 75 TC 54 Z9 67 U1 0 U2 15 PU CAROL DAVILA UNIV PRESS PI BUCHARESST PA 8 EROILOR SANITARI BLVD, BUCHARESST 76241, ROMANIA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD OCT-DEC PY 2005 VL 9 IS 4 BP 804 EP 817 DI 10.1111/j.1582-4934.2005.tb00381.x PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 999AF UT WOS:000234360300004 PM 16364192 ER PT J AU Szabova, L Yamada, SS Birkedal-Hansen, H Holmbeck, K AF Szabova, L Yamada, SS Birkedal-Hansen, H Holmbeck, K TI Expression pattern of four membrane-type matrix metalloproteinases in the normal and diseased mouse mammary gland SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID BREAST-CANCER; EXTRACELLULAR-MATRIX; TISSUE INHIBITOR; GROWTH; MICE; MORPHOGENESIS; PROGRESSION; LOCALIZATION; GELATINASE; CARCINOMAS AB Both mammary gland development and mammary carcinogenesis involve extensive remodeling of the mammary gland extracellular matrix. The expression of four membrane-type matrix metalloproteinases (MT-MMPs) with matrix remodeling potential in development and tumorigenesis was evaluated by in-situ hybridization on mouse mammary gland sections. MT1-MMP and MT3-MMP were found in the mammary stroma mainly around epithelial structures in both developing and mature mammary gland. In contrast, MT2-MMP was found exclusively in the mammary epithelium. Lactating gland expressed none of the examined MT-MMPs. Mammary gland tumors expressed MT1-MMP, MT2-MMP, and MT3-MMP while MT4-MMP was not expressed in any developmental or cancerous stage analyzed here. Our results suggest that MT1-MMP, MT2-MMP, and MT3-MMP may be involved in remodeling of both the normal and diseased mammary gland either directly or indirectly by activation of other MMPs. C1 NIDCR, Matrix Metalloproteinase Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Holmbeck, K (reprint author), NIDCR, Matrix Metalloproteinase Unit, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Rm 4A400,MSC4380,30 Convent Dr, Bethesda, MD 20892 USA. EM kenn.holmbeck@nih.gov FU NIDCR NIH HHS [Z01DE000676] NR 36 TC 28 Z9 32 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD OCT PY 2005 VL 205 IS 1 BP 123 EP 132 DI 10.1002/jcp.20385 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 960PD UT WOS:000231604700015 PM 15895410 ER PT J AU Morse, RP Kleta, R Alroy, J Gahl, WA AF Morse, RP Kleta, R Alroy, J Gahl, WA TI Novel form of intermediate Salla disease: Clinical and neuroimaging features SO JOURNAL OF CHILD NEUROLOGY LA English DT Article ID ACID STORAGE DISEASE AB The objective of this article is to describe the clinical, radiographic, and molecular genetic features of a new intermediate form of free sialic storage disease. Free sialic storage disease is a rare autosomal recessive lysosomal disorder that results from mutations in SLC17A5, a gene that codes for sialin, a lysosomal membrane sialic acid transporting protein. Infantile sialic acid storage disease has a severe phenotype, and Salla disease (Finnish variant) is generally milder in phenotype; intermediate forms have also been described. There have been few reports of magnetic resonance imaging (MRI) in the sialic acid storage disorders; leukodystrophy has been the characteristic finding, along with hypoplasia of the corpus callosum. An 8-month-old non-Finnish child presented with hypotonia and global developmental delay. Serial MRIs with magnetic resonance spectroscopy at 9 and 16 months revealed severe hypomyelination and hypogenesis of the corpus callosum. There was mild elevation of urinary sialic acid (4.5 times above normal). Electron microscopy of a skin biopsy showed lysosomal enlargement with oligosaccharide storage, and confirmatory molecular genetic testing revealed compound heterozygosity for two new SLC17A5 mutations. Free sialic storage disease of the intermediate type is an important part of the differential diagnosis of a hypotonic, delayed child with abnormal white matter on MRI. Intermediate types of free sialic acid overlap in phenotype with infantile sialic acid storage disease and the milder Salla disease and thus might be more difficult to identify clinically; the lack of Finnish ethnicity should not preclude testing for this probably under-recognized disorder. White-matter abnormalities appear to be characteristic of the entire phenotypic spectrum. C1 Dartmouth Coll, Hitchcock Med Ctr, Dept Pediat, Div Pediat Neurol, Lebanon, NH 03756 USA. NHGRI, Sect Human Biochem Genet, NIH, Med Genet Branch, Bethesda, MD 20892 USA. NIH, Off Rare Dis, Intramural Program, Off Director, Bethesda, MD 20892 USA. Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. Tufts Univ, Sch Vet Med, Dept Pathol, Boston, MA 02111 USA. Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. RP Morse, RP (reprint author), Dartmouth Coll, Hitchcock Med Ctr, Dept Pediat, Div Pediat Neurol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM richard_p_morse@hitchcock.org NR 5 TC 6 Z9 7 U1 0 U2 1 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD OCT PY 2005 VL 20 IS 10 BP 814 EP 816 DI 10.1177/08830738050200100601 PG 3 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 004BR UT WOS:000234727500006 PM 16417876 ER PT J AU Casanova, MF Christensen, JD Giedd, J Rumsey, JM Garver, DL Postel, GC AF Casanova, MF Christensen, JD Giedd, J Rumsey, JM Garver, DL Postel, GC TI Magnetic resonance imaging study of brain asymmetries in dyslexic patients SO JOURNAL OF CHILD NEUROLOGY LA English DT Article ID DEVELOPMENTAL DYSLEXIA; PLANUM TEMPORALE; RECOGNITION; TOMOGRAPHY; MEMORY; MAPS; MEN AB Research studies suggest that the left hemisphere is involved in the pathophysiology of dyslexia. Thus far, the exact location and nature of the purported lesion(s) remain a matter of contention. The present study describes the distribution of structural abnormalities as related to brain symmetry in the brains of dyslexic individuals. High-resolution three-dimensional magnetic resonance images (MRIs) were analyzed in 16 dyslexic men and 14 controls matched for sex, age, educational level, and handedness. A computerized image analysis system was used to assess the volumetric deformations required to match each brain with its left-right mirror image. The results showed significant abnormalities in five left hemisphere structures involving the extrapyramidal and limbic systems: amygdala, hippocampus proper, parahippocampal gyrus, putamen, and globus pallidus. The left hemisphere is thought to play a major role in the temporal analysis of information. This stream of temporal analysis is of importance in motor movements. Reading might have evolved as an exaptation to motor movements requiring the sequential analysis of information. C1 Univ Louisville, Dept Psychiat & Behav Sci, Louisville, KY 40292 USA. Univ Louisville, Dept Diagnost Radiol, Louisville, KY 40292 USA. NIH, Child Psychiat Branch, Bethesda, MD 20892 USA. NIH, Clin Neurosci Branch, Bethesda, MD 20892 USA. RP Casanova, MF (reprint author), Univ Louisville, Dept Psychiat & Behav Sci, 500 S Prston St,Suite 217,Bldg 55A, Louisville, KY 40292 USA. EM MOCASA02@louisville.edu RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU NIMH NIH HHS [MH61606, MH69991, MH62654] NR 49 TC 9 Z9 10 U1 2 U2 4 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD OCT PY 2005 VL 20 IS 10 BP 842 EP 847 DI 10.1177/08830738050200101401 PG 6 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 004BR UT WOS:000234727500014 PM 16417884 ER PT J AU Nussbaum, RL AF Nussbaum, RL TI Mining yeast in silico unearths a golden nugget for mitochondrial biology SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID CHAIN COMPLEX I; YARROWIA-LIPOLYTICA; DEFICIENCY; SUBUNIT AB NADH:ubiquinone oxidoreductase (complex I) of the electron transport chain is a multimeric mitochondrial enzyme of approximately 1000 kDa consisting of 46 different proteins encoded by both the mitochondrial and nuclear genomes. Little is known about the cellular mechanisms and protein chaperones that guide its assembly. In this issue of the jCI, Ogilvie et al. use genomic sequence data to compare the proteins produced by yeasts with and without complex I in order to generate a list of proteins whose human orthologs might serve as complex I assembly proteins (see the related article beginning on page 2784). The gene encoding one of these candidate proteins, B1 7.2L, was found to harbor a nonsense mutation in one of 28 patients with a deficiency of complex I. B17.21, associated with subcomplexes that are seen when complex I assembly is incomplete. The research described here combines clever model organism genomics and bioinformatics with sophisticated human molecular and biochemical genetics to identify the first mammalian protein required for the normal assembly of complex I. C1 NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Nussbaum, RL (reprint author), NHGRI, Genet Dis Res Branch, 49 Convent Dr,Room 4A72, Bethesda, MD 20892 USA. EM rlnuss@mail.nih.gov FU Intramural NIH HHS NR 17 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2005 VL 115 IS 10 BP 2689 EP 2691 DI 10.1172/JC126625 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 971IE UT WOS:000232376600017 PM 16200203 ER PT J AU Bowl, MR Nesbit, MA Harding, B Levy, E Jefferson, A Volpi, E Rizzoti, K Lovell-Badge, R Schlessinger, D Whyte, MP Thakker, RV AF Bowl, MR Nesbit, MA Harding, B Levy, E Jefferson, A Volpi, E Rizzoti, K Lovell-Badge, R Schlessinger, D Whyte, MP Thakker, RV TI An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID IDIOPATHIC HYPOPARATHYROIDISM; REGULATORY ELEMENTS; HDR SYNDROME; GENE; HYPOPITUITARISM; EXPRESSION; DISEASE; REGION; TISSUE; CELLS AB X-finked recessive hypoparathyroidism, due to parathyroid agenesis, has been mapped to a 906-kb region on Xq27 that contains 3 genes (ATP11C, U7snRNA, and SOX3), and analyses have not revealed mutations. We therefore characterized this region by combined analysis of single nucleotide polymorphisms and sequence-tagged sites. This identified a 23- to 25-kb deletion, which did not contain genes. However, DNA fiber-FISH and pulsed-field gel electrophoresis revealed an approximately 340-kb insertion that replaced the deleted fragment. Use of flow-sorted X chromosome-specific1ibraries and DNA sequence analyses revealed that the telomeric and centromeric breakpoints on X were, respectively, approximately 67 kb downstream of SOX3 and within a repetitive sequence. Use of a monochromosomal somatic cell hybrid panel and metaphase-FISH mapping demonstrated that-the insertion originated from 2p25 and contained a segment of the SNTG2 gene that lacked an open reading frame. However, the deletion-insertion [del(X)(q27.1) inv ins (X;2)(q27.1;p25.3)], which represents a novel abnormality causing hypoparathyroidism, could result in a position effect on SOX3 expression. Indeed, SOX3 expression was demonstrated, by in situ hybridization, in the developing parathyroid tissue of mouse embryos between 10.5 and 15.5 days post coitum. Thus,our results indicate a likely new role for SOX3 in the embryonic development of the parathyroid glands. C1 Univ Oxford, Churchill Hosp, OCDEM, Nuffield Dept Med,Acad Endocrine Unit, Oxford OX3 7LJ, England. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. Natl Inst Med Res, MRC, Div Dev Genet, London NW7 1AA, England. NIH, Genet Lab, Baltimore, MD USA. Natl Inst Aging, Baltimore, MD USA. Shriners Hosp Children, Ctr Metab Bone Dis & Mol Res, St Louis, MO USA. Washington Univ, Sch Med, Div Bone & Mineral Dis, St Louis, MO USA. RP Thakker, RV (reprint author), Univ Oxford, Churchill Hosp, OCDEM, Nuffield Dept Med,Acad Endocrine Unit, S Parks Rd, Oxford OX3 7LJ, England. EM rajesh.thakker@ndm.ox.ac.uk OI Thakker, Rajesh/0000-0002-1438-3220 FU Medical Research Council [MC_U117562207] NR 51 TC 50 Z9 54 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2005 VL 115 IS 10 BP 2822 EP 2831 DI 10.1172/JCI24156 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 971IE UT WOS:000232376600033 PM 16167084 ER PT J AU Espinel-Ingroff, A Fothergill, A Ghannoum, M Manavathu, E Ostrosky-Zeichner, L Pfaller, M Rinaldi, M Schell, W Walsh, T AF Espinel-Ingroff, A Fothergill, A Ghannoum, M Manavathu, E Ostrosky-Zeichner, L Pfaller, M Rinaldi, M Schell, W Walsh, T TI Quality control and reference guidelines for CLSI broth microdilution susceptibility method (M38-A document) for amphotericin B, itraconazole, posaconazole, and voriconazole SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article AB Although standard conditions are available for testing the susceptibilities of filamentous fungi to antifungal agents by the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards) broth microdilution assay, quality control QC) MIC limits have not been established for any mold-agent combination. This multicenter (eight-center) study documented the reproducibility of tests for one isolate of Paecilomyces variotii ATCC MYA-3630 and I I other mold isolates (three isolates of Aspergillus fumigatus; two isolates of A. terreus; one isolate each of A. flavus, A. nidulans, Fusarium monilifiorme, and F. solani; and two isolates of Seedosporium apiospermum) by the CLSI reference broth microdilution method (M38-A document). Control limits (amphotericin B,.1 to 4 mu g/ml; itraconazole, 0.06 to 0.5 mu g/ml; posaconazole, 0.03 to 0.25 mu g/ml; voriconazole, 0.0.15 to 0.12 mu g/ml) for the selected QC P. variotii ATCC NYA-3630 were established by the analysis of replicate MIC results. Reference isolates and corresponding MIC ranges were also established for 6 of the 12 molds evaluated. MIC limits were not proposed for the other five molds tested due to low testing reproducibility for these isolates. C1 Virginia Commonwealth Univ, Ctr Med, Richmond, VA 23298 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78285 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Wayne State Univ, Detroit, MI USA. Univ Texas, Sch Med, Houston, TX USA. Univ Iowa, Coll Med, Iowa City, IA USA. Duke Univ, Durham, NC USA. NCI, Bethesda, MD 20892 USA. RP Espinel-Ingroff, A (reprint author), Virginia Commonwealth Univ, Ctr Med, 1101 E Marshall St,Sanger Hall,Rm 7-049,POB 98004, Richmond, VA 23298 USA. EM avingrof@chsc.vcu.edu NR 7 TC 44 Z9 45 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2005 VL 43 IS 10 BP 5243 EP 5246 DI 10.1128/JCM.43.10.5243-5246.2005 PG 4 WC Microbiology SC Microbiology GA 976VV UT WOS:000232762500047 PM 16207990 ER PT J AU O'Mara, A AF O'Mara, A TI Who's taking care of the caregiver? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CANCER-PATIENTS; FAMILY CAREGIVERS; LIFE C1 NCI, Bethesda, MD 20892 USA. RP O'Mara, A (reprint author), NCI, Bethesda, MD 20892 USA. NR 14 TC 8 Z9 9 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 OCT 1 PY 2005 VL 23 IS 28 BP 6820 EP 6821 DI 10.1200/JCO.2005.96.008 PG 2 WC Oncology SC Oncology GA 969KC UT WOS:000232232000003 PM 16145057 ER PT J AU Whelan, TJ Goss, PE Ingle, JN Pater, JL Tu, DS Pritchard, K Liu, SF Shepherd, LE Palmer, M Robert, NJ Martino, S Muss, HB AF Whelan, TJ Goss, PE Ingle, JN Pater, JL Tu, DS Pritchard, K Liu, SF Shepherd, LE Palmer, M Robert, NJ Martino, S Muss, HB TI Assessment of quality of life in MA.17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADVANCED BREAST-CANCER; FIRST-LINE THERAPY; ADJUVANT BREAST; ANASTROZOLE; EXEMESTANE; EFFICACY; TOLERABILITY; COMBINATION; SYMPTOMS; ARIMIDEX AB Purpose To evaluate the impact of letrozole compared with placebo after adjuvant tamoxifen on quality of life (QOL) in the MA.17 trial. Methods Patients completed the Short Form 36-item Health Survey (SF-36) and the Menopause Specific Quality of Life Questionnaire (MENQOL) at baseline, 6 months, and annually. Mean change scores from baseline were compared between groups for summary measures and domains. A response analysis compared the proportion of patients who demonstrated an important change in QOL. Results Of 5,187 randomly assigned women in the trial, 3,612 (69.9%) participated in the QOL substudy: 1,799 were allocated to placebo and 1,813 were allocated to letrozole. No differences were seen between groups in mean change scores from baseline for the SF-36 physical and mental component summary scores at 6, 12, 24, and 36 months. Small (< 0.2 standard deviations) but statistically significant differences in mean change scores from baseline were seen for the SF-36 domains of physical functioning (12 months), bodily pain (6 months) and vitality (6 and 12 months), and the MENQOL vasomotor (6, 12, and 24 months),and sexual domains (12 and 24 months). On the response analysis, a significant difference was seen between groups for the bodily pain domain (percentage of patients reporting a worsening of QOL, 47% placebo v 51% letrozole; P =.009) and the vasomotor domain (22% placebo v 29% letrozole; P =.001). Conclusion Letrozole did not have an adverse impact on overall QOL. Small effects were seen in some domains consistent with a minority of patients experiencing changes in QOL compatible with a reduction in estrogen synthesis. C1 McMaster Univ, Hamilton, ON, Canada. NCI, Clin Trials Grp, Kingston, ON, Canada. Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. Harvard Univ, Sch Med, Boston, MA USA. Mayo Clin, Rochester, MN USA. Inova Fairfax Hosp, Falls Church, VA USA. John Wayne Canc Inst, Santa Monica, CA USA. Univ Vermont, Burlington, VT USA. RP Whelan, TJ (reprint author), Juravinski Canc Ctr, 699 Concess St,Rm 4-204, Hamilton, ON L8V 5C2, Canada. EM tim.whelan@hrcc.on.ca RI Whelan, Timothy/D-3185-2017 NR 24 TC 155 Z9 158 U1 0 U2 3 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 OCT 1 PY 2005 VL 23 IS 28 BP 6931 EP 6940 DI 10.1200/JCO.2005.11.181 PG 10 WC Oncology SC Oncology GA 969KC UT WOS:000232232000017 PM 16157934 ER PT J AU D'Adamo, DR Anderson, SE Albritton, K Yamada, J Riedel, E Scheu, K Schwartz, GK Chen, H Maki, RG AF D'Adamo, DR Anderson, SE Albritton, K Yamada, J Riedel, E Scheu, K Schwartz, GK Chen, H Maki, RG TI Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 05-08, 2004 CL New Orleans, LA SP Amer Soc Clin Oncol ID ENDOTHELIAL GROWTH-FACTOR; COMBINATION CHEMOTHERAPY; MYOCARDIAL-ISCHEMIA; COLORECTAL-CANCER; RANDOMIZED-TRIAL; ANGIOGENESIS; IFOSFAMIDE; THERAPY; TUMORS; VEGF AB Purpose To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). Patients and Methods Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m(2) intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m(2). Results A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m(2) doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m(2), respectively), one grade 3 (total doxorubicin 591 mg/m(2)), and one grade 4 (total doxorubicin 420 mg/m(2)). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. Conclusion The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination. C1 Mem Sloan Kettering Canc Ctr, Gastrointestinal Oncol Serv, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dev Chemotherapy Serv, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Biostat & Epidemiol, New York, NY 10021 USA. Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA. NCI, Invest Drug Branch, Clin Trials Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP D'Adamo, DR (reprint author), Mem Sloan Kettering Canc Ctr, Gastrointestinal Oncol Serv, 1275 York Ave, New York, NY 10021 USA. EM dadamod@mskcc.org FU NCI NIH HHS [N01-CM17105, P01 CA47179] NR 30 TC 158 Z9 170 U1 0 U2 8 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 OCT 1 PY 2005 VL 23 IS 28 BP 7135 EP 7142 DI 10.1200/JCO.2005.16.139 PG 8 WC Oncology SC Oncology GA 969KC UT WOS:000232232000041 PM 16192597 ER PT J AU Quinn, JA Desjardins, A Weingart, J Brem, H Dolan, ME Delaney, SM Vredenburgh, J Rich, J Friedman, AH Reardon, DA Sampson, JH Pegg, AE Moschel, RC Birch, R McLendon, RE Provenzale, JM Gururangan, S Dancey, JE Maxwell, J Tourt-Uhlig, S Herndon, JE Bigner, DD Friedman, HS AF Quinn, JA Desjardins, A Weingart, J Brem, H Dolan, ME Delaney, SM Vredenburgh, J Rich, J Friedman, AH Reardon, DA Sampson, JH Pegg, AE Moschel, RC Birch, R McLendon, RE Provenzale, JM Gururangan, S Dancey, JE Maxwell, J Tourt-Uhlig, S Herndon, JE Bigner, DD Friedman, HS TI Phase I trial of temozolomide plus O-6-benzylguanine for patients with recurrent or progressive malignant glioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY; HIGH-GRADE GLIOMA; BRAIN-TUMOR XENOGRAFTS; GLIOBLASTOMA-MULTIFORME; DNA-REPAIR; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; ANTITUMOR IMIDAZOTETRAZINES; ALKYLATING-AGENTS; MISMATCH REPAIR; 1ST RELAPSE AB Purpose We conducted a two-phase clinical trial in patients with progressive malignant glionna (MG). The first phase of this trial was designed to determine the dose of O-6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O-6-BG. In addition, plasma concentrations of O-6-BG and O-6-benzyl-8-oxoguanine were evaluated after O-6-BG. Patients and Methods For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O-6-BG infusion at 120 mg/m(2) followed by a continuous infusion at an initial dose of 30 mg/m(2)/d for 48 hours. The dose of the continuous infusion of O-6-BG escalated until tumor AGT was depleted. Once the O-6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O-6-BG infusion, was escalated until the MTD was determined. Results The O-6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m(2) over 1 hour followed by a continuous infusion of 30 mg/m(2)/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m(2) with dose-limiting toxicities limited to myelosuppression. Conclusion This study provides the foundation for a phase II trial of O-6-BG plus temozolomide in temozolomide-resistant MG. C1 Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. Johns Hopkins Univ Hosp, Dept Neurosurg, Baltimore, MD 21287 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. NCI, Invest Drug Branch, Bethesda, MD 20892 USA. Univ Chicago, Dept Med, Comm Canc Biol, Chicago, IL 60637 USA. Univ Chicago, Canc Res Inst, Chicago, IL 60637 USA. Milton S Hershey Med Ctr, Dept Cellular & Mol Physiol, Hershey, PA USA. AOI Pharmaceut, Lab Comparat Carcinogenesis, Memphis, TN USA. RP Quinn, JA (reprint author), Duke Univ, Brain Tumor Ctr, S Hosp, Room 047 Baker House,Trent Dr, Durham, NC 27710 USA. EM quinn008@mc.duke.edu FU NCI NIH HHS [CA14599, U01-CA62474]; NINDS NIH HHS [NS30245] NR 56 TC 137 Z9 139 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 OCT 1 PY 2005 VL 23 IS 28 BP 7178 EP 7187 DI 10.1200/JCO.2005.06.502 PG 10 WC Oncology SC Oncology GA 969KC UT WOS:000232232000046 PM 16192602 ER PT J AU Rubinstein, LV Korn, EL Freidlin, B Hunsberger, S Ivy, SP Smith, MA AF Rubinstein, LV Korn, EL Freidlin, B Hunsberger, S Ivy, SP Smith, MA TI Design issues of randomized phase II trials and a proposal for phase II screening trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; CLINICAL-TRIALS; FLEXIBLE DESIGN; GEMCITABINE; INHIBITOR; MUTATIONS; GEFITINIB; SELECTION; SURVIVAL; EFFICACY AB Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing "phase II screening trials," in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (alpha or type I error) and false-negative error rates (beta or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply. C1 NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Rubinstein, LV (reprint author), Room 8130,6130 Execut Plaza, Rockville, MD 20852 USA. EM rubinsteinl@ctep.nci.nih.gov NR 35 TC 154 Z9 157 U1 0 U2 4 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 OCT 1 PY 2005 VL 23 IS 28 BP 7199 EP 7206 DI 10.1200/JCO.2005.01.049 PG 8 WC Oncology SC Oncology GA 969KC UT WOS:000232232000048 PM 16192604 ER PT J AU Dores, GM Anderson, WF Devesa, SS AF Dores, GM Anderson, WF Devesa, SS TI Cutaneous lymphomas reported to the national cancer institute's surveillance, epidemiology, and end results program: Applying the new WHO-European organisation for research and treatment of cancer classification system SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NCI, NIH, Bethesda, MD 20892 USA. RP Dores, GM (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 5 TC 15 Z9 15 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 OCT 1 PY 2005 VL 23 IS 28 BP 7246 EP 7248 DI 10.1200/JCO.2005.03.0395 PG 3 WC Oncology SC Oncology GA 969KC UT WOS:000232232000075 PM 16192622 ER PT J AU James, LP Simpson, PM Farrar, HC Kearns, GL Wasserman, GS Blumer, JL Reed, MD Sullivan, JE Hinson, JA AF James, LP Simpson, PM Farrar, HC Kearns, GL Wasserman, GS Blumer, JL Reed, MD Sullivan, JE Hinson, JA CA Pediat Pharmacology Res Unit Netwo TI Cytokines and toxicity in acetaminophen overdose SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE acetaminophen; cytokines; monocyte chemoattractant protein 1 ID ACUTE LIVER-INJURY; MACROPHAGE INFLAMMATORY PROTEIN-2; INDUCED HEPATOTOXICITY; ALCOHOLIC HEPATITIS; CHEMOKINE EXPRESSION; N-ACETYLCYSTEINE; IFN-GAMMA; MICE; DISEASE; MOUSE AB Several cytokines have been reported to have hepatoprotective properties in animal models of acetaminophen toxicity. To investigate the relationships of cytokines and toxicity in acetaminophen overdose, blood samples were collected from patients following acute ingestions of acetaminophen. Samples for cytokine analysis were collected at the time of routine clinical monitoring in 111 patients (90 females; mean age 13.6 years). Plasma concentrations of interleukin 6, interleukin 8, interleukin 10, and monocyte chemoattractant protein 1 were analyzed by enzyme-linked immunosorbent assay. Patients were stratified by toxicity severity, defined by the maximal values of hepatic transaminase elevation. Levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 were higher in patients with serum alunine aminotransferase > 1000 IU/L, and monocyte chemoattractant protein 1 had the strongest association with toxicity. Monocyte chemoattractant protein 1 values were higher in patients with greater delays in N-acetylcysteine treatment and in patients with higher values of prothrombin time. Monocyte chemoattractant protein 1 elevation in acetaminophen overdose may represent an innate, immunomodulary response of the liver to earlier events in the toxicity. An understanding of the role of cytokine responses in acetaminophen overdose maybe relevant to the future development of new therapies for acetaminophen toxicity. C1 Arkansas Childrens Hosp, Dept Pediat, Sect Clin Pharmacol & Toxicol, Little Rock, AR 72202 USA. Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Pharmacol, Little Rock, AR 72205 USA. Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Childrens Mercy Hosp, Div Pediat Clin Pharmacol & Med Toxicol, Kansas City, MO 64108 USA. Case Western Reserve Univ, Dept Pediat & Pharmacol, Cleveland, OH 44106 USA. Rainbow Babies & Childrens Hosp, Div Pediat Pharmacol & Crit Care Med, Cleveland, OH 44106 USA. Univ Louisville, Dept Pediat, Louisville, KY 40292 USA. Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Kosair Childrens Hosp, Louisville, KY USA. NICHHD, Bethesda, MD 20892 USA. RP James, LP (reprint author), Arkansas Childrens Hosp, Dept Pediat, Sect Clin Pharmacol & Toxicol, 800 Marshall St, Little Rock, AR 72202 USA. EM Jameslaurap@uams.edu FU NICHD NIH HHS [2 HD 31323, 2U01 HD 31313, 2U10 HD 31324, U10 HD 94959 34]; NIDDK NIH HHS [DK 02971]; NIGMS NIH HHS [GM 58884] NR 32 TC 28 Z9 30 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2005 VL 45 IS 10 BP 1165 EP 1171 DI 10.1177/0091270005280296 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966VW UT WOS:000232051900006 PM 16172181 ER PT J AU Grant, BF Stinson, FS Hasin, DS Dawson, DA Chou, P Ruan, WJ Huang, B AF Grant, BF Stinson, FS Hasin, DS Dawson, DA Chou, P Ruan, WJ Huang, B TI Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; MANIC-DEPRESSIVE ILLNESS; MENTAL-HEALTH SURVEY; BIRTH-COHORT CHANGES; UNITED-STATES 1988; PERSONALITY-DISORDERS; DSM-IV; PSYCHIATRIC-DISORDERS; FOLLOW-UP AB Objective: To present nationally representative data on 12-month and lifetime prevalence, correlates, and comorbidity of bipolar I disorder. Method: The data were derived from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). Prevalences and associations of bipolar I disorder with sociodemographic correlates and Axis I and II disorders were determined. Results: Prevalences of 12-month and lifetime DSM-IV bipolar I disorder were 2.0% (95% Cl = 1.82 to 2.18) and 3.3% (95% CI = 2.76 to 3.84), respectively, and no sex differences were observed. The odds of bipolar I disorder were significantly greater among Native Americans, younger adults, and respondents who were widowed/separated/divorced and of lower socioeconomic status and significantly lower among Asians and Hispanics (p < .05). Men were significantly (p < .05) more likely to have unipolar mania and earlier onset and longer duration of manic episodes, while women were more likely to have mixed and major depressive episodes and to be treated for manic, mixed, and major depressive episodes. Bipolar I disorder was found to be highly and significantly related (p < .05) to substance use, anxiety, and personality disorders, but not to alcohol abuse. Conclusion: Bipolar I disorder is more prevalent in the U.S. population than previously estimated, highlighting the underestimation of the economic costs associated with this illness. Associations between bipolar I disorder and Axis I and II disorders were all significant, underscoring the need for systematic assessment of comorbidity among bipolar I patients. C1 NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, NIH,US Dept HHS, Bethesda, MD 20892 USA. Columbia Univ, Dept Epidemiol, New York, NY USA. Columbia Univ, Dept Psychiat, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Grant, BF (reprint author), NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, NIH,US Dept HHS, Room 3077,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov FU NIAAA NIH HHS [K05 AA014223] NR 109 TC 290 Z9 296 U1 13 U2 46 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD OCT PY 2005 VL 66 IS 10 BP 1205 EP 1215 PG 11 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 978ZJ UT WOS:000232911500001 PM 16259532 ER PT J AU Borrelli, B Sepinwall, D Ernst, D Bellg, AJ Czajkowski, S Breger, R DeFrancesco, C Levesque, C Sharp, DL Ogedegbe, G Resnick, B Orwig, D AF Borrelli, B Sepinwall, D Ernst, D Bellg, AJ Czajkowski, S Breger, R DeFrancesco, C Levesque, C Sharp, DL Ogedegbe, G Resnick, B Orwig, D TI A new tool to assess treatment fidelity and evaluation of treatment fidelity across 10 years of health behavior research SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE treatment fidelity; clinical trials; internal validity; health behavior change ID THERAPEUTIC ALLIANCE; RANDOMIZED TRIALS; CONSORT STATEMENT; CONCEPTUAL ISSUES; RECOMMENDATIONS; PSYCHOTHERAPY; THERAPISTS; INTEGRITY; QUALITY; RISK AB A. Bellg, B. Borrelli, et al. (2004) previously developed a framework that consisted of strategies to enhance treatment fidelity of health behavior interventions. The present study used this framework to (a) develop a measure of treatment fidelity and (b) use the measure to evaluate treatment fidelity in articles published in 5 journals over 10 years. Three hundred forty-two articles met inclusion criteria; 22% reported strategies to maintain provider skills, 27% reported checking adherence to protocol, 35% reported using a treatment manual, 54% reported using none of these strategies, and 12% reported using all 3 strategies. The mean proportion adherence to treatment fidelity strategies was .55; 15.5% of articles achieved greater than or equal to .80. This tool may be useful for researchers, grant reviewers, and editors planning and evaluating trials. C1 Brown Univ, Sch Med, Ctr Behav & Prevent Med, Providence, RI 02903 USA. Miriam Hosp, Providence, RI 02906 USA. Univ New Mexico, Dept Psychol, Ctr Alcoholism Substance Abuse & Addict, Albuquerque, NM 87131 USA. NHLBI, Behav Med Sci Res, NIH, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Div Hlth Promot & Sports Med, Portland, OR 97201 USA. SW Missouri State Univ, Dept Psychol, Springfield, MO 65804 USA. Univ Rochester, Sch Nursing, Rochester, NY 14627 USA. Columbia Univ, Dept Med, Behav Cardiovasc Hlth & Hypertens Program, New York, NY 10027 USA. Univ Maryland, Sch Nursing, College Pk, MD 20742 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Borrelli, B (reprint author), Brown Univ, Sch Med, Ctr Behav & Prevent Med, Coro Bldg W,1 Hoppin St,Suite 500, Providence, RI 02903 USA. EM belinda_borrelli@brown.edu FU NHLBI NIH HHS [R01 HL62165] NR 28 TC 181 Z9 181 U1 1 U2 20 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD OCT PY 2005 VL 73 IS 5 BP 852 EP 860 DI 10.1037/0022-006X.73.5.852 PG 9 WC Psychology, Clinical SC Psychology GA 984DL UT WOS:000233282600008 PM 16287385 ER PT J AU Seo, BM Miura, M Sonoyama, W Coppe, C Stanyon, R Shi, S AF Seo, BM Miura, M Sonoyama, W Coppe, C Stanyon, R Shi, S TI Recovery of stem cells from cryopreserved periodontal ligament SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE periodontal ligament stem cells (PDLSCs); osteoblast; cementum; cryopreservation ID IN-VIVO; PROGENITOR; MOUSE AB Human post-natal stem cells possess a great potential to be utilized in stem-cell-mediated clinical therapies and tissue engineering. It is not known whether cryopreserved human tissues contain functional post-natal stem cells. In this study, we utilized human periodontal ligament to test the hypothesis that cryopreserved human periodontal ligament contains retrievable postnatal stem cells. These cryopreserved periodontal ligament stem cells maintained normal periodontal ligament stem cell characteristics, including expression of the mesenchymal stem cell surface molecule STRO-1, single-colony-strain generation, multipotential differentiation, cementum/ periodontal-ligament-like tissue regeneration, and a normal diploid karyotype. Collectively, this study provides valuable evidence demonstrating a practical approach to the preservation of solid-frozen human tissues for subsequent post-natal stem cell isolation and tissue regeneration. The present study demonstrates that human post-natal stem cells can be recovered from cryopreserved human periodontal ligament, thereby providing a practical clinical approach for the utilization of frozen tissues for stem cell isolation. C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Comparat Mol Cytogenet Core, Genet Branch, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Dent, Dept Oral & Maxillofacial Surg, Seoul, South Korea. RP Shi, S (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 131,30 Convent Dr,MSC-4320, Bethesda, MD 20892 USA. EM sshi@dir.nidcr.nih.gov FU Intramural NIH HHS NR 21 TC 126 Z9 147 U1 0 U2 14 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD OCT PY 2005 VL 84 IS 10 BP 907 EP 912 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 966YY UT WOS:000232059900007 PM 16183789 ER PT J AU Yamaguchi, Y Hearing, VJ Itami, S Yoshikawa, K Katayama, I AF Yamaguchi, Y Hearing, VJ Itami, S Yoshikawa, K Katayama, I TI Mesenchymal-epithelial interactions in the skin: Aiming for site-specific tissue regeneration SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Review DE wound heating; fibroblast; keratinocyte; melanocyte; dickkopf 1 ID PALMOPLANTAR FIBROBLASTS; LANGERHANS CELLS; GENE-EXPRESSION; NEURAL CREST; BONE-MARROW; DIFFERENTIATION; PROTEINS; HETEROGENEITY; KERATINOCYTES; MELANOCYTES AB Since trunk skin (or non-palmoplantar skin) is less durable under mechanical stress than sole skin (palm, plantar or palmoplantar skin), conventional trunk-derived skin grafts (including the trunk dermis) commonly result in erosion and ulceration when transplanted on to plantar wounds caused by various injuries including, diabetes mellitus or collagen diseases (including systemic sclerosis, polyarthritis nodosa and rheumatoid arthritis). However, trunk-derived epidermis can adopt a ptantar phenotype, characterized by keratin 9 expression, hypopigmentation and thick suprabasal layers, through factors derived from ptantar dermal fibroblasts in the wounds. Thus, intractable plantar wounds with exposed bones can be treated with the combination of bone marrow exposure, occlusive dressing and epidermal grafting. The higher expression of dickkopf 1 (DKK1), an inhibitor of canonical Wnt/beta-catenin signals, in the plantar dermis partly explains these phenomena. Thus, mesenchymal-epithelial interactions play important roles not only in embryogenesis (the embryonic development) but also in maintaining the homeostasis of adult tissue. The topographical (site-specific) interactions of growth factors and substances, including DKKs, fibroblast growth factors (FGFs) and transforming growth factor-beta (TGF-beta) family proteins including bone morphogenetic proteins (BMPs), may explain the site-specific differences in the skin in addition to the expression patterns of HOX genes and sonic hedgehogs (Shhs). We review the importance of dermal-epidermal interactions in tissue homeostasis and regeneration, especially in palms and soles. (c) 2005 Published by Elsevier Ireland Ltd on behalf of Japanese Society for Investigative Dermatology. C1 Osaka Univ, Grad Sch Med, Dept Dermatol, Suita, Osaka 5650871, Japan. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Katayama, I (reprint author), Osaka Univ, Grad Sch Med, Dept Dermatol, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM katayama@derma.med.osaka-u.ac.jp RI Yamaguchi, Yuji/B-9312-2008 NR 57 TC 48 Z9 49 U1 4 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 J9 J DERMATOL SCI JI J. Dermatol. Sci. PD OCT PY 2005 VL 40 IS 1 BP 1 EP 9 DI 10.1016/j.jdermsci.2005.04.006 PG 9 WC Dermatology SC Dermatology GA 976UI UT WOS:000232758500001 PM 16157476 ER PT J AU MacLeod, RS Shome, S Stinstra, J Punske, BB Hopenfeld, B AF MacLeod, RS Shome, S Stinstra, J Punske, BB Hopenfeld, B TI Mechanisms of ischemia-induced ST-segment changes SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Conference of the International-Society-for-Computerized-Electrocardiology CY APR 12-17, 2005 CL Lihue, HI SP Int Soc Computerized Electrocardiol DE myocardial ischemia; simulation; computer modeling ID SUBENDOCARDIAL ISCHEMIA; MYOCARDIAL ISCHEMIA; CONDUCTION-VELOCITY; PORCINE HEART; INJURY; MODEL; ELECTROCARDIOGRAM; POTENTIALS AB Many aspects of ischemia-induced changes in the electrocardiogram lack solid biophysical underpinnings although variations in ST segments form the predominant basis for diagnostic and monitoring of patients. This incomplete knowledge certainly plays a role in the poor performance of some forms of electrocardiogram-based detection and characterization of ischemia, especially when it is limited to the subendocardium. The focus of our recent studies has been to develop a comprehensive mechanistic model of the electrocardiographic effects of ischemia. The computational component of this model is based on highly realistic heart geometry with anisotropic fiber structure and allows us to assign ischemic action potentials to contiguous regions that can span a prescribed thickness of the ventricles. A separate, high-resolution model of myocardial tissue provides us with a means of setting electrical characteristics of the heart, including the status of gap junctional coupling between cells. The experimental counterpart of this model consists of dog hearts, either in situ or isolated and perfused with blood, in which we control coronary blood flow by means of a cannula and blood pump. By reducing blood flow through the cannula for various durations, we can replicate any phase of ischemia from hyper acute to early infarction. Based on the results of these models, there is emerging a mechanism of the electrocardiographic response to ischemia that depends strongly on the anisotropic conductivity of the myocardium. Ischemic injury currents flow across the boundary between healthy and ischemic tissue, but it is their interaction with local fiber orientation and the associated conductivity that generates secondary currents that determine epicardial ST-segment potentials. Results from experiments support qualitatively the findings of the simulations and underscore the role of myocardial anisotropy in electrocardiography. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Utah, Nora Eccles Harrison CVRTI, Salt Lake City, UT 84112 USA. Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP MacLeod, RS (reprint author), Univ Utah, Nora Eccles Harrison CVRTI, Salt Lake City, UT 84112 USA. EM macleod@cvrti.utah.edu FU NHLBI NIH HHS [HL P41RR12553] NR 33 TC 11 Z9 11 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD OCT PY 2005 VL 38 IS 4 SU S BP 8 EP 13 DI 10.1016/j.jelectrocard.2005.06.095 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 982VZ UT WOS:000233191000002 PM 16226067 ER PT J AU Arca, B Lombardo, F Valenzuela, JG Francischetti, IMB Marinotti, O Coluzzi, M Ribeiro, JAC AF Arca, B Lombardo, F Valenzuela, JG Francischetti, IMB Marinotti, O Coluzzi, M Ribeiro, JAC TI An updated catalogue of salivary gland transcripts in the adult female mosquito, Anopheles gambiae SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE saliva; malaria; sialome; transcriplome ID AEDES-AEGYPTI; DROSOPHILA-MELANOGASTER; PROTEIN DATABASE; BINDING PROTEIN; GENE FAMILY; EXPRESSION; CALRETICULIN; SEQUENCE; VENOM; REPRESSION AB Salivary glands of blood-sucking arthropods contain a variety of compounds that prevent platelet and clotting functions and modify inflammatory and immunological reactions in the vertebrate host. In mosquitoes, only the adult female takes blood meals, while both sexes take sugar meals. With the recent description of the Anopheles gambiae genome, and with a set of similar to 3000 expressed sequence tags from a salivary gland cDNA library from adult female mosquitoes, we attempted a comprehensive description of the salivary transcriptome of this most important vector of malaria transmission. In addition to many transcripts associated with housekeeping functions, we found an active transposable element, a set of Wolbachia-like proteins, several transcription factors, including Forkhead, Hairy and doublesex, extracellular matrix components and 71 genes coding for putative secreted proteins. Fourteen of these 71 proteins had matching Edman degradation sequences obtained from SDS-PAGE experiments. Overall, 33 transcripts are reported for the first time as coding for salivary proteins. The tissue and sex specificity of these protein-coding transcripts were analyzed by RT-PCR and microarray experiments for insight into their possible function. Notably, two gene products appeared to be differentially spliced in the adult female salivary glands, whereas 13 contigs matched predicted intronic regions and may include additional alternatively spliced transcripts. Most An. gambiae salivary proteins represent novel protein families of unknown function, potentially coding for pharmacologically or microbiologically active substances. Supplemental data to this work can be found at http:// www.ncbi.nlm.nih.gov/projects/omes/index.html#Ag2. C1 NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Univ Naples Federico 2, Dept Struct & Funct Biol, I-80126 Naples, Italy. Univ Roma La Sapienza, Dept Publ Hlth, Parasitol Sect, I-00185 Rome, Italy. Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. RP Ribeiro, JAC (reprint author), NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM jribeiro@nih.gov RI Lombardo, Fabrizio/J-8511-2014; OI Lombardo, Fabrizio/0000-0002-8563-0612; Arca, Bruno/0000-0002-4029-0984; Marinotti, Osvaldo/0000-0002-7173-7160; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS NR 93 TC 111 Z9 115 U1 1 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD OCT PY 2005 VL 208 IS 20 BP 3971 EP 3986 DI 10.1242/jcb.01849 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 983GH UT WOS:000233218900015 PM 16215223 ER PT J AU Zhou, JS Brum, G Gonzalez, A Launikonis, BS Stern, MD Rios, E AF Zhou, JS Brum, G Gonzalez, A Launikonis, BS Stern, MD Rios, E TI Concerted vs. sequential. Two activation patterns of vast arrays of intracellular Ca2+ channels in muscle SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID FROG SKELETAL-MUSCLE; CALCIUM-RELEASE CHANNELS; MAMMALIAN MUSCLE; RYANODINE RECEPTORS; ELEMENTARY EVENTS; SPARKS; DEPOLARIZATION; ORGANIZATION; RESOLUTION; FIBERS AB To signal cell responses, Ca2+ is released from storage through intracellular Ca2+ channels. Unlike most plasmalemmal channels, these are clustered in quasi-crystalline arrays, which should endow them with unique properties. Two distinct patterns of local activation of Ca2+ release were revealed in images of Ca2+ sparks in permeabilized cells of amphibian muscle. In the presence of sulfate, an anion that enters the SR and precipitates Ca2+, sparks became wider than in the conventional, glutamate-based solution. Some of these were "protoplatykurtic" (had a flat top from early on), suggesting an extensive array of channels that activate simultaneously. Under these conditions the rate of production of signal mass was roughly constant during the rise time of the spark and could be as high as 5 mu m(3) ms(-1), consistent with a release current >50 pA since the beginning of the event. This pattern, called "concerted activation," was observed also in rat muscle fibers. When sulfate was combined with a reduced cytosolic [Ca2+] (50 nM) these sparks coexisted (and interfered) with a sequential progression of channel opening, probably mediated by Ca2+-induced Ca2+ release (CICR). Sequential propagation, observed only in frogs, may require parajunctional channels, of RyR isoform beta, which are absent in the rat. Concerted opening instead appears to be a property of RyR alpha in the amphibian and the homologous isoform 1 in the mammal. C1 Rush Univ, Sect Cellular Signaling, Chicago, IL 60612 USA. Univ Republica, Dept Biofis, Montevideo, Uruguay. Inst Venezolano Invest Cient, Caracas, Venezuela. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Rios, E (reprint author), Rush Univ, Sect Cellular Signaling, Chicago, IL 60612 USA. EM erios@rush.edu RI Launikonis, Bradley/K-6256-2015 FU NIAMS NIH HHS [R01 AR032808] NR 42 TC 17 Z9 17 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD OCT PY 2005 VL 126 IS 4 BP 301 EP 309 DI 10.1085/jgp.200509353 PG 9 WC Physiology SC Physiology GA 967VW UT WOS:000232120300001 PM 16186560 ER PT J AU Schlecht, NF Burk, RD Palefsky, JM Minkoff, H Xue, XA Massad, LS Bacon, M Levine, AM Anastos, K Gange, SJ Watts, DH Da Costa, MM Chen, ZG Bang, JY Fazzari, M Hall, C Strickler, HD AF Schlecht, NF Burk, RD Palefsky, JM Minkoff, H Xue, XA Massad, LS Bacon, M Levine, AM Anastos, K Gange, SJ Watts, DH Da Costa, MM Chen, ZG Bang, JY Fazzari, M Hall, C Strickler, HD TI Variants of human papillomaviruses 16 and 18 and their natural history in human immunodeficiency virus-positive women SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; CERVICAL INTRAEPITHELIAL NEOPLASIA; FEMALE UNIVERSITY-STUDENTS; POLYMERASE-CHAIN-REACTION; ASIAN-AMERICAN VARIANTS; HPV 16 E6; SEQUENCE VARIANTS; WORLDWIDE PERSPECTIVE; PERSISTENT INFECTION; NUCLEOTIDE-SEQUENCE AB Highly oncogenic human papillomavirus (HPV) 16 and 18 variants might be expected to be particularly aggressive in HIV-positive women. The association of HPV16 and 18 variant lineages with race, human immunodeficiency virus (HIV) coinfection, CD4(+) T-cell count, HIV-RNA level, time-to-clearance of HPV infection and presence of squamous intraepithelial lesions (SIL) among women in the Women's Interagency HIV Study was studied. Subjects were followed semi-annually with Pap smear and cervicovaginal lavage (CVL). HPV DNA was detected in CVLs using MY09/11L1 PCR assay. Specimens positive for HPV16/18 underwent E6 PCR and sequencing to determine the variant present. Specimens from 195 HPV16- and 162 HPV18-positive women were classified into variant lineages based on sequencing results. African variants of HPV16 and HPV18 were significantly more prevalent among African-Americans than among Caucasians [42 versus 14% (P=0(.)001) and 60 versus 13% (P < 0(.)001), respectively]. However, it was not possible to detect associations between the HPV16 or 18 variant lineages and other factors studied. African variants of HPV16/18 were more common in women of African descent living outside Africa, which could reflect mixing behaviours and/or immunogenetic factors. However, in a large population of HIV-infected women, the variant of HPV16 or 18 was unrelated to persistence of infection or presence of SIL. If non-European variants are more oncogenic, the effect may involve a late stage in cervical tumorigenesis. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Maimonides Hosp, Brooklyn, NY 11219 USA. So Illinois Univ, Sch Med, Springfield, IL USA. Henry M Jackson Fdn, Rockville, MD USA. Univ So Calif, Los Angeles, CA USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NICHHD, Bethesda, MD 20892 USA. RP Schlecht, NF (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM nschlech@aecom.yu.edu RI Chen, Zigui/E-8490-2017; OI Gange, Stephen/0000-0001-7842-512X FU NCI NIH HHS [R01 CA085178-06]; NCRR NIH HHS [M01-RR-00079, M-01-RR-00083]; NIAID NIH HHS [U01-AI-34993, U01-AI-31834, U01-AI-34994, U01-AI-35004, U01-AI-42590]; NICHD NIH HHS [U01-HD-32632] NR 53 TC 32 Z9 33 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD OCT PY 2005 VL 86 BP 2709 EP 2720 DI 10.1099/vir.0.81060-0 PN 10 PG 12 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 971LN UT WOS:000232385700007 PM 16186224 ER PT J AU Kaphingst, KA Rudd, RE Dejong, W Daltroy, LH AF Kaphingst, KA Rudd, RE Dejong, W Daltroy, LH TI Comprehension of information in three direct-to-consumer television prescription drug advertisements among adults with limited literacy SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article AB Direct-to-consumer (DTC) television advertisements present a number of facts about prescription drug risks and benefits in a brief time. This study assessed comprehension of information in three advertisements among 50 adults with limited literacy. Participants correctly answered an average of 59% of comprehension questions. The percentage of respondents correctly answering individual comprehension questions ranged from 26% to 92%. A multivariate analysis suggested that type of information ( risk vs. other) and channel ( text vs. audio) predicted comprehension. There was a significant interaction effect for literacy and place of birth. Our results suggest key areas for future research on comprehension of DTC advertising. C1 Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02215 USA. Brigham & Womens Hosp, RBB Arthrit Res Ctr, Boston, MA 02115 USA. RP Kaphingst, KA (reprint author), NHGRI, Social & Behav Res Branch, Bldg 2,Room 4E30,2 Ctr Dr,MSC 0249, Bethesda, MD 20892 USA. EM kkaphing@mail.nih.gov FU NIAMS NIH HHS [P60AR47782] NR 21 TC 22 Z9 22 U1 1 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1081-0730 J9 J HEALTH COMMUN JI J. Health Commun. PD OCT-NOV PY 2005 VL 10 IS 7 BP 609 EP 619 DI 10.1080/10810730500267647 PG 11 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA 981VA UT WOS:000233114900003 PM 16278198 ER PT J AU Lederer, DJ Kawut, SM Sonett, JR Vakiani, E Seward, SL White, JG Wilt, JS Marboe, CC Gahl, WA Arcasoy, SM AF Lederer, DJ Kawut, SM Sonett, JR Vakiani, E Seward, SL White, JG Wilt, JS Marboe, CC Gahl, WA Arcasoy, SM TI Successful bilateral lung transplantation for pulmonary fibrosis associated with the Hermansky-Pudlak syndrome SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article AB Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, a bleeding diathesis, and in a subset of patients, pulmonary fibrosis. Lung transplantation, the only curative therapy for pulmonary fibrosis, has not been previously reported as a successful treatment strategy for patients with HPS because the bleeding diathesis was thought to contraindicate major thoracic surgery. We successfully performed bilateral sequential lung transplantation in a patient with pulmonary fibrosis and HPS after transfusion of 6 units of platelets. Lung transplantation is a viable therapeutic option in patients with pulmonary fibrosis and only a mild bleeding diathesis associated with HPS. C1 Columbia Univ Coll Phys & Surg, Lung Transplantat Program, Div Pulm Allergy & Crit Care Med, Dept Med, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Div Gen Med, Dept Med, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Cardiothorac Surg, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. Univ Minnesota, Dept Lab Med & Pathol, Sch Med, Minneapolis, MN USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Arcasoy, SM (reprint author), Columbia Univ Coll Phys & Surg, Lung Transplantat Program, Div Pulm Allergy & Crit Care Med, Dept Med, 622 W 168th St,PH-14,Room 104, New York, NY 10032 USA. EM sa2059@columbia.edu NR 9 TC 18 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD OCT PY 2005 VL 24 IS 10 BP 1697 EP 1699 DI 10.1016/j.healun.2004.11.015 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 973EU UT WOS:000232506500035 PM 16210149 ER PT J AU Alter, HJ AF Alter, HJ TI HCV natural history: The retrospective and prospective in perspective SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material ID HEPATITIS-C INFECTION; NON-A; NON-B; FOLLOW-UP; OUTCOMES; VIRUS C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Alter, HJ (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM halter@mail.cc.nih.gov NR 11 TC 58 Z9 62 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD OCT PY 2005 VL 43 IS 4 BP 550 EP 552 DI 10.1016/j.jhep.2005.07.002 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 969KH UT WOS:000232232500001 PM 16099527 ER PT J AU Williams, JA Hathcock, KS Klug, D Harada, Y Choudhury, B Allison, JP Abe, R Hodes, RJ AF Williams, JA Hathcock, KS Klug, D Harada, Y Choudhury, B Allison, JP Abe, R Hodes, RJ TI Regulated costimulation in the thymus is critical for T cell development: Dysregulated CD28 costimulation can bypass the pre-TCR checkpoint SO JOURNAL OF IMMUNOLOGY LA English DT Article ID THYMOCYTE DEVELOPMENT; PHOSPHATIDYLINOSITOL 3-KINASE; ALLELIC EXCLUSION; ACTIVATED LCK; MUTANT MICE; IN-VITRO; B-CELLS; RECEPTOR; ALPHA; SURVIVAL AB Expression of CD28 is highly regulated during thymic development, with CD28 levels extremely low, on immature thymocytes but increasing dramatically as CD4(-)CD8(-) cells initiate expression of TCR beta. B7-1 and B7-2, the ligands for CD28, have a restricted distribution in the thymic cortex where immature thymocytes reside and are more highly expressed in the medulla where the most mature thymocytes are located. To determine the importance of this regulated CD28/B7 expression for T cell development, we examined the effect of induced CD28 signaling of immature thymocytes in CD28/B7-2 double-transgenic mice. Strikingly, we found that differentiation to the CD4(+)CD8(+) stage in CD28/B7-2 transgenics proceeds independent of the requirement for TCR beta expression manifest in wild-type thymoeytes, occurring even in Rag(-) or CD3 epsilon(-) knockouts. These findings indicate that signaling of immature thymocytes through CD28 in the absence of TCR- or pre-TCR-derived signals can promote an aberrant pathway of T cell differentiation and highlight the importance of finely regulated physiologic expression of CD28 and B7 in maintaining integrity of the "beta" checkpoint for pre-TCR/TCR-dependent thymic differentiation. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. Tokyo Univ Sci, Res Inst Biol Sci, Chiba, Japan. Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Hodes, RJ (reprint author), NCI, Expt Immunol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 4B10, Bethesda, MD 20892 USA. EM Richard_Hodes@nih.gov FU NCI NIH HHS [Z01 BC009281-19] NR 39 TC 28 Z9 28 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2005 VL 175 IS 7 BP 4199 EP 4207 PG 9 WC Immunology SC Immunology GA 967LL UT WOS:000232092600009 PM 16177059 ER PT J AU Liu, XL Taylor, BJ Sun, GP Bosselut, R AF Liu, XL Taylor, BJ Sun, GP Bosselut, R TI Analyzing expression of perforin, Runx3, and thpok genes during positive selection reveals activation of CD8-differentiation programs by MHC II-signaled thymocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL LINEAGE COMMITMENT; CD8(+) T-CELLS; TRANSCRIPTION FACTOR; NEGATIVE SELECTION; ANTIGEN RECEPTOR; THYMIC SELECTION; CD4 LINEAGE; DIFFERENTIAL REQUIREMENTS; STOCHASTIC MECHANISM; TRANSGENIC MICE AB Intrathymic positive selection matches CD4-CD8 lineage differentiation to MHC specificity. However, it is unclear whether MHC signals induce lineage choice or simply select thymocytes of the appropriate lineage. To investigate this issue, we assessed thymocytes undergoing positive selection for expression of the CD8 lineage markers perforin and Runx3. Using both population-based and single-cell RT-PCR analyses, we found large subsets of MHC class II (MHC-II)-signaled thymocytes expressing these genes within the CD4(+)8(+) and CD4(+)8(int), but not the CD4(+)8(-) populations of signaling competent mice. This indicates that MHC-II signals normally fail to impose CD4 differentiation and further implies that the number of mature CD8 single-positive (SP) thymocytes greatly underestimates CD8 lineage choice. We next examined whether MHC-II-restricted CD4(+)8(-) thymocytes remain competent to initiate CD8 lineage gene expression. In mice in which expression of the tyrosine kinase Zap70 and thereby TCR signaling were impaired selectively in SP thymocytes, MHC-II-signaled CD4(+)8(-) thymocytes expressed perforin and Runx3 and failed to up-regulate the CD4 marker Thpok. This indicated that impairing TCR signals at the CD4 SP stage switched gene expression patterns from CD4- to CD8-lineage specific. We conclude from these findings that MHC-II-signaled thymocytes remain competent to initiate CD8-specific gene expression even after CD8 down-regulation and that CD4 lineage differentiation is not fixed before the CD4 SP stage. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. NCI, FACS Cor, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 37,Room 3015, Bethesda, MD 20892 USA. EM remy@helix.nih.gov NR 64 TC 17 Z9 17 U1 2 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 OCT 1 PY 2005 VL 175 IS 7 BP 4465 EP 4474 PG 10 WC Immunology SC Immunology GA 967LL UT WOS:000232092600039 PM 16177089 ER PT J AU Milicic, A Price, DA Zimbwa, P Booth, BL Brown, HL Easterbrook, PJ Olsen, K Robinson, N Gileadi, U Sewell, AK Cerundolo, V Phillips, RE AF Milicic, A Price, DA Zimbwa, P Booth, BL Brown, HL Easterbrook, PJ Olsen, K Robinson, N Gileadi, U Sewell, AK Cerundolo, V Phillips, RE TI CD8(+) T cell epitope-flanking mutations disrupt proteasomal processing of HIV-1 Nef SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC LYMPHOCYTES-T; CLASS-I; TYPE-1 INFECTION; DOWN-REGULATION; IMMUNE CONTROL; QUANTITATIVE-ANALYSIS; DISEASE DEVELOPMENT; ESCAPE MUTATION; CONSERVED CORE AB CTL play a critical role in the control of HIV and SIV. However, intrinsic genetic instability enables these immunodeficiency viruses to evade detection by CTL through mutation of targeted antigenic sites. These mutations can impair binding of viral epitopes to the presenting MHC class I molecule or disrupt TCR-mediated recognition. In certain regions of the virus, functional constraints are likely to limit the capacity for variation within epitopes. Mutations elsewhere in the protein, however, might still enable immune escape through effects on Ag processing. In this study, we describe the coincident emergence of three mutations in a highly conserved region of Nef during primary HIV-1 infection. These mutations (R69K, A81G, and H87R) flank the HLA B*35-restricted VY8 epitope and persisted to fixation as the early CTL response to this Ag waned. The variant form of Nef showed a reduced capacity to activate VY8-specific CTL, although protein stability and expression levels were unchanged. This effect was associated with altered processing by the proteasome that caused partial destruction of the VY8 epitope. Our data demonstrate that a variant HIV genotype can significantly impair proteasomal epitope processing and substantiate the concept of immune evasion through diminished Ag generation. These observations also indicate that the scale of viral escape may be significantly underestimated if only intraepitope variation is evaluated. C1 Univ Oxford, James Martin Century Sch 21st, Oxford OX1 3SY, England. Univ Oxford, Nuffield Dept Clin Med, Oxford OX1 3SY, England. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Tumour Immunol Unit, Oxford OX3 9DU, England. Univ London Kings Coll, Guys Kings & St Thomas Sch Med, Acad Dept HIV & Genitourinary Med, London WC2R 2LS, England. RP Milicic, A (reprint author), Univ Oxford, James Martin Century Sch 21st, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. EM anita.milicic@medawar.ox.ac.uk RI Milicic, Anita/B-7693-2011; Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Cerundolo, Vincenzo/0000-0003-0040-3793 FU Medical Research Council [G108/441]; Wellcome Trust NR 75 TC 42 Z9 43 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 OCT 1 PY 2005 VL 175 IS 7 BP 4618 EP 4626 PG 9 WC Immunology SC Immunology GA 967LL UT WOS:000232092600057 PM 16177107 ER PT J AU Garvey, TL Dyer, KD Ellis, JA Bonville, CA Foster, B Prussin, C Easton, AJ Domachowske, JB Rosenberg, HF AF Garvey, TL Dyer, KD Ellis, JA Bonville, CA Foster, B Prussin, C Easton, AJ Domachowske, JB Rosenberg, HF TI Inflammatory responses to pneumovirus infection in IFN-alpha BR gene-deleted mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; INTERFERON REGULATORY FACTOR-3; ANTIVIRAL DEFENSE; EPITHELIAL-CELLS; VIRAL-INFECTION; IN-VIVO; DIFFERENTIAL EXPRESSION; PULMONARY INFLAMMATION; RIBONUCLEASE GENES; NS PROTEINS AB Pneumonia virus of mice (PVM; family Paramyxoviridae) is a natural pathogen of rodents that reproduces important clinical features of severe respiratory syncytial virus infection in humans. As anticipated, PVM infection induces transcription of IFN antiviral response genes preferentially in wild-type over IFN-alpha beta R gene-deleted (IFN-alpha beta R-/-) mice. However, we demonstrate that PVM infection results in enhanced expression of eotaxin-2 (CCL24), thymus and activation-regulated chemokine (CCL17), and the proinflammatory RNase mouse eosinophil-associated RNase (mEar) 11, and decreased expression of monocyte chemotactic protein-5, IFN-gamma-inducible protein-10, and TLR-3 in lung tissue of IFN-alpha beta R-/- mice when compared with wild type. No differential expression of chemokines MIP-1 alpha or MIP-2 or Th2 cytokines IL-4 or IL-5 was observed. Differential expression of proinflammatory mediators was associated with distinct patterns of lung pathology. The widespread granulocytic infiltration and intra-alveolar edema observed in PVM-infected, wild-type mice are replaced with patchy, dense inflammatory foci localized to the periphery of the larger blood vessels. Bronchoalveolar lavage fluid from IFN-alpha beta R-/- mice yielded 7- to 8-fold fewer leukocytes overall, with increased percentages of eosinophils, monocytes, and CD4(+) T cells, and decreased percentage of CD8(+) T cells. Differential pathology is associated with prolonged survival of the IFN-alpha beta R-/- mice (50% survival at 10.8 +/- 0.6 days vs the wild type at 9.0 +/- 0.3 days; p < 0.02) despite increased virus titers. Overall, our findings serve to identify novel transcripts that are differentially expressed in the presence or absence of IFN-alpha beta R-mediated. signaling, further elucidating interactions between the IFN and antiviral inflammatory responses in vivo. C1 NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. SUNY Syracuse, Upstate Med Univ, Syracuse, NY 13210 USA. Western Coll Vet Med, Saskatoon, SK, Canada. Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. RP Rosenberg, HF (reprint author), NIAID, NIH, Lab Allerg Dis, 9000 Rockville Pike,Bldg 10,Room 11N104, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 42 TC 43 Z9 43 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2005 VL 175 IS 7 BP 4735 EP 4744 PG 10 WC Immunology SC Immunology GA 967LL UT WOS:000232092600071 PM 16177121 ER PT J AU Patel, SY Ding, L Brown, MR Lantz, L Gay, T Cohen, S Martyak, LA Kubak, B Holland, SM AF Patel, SY Ding, L Brown, MR Lantz, L Gay, T Cohen, S Martyak, LA Kubak, B Holland, SM TI Anti-IFN-gamma autoantibodies in disseminated nontuberculous mycobacterial infections SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-GAMMA; CYTOKINE AUTOANTIBODIES; RHEUMATOID-ARTHRITIS; ANTIBODIES; INTERLEUKIN-12; AUTOIMMUNITY; TUBERCULOSIS; INDUCTION; GENETICS; IMMUNITY AB Although many patients with disseminated nontuberculous mycobacterial disease have molecular defects in the IFN-'Y/IL-12 axis, recent case reports have shown autoantibodies against IFN-gamma associated with severe nontuberculous mycobacterial infections. To check this finding in an independent population, we screened 35 patients with either disseminated or pulmonary nontuberculous mycobacterial infections for whom no molecular defect was known. We identified high-titer-neutralizing anti-IFN-gamma IgG in the plasma of six patients. All six patients were female, parous, of East Asian descent, and had disseminated infection, predominantly with rapidly growing mycobacteria. The anti-IFN-gamma IgG had in vitro biological activity on the IFN-y-dependent phosphorylation of STAT-I as well as on the UFN-gamma-dependent up-regulation of TNF-alpha and IL-12. In contrast, this anti-IFN-gamma Ab had no effect on IIFN-alpha-dependent STAT-1 phosphorylation. These patients confirm a novel syndrome linking autoimmunity and immunodeficiency. C1 NIAID, Lab Clin Infect Dis, Clin Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, Bethesda, MD 20892 USA. Tri City Med Ctr, Oceanside, CA 92056 USA. Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, Clin Res Ctr, NIH, Bldg 10,B3-4141 Mail Stop Code 1684, Bethesda, MD 20892 USA. EM smh@nih.gov NR 23 TC 90 Z9 92 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2005 VL 175 IS 7 BP 4769 EP 4776 PG 8 WC Immunology SC Immunology GA 967LL UT WOS:000232092600075 PM 16177125 ER PT J AU Goepfert, PA Horton, H McElrath, MJ Gurunathan, S Ferrari, G Tomaras, GD Montefiori, DC Allen, M Chiu, YL Spearman, P Fuchs, JD Koblin, BA Blattner, WA Frey, S Keefer, MC Baden, LR Corey, L AF Goepfert, PA Horton, H McElrath, MJ Gurunathan, S Ferrari, G Tomaras, GD Montefiori, DC Allen, M Chiu, YL Spearman, P Fuchs, JD Koblin, BA Blattner, WA Frey, S Keefer, MC Baden, LR Corey, L CA NIAID HIV Vaccine Trials Network TI High-dose recombinant canarypox vaccine expressing HIV-1 protein, in seronegative human subjects SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 10th Conference on Retroviruses and Opportunistic Infections CY FEB 10-14, 2003 CL BOSTON, MA ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL; IMMUNE-RESPONSES; CLINICAL-TRIAL; FOWLPOX VIRUS; VOLUNTEERS; VECTOR; IMMUNIZATION; COMBINATION; ENVELOPE AB Background. In clinical trials, canarypox ALVAC-human immunodeficiency virus (HIV) vaccines have been shown to elicit human HIV-specific cytotoxic T lymphocyte (CTL) responses in some but not all healthy uninfected adults. Methods. A clinical trial was conducted to examine whether the vaccine vCP1452 would elicit a greater HIV-specific CTL response when given at a dose of 10(8.0) TCID50 (60 participants) than when given at the regular dose, 10(7.26) TCID50 (40 participants); as a control, a placebo vaccine preparation also was administered (10 participants). Results. Two weeks after the last vaccination in a series, HIV-specific CTL responses were not significantly different when measured by either chromium-release assay (8% and 16% in the high- and regular-dose recipients, respectively) or interferon-gamma ELISpot assay (8% and 15% in the high- and regular-dose recipients, respectively); moreover, recipients of the higher dose had greater local and systemic reactions (P < .001). Conclusions. High reactogenicity associated with an increased dose of vCP1452 negates the need for further evaluation of this strategy to boost the frequency of HIV-specific CTL response in seronegative human subjects. Development of highly immunogenic canarypox vectors requires further work to optimize vector and insert design, as well as novel ways to increase dosage and to reduce reactogenicity. C1 Univ Alabama, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. HIV Vaccine Trials Network, Seattle, WA USA. Anentis, Swiftwater, PA USA. Duke Univ, Med Ctr, Cent Immunol Lab, Durham, NC USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. New York Blood Ctr, New York, NY 10021 USA. Univ Rochester, Med Ctr, Rochester, NY 14642 USA. St Louis Univ, Sch Med, St Louis, MO USA. Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Goepfert, PA (reprint author), Univ Alabama, Dept Med, Div Infect Dis, 908 20th St S,CCS 328, Birmingham, AL 35294 USA. EM paulg@uab.edu RI Ferrari, Guido/A-6088-2015; Tomaras, Georgia/J-5041-2016; OI Allen, Mary/0000-0001-8163-0714 FU NIAID NIH HHS [1U01 AI46725, 1U01 AI46747, 1U01 AI46757, 1U01 AI47976, 1U01 AI47980, 1U01 AI47985, 1U01 AI47996, 1U01 AI48001, 1U01 AI48017, 1U01 AI48021, 1U01 AI48022, 1U01 AI48023] NR 31 TC 53 Z9 53 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 OCT 1 PY 2005 VL 192 IS 7 BP 1249 EP 1259 DI 10.1086/432915 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 960WK UT WOS:000231623700018 PM 16136469 ER PT J AU Lee, EJ Kantor, R Zijenah, L Sheldon, W Emel, L Mateta, P Johnston, E Wells, J Shetty, AK Coovadia, H Maldonado, Y Jones, SA Mofenson, LM Contag, CH Bassett, M Katzenstein, DA AF Lee, EJ Kantor, R Zijenah, L Sheldon, W Emel, L Mateta, P Johnston, E Wells, J Shetty, AK Coovadia, H Maldonado, Y Jones, SA Mofenson, LM Contag, CH Bassett, M Katzenstein, DA CA HIVNET 023 Study Team TI Breast-milk shedding of drug-resistant HIV-1 subtype C in women exposed to single-dose nevirapine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 11th Conference on Retroviruses and Opportunistic Infections CY FEB 08-11, 2004 CL San Francisco, CA ID TO-CHILD TRANSMISSION; IMMUNODEFICIENCY-VIRUS TYPE-1; INTRAPARTUM; HIVNET-012 AB Single-dose nevirapine reduces intrapartum human immunodeficiency virus 1 type (HIV-1) transmission but may also select for nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance in breast milk ( BM) and plasma. Among 32 Zimbabwean women, median 8-week postpartum plasma and BM HIV-1 RNA levels were 4.57 and 2.13 log(10) copies/mL, respectively. BM samples from women with laboratory-diagnosed mastitis (defined as elevated BM Na+ levels) were 5.4-fold more likely to have HIV-1 RNA levels above the median. BM RT sequences were not obtained for 12 women with BM HIV-1 RNA levels below the lower limit of detection of the assay used. In 20 paired BM and plasma samples, 65% of BM and 50% of plasma RT sequences had NNRTI-resistance mutations, with divergent mutation patterns. C1 Stanford Univ, Sch Med, Div Infect Dis, Ctr AIDS Res, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Univ Zimbabwe, Sch Med, Harare, Zimbabwe. Zimbabwe AIDS Prevent Project, Harare, Zimbabwe. Univ Natal, Nelson Mandela Sch Med, ZA-4001 Durban, South Africa. RP Katzenstein, DA (reprint author), Stanford Univ, Sch Med, Div Infect Dis, Ctr AIDS Res, 300 Pasteur Dr,S-169, Stanford, CA 94305 USA. EM davidkk@stanford.edu OI Mofenson, Lynne/0000-0002-2818-9808 NR 15 TC 38 Z9 40 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2005 VL 192 IS 7 BP 1260 EP 1264 DI 10.1086/444424 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 960WK UT WOS:000231623700019 PM 16136470 ER PT J AU Li, QS Lifson, JD Duan, L Schacker, TW Reilly, C Carlis, J Estes, JD Haase, AT AF Li, QS Lifson, JD Duan, L Schacker, TW Reilly, C Carlis, J Estes, JD Haase, AT TI Potential roles of follicular dendritic cell-associated osteopontin in lymphoid follicle pathology and repair and in B cell regulation in HIV-1 and SIV infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; BONE SIALOPROTEIN; AUTOIMMUNE-DISEASE; PERIPHERAL-BLOOD; T-CELLS; ACTIVATION; ETA-1; GENE; MICE; EXPRESSION AB Osteopontin is a multifunctional protein with known roles in bone remodeling, wound healing, and normal and pathological immune responses. We showed in microarray studies that osteopontin gene expression is increased in human immunodeficiency virus type 1 (HIV-1)-infected lymphatic tissues after treatment, and we undertook mapping experiments to study osteopontin's possible functions in this context. We discovered species-specific colocalization of osteopontin with the follicular dendritic cell (FDC) network in lymphatic tissues in HIV-1 and simian immunodeficiency virus infections, and we found that changes in FDC-associated osteopontin covary with changes in lymphoid follicles during acute and late stages of infection and in response to treatment. We propose that this localization normally facilitates antibody production and plays a role in B cell abnormalities in infection and in the reconstitution of lymphoid follicles with treatment and that mapping genes identified in microarray studies is a useful experimental approach to gaining a better understanding of function in the context of a particular tissue and disease. C1 Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Biostat, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA. SAIC Frederick Inc, AIDS Vaccine Program, NCI, Frederick, MD USA. RP Haase, AT (reprint author), Univ Minnesota, Dept Microbiol, MMC 196,420 Delaware St SE, Minneapolis, MN 55455 USA. EM haase001@umn.edu FU NCI NIH HHS [N01-CO-124000]; NIAID NIH HHS [R01 AI 056997] NR 36 TC 7 Z9 8 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 OCT 1 PY 2005 VL 192 IS 7 BP 1269 EP 1276 DI 10.1086/444430 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 960WK UT WOS:000231623700021 PM 16136472 ER PT J AU Modjarrad, K Zulu, I Redden, DT Njobvu, L Lane, HC Bentwich, Z Vermund, SH AF Modjarrad, K Zulu, I Redden, DT Njobvu, L Lane, HC Bentwich, Z Vermund, SH TI Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BLOOD MONONUCLEAR-CELLS; IMMUNE ACTIVATION; VIRAL LOAD; INCREASED CCR5; T-CELL; INFECTION; DISEASE; AIDS; PROGRESSION AB Background. Infection with intestinal helminths may stimulate dysfunctional immune responses in human immunodeficiency virus (HIV)-infected persons. Studies have yielded conflicting results regarding the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA. Methods. We conducted a prospective study of 54 HIV-1- and helminth-coinfected and 57 HIV-1 -infected, helminth-uninfected asymptomatic adults living in Lusaka, Zambia, to assess the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA. Results. Median baseline viral load was 0.33 log 10 copies/mL lower in the helminth-infected group than in the uninfected group. Mean viral load between pretreatment and posttreatment visits increased in the helminth-infected (mean, 4.23 vs. 4.29 log 10 copies/mL;) and helminth-uninfected (mean, 4.39 vs. 4.52 log 10 copies/mL;) groups. Helminth-infected participants with high pretreatment viral loads had a mean 0.25-log(10) copies/ mL decrease after treatment (P = .3), and helminth-uninfected participants had a mean 0.02- log 10 copies/ mL decrease (P = .8). Conclusions. We did not find an overall association between treatment of intestinal helminth infections and reduction in viral load in coinfected adults. Future studies may need to focus on adults with intense helminth infections who live in rural areas or on adults or children who harbor higher helminth burdens and plasma concentrations of HIV-1 RNA. C1 Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. NIAID, NIH, Washington, DC USA. Univ Lusaka, Teaching Hosp, Dept Med, Lusaka, Zambia. AIDS Ctr, Rehovot, Israel. Ruth Ben Ari Inst Clin Immunol, Rehovot, Israel. RP Modjarrad, K (reprint author), Univ Alabama, Dept Epidemiol, 1530 3rd Ave S,BBRB 206B, Birmingham, AL 35294 USA. EM kmodjarrad@uasom.meis.uab.edu OI Vermund, Sten/0000-0001-7289-8698 FU FIC NIH HHS [R03 TW005929, R03 TW005929-01, R03 TW05929]; NIGMS NIH HHS [T32 GM008361] NR 37 TC 44 Z9 45 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 OCT 1 PY 2005 VL 192 IS 7 BP 1277 EP 1283 DI 10.1086/444543 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 960WK UT WOS:000231623700022 PM 16136473 ER PT J AU Bharti, K Arnheiter, H AF Bharti, K Arnheiter, H TI When pigment cells turn into neurons SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID GENE; TRANSDIFFERENTIATION; DIFFERENTIATION; RETINA; CHX10; MITF; EYE C1 NINDS, Mammalian Dev Sect, NIH, Bethesda, MD 20892 USA. RP Bharti, K (reprint author), NINDS, Mammalian Dev Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 12 TC 3 Z9 3 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2005 VL 125 IS 4 BP X EP XI DI 10.1111/j.0022-202X.2005.23876.x PG 2 WC Dermatology SC Dermatology GA 973XU UT WOS:000232556700002 PM 16185257 ER PT J AU Lanning, JL Wallace, JS Zhang, DM Diwakar, G Jiao, ZX Hornyak, TJ AF Lanning, JL Wallace, JS Zhang, DM Diwakar, G Jiao, ZX Hornyak, TJ TI Altered melanocyte differentiation and retinal pigmented epithelium transdifferentiation induced by Mash1 expression in pigment cell precursors SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE melanocyte; transgenic; pigment; development; RPE; transcription ID MAMMALIAN ACHAETE-SCUTE; MOUSE MICROPHTHALMIA LOCUS; TYROSINASE-RELATED PROTEIN; NEURAL CREST; DOPACHROME TAUTOMERASE; TRANSCRIPTION FACTORS; WAARDENBURG-SYNDROME; EYE DEVELOPMENT; CHICK RETINA; DNA-BINDING AB Transcription factor genes governing pigment cell development that are associated with spotting mutations in mice include members of several structural transcription factor classes but not members of the basic helix-loop-helix (bHLH) class, important for neurogenesis and myogenesis. To determine the effects of bHLH factor expression on pigment cell development, the neurogenic bHLH factor Mash1 was expressed early in pigment cell development in transgenic mice from the dopachrome tautomerase (Dct) promoter. Dct.Mash1 transgenic founders exhibit variable microphthalmia and patchy coat color hypopigmentation. Transgenic F1 mice exhibit microphthalmia with complete coat color dilution. Marker analysis demonstrates that Mash1 expression in the retinal pigmented epithelium (RPE) initiates neurogenesis in this cell layer, whereas expression in remaining neural crest-derived melanocytes alters their differentiation, in part by profoundly downregulating expression of the p (pink-eyed dilution) gene, while maintaining their cell fate. The effects of transcriptional perturbation of pigment cell precursors by Mash1 further highlight differences between pigment cells of distinct developmental origins, and suggest a mechanism for the alteration of melanogenesis to result in marked coat color dilution. C1 NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. Henry Ford Hlth Syst, Dept Dermatol, Detroit, MI USA. RP Hornyak, TJ (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10-12N242, Bethesda, MD 20814 USA. EM hornyakt@mail.nih.gov FU NIAMS NIH HHS [K08 AR01992, R01 AR47951, R03 AR45001] NR 64 TC 9 Z9 9 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2005 VL 125 IS 4 BP 805 EP 817 DI 10.1111/j.0022-202X.2005.23819.x PG 13 WC Dermatology SC Dermatology GA 973XU UT WOS:000232556700027 PM 16185282 ER PT J AU Lee, JL Kim, A Kopelovich, L Bickers, DR Athar, M AF Lee, JL Kim, A Kopelovich, L Bickers, DR Athar, M TI Differential expression of E prostanoid receptors in murine and human non-melanoma skin cancer SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE basal cell carcinoma; cyclooxygenase; non-melanoma skin cancer; prostaglandin E-2 (PGE(2)); squamous cell carcinoma ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BASAL-CELL CARCINOMAS; AGONIST-INDUCED INTERNALIZATION; PROSTAGLANDIN EP3 RECEPTOR; BREAST-CANCER; MOUSE SKIN; CYCLOOXYGENASE-2 EXPRESSION; COX-2; ULTRAVIOLET; MICE AB Enhanced prostaglandin production via upregulated cyclooxygenase-2 (COX-2) expression is a likely contributing factor in ultraviolet B (UVB)-induced non-melanoma skin cancer (NMSC), which consists primarily of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The four E prostanoid (EP) receptors, designated EP, through EP4, are known to bind prostaglandin E-2 (PGE(2)), the major prostaglandin present in the skin. We used murine models of UVB-induced SCC and BCC, as well as human NMSC from sun-exposed sites, to investigate the expression of EP receptors during UVB-induced tumorigenesis. We observed that UVB-induced murine SCC are associated with markedly altered expression patterns of the EP receptors when compared with non-irradiated skin. In contrast, expression of all EP receptors was largely absent in UVB-induced murine BCC. We also observed expression of all four EP receptors in human SCC, with altered expression of their mRNA levels as compared with adjacent tumor-free skin. Consistent with our murine studies, no EP receptor expression was detected in human BCC, and their mRNA expression levels showed no change from the adjacent non-tumor-bearing skin. These data suggest that altered EP receptor expression may play a differential role in the development of UVB-induced SCC and BCC in murine and human skin. C1 Columbia Univ Coll Phys & Surg, Dept Dermatol, Vanderbilt Clin 15 204, New York, NY 10032 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Athar, M (reprint author), Columbia Univ Coll Phys & Surg, Dept Dermatol, Vanderbilt Clin 15 204, 630 W 168th St, New York, NY 10032 USA. EM ma493@columbia.edu FU NCI NIH HHS [R01 CA-97249-01, T32 CA09685, N01-CN-15011-72, N01-CN-15109, N01-CN-35105, N01-CN-35006-72, U19 CA 81888, CA-10106-01]; NIAMS NIH HHS [P30 AR 44535, K01-AR048582] NR 34 TC 45 Z9 47 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2005 VL 125 IS 4 BP 818 EP 825 DI 10.1111/j.0022-202X.2005.23829.x PG 8 WC Dermatology SC Dermatology GA 973XU UT WOS:000232556700028 PM 16185283 ER PT J AU Wang, JP Vokkarane, VM Jothi, R Qi, XT Raghavachari, B Jue, JP AF Wang, JP Vokkarane, VM Jothi, R Qi, XT Raghavachari, B Jue, JP TI Dual-homing protection in IP-over-WDM networks SO JOURNAL OF LIGHTWAVE TECHNOLOGY LA English DT Article DE dual homing; lightpath; protection; wavelength division multiplexing (WDM) ID COMPUTER-NETWORKS; DESIGN; SURVIVABILITY; COST; RING AB A fault-tolerant scheme, called dual homing, is generally used in IP-based access networks to increase the availability of the networks. In a dual-homing architecture, a host is connected to two different access routers; therefore, it is unlikely that the host will be denied access to the network as the result of an access line break, a defective power supply in the access router, or congestion of the access router. This dual-homing architecture in the access network imposes the overhead to provide protection in the core network. Scaling the next-generation IP-over-wavelength-division-multiplexing (WDM) Internet, and being able to support a growing number of such dual-homing connections, as well as protection, demands a scalable mechanism to contain this overhead for protection in the WDM networks. This paper studies the coordinated protection design to reduce the protection cost in the WDAI core network, given a dual-homing infrastructure in the access network. The protection problem is considered for both static and dynamic traffic. Several solutions are proposed, and the performances of the solutions are compared. We also prove that one of the proposed algorithms gives a solution that, in the worst case, is at most 413 times the cost of the optimal solution. C1 Georgia So Univ, Dept Comp Sci, Statesboro, GA 30460 USA. Univ Massachusetts Dartmouth, Dept Comp & Informat Sci, N Dartmouth, MA 02747 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Hong Kong Univ Sci & Technol, Dept Ind Engn & Engn Management, Hong Kong, Hong Kong, Peoples R China. Univ Texas, Dept Comp Sci, Richardson, TX 75080 USA. RP Wang, JP (reprint author), Georgia So Univ, Dept Comp Sci, Statesboro, GA 30460 USA. EM jpwang@gerogiasouthern.edu; vvokkarane@umassd.edu; jothi@ncbi.nim.nih.gov; ieemqi@ust.hk; rbk@utdallas.edu; jjue@utdallas.edu RI Qi, Xiangtong/C-1370-2008; Wang, Jianping/H-3974-2011; Jothi, Raja/G-3780-2015; OI Qi, Xiangtong/0000-0003-4573-0157; WANG, Jianping /0000-0002-9318-1482 NR 15 TC 10 Z9 10 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0733-8724 J9 J LIGHTWAVE TECHNOL JI J. Lightwave Technol. PD OCT PY 2005 VL 23 IS 10 BP 3111 EP 3124 DI 10.1109/JLT.2005.856321 PG 14 WC Engineering, Electrical & Electronic; Optics; Telecommunications SC Engineering; Optics; Telecommunications GA 978ZM UT WOS:000232911800029 ER PT J AU Sabol, SL Brewer, HB Santamarina-Fojo, S AF Sabol, SL Brewer, HB Santamarina-Fojo, S TI The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver SO JOURNAL OF LIPID RESEARCH LA English DT Article DE ATP binding cassette transporter; liver X receptor; retinoid X receptor; cholesterol; hepatocyte; oxysterols; T-0901317; promoter; transcription start site ID DROSOPHILA-WHITE GENE; BINDING CASSETTE TRANSPORTERS; CELLULAR CHOLESTEROL EFFLUX; HIGH-DENSITY-LIPOPROTEIN; X-RECEPTOR; NUCLEAR RECEPTOR; OXYSTEROL RECEPTORS; CONSERVED SEQUENCES; RXR HETERODIMERS; GENOME BROWSER AB The ABC transporter ABCG1 ( ATP binding cassette transporter G1), expressed in macrophages, liver, and other tissues, has been implicated in the efflux of cholesterol to high density lipoprotein. The ABCG1 gene is transcriptionally activated by cholesterol loading and activators of liver X receptors ( LXRs) and retinoid X receptors ( RXRs) through genomic sequences that have not been fully characterized. Here we show that ABCG1 mRNA is induced by LXR agonists in RAW264.7 macrophage cells, HepG2 hepatoma cells, and primary mouse hepatocytes. We identify two evolutionarily highly conserved LXR response elements ( LXREs), LXRE- A and LXRE- B, located in the first and second introns of the human ABCG1 gene. Each element conferred robust LXR- agonist responsiveness to ABCG1 promoterdirected luciferase gene constructs in RAW264.7 and HepG2 cells. Overexpression of LXR/ RXR activated the ABCG1 promoter in the presence of LXRE- A or LXRE- B sequences. In gel- shift assays, LXR/ RXR heterodimers bound to wild- type but not to mutated LXRE- A and LXRE- B sequences. In chromatin immunoprecipitation assays, LXR and RXR were detected at LXRE- A and - B regions of DNA of human THP- 1 macrophages. These studies clarify the mechanism of transcriptional upregulation of the ABCG1 gene by oxysterols in macrophages and liver, two key tissues where ABCG1 expression may affect cholesterol balance and atherogenesis. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Sabol, SL (reprint author), NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. EM slsabol@mail.nih.gov FU Intramural NIH HHS NR 65 TC 83 Z9 94 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2005 VL 46 IS 10 BP 2151 EP 2167 DI 10.1194/jlr.M500080-JLR200 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 965UE UT WOS:000231975000012 PM 16024918 ER PT J AU Masood, A Stark, KD Salem, N AF Masood, A Stark, KD Salem, N TI A simplified and efficient method for the analysis of fatty acid methyl esters suitable for large clinical studies SO JOURNAL OF LIPID RESEARCH LA English DT Article DE fatty acid analysis; plasma; transesterification method; robotic chemistry; fast gas chromatographic analysis ID CORONARY-HEART-DISEASE; MYOCARDIAL-INFARCTION; LIPID EXTRACTION; BLOOD; RISK; TRANSESTERIFICATION; METABOLISM; SUICIDE; TISSUES; PLASMA AB Conventional sample preparation for fatty acid analysis is a complicated, multiple- step process, and gas chromatography ( GC) analysis alone can require > 1 h per sample to resolve fatty acid methyl esters ( FAMEs). Fast GC analysis was adapted to human plasma FAME analysis using a modified polyethylene glycol column with smaller internal diameters, thinner stationary phase films, increased carrier gas linear velocity, and faster temperature ramping. Our results indicated that fast GC analyses were comparable to conventional GC in peak resolution. A conventional transes-terification method based on Lepage and Roy was simplified to a one- step method with the elimination of the neutralization and centrifugation steps. A robotics- amenable method was also developed, with lower methylation temperatures and in an open- tube format using multiple reagent additions. The simplified methods produced results that were quantitatively similar and with similar coefficients of variation as compared with the original Lepage and Roy method. The present streamlined methodology is suitable for the direct fatty acid analysis of human plasma, is appropriate for research studies, and will facilitate large clinical trials and make possible population studies. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD USA. Univ Waterloo, Lab Nutrit & Nutraceut Res, Dept Kinesiol, Waterloo, ON, Canada. RP Salem, N (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD USA. EM nsalem@niaaa.nih.gov RI Stark, Ken/I-1347-2016 OI Stark, Ken/0000-0001-7828-4072 FU Intramural NIH HHS NR 39 TC 116 Z9 120 U1 3 U2 29 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2005 VL 46 IS 10 BP 2299 EP 2305 DI 10.1194/jlr.D500022-JLR200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 965UE UT WOS:000231975000028 PM 16061957 ER PT J AU Wideroff, L Vadaparampil, ST Greene, MH Taplin, S Olson, L Freedman, AN AF Wideroff, L Vadaparampil, ST Greene, MH Taplin, S Olson, L Freedman, AN TI Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PRIMARY-CARE PHYSICIANS; BREAST-CANCER; FAMILY-HISTORY; SUSCEPTIBILITY; ATTITUDES; EDUCATION; PREDISPOSITION; PROFESSIONALS; RISK AB Background: Clinically relevant genetics knowledge is essential for appropriate assessment and management of inherited cancer risk, and for effective communication with patients. This national physician survey assessed knowledge regarding basic cancer genetics concepts early in the process of introduction of predictive genetic testing for breast/ ovarian and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. Methods: A stratified random sample was selected from the American Medical Association Masterfile of all licensed physicians. In total, 1251 physicians ( 820 in primary care, 431 in selected subspecialties) responded to a 15 minute questionnaire ( response rate 71%) in 1999 - 2000. Multivariate logistic regression analyses were conducted to identify demographic and practice characteristics associated with accurate response to three knowledge questions. Results: Of the study population, 37.5% was aware of paternal inheritance of BRCA1/2 mutations, and 33.8% recognised that these mutations occur in,10% of breast cancer patients. Only 13.1% accurately identified HNPCC gene penetrance as > 50%. Obstetrics/gynaecology physicians, oncologists, and general surgeons were significantly more likely than general and family practitioners to respond accurately to the breast/ ovarian questions, as were gastroenterologists to the HNPCC question. Conclusions: These nationally representative data indicate limited physician knowledge about key cancer genetics concepts in 1999 - 2000, particularly among general primary care physicians. Specialists were more knowledgeable about syndromes they might treat or refer elsewhere. Recent dissemination of practice guidelines and continued expansion of relevant clinical literature may enhance knowledge over time. In addition to educational efforts to assist physicians with the growing knowledge base, more research is needed to characterise the organisational changes required within the healthcare system to provide effective cancer genetics services. C1 NCI, ARP, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Hlth Outcomes & Behav Program, Tampa, FL 33682 USA. ABT Associates Inc, Chicago, IL USA. RP Wideroff, L (reprint author), NCI, ARP, Div Canc Control & Populat Sci, EPN 4005 MSC 7344,6130 Execut Blvd, Bethesda, MD 20892 USA. EM wideroff@nih.gov RI Hernandez, Jessica/G-6527-2011 FU NCI NIH HHS [N01-PC-85079] NR 42 TC 89 Z9 90 U1 1 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD OCT PY 2005 VL 42 IS 10 BP 749 EP 755 DI 10.1136/jmg.2004.030296 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 970EW UT WOS:000232289000002 PM 15784723 ER PT J AU Bhanu, NV Singh, UB Chakraborty, M Suresh, N Arora, J Rana, T Takkar, D Seth, P AF Bhanu, NV Singh, UB Chakraborty, M Suresh, N Arora, J Rana, T Takkar, D Seth, P TI Improved diagnostic value of PCR in the diagnosis of female genital tuberculosis leading to infertility SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; LINKED-IMMUNOSORBENT-ASSAY; MYCOBACTERIUM-TUBERCULOSIS; DNA; AMPLIFICATION; ELISA AB Histopathological and mycobacteriological examinations have limited utility in the diagnosis of genital tuberculosis. In this double-blind study, 61 samples, consisting of endometrial aspirates (EAs), endometrial biopsies (EBs) and fluid from the pouch of Douglas (POD), from 25 women suffering from infertility were investigated for the presence of the mpt64 gene of Mycobacterium tuberculosis by PCR and correlated with laparoscopic findings. PCR demonstrated M. tuberculosis DNA in 14 out of 25 patients (56(.)0%), compared to one smear with acid-fast bacilli (1(.)6%) and two culture-positive samples (3(.)2%). The presence of M. tuberculosis DNA was observed in 53(.)3% of EBs, 47(.)6% of EAs and 16(.)0% of POD fluid samples. All patients with laparoscopy suggestive of tuberculosis, 60% of those with a probable diagnosis and 33% of those with incidental findings were positive by PCR. However, one EA sample from an infertile patient with normal laparoscopy was also positive. Multiple sampling from different sites and amplification of the mpt64 gene segment by PCR offered increased sensitivity in determining tuberculous aetiology in female infertility. C1 All India Inst Med Sci, Dept Microbiol, New Delhi 110029, India. All India Inst Med Sci, Dept Gynaecol, New Delhi 110029, India. NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Singh, UB (reprint author), All India Inst Med Sci, Dept Microbiol, New Delhi 110029, India. EM urvashi00@hotmail.com RI Veerapu, Naga Suresh/F-4338-2011 NR 23 TC 58 Z9 66 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-2615 J9 J MED MICROBIOL JI J. Med. Microbiol. PD OCT PY 2005 VL 54 IS 10 BP 927 EP 931 DI 10.1099/jmm.0.45943-0 PG 5 WC Microbiology SC Microbiology GA 971JG UT WOS:000232379500004 PM 16157545 ER PT J AU Mahalanabis, M Hirsch, VM Haigwood, NL AF Mahalanabis, M Hirsch, VM Haigwood, NL TI Infection with a molecularly cloned SIVsm virus elicits high titer homologous neutralizing antibodies with heterologous neutralizing activity SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 22nd Annual Symposium on Nonhuman Primate Models for AIDS CY NOV 03-06, 2004 CL San Antonio, TX SP SW Natl Primate Res Ctr DE broad neutralization; N-linked glycosylation; simian immunodeficiency virus ID SIMIAN IMMUNODEFICIENCY VIRUS; HUMAN MONOCLONAL-ANTIBODIES; HIV-1/SIV CHIMERIC VIRUS; ENVELOPE GLYCOPROTEIN; LINKED GLYCOSYLATION; TYPE-1 INFECTION; RHESUS-MONKEYS; MACAQUES; EVOLUTION; PROTECTION AB We have evaluated the homologous and heterologous neutralizing antibody response in a cohort of six Macaca nemestrina infected with the cloned virus SIVsm62d that showed different levels of envelope diversification. Two progressor macaques developed AIDS by 1.5 years post-inoculation and four non-progressors were asymptomatic for 3 years of follow-up. All macaques developed high titers of neutralizing antibodies against homologous SIVsm viruses and intermediate titers against SIVsmB670. Heterologous virus neutralization of SIVmac, SIVmne, and HIV-2 was detected at much lower levels in both progressor macaques; only one of four non-progressors had evidence for broader neutralizing antibody activity. We noted changes in potential N-linked glycosylation (PNG) sites in V1/V2, C2, and V4 that were common to multiple macaques. These results support a model for viral neutralization where heterologous neutralization is, in part, driven by a strong homologous response and may be coupled to changes in PNG sites in envelope. C1 Seattle Biomed Res Inst, Seattle, WA 98109 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. NIAID, Mol Microbiol Lab, Twinbrook Facil 2, Rockville, MD USA. RP Haigwood, NL (reprint author), Seattle Biomed Res Inst, 307 Westlake Ave N,Suite 500, Seattle, WA 98109 USA. EM nancy.haigwood@sbri.org NR 34 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2005 VL 34 IS 5-6 SI SI BP 253 EP 261 DI 10.1111/j.1600-0684.2005.00123.x PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 959LD UT WOS:000231518300005 PM 16128920 ER PT J AU Boyer, JD Robinson, TM Kutzler, MA Parkinson, R Calarota, SA Sidhu, MK Muthumani, K Lewis, M Pavlakis, G Felber, B Weiner, D AF Boyer, JD Robinson, TM Kutzler, MA Parkinson, R Calarota, SA Sidhu, MK Muthumani, K Lewis, M Pavlakis, G Felber, B Weiner, D TI SIV DNA vaccine co-administered with IL-12 expression plasmid enhances CD8 SIV cellular immune responses in cynomolgus macaques SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 22nd Annual Symposium on Nonhuman Primate Models for AIDS CY NOV 03-06, 2004 CL San Antonio, TX SP SW Natl Primate Res Ctr DE vaccine; DNA; IL-12; HIV; SIV ID INTERFERON-GAMMA PRODUCTION; MEDIATED PROTECTIVE IMMUNITY; T-CELLS; STIMULATORY FACTOR; IN-VIVO; IFN-GAMMA; CD8-T-CELL MEMORY; CD4-T-CELL HELP; RHESUS-MONKEYS; NK-CELLS AB Current evidence suggests that a strong induced CD8 human immunodeficiency virus type 1 (HIV-1)-specific cell mediated immune response may be an important aspect of an HIV vaccine. The response rates and the magnitude of the CTL responses induced by current DNA vaccines in humans need to be improved and cellular immune responses to DNA vaccines can be enhanced in mice by co-delivering DNA plasmids expressing immune modulators. Two reported to work well in the mouse systems are interleukin (IL)-12 and CD40L. We sought to compare these molecular adjuvants in a primate model system. The cDNA for macaque IL-12 and CD40L were cloned into DNA vectors. Groups of cynomolgus macaques were immunized with 2 mg of plasmid expressing SlVgag alone or in combination with either IL-12 or CD40L. CD40L did not appear to enhance the cellular immune response to SlVgag antigen. However, more robust results were observed in animals co-injected with the IL-12 molecular adjuvant. The IL-12 expanded antigen-specific IFN-gamma positive effector cells as well as granzyme B production. The vaccine immune responses contained both a CD8 component as well a CD4 component. The adjuvanted DNA vaccines illustrate that IL-12 enhances a CD8 vaccine immune response, however, different cellular profiles. C1 Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Wyeth, Vaccine Discovery, Pearl River, NY USA. Bioqual, Frederick, MD USA. NCI, Bethesda, MD 20892 USA. RP Weiner, D (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM dbweiner@mail.med.upenn.edu RI Muthumani, Karuppiah/D-1092-2009 NR 56 TC 71 Z9 71 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2005 VL 34 IS 5-6 SI SI BP 262 EP 270 DI 10.1111/j.1600-0684.2005.00124.x PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 959LD UT WOS:000231518300006 PM 16128921 ER PT J AU Cline, AN Bess, JW Piatak, M Lifson, JD AF Cline, AN Bess, JW Piatak, M Lifson, JD TI Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 22nd Annual Symposium on Nonhuman Primate Models for AIDS CY NOV 03-06, 2004 CL San Antonio, TX SP SW Natl Primate Res Ctr DE plasma; processing; quantitative; RNA; reverse transcription-polymerase chain reaction ID IMMUNODEFICIENCY VIRUS-INFECTION; POLYMERASE CHAIN-REACTION; DENDRITIC-CELL VACCINE; HIV-1 INFECTION; TYPE-1 RNA; PCR ASSAY; INACTIVATION; QUANTITATION; DNA; REPLICATION AB As new assay methods for quantitative reverse transcription-polymerase chain reaction (RT-PCR), such as real time RT-PCR techniques, approach theoretical limits of per reaction sensitivity, further increments in the sensitivity of measurements of viral load can only be achieved by increasing the amount of input RNA per reaction. We describe a robust, convenient, rapid integrated approach for specimen preparation and real time RT-PCR assay for plasma simian immunodeficiency virus (SIV) RNA viral load that provides a threshold sensitivity of 10 copy Eq/ml, and tolerates less than optimally processed specimens. The method provides accurate quantitation of viral load for the SIV virus isolates in common use for non-human primate studies. We demonstrate the utility of the method in sensitively tracking viral load in an animal showing effective control of viral replication to levels below the threshold for quantitation in conventional assays. C1 SAIC Frederick Inc, NCI Frederick, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Lifson, JD (reprint author), SAIC Frederick Inc, NCI Frederick, AIDS Vaccine Program, Bldg 535,5th Floor, Frederick, MD 21702 USA. EM lifson@ncifcrf.gov RI Bess, Jr., Julian/B-5343-2012 FU NCI NIH HHS [N01-CO-12400] NR 28 TC 203 Z9 204 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2005 VL 34 IS 5-6 SI SI BP 303 EP 312 PG 10 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 959LD UT WOS:000231518300010 PM 16128925 ER PT J AU Zhang, M Liu, J Jiang, M Wu, DM Sonawane, K Guy, HR Tseng, GN AF Zhang, M Liu, J Jiang, M Wu, DM Sonawane, K Guy, HR Tseng, GN TI Interactions between charged residues in the transmembrane segments of the voltage-sensing domain in the hERG channel SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE voltage-gated K channel; structure-function relationship; mutagenesis; voltage clamp; Xenopus laevis; oocytes ID DEPENDENT K+ CHANNEL; POTASSIUM CHANNELS; MOLECULAR-MOVEMENT; SENSOR; PORE; ACTIVATION; CONFORMATION; KINETICS; CURRENTS; ENCODES AB Studies on voltage-gated K channels such as Shaker have shown that positive charges in the voltage-sensor (S4) can form salt bridges with negative charges in the surrounding transmembrane segments in a state-dependent manner, and different charge pairings can stabilize the channels in closed or open states. The goal of this study is to identify such charge interactions in the hERG channel. This knowledge can provide constraints on the spatial relationship among transmembrane segments in the channel's voltage-sensing domain, which are necessary for modeling its structure. We first study the effects of reversing S4's positive charges on channel activation. Reversing positive charges at the outer (K525D) and inner (K538D) ends of S4 markedly accelerates hERG activation, whereas reversing the 4 positive charges in between either has no effect or slows activation. We then use the 'mutant cycle analysis' to test whether D456 (outer end of S2) and D411 (inner end of S1) can pair with K525 and K538, respectively. Other positive charges predicted to be able, or unable, to interact with D456 or D411 are also included in the analysis. The results are consistent with predictions based on the distribution of these charged residues, and confirm that there is functional coupling between D456 and K525 and between D411 and K538. C1 Virginia Commonwealth Univ, Dept Physiol, Richmond, VA 23298 USA. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Tseng, GN (reprint author), Virginia Commonwealth Univ, Dept Physiol, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM gtseng@hsc.vcu.edu OI Sonawane, Kailas/0000-0003-0156-7466 FU NHLBI NIH HHS [HL 46451, HL 67840] NR 38 TC 30 Z9 31 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD OCT PY 2005 VL 207 IS 3 BP 169 EP 181 DI 10.1007/s00232-005-0812-1 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 019XH UT WOS:000235871000006 PM 16550488 ER PT J AU Gannot, G Tangrea, MA Gillespie, JW Erickson, HS Wallis, BS Leakan, RA Knezevic, V Hartmann, DP Chuaqui, RF Emmert-Buck, MR AF Gannot, G Tangrea, MA Gillespie, JW Erickson, HS Wallis, BS Leakan, RA Knezevic, V Hartmann, DP Chuaqui, RF Emmert-Buck, MR TI Layered peptide arrays - High-throughput antibody screening of clinical samples SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID PRIMARY SJOGRENS-SYNDROME; PROTEIN MICROARRAYS; AUTOANTIBODIES; ANTIGENS; ASSAY; IMMUNOASSAY; AUTOANTIGEN; INFECTION; SALIVARY AB High-throughput methods to detect and quantify antibodies in sera and other patient specimens have use for many clinical and laboratory studies, including those associated with cancer detection, microbial exposures, and autoimmune diseases. We developed a new technique, termed layered peptide array (LPA), to serve as a screening tool to detect antibodies in a highly multiplexed format. We demonstrate here that a prototype LPA was capable of producing approximately 5000 measurements per experiment and appeared to be scalable to higher throughput levels. Sera and saliva from Sjogren's syndrome patients served as a test set to examine antibody titers in clinical samples. The LPA platform exhibited both a high sensitivity (100%) and high specificity (94%) for correctly identifying SSB antigen-positive samples. The multiplex capability of the platform was also confirmed when serum and saliva samples were analyzed for antibody reactivity to several peptides, including Sjogren's syndrome antigens A and B. The data indicate that LPA analysis will be a useful method for a number of screening applications. C1 NCI, Pathogenet Unit, Ctr Adv Technol, Lab Pathol ,NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. 20 20 GeneSyst, Rockville, MD USA. Georgetown Univ, Washington, DC 20057 USA. RP Emmert-Buck, MR (reprint author), NCI, Pathogenet Unit, Ctr Adv Technol, Lab Pathol ,NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM mbuck@helix.nih.gov NR 28 TC 20 Z9 20 U1 2 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD OCT PY 2005 VL 7 IS 4 BP 427 EP 436 DI 10.1016/S1525-1578(10)60573-9 PG 10 WC Pathology SC Pathology GA 972ED UT WOS:000232436000001 PM 16237212 ER PT J AU Hsieh, CL Xie, Z Liu, ZY Green, JE Martin, WD Datta, MW Yeung, F Pan, D Chung, LWK AF Hsieh, CL Xie, Z Liu, ZY Green, JE Martin, WD Datta, MW Yeung, F Pan, D Chung, LWK TI A luciferase transgenic mouse model: visualization of prostate development and its androgen responsiveness in live animals SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID TISSUE-SPECIFIC EXPRESSION; REPORTER GENE-EXPRESSION; ANTIGEN GENE; LIVING MICE; REGULATED EXPRESSION; HORMONAL-REGULATION; UPSTREAM ENHANCER; IN-VIVO; CANCER; PROMOTER AB Numerous mouse models of prostate carcinogenesis have been developed, but hitherto there has been no model in which the prostate gland could be imaged in live animals. The transgenic model generated here targeted mouse prostate gland using a firefly luciferase enzyme under the control of a small but highly active and specific supra prostate-specific antigen (sPSA) promoter. We evaluated postnatal prostate development, involution and androgen-induced restoration of prostate growth in adult transgenic mice using bioluminescence imaging. Results of our study showed that: (i) the prostate gland of male offspring did not yield a significant bioluminescence signal until after sexual maturity. Luciferase was detected in the luminal epithelial cells of the ventral and dorsolateral lobes of the prostate gland and Caput epididymis, with little or no activity in 18 other organs evaluated. (ii) While a constant high level of bioluminescence was detected in the mouse prostate from 5 to 35 weeks of age, a slight drop in bioluminescence was detected at 36 to 54 weeks. (iii) Upon castration, the luciferase activity signal associated with mouse prostate detected by a cooled charge-coupled device camera was dramatically reduced. This signal could be rapidly restored to pre-castration levels after androgen administration. Androgen-induced luciferase activity subsided to nearly basal levels 5 days following the last injection. These data demonstrate that a bioluminescent mouse model with luciferase activity restricted to the prostate gland under the control of a (sPSA) promoter can be used on a real-time basis in live animals to investigate the development and responsiveness of the prostate gland to exogenously administered androgen. This model can be extended to detect the responsiveness of the prostate gland to therapy and used as a founder strain to visualize tumors in hosts with different genetic backgrounds. C1 Emory Univ, Sch Med, Mol Urol & Therapeut Program, Dept Urol, Atlanta, GA 30322 USA. NCI, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. RP Hsieh, CL (reprint author), Emory Univ, Sch Med, Mol Urol & Therapeut Program, Dept Urol, 1365B Clifton Rd,NE Suite B4100, Atlanta, GA 30322 USA. EM chsieh2@emory.edu FU NCI NIH HHS [1PO1CA098912-01] NR 50 TC 25 Z9 26 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD OCT PY 2005 VL 35 IS 2 BP 293 EP 304 DI 10.1677/jme.1.01722 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 976DV UT WOS:000232713900009 PM 16216910 ER PT J AU Peters, JM Cheung, C Gonzalez, FJ AF Peters, JM Cheung, C Gonzalez, FJ TI Peroxisome proliferator-activated receptor-alpha and liver cancer: where do we stand? SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Review DE peroxisome proliferator-activated receptor-alpha (PPAR alpha); hepatocarcinogenesis; fibrates; human cancer ID ACYL-COA OXIDASE; MORTALITY FOLLOW-UP; <4-CHLORO-6-(2,3-XYLIDINO)-2-PYRIMIDINYLTHIO>ACETIC ACID WY-14,643; NUCLEAR HORMONE-RECEPTORS; REPLICATIVE DNA-SYNTHESIS; LOWER SERUM-CHOLESTEROL; ISCHEMIC-HEART-DISEASE; PPAR-ALPHA; HEPATIC PEROXISOME; SPECIES-DIFFERENCES AB The peroxisome proliferator-activated receptor-alpha (PPAR alpha), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPAR alpha is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPAR alpha occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPAR alpha agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPAR alpha also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPAR alpha. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPAR alpha target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPAR alpha in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPAR alpha agonist-induced hepatocarcinogenesis. C1 Penn State Univ, Dept Vet Sci, University Pk, PA 16802 USA. Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet Sci, 312 Life Sci Bldg, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Peters, Jeffrey/D-8847-2011 FU NCI NIH HHS [CA89607, CA97999] NR 106 TC 157 Z9 159 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0946-2716 J9 J MOL MED-JMM JI J. Mol. Med. PD OCT PY 2005 VL 83 IS 10 BP 774 EP 785 DI 10.1007/s00109-005-0678-9 PG 12 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 971RL UT WOS:000232401600004 PM 15976920 ER PT J AU Pettit, GR Minardi, MD Rosenberg, HJ Hamel, E Bibby, MC Martin, SW Jung, MK Pettit, RK Cuthbertson, TJ Chapuis, JC AF Pettit, GR Minardi, MD Rosenberg, HJ Hamel, E Bibby, MC Martin, SW Jung, MK Pettit, RK Cuthbertson, TJ Chapuis, JC TI Antineoplastic agents. 509. Synthesis of fluorcombstatin phosphate and related 3-halostilbenes SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID COMBRETASTATIN A4 PHOSPHATE; TUMOR BLOOD-FLOW; ANTIMITOTIC AGENTS; MULTIPLE-MYELOMA/; A-4 PHOSPHATE; CELL-LINES; IN-VITRO; ANGIOGENESIS; TUBULIN; ANALOGS AB The present SAR study of combretastatin A-3 (3a) focused on replacement of the 3-hydroxyl group by a series of halogens. That approach with Z-stilbenes resulted in greatly enhanced (> 10-100-fold) cancer cell growth inhibition against a panel of human cancer cell lines and the murine P388 lymphocytic leukemia cell line. Synthesis of the 3-fluoro-Z-stilbene designated fluorcombstatin (11a) and its potassium 3'-O-phosphate derivative (16c) by the route 7 -> 8a -> 11a -> 14 -> 16c illustrates the general synthetic pathway. The 3'-O-phosphoric acid ester (15) of 3-bromo-Z-stilbene 13a was also converted to representative cation salts to evaluate the potential for improved aqueous solubility, and the potassium salt (16 mg/mL in water) proved most useful. The fluoro (11a), chloro (12a), and bromo (13a) halocombstatins were nearly equivalent to combretastatin A-4 (1a) as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin. The tubulin binding in cell-free systems was also retained in human umbilical vein endothelial cells. All three halocombstatins retained the powerful human cancer cell line inhibitory activity of combretastatin A-4 (la) and proved superior to combretastatin A-3 (3a). In addition, the halocombstatins targeted Gram-positive bacteria and Cryptococcus neoformans. C1 Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Biochem & Chem, Tempe, AZ 85287 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Univ Bradford, Canc Res Unit, Bradford BD7 1DP, W Yorkshire, England. NCI, Sci Applicat Int Corp, NIH, Frederick, MD 21702 USA. RP Pettit, GR (reprint author), Arizona State Univ, Canc Res Inst, POB 872404, Tempe, AZ 85287 USA. FU NCI NIH HHS [CA44344-08-12, R01 CA90441-01-05] NR 48 TC 31 Z9 36 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD OCT PY 2005 VL 68 IS 10 BP 1450 EP 1458 DI 10.1021/np058038i PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 983DR UT WOS:000233211800002 PM 16252907 ER PT J AU Daly, JW Spande, TF Garraffo, HM AF Daly, JW Spande, TF Garraffo, HM TI Alkaloids from amphibian skin: A tabulation of over eight-hundred compounds SO JOURNAL OF NATURAL PRODUCTS LA English DT Review ID DENDROBATID POISON FROGS; RESONANCE SPECTRAL ASSIGNMENTS; ENANTIOSELECTIVE SYNTHESIS; ABSOLUTE STEREOCHEMISTRY; PUMILIOTOXIN ALKALOIDS; DART FROGS; BATRACHOTOXIN ALKALOIDS; PHYLLOBATES-AUROTAENIA; EPIPEDOBATES-TRICOLOR; STRUCTURAL DEFINITION AB A diverse array of biologically active, lipid-soluble alkaloids have been discovered in amphibian skin. Such alkaloids include the following: the steroidal samandarines from salamanders, the batrachotoxins, histrionicotoxins, gephyrotoxins, and epibatidine from neotropical poison frogs (Dendrobatidae), the pumiliotoxins, allopumiliotoxins, homopumiliotoxins, and decahydroquinolines from certain genera of anurans from four families (Dendrobatidae, Mantellidae, Bufonidae, and Myobatrachidae), a variety of izidines (pyrrolizidines, indolizidines, quinolizidines, lehmizidines), pyrrolidines, piperidines, various tricyclics (related in structures to the coccinellines), and spiropyrrolizidines from the first three of these four families, the pseudophrynamines from one genus of Australian frogs, and a variety of unclassified alkaloids as yet of undetermined structure. With the exception of the samandarines and the pseudophrynamines, all alkaloids appear to be derived from dietary sources. Although only a few of the over 800 amphibian skin alkaloids have been detected in arthropods, putative arthropod sources for the batrachotoxins and coccinelline-like tricyclics (beetles), the pumiliotoxins (ants, mites), the decahydroquinolines, izidines, pyrrolidines, and piperidines (ants), and the spiropyrrolizidines (millipedes) have been discovered. Ants are likely sources for histrionicotoxins, lebmizidines, and tricyclic gephyrotoxins. Epibatidines represent an important alkaloid class without a putative dietary source. The structures for many of these alkaloids have been rigorously established, while the structures of others represent tentative proposals, based only on mass spectral and FTIR spectral data, along with analogies to structures of well-defined alkaloids. C1 NIDDKD, Bioorgan Chem Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. EM jdaly@nih.gov NR 95 TC 404 Z9 410 U1 9 U2 84 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD OCT PY 2005 VL 68 IS 10 BP 1556 EP 1575 DI 10.1021/np0580560 PG 20 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 983DR UT WOS:000233211800021 PM 16252926 ER PT J AU Prat, E Tomaru, U Sabater, L Park, DM Granger, R Kruse, N Ohayon, JM Bettinotti, MP Martin, R AF Prat, E Tomaru, U Sabater, L Park, DM Granger, R Kruse, N Ohayon, JM Bettinotti, MP Martin, R TI HLA-DRB5*0101 and-DRB1*1501 expression in the multiple sclerosis-associated HLA-DR15 haplotype SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE MHC; multiple sclerosis; antigen presenting molecules; antigen presenting cells ID MYELIN BASIC-PROTEIN; T-CELL RESPONSE; AUTOIMMUNE-DISEASES; MOLECULAR MIMICRY; MESSENGER-RNA; ALPHA-BETA; ANTIGEN; GENES; MHC; RECOGNITION AB The HLA region, and particularly the DR15 haplotype (containing the two DRB* genes DRB1*1501 and DRB5*0101 and the tightly linked DQ alleles DQA*0102 and DQB1*0602, which together form the DQw6 molecule) in Caucasians, shows the strongest genetic association with multiple sclerosis (MS). In the DR15 haplotype, two beta-chains HLA-DRB1*1501 and -DRB5*0101 are co-expressed resulting in two different surface HLA-DR alpha beta heterodimers, DR2b and DR2a. Most previous studies focused on DRB1*1501, however, both DR2a, and DR2b may contribute to MS pathogenesis via antigen presentation to myelin-specific T lymphocytes. We therefore analyzed the expression of the two DR15 genes in various antigen presenting cells (APCs), central nervous system and thymic tissues. Transcript levels were higher for DRB5*0101 in all cell types and tissues. Both HLA-DR heterodimers were expressed at significant levels on the cell surface, where they showed a differential expression pattern in different APCs. They were similarly regulated after stimulation with interferon-gamma and interieukin-4. Finally, immunohistochemistry experiments indicated that both molecules were expressed in thymic tissue. Our results encourage future research to investigate the potential functional relevance of both genes for the pathogenesis of MS. (C) 2005 Elsevier B.V. All rights reserved. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Hosp Germans Trias & Pujol, Ctr Transfus & Tissue Bank, Lab Immunobiol Res & Applicat Diag, Badalona 08916, Spain. NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Neurol, D-97080 Wurzburg, Germany. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr DR, Bethesda, MD 20892 USA. EM martinr@ninds.nih.gov RI Park, Deric/C-5675-2013 NR 38 TC 33 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT PY 2005 VL 167 IS 1-2 BP 108 EP 119 DI 10.1016/j.jneuroim.2005.04.027 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 970XA UT WOS:000232344500013 PM 16111772 ER PT J AU Chen, DF Fetz, EE AF Chen, DF Fetz, EE TI Characteristic membrane potential trajectories in primate sensorimotor cortex neurons recorded in vivo SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID V PYRAMIDAL NEURONS; CAT NEOCORTICAL NEURONS; LOCAL-FIELD POTENTIALS; MOTOR CORTEX; AWAKE MONKEYS; ELECTROPHYSIOLOGICAL PROPERTIES; MORPHOLOGICAL PROPERTIES; INHIBITORY INTERNEURONS; GABAERGIC INTERNEURONS; INTRACELLULAR ANALYSIS AB We examined the membrane potentials and firing properties of motor cortical neurons recorded intracellularly in awake, behaving primates. Three classes of neuron were distinguished by 1) the width of their spikes, 2) the shape of the afterhyperpolarization (AHP), and 3) the distribution of interspike intervals. Type I neurons had wide spikes, exhibited scoop-shaped AHPs, and fired irregularly. Type II neurons had narrower spikes, showed brief postspike afterdepolarizations before the AHP, and sometimes fired high-frequency doublets. Type III neurons had the narrowest spikes, showed a distinct post-AHP depolarization, or "rebound AHP" (rAHP), lasting nearly 30 ms, and tended to fire at 25 - 35 Hz. The evidence suggests that an intrinsic rAHP may confer on these neurons a tendency to fire at a preferred frequency governed by the duration of the rAHP and may contribute to a "pacemaking" role in generating cortical oscillations. C1 Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Dept Physiol & Biophys, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. RP Chen, DF (reprint author), Natl Inst Neurol Disorders & Stroke, 6001 Execut Blvd,MSC 9523, Bethesda, MD 20892 USA. EM daofen.chen@nih.gov FU NCRR NIH HHS [RR-00166]; NINDS NIH HHS [NS-12542] NR 93 TC 41 Z9 41 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD OCT PY 2005 VL 94 IS 4 BP 2713 EP 2725 DI 10.1152/jn.00024.2005 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 963VL UT WOS:000231834200037 PM 15987766 ER PT J AU Pluta, RM Jung, CS Harvey-White, J Whitehead, A Shilad, S Espey, MG Oldfield, EH AF Pluta, RM Jung, CS Harvey-White, J Whitehead, A Shilad, S Espey, MG Oldfield, EH TI In vitro and in vivo effects of probucol on hydrolysis of asymmetric dimethyl L-arginine and vasospasm in primates SO JOURNAL OF NEUROSURGERY LA English DT Article DE vasospasm; endogenous nitric oxide synthase inhibitor; asymmetric dimethyl L-arginine; bilirubin oxidation product; probucol; Macaca cynomolgus ID NITRIC-OXIDE SYNTHASE; ANEURYSMAL SUBARACHNOID HEMORRHAGE; VASCULAR ENDOTHELIAL-CELLS; CEREBRAL VASOSPASM; CEREBROSPINAL-FLUID; SODIUM-NITROPRUSSIDE; INDUCED CYTOTOXICITY; BLOOD-FLOW; HEMOGLOBIN; PLASMA AB Object. Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl L-arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), are associated with delayed vasospasm after subarachnoid hemorrhage (SAH); however, the source, cellular mechanisms, and pharmacological inhibition of ADMA production following SAH are unknown. Methods. In an in vitro experiment involving human umbilical vein endothelial cells (HUVECs), the authors examined mechanisms potentially responsible for increased ADMA levels during vasospasm and investigated whether this increase can be inhibited pharmacologically. In a second study, an in vivo experiment, the authors used probucol, which effectively inhibited ADMA increase in HUVEC cultures in vitro, in a randomized double-blind placebo-controlled experiment in a primate model of delayed cerebral vasospasm after SAH. Oxidized low-density lipids (OxLDLs; positive control; p < 0.02) and bilirubin oxidation products (BOXes; p < 0.01), but not oxyhemoglobin (p = 0.74), increased ADMA levels in HUVECs. Probucol inhibited changes in ADMA levels evoked by either OxLDLs (p < 0.001) or BOXes (p < 0.01). Comparable changes were observed in cell lysates. In vivo probucol (100 mg/kg by mouth daily) did not alter serum ADMA levels on Days 7, 14, and 21 after SAH compared with levels before SAH, and these levels were not different from those observed in the placebo group (p = 0.3). Despite achieving therapeutic levels in plasma and measurable levels in CSF, probucol neither prevented increased CSF ADMA levels nor the development of vasospasm after SAH. Increased CSF ADMA and decreased nitrite levels in both groups were strongly associated with the degree of delayed vasospasm after SAH (correlation coefficient [CC] 0.5, 95% confidence interval [CI] 0.19-0.72, p < 0.002 and CC -0.43, 95% Cl -0.7 to -0.05, p < 0.03, respectively). Conclusions. Bilirubin oxidation products, but not oxyhemoglobin, increased ADMA levels in the HUVEC. Despite its in vitro ability to lower ADMA levels, probucol failed to inhibit increased CSF ADMA and decreased nitrite levels, and it did not prevent delayed vasospasm in a primate SAH model. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Lab Physiol Studies, Bethesda, MD USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Frankfurt, Dept Neurosurg, D-6000 Frankfurt, Germany. RP Pluta, RM (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM rysiek@ninds.nih.gov NR 72 TC 19 Z9 19 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD OCT PY 2005 VL 103 IS 4 BP 731 EP 738 DI 10.3171/jns.2005.103.4.0731 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 971LG UT WOS:000232385000022 PM 16266057 ER PT J AU Jacobson, S Lipkin, WI AF Jacobson, S Lipkin, WI TI Reviews in NeuroVirology: An introduction SO JOURNAL OF NEUROVIROLOGY LA English DT Editorial Material C1 Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10025 USA. RP Jacobson, S (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov; wil2001@columbia.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2005 VL 11 IS 5 BP 411 EP 411 DI 10.1080/13550280500406108 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 984VV UT WOS:000233334500001 ER PT J AU Chesebro, B Race, R Kercher, L AF Chesebro, B Race, R Kercher, L TI Scrapie pathogenesis in brain and retina: Effects of prion protein expression in neurons and astrocytes SO JOURNAL OF NEUROVIROLOGY LA English DT Review DE brain; neurodegeneration; prion disease; prion protein; retina; scrapie; transmissible spongiform encephalopathy ID PRP KNOCKOUT MICE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; HAMSTER SCRAPIE; TRANSGENIC MICE; INFECTION; SUSCEPTIBILITY; REPLICATION; SPLEEN AB Brain damage in the transmissible spongiform encephalopathies or prion diseases is associated with the conversion of normal host prion protein to an abnormal protease-resistant isoform, and expression of prion protein is required for susceptibility to these diseases. This article reviews the data on studies using transgenic mice expressing prion protein in specific individual cell types to study the roles of these cell types in prion disease pathogenesis. Surprisingly damage to neurons in brain and retina appeared to require different prion protein - expressing cells, suggesting that different pathogenic mechanisms operate in these two neuronal tissues. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bchesebro@nih.gov NR 27 TC 6 Z9 6 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2005 VL 11 IS 5 BP 476 EP 480 DI 10.1080/13550280500187583 PG 5 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 984VV UT WOS:000233334500009 PM 16287689 ER PT J AU Lei, XG Cheng, WH AF Lei, Xin Gen Cheng, Wen-Hsing TI New roles for an old selenoenzyme: Evidence from glutathione peroxidase-1 null and overexpressing mice SO JOURNAL OF NUTRITION LA English DT Article DE glutathione peroxidase-1; selenium; signaling; oxidative stress; insulin resistance ID SELENIUM-DEFICIENT RATS; OXIDATIVE STRESS; ACETAMINOPHEN TOXICITY; LIPID-PEROXIDATION; INSULIN-RESISTANCE; SELENOPROTEIN-P; TRANSGENIC MICE; LIVER NECROSIS; OXIDANT STRESS; PROTECTS MICE AB Cellular glutathione peroxidase-1 (GPX1) is the first identified and the most abundant selenoprotein in mammals. Although GPX1 has been widely considered to be a major antioxidant enzyme, there has been no direct evidence for such role in vivo until GPX1 trainsgenic and null mice became available 10 y ago. Using these new models, we demonstrated that GPX1 protects against oxidative stress mediated by reactive oxygen species (ROS), and the physiologic importance of this protection varies with insult level and body Se status. Full expression of GPX1 is needed, and overexpression of GPX1 is beneficial for Seadequate mice to defend against severe oxidative stress. This function of GPX1 is associated with attenuating the prooxidant-induced oxidation of NADPH, NADH, lipid, and protein in various tissues. In Se-deficient mice, a minute amount of GPX1 activity (4% of adequate levels) protects against hepatic aponecrosis induced by mild oxidative stress. In contrast, knockout of GPX1 renders mice and their hepatocytes resistant to oxidative stress related to reactive nitrogen species (FINS). More intriguingly, mice overexpressing GPX1 develop insulin resistance and obesity, accompanied by a downregulation of insulin-mediated phosphorylations of insulin receptor and Akt protein. In conclusion, GPX1 seems to play contrasting roles in coping with ROS vs. FINS, and its metabolic functions extend beyond redox regulation. C1 [Lei, Xin Gen] Cornell Univ, Dept Anim Sci, Ithaca, NY 14853 USA. [Cheng, Wen-Hsing] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Lei, XG (reprint author), Cornell Univ, Dept Anim Sci, Ithaca, NY 14853 USA. EM XL20@cornell.edu FU NIDDK NIH HHS [DK53018, R01 DK053018] NR 58 TC 36 Z9 37 U1 0 U2 2 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD OCT PY 2005 VL 135 IS 10 BP 2295 EP 2298 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 971IU UT WOS:000232378200002 PM 16177185 ER PT J AU Guo, TL Chi, RP Germolec, DR White, KL AF Guo, Tai L. Chi, Rui Ping Germolec, Dori R. White, Kimber L., Jr. TI Stimulation of the immune response in B6C3F1 mice by genistein is affected by exposure duration, gender, and litter order SO JOURNAL OF NUTRITION LA English DT Article DE genistein; developmental exposure; immune stimulation and litter order ID ESTROGEN-RECEPTOR-ALPHA; SPRAGUE-DAWLEY RATS; PHYTO-ESTROGENS; GENE-EXPRESSION; CELL RESPONSES; IN-VIVO; PHYTOESTROGENS; METHYLATION; BETA; PERSISTENCE AB The objective of this study was to determine whether immune responses could be differentially modulated by the phytoestrogen genistein (GEN) in mice from the 1 st and 2nd litters, and whether the effects were persistent or reversible. B6C3F1 mice were exposed to a control or GEN-containing diet at 25, 250, and 1250 mu g/g for the 1st litters, and 500 mu g/g for the 2nd litters from d 0 of gestation to postnatal day (PND) 22, and through feeding after weaning. At PND42, anti-CD3 anti body-sti m u lated splenic T-cell proliferation and the percentages of T cells were increased in mice from the 1 st litters at 250 and 1250 mu g/g GEN but not from the 2nd litters. At PND84, the activity of IL-2-treated NK cells was significantly increased by GEN in mice from the 2nd litters but not from the 1 st litters. The activity of cytotoxic T cells (CTLs) was also significantly increased by GEN in male mice from the 2nd litters. However, the increases in the CTL activity were not significant when the male mice were shifted from GEN-containing food to control food at PND22. Additionally, the increases in T-cell activities in female mice from the 1 st litters and male mice from the 2nd litters were associated with a decrease in the percentage of CD4(+)CD25(+) T regulatory cells. Overall, the results demonstrated that GEN could enhance the immune responses in mice from the 1 st and 2nd litters; however, the effects varied depending on the exposure duration, gender, and litter order. C1 [Guo, Tai L.; Chi, Rui Ping; White, Kimber L., Jr.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Germolec, Dori R.] NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Guo, TL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM tlguo@hsc.vcu.edu FU NIEHS NIH HHS [N01-ES-05454, N01ES05454, R21ES012286, R21 ES012286] NR 44 TC 8 Z9 9 U1 0 U2 2 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD OCT PY 2005 VL 135 IS 10 BP 2449 EP 2456 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 971IU UT WOS:000232378200028 PM 16177211 ER PT J AU Fallon, EM Tanofsky-Kraff, M Norman, AC McDuffie, JR Taylor, ED Cohen, ML Young-Hyman, D Keil, M Kolotkin, RL Yanovski, JA AF Fallon, EM Tanofsky-Kraff, M Norman, AC McDuffie, JR Taylor, ED Cohen, ML Young-Hyman, D Keil, M Kolotkin, RL Yanovski, JA TI Health-related quality of life in overweight and nonoverweight black and white adolescents SO JOURNAL OF PEDIATRICS LA English DT Article ID WEIGHT-LOSS; AFRICAN-AMERICAN; OBESE CHILDREN; BODY-IMAGE; QUESTIONNAIRE; IMPACT; WOMEN; PERCEPTIONS; ADJUSTMENT; PREFERENCE AB Objectives To assess the impact of obesity on quality of life (QOL) in black and white adolescents. Study design One hundred ten overweight (body mass index [BMI], 41.7 +/- 8.9 kg/m(2)) and 34 nonoverweight adolescents (BMI, 20.6 +/- 2.9 kg/m(2)) and their parents completed measures of QOL. Results Overweight was associated with poorer adolescent-reported QOL and parent reports of their children's QOL. Examining groups by weight status and race, overweight whites reported the greatest impairment on Social/Interpersonal, Self-Esteem, and Physical Appearance QOL (all P < .01), whereas parents of overweight blacks reported the poorest General Health Perceptions scores regarding their children. Interactions between BMI z-score and race were detected for Social/Interpersonal, Self-esteem, Daily Living, Self-Efficacy, Self-regard, and Physical Appearance QOL (all P < .05): Higher BMI in whites was associated with greater impairments in QOL than in blacks. Parents reported similar relations for their children. Conclusions According to adolescent and parent reports, overweight is associated with poorer QOL in adolescence, regardless of race; however, compared with overweight white adolescents, blacks report less impairment in QOL. Future research is required to determine whether differences in QOL are predictive of treatment success. C1 NICHD, Unit Growth & Obes, DEB, NIH, Bethesda, MD 20892 USA. NIDDKD, Div Nutr Res Coordinat, NIH, DHHS, Bethesda, MD 20892 USA. Duke Univ, Hlth Syst, Dept Family & Community Med, Durham, NC USA. RP Tanofsky-Kraff, M (reprint author), NICHD, Unit Growth & Obes, DEB, NIH, 10 Ctr Dr,CRC Room 1-3330, Bethesda, MD 20892 USA. OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z99 HD999999, Z01 HD000641-12]; NICHD NIH HHS [Z01 HD000641] NR 38 TC 88 Z9 90 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2005 VL 147 IS 4 BP 443 EP 450 DI 10.1016/j.jpeds.2005.05.039 PG 8 WC Pediatrics SC Pediatrics GA 978HX UT WOS:000232865300011 PM 16227028 ER PT J AU Costa, PT Patriciu, NS McCrae, RR AF Costa, PT Patriciu, NS McCrae, RR TI Lessons from longitudinal studies for new approaches to the DSM-V: The FFM and FFT SO JOURNAL OF PERSONALITY DISORDERS LA English DT Article ID AXIS-II AB After brief comments about each target article, we discuss their significance for the DSM-V, the implications for personality disorders of universal trait developmental trends, and our emerging theoretical model, the Five-Factor Theory, which provides an integrative context for these remarkable findings. C1 NIA, Lab Personal & Cognit, NIH, DHHS, Bethesda, MD 20892 USA. RP Costa, PT (reprint author), Ctr Gerontol Res, Box 03,5600 Nathans Shock Dr, Baltimore, MD 21224 USA. EM costap@mail.nih.gov OI Costa, Paul/0000-0003-4375-1712 NR 15 TC 9 Z9 9 U1 0 U2 7 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0885-579X J9 J PERS DISORD JI J. Pers. Disord. PD OCT PY 2005 VL 19 IS 5 BP 533 EP 539 DI 10.1521/pedi.2005.19.5.533 PG 7 WC Psychiatry SC Psychiatry GA 983RJ UT WOS:000233249500006 PM 16274281 ER PT J AU Lowes, S Sykes, D Breen, CM Ragone, LJ Miller, DS AF Lowes, S Sykes, D Breen, CM Ragone, LJ Miller, DS TI Multiple components of 2,4-dichlorophenoxyacetic acid uptake by rat choroid plexus SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ORGANIC ANION TRANSPORTER-3; CEREBROSPINAL FLUID; BLOOD; INVOLVEMENT; EXPRESSION; BARRIER; BRAIN; RESISTANCE; PROTECTS; SLC22A8 AB Initial rates of uptake of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D; 20 mu M) were measured in intact lateral choroid plexus from rat. Although inhibition of uptake by millimolar concentrations of estrone sulfate (ES) and unlabeled 2,4-D was maximal at 85%, inhibition by p-aminohippurate (PAH) saturated at about 50%. Inhibition by ES plus PAH was no greater than by ES or 2,4-D alone. Thus, inhibition studies indicated three distinct components of uptake; two mediated and one not. The sodium-dependent component of 2,4-D uptake coincided with the PAH-sensitive component, indicating uptake mediated by organic anion transporter subtype (Oat) 3. Consistent with this, efflux of 2,4-D from preloaded tissue was accelerated by all Oat3 substrates tested, and 2,4-D increased the efflux of the Oat3 substrate, PAH. Consistent with the inhibition data, kinetic analysis showed three components of 2,4-D uptake: a nonmediated component ( linear kinetics), a high-affinity component, and a low-affinity component. The high-affinity component appeared to coincide with the PAH-sensitive and sodium-dependent component characterized in inhibition studies. The PAH-insensitive, low-affinity component was inhibited by ES, dehydroepiandrosterone sulfate, and taurocholate but not by 5-hydroxyindole acetic acid. Thus, the first step in transport of 2,4-D from cerebrospinal fluid to blood involves two transporters: Oat3 and a PAH-insensitive, sodium-independent transporter. Based on inhibitor profile, the latter may be Oatp3. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov NR 25 TC 3 Z9 5 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2005 VL 315 IS 1 BP 136 EP 143 DI 10.1124/jpet.105.087056 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966EL UT WOS:000232002600016 PM 15958719 ER PT J AU Xu, H Wang, XY Zimmerman, D Boja, ES Wang, JH Bilsky, EJ Rothman, RB AF Xu, H Wang, XY Zimmerman, D Boja, ES Wang, JH Bilsky, EJ Rothman, RB TI Chronic morphine up-regulates G alpha 12 and cytoskeletal proteins in Chinese hamster ovary cells expressing the cloned mu opioid receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PEPTIDE RECEPTOR; RAT STRIATUM; DEPENDENCE; TOLERANCE; DESENSITIZATION; RGS9; TRANSCRIPTION; INVOLVEMENT; ADAPTATIONS; MECHANISMS AB A growing body of literature indicates that chronic morphine exposure alters the expression and function of cytoskeletal proteins in addition to the well established interactions between mu opioid receptors and G proteins. In the present study, we hypothesized that chronic morphine alters the expression and functional effects of G alpha 12, a G protein that regulates downstream cytoskeletal proteins via its control of RhoA. Our results showed that chronic morphine treatment decreased the expression of G alpha i2 (64%) and G alpha i3 (60%), had no effect of G alpha o, and increased G alpha 12 (66%) expression in Chinese hamster ovary (CHO) cells expressing the cloned human mu opioid receptors (hMOR-CHO cells) but not in cells expressing a mutant mu opioid receptor that do not develop morphine tolerance and dependence (T394A-CHO cells). Morphine treatment had no significant effect on PAR-1 thrombin receptor-activated G protein activity, as measured by thrombin-stimulated guanosine 5'-O-(3-[S-35]thio) triphosphate binding. Chronic morphine treatment significantly enhanced thrombin-stimulated RhoA activity and thrombin-stimulated expression of alpha-actinin, a cytoskeletal anchoring protein, in hMOR-CHO cells. Proteomic analysis of two-dimensional gel spots prepared from hMOR-CHO cells showed that morphine treatment affected the expression of a number of proteins associated with morphological changes. Up-regulation of G alpha 12 and alpha-actinin by chronic morphine was also observed in mouse brain. Viewed collectively, these findings indicate, for the first time, that chronic morphine enhances the G alpha 12-associated signaling system, which is involved in regulating cellular morphology and growth, supporting other findings that chronic morphine may alter cellular morphology, in addition to cellular function. C1 NIA, Clin Psychopharmacol Sect, Intramural Res Program, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. NHLBI, Biophys Chem Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD USA. Univ New England, Coll Osteopath Med, Dept Pharmacol, Biddeford, ME USA. RP Rothman, RB (reprint author), NIA, Clin Psychopharmacol Sect, Intramural Res Program, Dept Hlth & Human Serv,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rrothman@intra.nida.nih.gov OI Bilsky, Edward/0000-0002-4664-5256 NR 35 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2005 VL 315 IS 1 BP 248 EP 255 DI 10.1124/jpet.105.089367 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966EL UT WOS:000232002600028 PM 15987828 ER PT J AU Igarashi, H Ito, T Mantey, SA Pradhan, TK Hou, W Coy, DH Jensen, RT AF Igarashi, H Ito, T Mantey, SA Pradhan, TK Hou, W Coy, DH Jensen, RT TI Development of simplified vasoactive intestinal peptide analogs with receptor selectivity and stability for human vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide receptors SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PIG PANCREATIC ACINI; GUINEA-PIG; VPAC(2) RECEPTOR; VIP RECEPTOR; IN-VITRO; AGONIST; RO-25-1553; CANCER; PHARMACOLOGY; TC-99M-VIP AB Vasoactive intestinal peptide (VIP) is a widespread neurotransmitter whose physiological and pathophysiological actions are mediated by two receptor classes, VIP/pituitary adenylate cyclase-activating polypeptide (VPAC) 1 and VPAC(2). VIP is a 28-amino acid peptide that is rapidly degraded and simplified; metabolically stable analogs are needed. In this study, we use information from studies of the VIP pharmacophore for VPAC(1)/VPAC(2) to design nine simplified VIP analogs that could have high affinity and selectivity for each VPAC or that retained high affinity for both VPACs and were metabolically stable. From binding studies of their abilities to directly interact with hVPAC(1) (T47D cells, hVPAC(1)-transfected cells) and hVPAC(2) (Sup T-1-and VPAC(2)-transfected cells) and to stimulate adenylate cyclase in each, two analogs [(Ala(2,8,9,11,19,22,24,25,27,28))VIP and (Ala(2,8,9,11,19,24-28))VIP] were found to have > 2000-and > 600-fold selectivity for hVPAC(1). None of the nine analogs had hVPAC(2) selectivity. However, two simplified analogs [(Ala(2,8,9, 16,19,24)) VIP and (Ala(2,8,9,16,19,24,25)) VIP] retained high affinity and potency for both hVPACs. I-125-[Ala(2,8,9,16,19,24,25)]VIP was much more metabolically stable than 125I- VIP. The availability of these simplified analogs of VIP, which are metabolically stable and have either hVPAC(1) selectivity or retain high affinity for both hVPACs, should be useful for exploring the role of VPAC subtypes in mediating VIPs' actions as well as being useful therapeutically and for exploring the usefulness of VIP receptor imaging of tumors and VIP receptor-mediated tumor cytotoxicity. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Tulane Univ, Hlth Sci Ctr, Peptide Res Labs, Dept Med, New Orleans, LA 70118 USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov NR 40 TC 18 Z9 19 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2005 VL 315 IS 1 BP 370 EP 381 DI 10.1124/jpet.105.088823 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966EL UT WOS:000232002600043 PM 15994369 ER PT J AU Desai, RI Kopajtic, TA French, D Newman, AH Katz, JL AF Desai, RI Kopajtic, TA French, D Newman, AH Katz, JL TI Relationship between in vivo occupancy at the dopamine transporter and behavioral effects of cocaine, GBR 12909 [1-{2-[bis-(4-fluorophenyl) methoxy]ethyl}-4-(3-phenylpropyl)piperazine], and benztropine analogs SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID UPTAKE INHIBITORS; UPTAKE SITES; NONHUMAN-PRIMATES; BINDING-SITES; INVIVO; LIGANDS; RAT; MAZINDOL; GBR12909; MONKEYS AB Analogs of benztropine (BZT) bind to the dopamine (DA) transporter and inhibit DA uptake but often have behavioral effects that differ from those of cocaine and other DA-uptake inhibitors. To better understand these differences, we examined the relationship between locomotor-stimulant effects of cocaine, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)-piperazine (GBR 12909), and BZT analogs [(3 alpha-[bis(4'-fluorophenyl) methoxy]-tropane) (AHN 1-055) and (N-allyl-3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane) (AHN 2-005)] and their in vivo displacement of the DA transporter ligand [I-125]3 beta-(4-iodophenyl)- tropan-2 beta-carboxylic acid isopropyl ester hydrochloride (RTI-121) in striatum. Cocaine, GBR 12909, and BZT analogs each displaced [I-125]RTI-121 and stimulated locomotor activity in a dose- and time-dependent manner. The time course revealed a slower onset of both effects for AHN 1-055 and AHN 2-005 compared with cocaine and GBR 12909. The BZT analogs were less effective than cocaine and GBR 12909 in stimulating locomotor activity. Locomotor stimulant effects of cocaine were generally greater than predicted by the regression of displacement of [I-125]RTI-121 and effect at short times after injection and less than predicted at longer times after injection. This result suggests that the apparent rate of occupancy of the DA transporter, in addition to percentage of sites occupied, contributes to the behavioral effects of cocaine. The present results suggest that among drugs that act at the DA transporter, the slower apparent rates of occupancy with the DA transporter by the BZT analogs may contribute in an important way to differences in their effectiveness. C1 NIDA, Intramural Res Program, Psychobiol Sect,Medicat Discovery Res Branch, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Med Chem Sect,Medicat Discovery Res Branch, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), NIDA, Intramural Res Program, Psychobiol Sect,Medicat Discovery Res Branch, Dept Hlth & Human Serv,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 NR 39 TC 31 Z9 31 U1 2 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2005 VL 315 IS 1 BP 397 EP 404 DI 10.1124/jpet.105.091231 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966EL UT WOS:000232002600046 PM 16014753 ER PT J AU Jutkiewicz, EM Kaminsky, ST Rice, KC Traynor, JR Woods, JH AF Jutkiewicz, EM Kaminsky, ST Rice, KC Traynor, JR Woods, JH TI Differential behavioral tolerance to the delta-opioid agonist SNC80 ([(+)-4-[(alpha R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyp henyl)methyl]-N,N-diethylbenzamide) in Sprague-Dawley rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MESSENGER-RNA EXPRESSION; RHESUS-MONKEYS; RECEPTOR AGONIST; DOWN-REGULATION; SQUIRREL-MONKEYS; G-PROTEINS; BW373U86; EFFICACY; BINDING; BRAIN AB Nonpeptidic delta-opioid agonists produce a number of behaviors, such as antidepressant-like effects, locomotor stimulation, antinociception, and convulsions. To consider this class of compounds as potential therapeutics for humans, the effects of delta-opioid agonists after repeated administration must be evaluated. Therefore, the present study investigated the effects of repeated delta-opioid agonist, SNC80 ([(+)-4-[(alpha R)-alpha-[(2S, 5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]- N, N-diethylbenzamide), administration on its antidepressant-like effects in the forced swim test, locomotor activity, and convulsions in male Sprague- Dawley rats. Tolerance developed rapidly to the convulsive and locomotor- stimulating effects of SNC80 but not to the antidepressant-like effects. In addition, tolerance was evaluated at the level of the receptor-G protein interaction by measuring 5'-O-(3-[S-35]thio)triphosphate binding in brains from rats that were pretreated with SNC80. With various exposure durations to SNC80, some brain regions demonstrated tolerance at different times, suggesting that adaptations in the delta-opioid system may occur during agonist exposure. Overall, the lack of observable tolerance to the antidepressant-like effects of SNC80 indicates that this class of compounds has potential as a novel antidepressant therapy. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jutkiewicz, EM (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB III, Ann Arbor, MI 48109 USA. EM ejutkiew@umich.edu FU NIDA NIH HHS [DA00254, K21 DA000254, P01 DA000254, P50 DA000254, T32 DA007267, T32 DA07267]; NIGMS NIH HHS [T32 GM007767, T32 GM07767] NR 35 TC 25 Z9 25 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2005 VL 315 IS 1 BP 414 EP 422 DI 10.1124/jpet.105.088831 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966EL UT WOS:000232002600048 PM 16014751 ER PT J AU Bouillon, R Moody, T Sporn, M Barrett, JC Norman, AW AF Bouillon, R Moody, T Sporn, M Barrett, JC Norman, AW TI NIH deltanoids meeting on Vitamin D and cancer conclusion and strategic options SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT Workshop on Vitamin D and Cancer Treatment and Prevention CY NOV 17-19, 2004 CL NIH, Bethesda, MD SP Vitamin D Workshop Inc HO NIH DE cancer; Vitamin D; 1, alpha,25-(OH)(2)D-3; vitamin D analogs; deltanoids AB A meeting on "Cancer Chemoprevention and Cancer Treatment; role of vitamin D, 1 alpha,25-(OH)(2)D-3 and deltanoids" was held on the NIH Congres, Bethesda in November 2004. The following conclusions were presented at the end of this symposium. Vitamin D deficiency and insufficiency are worldwide problems and are associated with several health problems including higher cancer prevalence. There is convincing evidence that the active vitamin D hormone, 1 alpha,25(OH)(2)D-3, can decrease cell proliferation, modify cell apoptosis and control malignant cell growth. Therefore academia, public funding agencies and industry should urgently design appropriate studies to better define the causal relationship between vitamin D nutrition and cancer, define the optimal vitamin D nutrition based on accurate 25(OH)D measurement and inform the public and medical profession accordingly. Selective vitamin D receptor modulators are a potentially interesting new class of chemopreventive and chemotherapeutic agents as demonstrated by several first generation analogs have provided a convincing proof of concept. In the mean time, the public should be informed about the risks of vitamin D deficiency and insufficiency and appropriate steps should be taken to improve the vitamin D nutritional status of large parts of the world population. (c) 2005 Elsevier Ltd. All rights reserved. C1 Katholieke Univ Leuven, Lab Expt Geneeskunde & Endocrinol, B-3000 Louvain, Belgium. Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA. NCI, Bethesda, MD 20892 USA. Dartmouth Coll Sch Med, Dept Pharmacol, Hanover, NH 03755 USA. RP Bouillon, R (reprint author), Katholieke Univ Leuven, Lab Expt Geneeskunde & Endocrinol, B-3000 Louvain, Belgium. EM roger.bouillon@med.kuleuven.ac.be NR 0 TC 13 Z9 13 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD OCT PY 2005 VL 97 IS 1-2 BP 3 EP 5 DI 10.1016/j.jsbmb.2005.06.016 PG 3 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 987UP UT WOS:000233543100002 PM 16043351 ER PT J AU Compton, WM Stein, JB Robertson, EB Pintello, D Pringle, B Volkow, ND AF Compton, WM Stein, JB Robertson, EB Pintello, D Pringle, B Volkow, ND TI Charting a course for health services research at the National Institute on Drug Abuse SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE drug abuse; health services; quality; financing; organization ID PROPENSITY SCORE; TRANSLATION; MODEL; CARE AB Through research, we continue to develop and refine an array of safe and efficacious interventions to prevent and treat drug abuse; however, these interventions have not led to widespread improvements in prevention and treatment services in nonresearch settings. In addition, investigator-initiated research rarely examine or refine interventions that practitioners have found relevant and that are widely practiced. To address these problems, the National Institute on Drug Abuse convened a blue ribbon task force to examine its health services research program. The report served as a catalyst for the institute to promote a vigorous program of research that seeks to examine prevention and treatment intervention delivery systems and policies that facilitate provision of effective care in a range of real world settings. Findings from this research should help address the translational bottleneck of bringing evidence-based interventions into the community. (c) 2005 Elsevier Inc. All rights reserved. C1 Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. RP Stein, JB (reprint author), Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd,NSC 9589, Bethesda, MD 20892 USA. EM jstein1@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 25 TC 34 Z9 34 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD OCT PY 2005 VL 29 IS 3 BP 167 EP 172 DI 10.1016/j.jsat.2005.05.008 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 975EF UT WOS:000232643100002 PM 16183465 ER PT J AU Winterfield, L Schultz, J Stratakis, CA Cowen, EW AF Winterfield, L Schultz, J Stratakis, CA Cowen, EW TI Gynecomastia and mucosal lentigines in an 8-year-old boy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review ID PEUTZ-JEGHERS-SYNDROME; SERTOLI-CELL TUMOR; SEX-CORD TUMOR; CARNEY-COMPLEX; PREPUBERTAL GYNECOMASTIA; ANNULAR TUBULES; DISEASE C1 NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov NR 14 TC 6 Z9 6 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2005 VL 53 IS 4 BP 660 EP 662 DI 10.1016/j.jaad.2005.06.050 PG 3 WC Dermatology SC Dermatology GA 967BZ UT WOS:000232067800015 PM 16198789 ER PT J AU Cesari, M Kritchevsky, SB Penninx, BWHJ Nicklas, BJ Simonsick, EM Newman, AB Tylavsky, FA Brach, JS Satterfield, S Bauer, DC Visser, M Rubin, SM Harris, TB Pahor, M AF Cesari, M Kritchevsky, SB Penninx, BWHJ Nicklas, BJ Simonsick, EM Newman, AB Tylavsky, FA Brach, JS Satterfield, S Bauer, DC Visser, M Rubin, SM Harris, TB Pahor, M TI Prognostic value of usual gait speed in well-functioning older people-results from the health, aging and body composition study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE physical performance; gait speed; lower extremity limitation; death; hospitalization ID PHYSICAL PERFORMANCE; SUBSEQUENT DISABILITY; WALKING SPEED; MUSCLE MASS; AGED 70; MORTALITY; WOMEN; POPULATION; PREDICTOR; DEPENDENCE AB To define clinically relevant cutpoints for usual gait speed and to investigate their predictive value for health-related events in older persons. Prospective cohort study. Health, Aging and Body Composition Study. Three thousand forty-seven well-functioning older persons (mean age 74.2). Usual gait speed on a 6-m course was assessed at baseline. Participants were randomly divided into two groups to identify (Sample A; n=2,031) and then validate (Sample B; n=1,016) usual gait-speed cutpoints. Rates of persistent lower extremity limitation events (mean follow-up 4.9 years) were calculated according to gait speed in Sample A. A cutpoint (defining high- (< 1 m/s) and low risk (>= 1 m/s) groups) was identified based on persistent lower extremity limitation events. The predictive value of the identified cutpoints for major health-related events (persistent severe lower extremity limitation, death, and hospitalization) was evaluated in Sample B using Cox regression analyses. A graded response was seen between risk groups and health-related outcomes. Participants in the high-risk group had a higher risk of persistent lower extremity limitation (rate ratio (RR)=2.20, 95% confidence interval (CI)=1.76-2.74), persistent severe lower extremity limitation (RR=2.29, 95% CI=1.63-3.20), death (RR=1.64, 95% CI=1.14-2.37), and hospitalization (RR=1.48, 95% CI=1.02-2.13) than those in the low-risk group. Usual gait speed of less than 1 m/s identifies persons at high risk of health-related outcomes in well-functioning older people. Provision of a clinically meaningful cutpoint for usual gait speed may facilitate its use in clinical and research settings. C1 Univ Florida, Inst Aging, Coll Med, Dept Aging & Geriatr Res, Gainesville, FL 32608 USA. Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. Vrije Univ Amsterdam, Dept Psychiat, NL-1081 HV Amsterdam, Netherlands. Vrije Univ Amsterdam, Inst Res Extramural Med, NL-1081 HV Amsterdam, Netherlands. NIA, Intramural Res Program, Baltimore, MD 21224 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA 15260 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 38163 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Cesari, M (reprint author), Univ Florida, Inst Aging, Coll Med, Dept Aging & Geriatr Res, 1329 SW 16th St,Room 5273, Gainesville, FL 32608 USA. EM mcesari@aging.ufl.edu RI Cesari, Matteo/A-4649-2008; Newman, Anne/C-6408-2013; OI Cesari, Matteo/0000-0002-0348-3664; Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, P30-AG-021332-02] NR 27 TC 396 Z9 403 U1 2 U2 34 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2005 VL 53 IS 10 BP 1675 EP 1680 DI 10.1111/j.1532-5415.2005.53501.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 966FR UT WOS:000232006000004 PM 16181165 ER PT J AU McDermott, MM Ferrucci, L Liu, K Criqui, MH Greenland, P Green, D Guralnik, JM Ridker, PM Taylor, LM Rifai, N Tian, L Zheng, J Pearce, WH Schneider, JR Vonesh, E AF McDermott, MM Ferrucci, L Liu, K Criqui, MH Greenland, P Green, D Guralnik, JM Ridker, PM Taylor, LM Rifai, N Tian, L Zheng, J Pearce, WH Schneider, JR Vonesh, E TI D-dimer and inflammatory markers as predictors of functional decline in men and women with and without peripheral arterial disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE peripheral vascular disease; intermittent claudication; inflammation; C-reactive protein; physical functioning ID C-REACTIVE PROTEIN; ANKLE BRACHIAL INDEX; LOWER-EXTREMITY FUNCTION; CHRONIC HEART-FAILURE; PRODUCT D-DIMER; 6-MINUTE WALK; MYOCARDIAL-INFARCTION; HEMOSTATIC FACTORS; TREADMILL WALKING; PHYSICAL-ACTIVITY AB OBJECTIVES: To determine whether higher circulating levels of inflammatory and thrombotic markers are associated with greater decline in lower extremity performance. DESIGN: Prospective cohort. SETTING: Academic medical center. PARTICIPANTS: Three hundred thirty-seven men and women with lower extremity peripheral arterial disease (PAD) and 215 without PAD. MEASUREMENTS: Objective measures of leg function, including the 6-minute walk and Short Physical Performance Battery (SPPB), were obtained at baseline and annually for 3 years. D-dimer, high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen levels were measured at baseline. Participants were categorized into one of three groups, ranging from low to high levels of inflammation, depending on the number of individual blood factors in the lowest and highest tertiles for each corresponding blood factor. RESULTS: Adjusting for age, sex, race, ankle brachial index, comorbidities, and other confounders, greater inflammation was associated with greater decline in the SPPB (P=.008). Results were similar when repeated in participants with and without PAD separately (P for trend=.04 for participants with PAD and .07 for participants without PAD). In fully adjusted analyses, there were no significant associations between inflammation group and decline in 6-minute walk performance. CONCLUSIONS: Higher baseline levels of inflammatory markers and D-dimer were associated with greater decline in the SPPB at 3-year follow-up in persons with and without PAD. C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Oregon Hlth Sci Univ, Div Vasc Surg, Portland, OR 97201 USA. NW Hosp, Dept Prevent Med, Evanston, IL USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU NCRR NIH HHS [RR-00048]; NHLBI NIH HHS [R01-HL58099, R01-HL64739] NR 46 TC 38 Z9 38 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2005 VL 53 IS 10 BP 1688 EP 1696 DI 10.1111/j.1532-5415.2005.53510.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 966FR UT WOS:000232006000006 PM 16181167 ER PT J AU Qin, JX Jones, M Travaglini, A Song, JM Li, JB White, RD Tsujino, H Greenberg, NL Zetts, AD Panza, JA Thomas, JD Shiota, T AF Qin, JX Jones, M Travaglini, A Song, JM Li, JB White, RD Tsujino, H Greenberg, NL Zetts, AD Panza, JA Thomas, JD Shiota, T TI The accuracy of left ventricular mass determined by real-time three-dimensional echocardiography in chronic animal and clinical studies: A comparison with postmortem examination and magnetic resonance imaging SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article; Proceedings Paper CT 49th Congress of the American-College-of-Cardiology CY MAR 07-10, 1999 CL ATLANTA, GA SP Amer Coll Cardiol ID TWO-DIMENSIONAL ECHOCARDIOGRAPHY; IN-VIVO VALIDATION; ANATOMIC VALIDATION; VOLUME; STROKE; VITRO; MODEL AB Real-time 3-dimensional echocardiography (RT3DE), 2-dimensional echocardiography (2DE), and M-mode echocardiography were performed in 28 sheep with cardiac pathologies and 27 patients with heart disease to demonstrate the superiority of RT3DE over M-mode and 2DE for the determination of left ventricular mass. Postmortem examination and magnetic resonance imaging were used as a reference standard for the animal and clinical studies, respectively. In the animal study, the highest concordance correlation (0.92) was obtained between the actual weight of left ventricular mass and that estimated by RT3DE (0.69 for 2DE and 0.77 for M-mode, P < .001). In the clinical study, RT3DE also provided the best concordance correlation with left ventricular mass determined by magnetic resonance imaging (0.91 for RT3DE, 0.83 for 2DE, and 0.38 for M-mode; P < .0001). C1 Cleveland Clin Fdn, Dept Cardiovasc Med, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Shiota, T (reprint author), Cleveland Clin Fdn, Dept Cardiovasc Med, Desk F15,9500 Euclid Ave, Cleveland, OH 44195 USA. EM shiotat@ccf.org OI White, Richard D./0000-0002-1133-7819 NR 23 TC 16 Z9 24 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD OCT PY 2005 VL 18 IS 10 BP 1037 EP 1043 DI 10.1016/j.echo.2005.04.012 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 972MP UT WOS:000232458200008 PM 16198880 ER PT J AU Frokiaer, J Nielsen, S Knepper, MA AF Frokiaer, J Nielsen, S Knepper, MA TI Molecular physiology of renal aquaporins and sodium transporters: Exciting approaches to understand regulation of renal water handling SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID UREA TRANSPORTERS; VASOPRESSIN; PHOSPHORYLATION; KIDNEY; CHANNEL; RAT C1 Univ Aarhus, Water & Salt Res Ctr, Aarhus, Denmark. NHLBI, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Aarhus Univ Hosp, Dept Clin Physiol, Skejby Brandstrupgaardsvej, DK-8230 Aarhus, Denmark. EM jf@ki.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 16 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2005 VL 16 IS 10 BP 2827 EP 2829 DI 10.1681/ASN.2005080850 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 968DH UT WOS:000232141600001 PM 16148036 ER PT J AU Hoorn, EJ Hoffert, JD Knepper, MA AF Hoorn, EJ Hoffert, JD Knepper, MA TI Combined proteomics and pathways analysis of collecting duct reveals a protein regulatory network activated in vasopressin escape SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID STEROID-RECEPTOR COACTIVATOR-1; INDUCED ANTIDIURESIS; C-MYC; UREA TRANSPORTERS; TYROSINE KINASE; RENAL ESCAPE; GENE; KIDNEY; RAT; EXPRESSION AB Low sensitivity is characteristic of many proteomics methods. Presented here is an approach that combines proteomics based on difference gel electrophoresis (DIGE) with bioinformatic pathways analysis to identify both abundant and relatively nonabundant proteins in inner medullary collecting duct (IMCD) altered in abundance during escape from vasopressin-induced antidiuresis. Rats received the vasopressin analog dDAVP by osmotic minipump plus either a daily water load (vasopressin escape) or only enough water to replace losses (control). Immunoblotting confirmed the hallmark of vasopressin escape, a decrease in aquaporin-2, and demonstrated a decrease in the abundance of the urea transporter UT-A3. DIGE identified 22 mostly high-abundance proteins regulated during vasopressin escape. These proteins were analyzed using pathways analysis software to reveal protein clusters incorporating the proteins identified by DIGE. A single dominant cluster emerged that included many relatively low-abundance proteins (abundances too low for DIGE identification), including several transcription factors. Immunoblotting confirmed a decrease in total and phosphorylated c-myc, a decrease in c-fos, and increases in c-jun and p53. Furthermore, immunoblotting confirmed hypothesized changes in other proteins in the proposed network: Increases in c-src, receptor for activated C kinase 1, calreticulin, and caspase 3 and decreases in steroid receptor co-activator 1, Grp78/BiP, and annexin A4. This combined approach proved capable of uncovering regulatory proteins that are altered in response to a specific physiologic perturbation without being detected directly by DIGE. The results demonstrate a dominant protein regulatory network in IMCD cells that is altered in association with vasopressin escape, providing a new framework for further studies of signaling in IMCD. C1 NHLBI, Lab Kidney & Electrocyte Metab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Lab Kidney & Electrocyte Metab, NIH, 10 Ctr Dr,Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NHLBI NIH HHS [Z01-HL-01282-KE] NR 42 TC 25 Z9 25 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2005 VL 16 IS 10 BP 2852 EP 2863 DI 10.1681/ASN.2005030322 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 968DH UT WOS:000232141600006 PM 16079266 ER PT J AU Choi, SW Ryu, OH Choi, SJ Song, IS Bleyer, AJ Hart, TC AF Choi, SW Ryu, OH Choi, SJ Song, IS Bleyer, AJ Hart, TC TI Mutant Tamm-Horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID JUVENILE HYPERURICAEMIC NEPHROPATHY; CHEMICAL CHAPERONES; STORAGE DISEASES; QUALITY-CONTROL; UMOD GENE; UROMODULIN; PROTEIN; MUTATIONS; CELLS; MECHANISMS AB As a consequence of uromodulin gene mutations, individuals develop precocious hyperuricemia, gout, and progressive renal failure. In vitro studies suggest that pathologic accumulation of uromodulin/Tamm-Horsfall glycoprotein (THP) occurs in the endoplasmic reticulum (ER), but the pathophysiology of renal damage is unclear. It was hypothesized that programmed cell death triggered by accumulation of misfolded THP in the ER causes progressive renal disease. Stably transfected human embryonic kidney 293 cells and immortalized thick ascending limb of Henle's loop cells with wild-type and mutated uromodulin cDNA were evaluated to test this hypothesis. Immunocytochemistry, ELISA, and deglycosylation studies indicated that accumulation of mutant THP occurred in the ER. FACS analyses showed a significant increase in early apoptosis signal in human embryonic kidney 293 and thick ascending limb of Henle's loop cells that were transfected with mutant uromodulin constructs. Colchicine and sodium 4-phenylbutyrate treatment increased secretion of THP from the ER to the cell membrane and into the culture media and significantly improved cell viability. These findings, indicate that intracellular accumulation of THP facilitates apoptosis and that this may provide the pathologic mechanism responsible for the progressive renal damage associated with uromodulin gene mutations. Colchicine and sodium 4-phenylbutyrate reverse these processes and could potentially be beneficial in ameliorating the progressive renal damage in uromodulin-associated kidney diseases. C1 NIDCR, Human Craniofacial Genet Sect, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC USA. RP Choi, SW (reprint author), NIDCR, Human Craniofacial Genet Sect, NIH, 10 Ctr Dr,Bldg 10,Room 5-2531, Bethesda, MD 20892 USA. EM thart@mail.nih.gov FU NIDDK NIH HHS [DK62252] NR 37 TC 34 Z9 37 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2005 VL 16 IS 10 BP 3006 EP 3014 DI 10.1681/ASN.2005050461 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 968DH UT WOS:000232141600022 PM 16135773 ER PT J AU Kotzin, S AF Kotzin, S TI Joseph Leiter, FMLA, 1915-2005 SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Biographical-Item C1 Natl Lib Med, Bibliog Serv Div, Bethesda, MD 20894 USA. RP Kotzin, S (reprint author), Natl Lib Med, Bibliog Serv Div, Bethesda, MD 20894 USA. EM kotzin@nlm.nih.gav NR 1 TC 0 Z9 0 U1 0 U2 0 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2005 VL 93 IS 4 BP 512 EP 513 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 975DN UT WOS:000232641300023 ER PT J AU Dutcher, GA Hamasu, C AF Dutcher, GA Hamasu, C TI Community-based organizations' perspective on health information outreach: a panel discussion SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Editorial Material AB Objective: A panel was convened to elicit guidance for librarians in initiating and implementing community-based health information outreach. Participants: Participants included a panel of individuals from communities or community organizations who represented the types of groups with which librarians or information specialists need to interact and an audience who represented health sciences libraries, public libraries, academic institutions, government agencies, funding agencies, and community-based organizations and could contribute to a discussion on community-based health information outreach. Program: The panel was presented with a hypothetical community setting and asked to respond to a series of questions: What do librarians need to learn about the community before they make their visits? What methods of outreach have been successful in your work? How would you implement and sustain a health information program in your community? How would health information interventions reduce racial and ethnic disparities in health? Main Results: The panel helped to frame many of the issues that may confront librarians as they initiate information-related programs in communities. Conclusion: There is clear consensus on the need for librarians to make the effort to reach out into the community, to make the contacts, to seek to understand the community, to talk with leaders, and to respect the community as they promote and teach the use of health information resources. It was confirmed that librarians and libraries have an important role in diminishing health disparities by improving access to health information. C1 Natl Lib Med, Off Outreach & Special Populat, Div Specialized Informat Serv, Bethesda, MD 20894 USA. Univ Utah, Eccles Hlth Sci Lib, Natl Network Lib Med Midcontinental Reg, Salt Lake City, UT 84112 USA. RP Dutcher, GA (reprint author), Natl Lib Med, Off Outreach & Special Populat, Div Specialized Informat Serv, Bethesda, MD 20894 USA. EM dutcher@nlm.nih.gov; chamasu@rml4.utah.edu NR 0 TC 5 Z9 5 U1 0 U2 1 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2005 VL 93 IS 4 SU S BP S35 EP S42 PG 8 WC Information Science & Library Science SC Information Science & Library Science GA 976IG UT WOS:000232726300004 PM 16239956 ER PT J AU Friedman, CR AF Friedman, CR TI "Smallball" evaluation: a prescription for studying community-based information interventions SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article; Proceedings Paper CT Symposium on Community-Based Health Information Outreach CY DEC 02, 2004 CL Bethesda, MD ID SYSTEM AB Objectives: This paper argues that focused evaluation studies of community-based informational interventions conducted over the life-cycle of the project ("smallball" studies) are more informative and useful than randomized experiments conducted only at the project's conclusion ("powerball" studies). Method: Based on two contrasting strategies in baseball, smallball and powerball studies are compared and contrasted, emphasizing how the distinctive features of community-based interventions lend advantage to smallball approaches. Results: Smallball evaluations have several important advantages over powerball evaluations: before system development, they ensure that information resources address real community needs; during deployment, they ensure that the systems are suited to the capabilities of the users and to community constraints; and, after deployment, they enable as much as possible to be learned about the effects of the intervention in environments where randomized studies are usually impossible. Implications: Many in informatics see powerball studies as the only legitimate form of evaluation and so expect powerball studies to be done. These expectations should be revised in favor of smallball studies. C1 Natl Lib Med, Extramural Programs Div, Bethesda, MD 20892 USA. RP Friedman, CR (reprint author), Natl Lib Med, Extramural Programs Div, 6705 Rockledge Dr,Suite 301, Bethesda, MD 20892 USA. EM friedmc1@mail.nih.gov NR 4 TC 17 Z9 17 U1 0 U2 1 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2005 VL 93 IS 4 SU S BP S43 EP S48 PG 6 WC Information Science & Library Science SC Information Science & Library Science GA 976IG UT WOS:000232726300005 PM 16239957 ER PT J AU Siegel, ER Wood, FB Dutcher, GA Ruffin, A Logan, RA Scott, JC AF Siegel, ER Wood, FB Dutcher, GA Ruffin, A Logan, RA Scott, JC TI Assessment of the National Library of Medicine's health disparities plan: a focus on Native American outreach SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article; Proceedings Paper CT Symposium on Community-Based Health Information Outreach CY DEC 02, 2004 CL Bethesda, MD AB Objectives: Overcoming health disparities between majority and minority populations is a significant national challenge. This paper assesses outreach to Native Americans (American Indians, Alaska Natives, and Native Hawaiians) by the National Library of Medicine (NLM). A companion paper details NLM's portfolio of Native American outreach projects. Method: NLM's Native American outreach is assessed in light of the presentations at a community-based health information outreach symposium and the goals set by NLM's plan to reduce health disparities. Results: NLM's current portfolio of Native American outreach projects appears most advanced in meeting the goal set in area 1 of the health disparities plan, "Promote use of health information by health professionals and the public." NLM's portfolio also shows significant strength and good progress regarding area 2 of the plan, "Expand partnerships among various types of libraries and community-based organizations." The portfolio is weaker in area 3, "Conduct and support informatics research." More knowledge-building efforts would benefit NLM, the National Network of Libraries of Medicine, and Native American and community-based organizations. Implications: The current Native American outreach portfolio should be continued, but new approaches are needed for evaluating Native American outreach and for forging collaborations with Native American groups, approaches grounded in consultation and mutual understanding of needs and perspectives. C1 Natl Lib Med, Off Hlth Informat Programs Dev, Bethesda, MD 20894 USA. Natl Lib Med, Off Outreach & Special Populat, Specialized Informat Serv Div, Bethesda, MD 20894 USA. Natl Lib Med, Natl Network Off, Bethesda, MD 20894 USA. Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. Ctr Publ Serv Commun, Arlington, VA 22207 USA. RP Siegel, ER (reprint author), Natl Lib Med, Off Hlth Informat Programs Dev, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM siegel@nlm.nih.gov; fredwood@mail.nih.gov; dutcherg@mail.nlm.nih.gov; ruffina@mail.nlm.nih.gov; logan@nlm.nih.gov; jcscott@cpsc.com NR 16 TC 1 Z9 1 U1 2 U2 2 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2005 VL 93 IS 4 SU S BP S10 EP S20 PG 11 WC Information Science & Library Science SC Information Science & Library Science GA 976IG UT WOS:000232726300002 PM 16239954 ER PT J AU Wood, FB Siegel, ER Dutcher, GA Ruffin, A Logan, RA AF Wood, FB Siegel, ER Dutcher, GA Ruffin, A Logan, RA TI The National Library of Medicine's Native American outreach portfolio: a descriptive overview SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article; Proceedings Paper CT Symposium on Community-Based Health Information Outreach CY DEC 02, 2004 CL Bethesda, MD AB Objectives: This paper provides the most complete accounting of the National Library of Medicines (NLM's) Native outreach since 1995, when there were only a few scattered projects. Method: The descriptive overview is based on a review of project reports, inventories, and databases and input from the NLM Specialized Information Services Division, National Network Office of the Library Operations Division, National Network of Libraries of Medicine, and Office of Health Information Programs Development of the Office of the NLM Director. The overview focuses on NLM-supported or sponsored outreach initiatives involving Native peoples: American Indians, Alaska Natives, and Native Hawaiians. Results: The review of NLM's relevant activities resulted in a portfolio of projects that clustered naturally into the following areas: major multisite projects: Tribal Connections and related, Native American Information Internship Project: Sacred Root, tribal college outreach and tribal librarianship projects, collaboration with inter-tribal and national organizations, participation in Native American Powwows, Native American Listening Circle Project, Native American Health Information, and other Native American outreach projects. Implications: NLM's Native American Outreach reached programmatic status as of late 2004. The companion paper identifies several areas of possible new or enhanced Native outreach activities. Both papers highlight the importance of solid reporting and evaluation to optimize project results and programmatic balance and priorities. C1 Natl Lib Med, Off Hlth Informat Programs Dev, Bethesda, MD 20894 USA. Natl Lib Med, Off Outreach & Special Populat, Specialized Informat Serv Div, Bethesda, MD 20894 USA. Natl Lib Med, Natl Network Off, Bethesda, MD 20894 USA. Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. Ctr Publ Serv Commun, Arlington, VA 22207 USA. RP Wood, FB (reprint author), Natl Lib Med, Off Hlth Informat Programs Dev, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM fredwood@mail.nih.gov; siegel@nlm.nih.gov; dutcherg@mail.nlm.nih.gov; ruffina@mail.nlm.nih.gov; logan@nlm.nih.gov NR 12 TC 3 Z9 3 U1 1 U2 2 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2005 VL 93 IS 4 SU S BP S21 EP S34 PG 14 WC Information Science & Library Science SC Information Science & Library Science GA 976IG UT WOS:000232726300003 PM 16239955 ER PT J AU Romero, R Erez, O Espinoza, J AF Romero, R Erez, O Espinoza, J TI Intrauterine infection, preterm labor, and cytokines SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Editorial Material ID TUMOR-NECROSIS-FACTOR; INTERLEUKIN-1 RECEPTOR ANTAGONIST; FETAL INFLAMMATORY RESPONSE; AMNIOTIC-FLUID INFECTION; PREGNANT RHESUS-MONKEYS; WHITE-MATTER LESIONS; BRONCHOPULMONARY DYSPLASIA; FACTOR-ALPHA; INTRAAMNIOTIC INFLAMMATION; PROSTAGLANDIN PRODUCTION C1 Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHD, DHHS,NIH, Perinatol Res Branch, Bethesda, MD USA. RP Romero, R (reprint author), NICHD, DHHS, NIH, Perinatol Res Branch, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU Intramural NIH HHS NR 67 TC 34 Z9 36 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD OCT PY 2005 VL 12 IS 7 BP 463 EP 465 DI 10.1016/j.jsgi.2005.09.001 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 976XQ UT WOS:000232767400001 PM 16202922 ER PT J AU Goldberg, SN Bonn, J Dodd, G Dupuy, D Geschwind, JH Hicks, M Hume, KM Lee, FT Lewis, CA Lencioni, RA Omary, RA Rundback, JH Silverman, S Dorfman, GS AF Goldberg, SN Bonn, J Dodd, G Dupuy, D Geschwind, JH Hicks, M Hume, KM Lee, FT Lewis, CA Lencioni, RA Omary, RA Rundback, JH Silverman, S Dorfman, GS TI Society of Interventional Radiology Interventional Oncology Task Force: Interventional oncology research vision statement and critical assessment of the state of research affairs SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article C1 Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. Univ Texas, Hlth Sci Ctr, Dept Radiol, San Antonio, TX 78285 USA. Univ Texas, MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. Brown Univ, Rhode Isl Hosp, Div Ultrasound, Providence, RI 02912 USA. Johns Hopkins Univ Hosp, Dept Intervent Radiol, Baltimore, MD 21287 USA. Natl Canc Inst, Div Canc Treatment & Diagnosis, Bethesda, MD USA. Soc Intervent Radiol Fdn, Fairfax, VA USA. Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. Grady Hlth Syst, Atlanta, GA USA. Northwestern Univ, Sch Med, Dept Radiol, Chicago, IL 60611 USA. Columbia Presbyterian Med Ctr, Dept Vasc & Intervent Radiol, New York, NY 10032 USA. Univ Pisa, Dept Radiol, Pisa, Italy. RP Goldberg, SN (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 1 Deaconess Rd,WCC 308B, Boston, MA 02215 USA. EM sgoldber@caregroup.harvard.edu OI Dupuy, Damian/0000-0003-0524-5982 NR 0 TC 12 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2005 VL 16 IS 10 BP 1287 EP 1294 DI 10.1097/01.RVI.0000182220.11020.55 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 973EG UT WOS:000232505100002 PM 16221897 ER PT J AU Koh, PO Kang, BI Kim, GS Oh, YS Won, CK AF Koh, PO Kang, BI Kim, GS Oh, YS Won, CK TI The effect of thrombin on astrocyte stellation with regional specificity SO JOURNAL OF VETERINARY MEDICAL SCIENCE LA English DT Article DE cell culture; morphology; regional heterogeneity ID MESSENGER-RNA; RECEPTOR; RAT; LOCALIZATION; EXPRESSION; GLUTAMATE; CULTURES; SUBUNIT; INVITRO; SYSTEM AB In this study, we have examined the possible existence of astrocyte regional heterogeneity in thrombin effect on astrocyte stellation. Neonatal astrocytes were cultured for 2 weeks from six different regions of the neonatal rat brain, including the cerebral cortex, hippocampus, brainstem, midbrain, hypothalamus and cerebellum. Culture medium was changed to DMEM containing 8-CPT-cyclic AMP (cAMP) or isoproterenol plus various concentrations of thrombin for 2 hr. Thrombin effectively blocked both cAMP- and isoproterenol-induced cell stellation in a dose-dependent manner in all regional astrocytes except cerebellar astrocytes. RT-PCR analysis showed that thrombin receptor mRNA was expressed in all regional astrocytes, suggesting that cerebellar astrocytes may maintain a unique signaling pathway downstream of the thrombin receptor. C1 Gyeongsang Natl Univ, Coll Vet Med, Dept Anat, Inst Anim Med, Jinju 660701, South Korea. Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH,DHHS, Bethesda, MD 20892 USA. RP Won, CK (reprint author), Gyeongsang Natl Univ, Coll Vet Med, Dept Anat, Inst Anim Med, Jinju 660701, South Korea. FU NINDS NIH HHS [NS-34877] NR 18 TC 0 Z9 0 U1 1 U2 1 PU JAPAN SOC VET SCI PI TOKYO PA UNIV TOKYO, 1-1-1 YAYOI, BUNKYO-KU, TOKYO, 103, JAPAN SN 0916-7250 J9 J VET MED SCI JI J. Vet. Med. Sci. PD OCT PY 2005 VL 67 IS 10 BP 1047 EP 1050 DI 10.1292/jvms.67.1047 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 985BP UT WOS:000233351400013 PM 16276062 ER PT J AU Crise, B Li, Y Yuan, CC Morcock, DR Whitby, D Munroe, DJ Arthur, LO Wu, XL AF Crise, B Li, Y Yuan, CC Morcock, DR Whitby, D Munroe, DJ Arthur, LO Wu, XL TI Simian immunodeficiency virus integration preference is similar to that of human immunodeficiency virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID RETROVIRAL DNA-INTEGRATION; TARGET SITE SELECTION; HUMAN GENOME; EXPRESSED GENES; CD34(+) CELLS; IN-VITRO; HIV-1; TRANSCRIPTION; PROTEINS; SEQUENCE AB Simian immunodeficiency virus (SIV) is a useful model for studying human immunodeficiency virus (HIV) pathogenesis and vaccine efficacy. As with all other retroviruses, integration is a necessary step in the replication cycle of SIV. The location of the retrovirus integration site is known to impact on viral gene expression, establishment of viral latency, and other aspects of the replication cycle of a retrovirus. In this study, 148 SIV provirus integration sites were sequenced and mapped in the human genome. Our analysis showed that SIV integration, like that of HIV type 1 (HIV-1), exhibited a strong preference for actively transcribed regions in the genome (A. R. Schroder et al., Cell 110:521-529,2002) and no preference for the CpG islands or transcription start sites, in contrast to observations for murine leukemia virus (X. Wu et al., Science 300:1749-1751, 2003). The parallel integration target site preferences of SIV and HIV-1 suggest that these lentiviruses may share similar mechanisms for target site selection and that SIV serves as an accurate model of HIV-1 with respect to integration. C1 NCI, Lab Mol Technol, Sci Applicat Int Corp, Frederick, MD 21701 USA. NCI, AIDS Vaccine Program, Frederick, MD 21701 USA. NCI, AIDS Vaccine Program, Frederick, MD 21701 USA. NCI, Lab Mol Technol, Frederick, MD 21701 USA. RP Wu, XL (reprint author), NCI, Lab Mol Technol, Sci Applicat Int Corp, 915 Toll House Ave, Frederick, MD 21701 USA. EM forestwu@mail.nih.gov FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 44 TC 48 Z9 51 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 19 BP 12199 EP 12204 DI 10.1128/JVI.79.19.12199-12204.2005 PG 6 WC Virology SC Virology GA 966AR UT WOS:000231992500007 PM 16160146 ER PT J AU Wyss, S Dimitrov, AS Baribaud, F Edwards, TG Blumenthal, R Hoxie, JA AF Wyss, S Dimitrov, AS Baribaud, F Edwards, TG Blumenthal, R Hoxie, JA TI Regulation of human immunodeficiency virus type 1 envelope glycoprotein fusion by a membrane-interactive domain in the gp41 cytoplasmic tail SO JOURNAL OF VIROLOGY LA English DT Review ID MURINE-LEUKEMIA-VIRUS; CELL-SURFACE EXPRESSION; RETROVIRAL TRANSMEMBRANE PROTEIN; TYROSINE-BASED SIGNAL; PFIZER MONKEY VIRUS; HIV-1 GP41; R-PEPTIDE; NEUTRALIZATION SENSITIVITY; CHEMOKINE RECEPTORS; CLATHRIN ADAPTER AB Truncation of the human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) gp41 cytoplasmic tail (CT) can modulate the fusogenicity of the envelope glycoprotein (Env) on infected cells and virions. However, the CT domains involved and the underlying mechanism responsible for this "inside-out" regulation of Env function are unknown. HIV and SIV CTs are remarkably long and contain amphipathic alpha-helical domains (LLP1, LLP2, and LLP3) that likely interact with cellular membranes. Using a cell-cell fusion assay and a panel of HIV Envs with stop codons at various positions in the CT, we show that truncations of gp41 proximal to the most N-terminal alpha helix, LLP2, increase fusion efficiency and expose CD4-induced epitopes in the Env ectodomain. These effects were not seen with a truncation distal to this domain and before LLP1. Using a dye transfer assay to quantitate fusion kinetics, we found that these truncations produced a two-to fourfold increase in the rate of fusion. These results were observed for X4-, R5-, and dual-tropic Envs on CXCR4- and CCR5-expressing target cells and could not be explained by differences in Env surface expression. These findings suggest that distal to the membrane-spanning domain, an interaction of the gp41 LLP2 domain with the cell membrane restricts Env fusogenicity during Env processing. As with murine leukemia viruses, where cleavage of a membrane-interactive R peptide at the C terminus is required for Env to become fusogenic, this restriction of Env function may serve to protect virus-producing cells from the membrane-disruptive effects of the Env ectodomain. C1 Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. NCI, Canc Res Ctr, Nanobiol Program, NIH, Ft Detrick, MD 21702 USA. RP Hoxie, JA (reprint author), Univ Penn, Dept Med, Div Hematol Oncol, Rm 356,Biomed Res Bldg 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM hoxie@mail.med.upenn.edu FU NIAID NIH HHS [R01 AI045378, P30 AI045008, R01 AI45378, P30 AI45008] NR 102 TC 86 Z9 90 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 19 BP 12231 EP 12241 DI 10.1128/JVI.79.19.12231-12241.2005 PG 11 WC Virology SC Virology GA 966AR UT WOS:000231992500010 PM 16160149 ER PT J AU Raviv, Y Viard, M Bess, JW Chertova, E Blumenthal, R AF Raviv, Y Viard, M Bess, JW Chertova, E Blumenthal, R TI Inactivation of retroviruses with preservation of structural integrity by targeting the hydrophobic domain of the viral envelope SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; NEUTRALIZING ANTIBODIES; NUCLEOCAPSID PROTEIN; TYPE-1; HIV; SIV; GLYCOPROTEIN; PROTECTION; MACAQUES AB We describe a new approach for the preparation of inactivated retroviruses for vaccine application. The lipid domain of the viral envelope was selectively targeted to inactivate proteins and lipids therein and block fusion of the virus with the target cell membrane. In this way, complete elimination of the infectivity of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) could be achieved with preservation of antigenic determinants on the surface of the viral envelope. Inactivation was accomplished by modification of proteins and lipids in the viral envelope using the hydrophobic photoinduced alkylating probe 1,5 iodonaphthylazide (INA). Treatment of HIV and SIV isolates with INA plus light completely blocked fusion of the viral envelope and abolished infectivity. The inactivated virus remained structurally unchanged, with no detectable loss of viral proteins. Modifications to envelope and nucleocapsid proteins were detected by changes in their elution pattern on reverse-phase high-performance liquid chromatography. These modifications had no effect on primary and secondary structure epitopes as determined by monoclonal antibodies. Likewise, the inactivated HIV reacted as well as the live virus with the conformation-sensitive and broadly neutralizing anti-HIV type 1 monoclonal antibodies 2612, b12, and 4E10. Targeting the lipid domain of biological membranes with hydrophobic alkylating compounds could be used as a general approach for inactivation of enveloped viruses and other pathogenic microorganisms for vaccine application. C1 NCI, Canc Res Ctr, Nanobiol Program, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC, Frederick, MD 21702 USA. NCI, AIDS Vaccine Program, SAIC, Frederick, MD 21702 USA. RP Raviv, Y (reprint author), NCI, Canc Res Ctr, Nanobiol Program, Bldg 469,Room 215, Frederick, MD 21702 USA. EM yraviv@ncifcrf.gov RI Bess, Jr., Julian/B-5343-2012 FU Intramural NIH HHS NR 32 TC 20 Z9 21 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 19 BP 12394 EP 12400 DI 10.1128/JVI.79.19.12394-12400.2005 PG 7 WC Virology SC Virology GA 966AR UT WOS:000231992500027 PM 16160166 ER PT J AU Yuste, E Johnson, W Pavlakis, GN Desrosiers, RC AF Yuste, E Johnson, W Pavlakis, GN Desrosiers, RC TI Virion envelope content, infectivity, and neutralization sensitivity of simian immunodeficiency virus SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-SURFACE EXPRESSION; GLYCOPROTEIN CYTOPLASMIC DOMAIN; RHESUS MONOCLONAL-ANTIBODIES; AMINO-ACID SUBSTITUTIONS; TYROSINE-BASED SIGNAL; TYPE-1 ENVELOPE; ENV INCORPORATION; CLATHRIN ADAPTER; INTRACYTOPLASMIC DOMAIN; CYTOSOLIC DOMAIN AB A truncating E767stop mutation was introduced into the envelope glycoprotein of simian immunodeficiency virus (SIV) strain SIV239-M5 (moderately sensitive to antibody-mediated neutralization and lacking five sites for N-linked carbohydrate attachment) and strain SIV316 (very sensitive to neutralization, with eight amino acid changes from the neutralization-resistant parental molecular clone, SIV239). The truncating mutation increased Env content in virions, increased infectivity, and decreased sensitivity to antibody-mediated neutralization in both strains. However, the magnitude of the effect on infectivity and neutralization sensitivity differed considerably between the two strains. In the context of strain SIV239-M5, truncation increased Env content in virions approximately 10-fold and infectivity in a reporter cell assay 24-fold. The truncated SIV239-M5 was only slightly more resistant to neutralization by polyclonal monkey sera and by monoclonal antibodies than SIV239-M5 with a full-length envelope glycoprotein. In the context of strain SIV316, truncation increased infectivity a dramatic 480-fold, while envelope content in virions was increased only about 14-fold. This dramatic increase in infectivity cannot be simply explained by the increase in envelope content and is likely due to an increase in inherent infectivity, i.e., infectivity per spike, that results from truncation. The truncated SIV316 was extremely resistant to antibody-mediated neutralization. In fact, it was not neutralized by any of the antibodies tested. When increasing amounts of SIV316 envelope glycoprotein (full length) were provided in trans to SIV316, infectivity was increased and sensitivity to neutralization was decreased, but to nowhere near the degree that was obtained when truncated SIV316 envelope glycoprotein was used. Truncated forms of SIV239 and SIV239-M5 required higher levels of soluble CD4 for inhibition of infection than their nontruncated forms; truncated SIV316 did not. Our results suggest that envelope content in SIV virions, infectivity, and resistance to antibody-mediated neutralization can be increased not only by truncation of the cytoplasmic domain but also by provision of excess envelope in trans. The striking increase in infectivity that results from truncation in the context of SIV316 appears to be due principally to an increase in inherent infectivity per spike. C1 Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. NCI, Canc Res Ctr, Human Retrovirus Sect, Frederick, MD 21702 USA. RP Desrosiers, RC (reprint author), Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Dept Microbiol & Mol Genet, 1 Pine Hill Dr,Box 9102, Southborough, MA 01772 USA. EM ronald_desrosiers@hms.harvard.edu FU NCRR NIH HHS [K26 RR000168, P51 RR000168, RR00168]; NIAID NIH HHS [R01 AI050421, R01 AI057039, R01-AI057039, R01AI50421] NR 59 TC 32 Z9 32 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 19 BP 12455 EP 12463 DI 10.1128/JVI.79.19.12455-12463.2005 PG 9 WC Virology SC Virology GA 966AR UT WOS:000231992500034 PM 16160173 ER PT J AU Biacchesi, S Pham, QN Skiadopoulos, MH Murphy, BR Collins, PL Buchholz, UJ AF Biacchesi, S Pham, QN Skiadopoulos, MH Murphy, BR Collins, PL Buchholz, UJ TI Infection of nonhuman primates with recombinant human metapneumovirus lacking the SH, G, or M2-2 protein categorizes each as a nonessential accessory protein and identifies vaccine candidates SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; REPLICATION IN-VITRO; G-GLYCOPROTEIN; YOUNG-CHILDREN; TRACT DISEASE; EXPRESSION; CHALLENGE; DELETION; LIVE; RESISTANCE AB Recombinant human metapneumovirus (HMPV) in which the SH, G, or M2 gene or open reading frame was deleted by reverse genetics was evaluated for replication and vaccine efficacy following topical administration to the respiratory tract of African green monkeys, a permissive primate host. Replication of the ASH virus was only marginally less efficient than that of wild-type HMPV, whereas the Delta G and Delta M2-2 viruses were reduced sixfold and 160-fold in the upper respiratory tract and 3,200-fold and 4,000-fold in the lower respiratory tract, respectively. Even with the highly attenuated mutants, there was unequivocal HMPV replication at each anatomical site in each animal. Thus, none of these three proteins is essential for HMPV replication in a primate host, although G and M2-2 increased the efficiency of replication. Each gene-deletion virus was highly immunogenic and protective against wild-type HMPV challenge. The Delta G and Delta M2-2 viruses are promising vaccine candidates that are based on independent mechanisms of attenuation and are appropriate for clinical evaluation. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), NIAID, NIH, Bldg 50,Room 6505,50 S Dr,MSC 8007, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov RI Biacchesi, Stephane/A-6924-2010 NR 34 TC 97 Z9 101 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 19 BP 12608 EP 12613 DI 10.1128/JVI.79.19.12608-12613.2005 PG 6 WC Virology SC Virology GA 966AR UT WOS:000231992500051 PM 16160190 ER PT J AU Jones, KS Petrow-Sadowski, C Bertolette, DC Huang, Y Ruscetti, FW AF Jones, KS Petrow-Sadowski, C Bertolette, DC Huang, Y Ruscetti, FW TI Heparan sulfate Proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4(+) T cells SO JOURNAL OF VIROLOGY LA English DT Article ID HERPES-SIMPLEX-VIRUS; ENVELOPE GLYCOPROTEIN; SURFACE GLYCOPROTEIN; SYNCYTIUM FORMATION; HTLV-I; ENCEPHALITIS-VIRUS; ENDOTHELIAL-CELLS; PERIPHERAL-BLOOD; E2 GLYCOPROTEIN; KIDNEY-CELLS AB Heparan sulfate proteoglycans (HSPGs) are used by a number of viruses to facilitate entry into host cells. For the retrovirus human T-cell leukemia virus type 1 (HTLV-1), it has recently been reported that HSPGs are critical for efficient binding of soluble HTLV-1 SU and the entry of HTLV pseudotyped viruses into non-T cells. However, the primary in vivo targets of HTLV-1, CD4(+) T cells, have been reported to express low or undetectable levels of HSPGs. For this study, we reexamined the expression of HSPGs in CD4(+) T cells and examined their role in HTLV-1 attachment and entry. We observed that while quiescent primary CD4(+) T cells do not express detectable levels of HSPGs, HSPGs are expressed on primary CD4(+) T cells following immune activation. Enzymatic modification of HSPGs on the surfaces of either established CD4(+) T-cell lines or primary CD4(+) T cells dramatically reduced the binding of both soluble HTLV-1 SU and HTLV-1 virions. HSPGs also affected the efficiency of HTLV-1 entry, since blocking the interaction with HSPGs markedly reduced both the internalization of HTLV-1 virions and the titer of HTLV-1 pseudotyped viral infection in CD4(+) T cells. Thus, HSPGs play a critical role in the binding and entry of HTLV-1 into CD4(+) T cells. C1 NCI Frederick, SAIC, Basic Res Program, Ft Detrick, MD 21702 USA. NCI Frederick, Canc Res Ctr, Expt Immunol Lab, Ft Detrick, MD 21702 USA. RP Jones, KS (reprint author), NCI Frederick, SAIC, Basic Res Program, Ft Detrick, MD 21702 USA. EM jonesk@ncifcrf.gov FU NCI NIH HHS [CO-12400, N01CO12400] NR 82 TC 100 Z9 105 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 20 BP 12692 EP 12702 DI 10.1128/JVI.79.20.12692-12702.2005 PG 11 WC Virology SC Virology GA 969OI UT WOS:000232243200010 PM 16188972 ER PT J AU Nishigaki, K Hanson, C Thompson, D Yugawa, T Ruscetti, S AF Nishigaki, K Hanson, C Thompson, D Yugawa, T Ruscetti, S TI Activation of the Jun N-terminal kinase pathway by friend spleen focus-forming virus and its role in the growth and survival of friend virus-induced erythroleukemia cells SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; SIGNAL-TRANSDUCTION PATHWAY; PROVIRAL INTEGRATION SITE; BREAST-CANCER CELLS; P38 MAP KINASE; ERYTHROID-CELLS; ERYTHROPOIETIN RECEPTOR; TRANSCRIPTION FACTOR; CONSTITUTIVE ACTIVATION; ENVELOPE GLYCOPROTEIN AB Members of the mitogen-activated protein kinase (MAPK) family, including Jun amino-terminal kinase (JNK) and extracellular signal-related kinase (ERK), play an important role in the proliferation of erythroid cells in response to erythropoietin (Epo). Erythroid cells infected with the Friend spleen focus-forming virus (SFFV) proliferate in the absence of Epo and show constitutive activation of Epo signal transduction pathways. We previously demonstrated that the ERK pathway was constitutively activated in Friend SFFV-infected erythroid cells, and in this study JNK is also shown to be constitutively activated. Pharmacological inhibitors of both the ERK and JNK pathways stopped the proliferation of primary erythroleukemic cells from Friend SFFV-infected mice, with little induction of apoptosis, and furthermore blocked their ability to form Epo-independent colonies. However, only the JNK inhibitor blocked the proliferation of erythroleukemia cell lines derived from these mice. The JNK inhibitor caused significant apoptosis in these cell lines as well as an increase in the fraction of cells in G(2)/M and undergoing endoreduplication. In contrast, the growth of erythroleukemia cell lines derived from Friend murine leukemia virus (MuLV)-infected mice was inhibited by both the MEK and JNK inhibitors. JNK is important for AP1 activity, and we found that JNK inhibitor treatment reduced AP1 DNA-binding activity in primary erythroleukemic splenocytes from Friend SFFV-infected mice and in erythroleukemia cell lines from Friend MuLV-infected mice but did not alter AP1 DNA binding in erythroleukemia cell lines from Friend SFFV-infected mice. These data suggest that JNK plays an important role in cell proliferation and/or the survival of erythroleukemia cells. C1 NCI, Lab Canc Prevent, Ft Detrick, MD 21702 USA. RP Ruscetti, S (reprint author), NCI, Lab Canc Prevent, Bldg 469,Room 205, Ft Detrick, MD 21702 USA. EM ruscetti@ncifcrf.gov NR 63 TC 14 Z9 15 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 20 BP 12752 EP 12762 DI 10.1128/JVI.79.20.12752-12762.2005 PG 11 WC Virology SC Virology GA 969OI UT WOS:000232243200016 PM 16188978 ER PT J AU Best, SM Morris, KL Shannon, JG Robertson, SJ Mitzel, DN Park, GS Boer, E Wolfinbarger, JB Bloom, ME AF Best, SM Morris, KL Shannon, JG Robertson, SJ Mitzel, DN Park, GS Boer, E Wolfinbarger, JB Bloom, ME TI Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist SO JOURNAL OF VIROLOGY LA English DT Article ID DENGUE VIRUS-INFECTION; HUMAN DENDRITIC CELLS; WEST-NILE-VIRUS; ENCEPHALITIS-VIRUS; ALPHA-INTERFERON; JAPANESE ENCEPHALITIS; ANTIVIRAL RESPONSES; IMMUNE-SYSTEM; JANUS KINASES; HEPATITIS-C AB The tick-borne encephalitis (TBE) complex of viruses, genus Flavivirus, can cause severe encephalitis, meningitis, and/or hemorrhagic fevers. Effective interferon (IFN) responses are critical to recovery from infection with flaviviruses, and the mosquito-borne flaviviruses can inhibit this response. However, little is known about interactions between IFN signaling and TBE viruses. Langat virus (LGTV), a member of the TBE complex of viruses, was found to be highly sensitive to the antiviral effects of IFN. However, LGTV infection inhibited IFN-induced expression of a reporter gene driven by either IFN-alpha/beta- or IFN-gamma-responsive promoters. This indicated that LGTV can inhibit the IFN-mediated JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway of signal transduction. The mechanism of inhibition was due to blocks in the phosphorylation of both Janus kinases, Jak1 and Tyk2, during IFN-alpha signaling and at least a failure of Jak1 phosphorylation following IFN-gamma stimulation. To determine the viral protein(s) responsible, we individually expressed all nonstructural (NS) proteins and examined their ability to inhibit signal transduction. Expression of NS5 alone inhibited STAT1 phosphorylation in response to IFN, thus identifying NS5 as a potential IFN antagonist. Examination of interactions between NS5 and cellular proteins revealed that NS5 associated with IFN-alpha/beta and -gamma receptor complexes. Importantly, inhibition of JAK-STAT signaling and NS5-IFN receptor interactions were demonstrated in LGTV-infected human monocyte-derived dendritic cells, important target cells for early virus replication. Because NS5 may interfere with both innate and acquired immune responses to virus infection, this protein may have a significant role in viral pathogenesis. C1 NIAID, Rocky Mt Lab, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Lab, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Best, SM (reprint author), NIAID, Rocky Mt Lab, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov RI Shannon, Jeffrey/A-5735-2009 OI Shannon, Jeffrey/0000-0003-4211-4308 NR 57 TC 156 Z9 169 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2005 VL 79 IS 20 BP 12828 EP 12839 DI 10.1128/JVI.79.20.12828-12839.2005 PG 12 WC Virology SC Virology GA 969OI UT WOS:000232243200023 PM 16188985 ER PT J AU Abbatecola, AM Ferrucci, L Ceda, G Russo, CR Lauretani, F Bandinelli, S Barbieri, M Valenti, G Paolisso, G AF Abbatecola, AM Ferrucci, L Ceda, G Russo, CR Lauretani, F Bandinelli, S Barbieri, M Valenti, G Paolisso, G TI Insulin resistance and muscle strength in older persons SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID HOMEOSTASIS MODEL ASSESSMENT; HUMAN SKELETAL-MUSCLE; HANDGRIP STRENGTH; ELDERLY-MEN; WOMEN; GLUCOSE; AGE; SARCOPENIA; PLASMA; MASS AB Background. The functional consequences of an age-related insulin resistance (IR) state on muscle functioning are unknown. Because insulin is needed for adequate muscle function, an age-related insulin-resistant state may also be a determining factor. We evaluated the relationship between IR and handgrip muscle strength in men and women from a large population-based study (n = 968). Methods. The degree of IR was evaluated by the homeostasis model assessment (HOMA) and muscle strength was assessed using handgrip. Results. Simple sex-stratified correlations demonstrated that, in men, body mass index-adjusted handgrip strength correlated positively with physical activity (r = 0.321; p < .001), muscle area (r = 0.420; p < .001), muscle density (r = 0.263; p = .001), plasma albumin (r = 0.156; p = .001), insulin-like growth factor-1 (r = 0.258; p < .001), calcium (r = 0.140; p = .006), and testosterone (r = 0.325; p < .001) concentrations, whereas a negative association was found for age (r = -0.659; p < .001) and myoglobin plasma levels (r = -0.164; p = .001). In women, body mass index-adjusted handgrip strength correlated positively with physical activity (r = 0.280; p < .001), muscle area (r = 0.306; p < .001), muscle density (r = -0.341; p = .001), plasma albumin (r = 0.140; p = .001), and insulin-like growth factor-1 (r = 0.300; p < .001), whereas a negative association was found for age (r = -0.563; p < .001), myoglobin levels (r = -0.164; p = .001), and IR (r = -0.130; p = .04). Conclusions. Sex-stratified analyses adjusted for multiple confounders showed that the relationship between IR and handgrip strength was found significant in women, whereas it was negligible and not significant in men. C1 Univ Naples, Dept Geriatr Med & Metab Dis 2, Div Med Interna 4, I-80138 Naples, Italy. INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. Univ Parma, Dept Geriatr, I-43100 Parma, Italy. RP Paolisso, G (reprint author), Univ Naples, Dept Geriatr Med & Metab Dis 2, Div Med Interna 4, Piazza Miraglia 2, I-80138 Naples, Italy. EM giuseppe.paolisso@unina2.it RI Barbieri, Michelangela/K-2192-2016; Lauretani, Fulvio/K-5115-2016; OI Barbieri, Michelangela/0000-0002-9223-5792; Paolisso, Giuseppe/0000-0002-2137-455X; Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 NR 40 TC 42 Z9 43 U1 0 U2 4 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2005 VL 60 IS 10 BP 1278 EP 1282 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 985XN UT WOS:000233412100009 PM 16282559 ER PT J AU Dwyer, JT Larive, B Leung, J Rocco, MV Greene, T Burrowes, J Chertow, GM Cockram, DB Chumlea, WC Daugirdas, J Frydrych, A Kusek, JW AF Dwyer, JT Larive, B Leung, J Rocco, MV Greene, T Burrowes, J Chertow, GM Cockram, DB Chumlea, WC Daugirdas, J Frydrych, A Kusek, JW CA HEMO Study Group TI Are nutritional status indicators associated with mortality in the Hemodialysis (HEMO) Study ? SO KIDNEY INTERNATIONAL LA English DT Article DE nutrition; serum albumin; BMI; body weight; hemodialysis; anthropometry ID BODY WATER VOLUMES; CARDIAC-DISEASE; MEMBRANE FLUX; MALNUTRITION; INFLAMMATION; RISK; PREDICTORS AB Background. The purpose of this study was to determine if indicators of nutritional status were associated with subsequent mortality in hemodialysis patients. Methods. Twelve selected nutrition indicators were measured prior to randomization in the Mortality and Morbidity in Hemodialysis (HEMO) Study. Relative risks (RR) of mortality were assessed at < 6 months and > 6 months of follow-up using Cox regression after controlling for case mix, comorbidity, and treatment assignment (high vs. standard Kt/V and high vs. low membrane flux). Results. Low values of most nutritional status indicators were associated with increased RR of mortality. RRs were greatest over the short term (< 6 months) and diminished with increasing follow-up (> 6 months). Increases in body mass index (BMI) at lower levels (e.g., <= 25 kg/m(2)) and increases in serum albumin at any level were associated with reduced short-term RR, even after adjusting for case mix, treatment assignment, and for the joint effects of equilibrated normalized protein catabolic rate, total cholesterol, and serum creatinine. For > 6 months' follow-up, increases in values among those with lower levels of BMI and serum albumin (<= 3.635 g/dL) and increases in all serum creatinine levels were associated with lower RR. Conclusion. Nutrition indicators are associated with subsequent mortality in a time-dependent manner, with greatest effects at < 6 months of follow-up. The RR for these indicators may also vary within different ranges of values. C1 Tufts Univ, New England Med Ctr, Frances Stern Nutr Ctr, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. Cleveland Clin Fdn, Dept Epidemiol & Biostat, Cleveland, OH 44195 USA. Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. Long Isl Univ, Dept Nutr, Brookville, NY USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. Abbott Labs, Ross Prod Div, Med & Regulatory Affairs, Columbus, OH USA. Wright State Univ, Sch Med, Kettering, OH USA. Univ Illinois, Dept Med, Nephrol Sect, Chicago, IL USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Dwyer, JT (reprint author), Tufts Univ, New England Med Ctr, Frances Stern Nutr Ctr, Box 783,NEMCH,750 Washington St, Boston, MA 02111 USA. EM JDwyer1@tufts-nemc.org OI Dwyer, Johanna/0000-0002-0783-1769 NR 37 TC 54 Z9 61 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD OCT PY 2005 VL 68 IS 4 BP 1766 EP 1776 DI 10.1111/j.1523-1755.2005.00593.x PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 963JT UT WOS:000231801300041 PM 16164653 ER PT J AU Cole, K AF Cole, K TI Change the procedure SO LAB ANIMAL LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Cole, K (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD OCT PY 2005 VL 34 IS 9 BP 20 EP 21 DI 10.1038/laban1005-20b PG 2 WC Veterinary Sciences SC Veterinary Sciences GA 970YQ UT WOS:000232348700004 PM 16195731 ER PT J AU Gray, RH Li, XB Kigozi, G Serwadda, D Brahmbhott, H Wabwire-Mangen, F Nalugoda, F Kiddugavu, M Sewankambo, N Quinn, TC Reynolds, SJ Wawer, MJ AF Gray, RH Li, XB Kigozi, G Serwadda, D Brahmbhott, H Wabwire-Mangen, F Nalugoda, F Kiddugavu, M Sewankambo, N Quinn, TC Reynolds, SJ Wawer, MJ TI Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study SO LANCET LA English DT Article ID UTERINE EPITHELIAL-CELLS; SEXUALLY-TRANSMITTED-DISEASES; SIV VAGINAL TRANSMISSION; PERINATAL TRANSMISSION; MENSTRUAL-CYCLE; COITAL ACT; INFECTION; WOMEN; COHORT; TRACT AB Background HIV acquisition is significantly higher during pregnancy than in the postpartum period. We did a prospective study to estimate HIV incidence rates during pregnancy and lactation. Methods We assessed 2188 HIV-negative sexually active women with 2625 exposure intervals during pregnancy and 2887 intervals during breastfeeding, and 8473 non-pregnant and non-lactating women with 24 258 exposure intervals. Outcomes were HIV incidence rates per 100 person years and incidence rate ratios estimated by Poisson multivariate regression, with the non-pregnant or non-lactating women as the reference group. We also assessed the husbands of the married women to study male risk behaviours. Findings HIV incidence rates were 2.3 per 100 person years during pregnancy, 1.3 per 100 person years during breastfeeding, and 1.1 per 100 person years in the non-pregnant and non-lactating women. The adjusted incidence rate ratios were 2.16 (95% Cl 1 . 39-3.37) during pregnancy and 1 . 16 (0.82-1.63) during breastfeeding. Pregnant women and their male partners reported significantly fewer external sexual partners than did the other groups. in married pregnant women who had a sexual relationship with their male spouses, the HIV incidence rate ratio was 1.36 (0.63-2.93). in married pregnant women in HIV-discordant relationships (ie, with HIV-positive men) the incidence rate ratio was 1.76 (0.62-4.03). Interpretation The risk of HIV acquisition rises during pregnancy. This change is unlikely to be due to sexual risk behaviours, but might be attributable to hormonal changes affecting the genital tract mucosa or immune responses. HIV prevention efforts are needed during pregnancy to protect mothers and their infants. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Uganda Virus Res Inst, Rakai Hlth Sci Programme, Entebbe, Uganda. Makerere Univ, Inst Publ Hlth, Kampala, Uganda. Makerere Univ, Sch Med, Kampala, Uganda. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Suite 4030, Baltimore, MD 21205 USA. EM rgray@jhsph.edu OI Sewankambo, Nelson/0000-0001-9362-053X FU NICHD NIH HHS [5P30HD06826]; PHS HHS [R01 A13426S, R01 A134826] NR 28 TC 201 Z9 208 U1 0 U2 3 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD OCT 1 PY 2005 VL 366 IS 9492 BP 1182 EP 1188 DI 10.1016/S0140-6736(05)67481-8 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 970LK UT WOS:000232311300028 PM 16198767 ER PT J AU Murray, HW Berman, JD Davies, CR Saravia, NG AF Murray, HW Berman, JD Davies, CR Saravia, NG TI Advances in leishmaniasis SO LANCET LA English DT Review ID INDIAN VISCERAL LEISHMANIASIS; AMERICAN CUTANEOUS LEISHMANIASIS; LIPOSOMAL AMPHOTERICIN-B; DIRECT AGGLUTINATION-TEST; HIV-INFECTED PATIENTS; INTRALESIONAL MEGLUMINE ANTIMONIATE; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; MACROPHAGE GENE-EXPRESSION; AZAR DERMAL LEISHMANIASIS AB Governed by parasite and host factors and immunoinflammatory responses, the clinical spectrum of leishmaniasis encompasses subclinical (inapparent), localised (skin lesions), and disseminated infection (cutaneous, mucosal, or visceral). Symptomatic disease is subacute or chronic and diverse in presentation and outcome. Clinical characteristics vary further by endemic region. Despite T-cell-dependent immune responses, which produce asymptomatic and self-healing infection, or appropriate treatment, intracellular infection is probably life-long since targeted cells (tissue macrophages) allow residual parasites to persist. There is an epidemic of cutaneous leishmaniasis in Afghanistan and Pakistan and of visceral infection in India and Sudan. Diagnosis relies on visualising parasites in tissue or serology; culture and detection of parasite DNA are useful in the laboratory. Pentavalent antimony is the conventional treatment; however, resistance of visceral infection in India has spawned new treatment approaches-amphotericin B and its lipid formulations, injectable paromomycin, and oral miltefosine. Despite tangible advances in diagnosis, treatment, and basic scientific research, leishmaniasis is embedded in poverty and neglected. Current obstacles to realistic prevention and proper management include inadequate vector (sandfly) control, no vaccine, and insufficient access to or impetus for developing affordable new drugs. C1 Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10021 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1, England. Ctr Int Entrenamiento & Invest Med, Cali, Colombia. RP Murray, HW (reprint author), Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10021 USA. EM hwmurray@med.cornell.edu FU NIAID NIH HHS [AI 16963]; Wellcome Trust NR 199 TC 840 Z9 863 U1 17 U2 97 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD OCT-NOV PY 2005 VL 366 IS 9496 BP 1561 EP 1577 DI 10.1016/S0140-6736(05)67629-5 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA 979ZX UT WOS:000232984800026 PM 16257344 ER PT J AU Hope, WW Walsh, TJ Denning, DW AF Hope, WW Walsh, TJ Denning, DW TI Laboratory diagnosis of invasive aspergillosis SO LANCET INFECTIOUS DISEASES LA English DT Review ID POLYMERASE-CHAIN-REACTION; LINKED-IMMUNOSORBENT-ASSAY; REAL-TIME PCR; CELL TRANSPLANT RECIPIENTS; CHRONIC GRANULOMATOUS-DISEASE; BRONCHOALVEOLAR LAVAGE FLUID; LATEX AGGLUTINATION-TEST; PLASMA (1->3)-BETA-D-GLUCAN MEASUREMENT; STRAND CONFORMATIONAL POLYMORPHISM; RECEIVING PIPERACILLIN-TAZOBACTAM AB invasive aspergillosis occurs in a wide range of clinical scenarios, is protean in its manifestations, and is still associated with an unacceptably high mortality rate. Early diagnosis is critical to a favourable outcome, but is difficult to achieve with current methods. Deep tissue diagnostic specimens are often difficult to obtain from critically ill patients. Newer antifungal agents exhibit differential mould activity, thus increasing the importance of establishing a specific diagnosis of invasive aspergillosis. For these reasons, a range of alternate diagnostic strategies have been investigated. Most investigative efforts have focused on molecular and serological diagnostic techniques. The detection of metabolites produced by Aspergillus spp and a range of aspergillus-specific antibodies represent additional, but relatively underused, diagnostic avenues. The detection of galactomannan has been incorporated into diagnostic criteria for invasive aspergillosis, reflecting an increased understanding of the performance, utility, and limitations of this technique. Measurement of (1,3)-beta-D glucan in blood may he useful as a preliminary screening tool for invasive aspergillosis, despite the fact that this antigen can be detected in a number of other fungi. There have been extensive efforts directed toward the detection of Aspergillus spp DNA, but a lack of technical standardisation and relatively poor understanding of DNA release and kinetics continues to hamper the broad applicability of this technique. This review considers the application, utility, and limitations of the currently available and investigational diagnostic modalities for invasive aspergillosis. C1 Wythenshawe Hosp, Educ & Res Ctr, Manchester M23 9LT, Lancs, England. Univ Manchester, Sch Med, Manchester M13 9PL, Lancs, England. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Denning, DW (reprint author), Wythenshawe Hosp, Educ & Res Ctr, Southmoor Rd, Manchester M23 9LT, Lancs, England. EM ddenning@manchester.ac.uk OI Denning, David/0000-0001-5626-2251; Hope, William/0000-0001-6187-878X NR 132 TC 258 Z9 297 U1 2 U2 21 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD OCT PY 2005 VL 5 IS 10 BP 609 EP 622 DI 10.1016/S1473-3099(05)70238-3 PG 14 WC Infectious Diseases SC Infectious Diseases GA 969ZA UT WOS:000232273700016 PM 16183515 ER PT J AU Scripture, CD Sparreboom, A Figg, WD AF Scripture, CD Sparreboom, A Figg, WD TI Modulation of cytochrome P450 activity: implications for cancer therapy SO LANCET ONCOLOGY LA English DT Article ID HUMAN LIVER-MICROSOMES; BODY-SURFACE AREA; DRUG-METABOLISM; ANTICANCER AGENTS; P-GLYCOPROTEIN; BREAST-CANCER; CLINICAL PHARMACOKINETICS; IRINOTECAN METABOLISM; ADJUVANT BREAST; HUMAN CYP2B6 AB Although metabolism mediated by cytochrome P450 isoenzymes is known to play a major part in the biotransformation of anticancer agents in vivo, few clinical studies have investigated activity of cytochrome P450s and therapeutic outcome in people with cancer. Variability between individuals in the pharmacokinetics of cancer chemotherapy has important consequences in terms of therapeutic efficacy and safety. We discuss here the effect of drug metabolism mediated by cytochrome P450 on therapeutic outcome. As examples, the biotransformation pathways of cyclophosphamide, ifosfamide, tamoxifen, docetaxel, paclitaxel, and irinotecan are discussed. Since most anticancer agents are transformed by enzymes, better knowledge of their metabolic pathways could help improve treatment outcome and safety. Furthermore, a more complete understanding of the metabolism of anticancer agents through phenotyping and genotyping approaches will facilitate the prediction of interactions between drugs. More clinical evidence is needed on the metabolic transformation and drug interactions with these agents to improve cancer therapeutics. C1 NCI, Clin Pharmacol Res Core, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 76 TC 70 Z9 84 U1 2 U2 12 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD OCT PY 2005 VL 6 IS 10 BP 780 EP 789 DI 10.1016/S1470-2045(05)70388-0 PG 10 WC Oncology SC Oncology GA 972WK UT WOS:000232483700030 PM 16198984 ER PT J AU Savani, BN Srinivasan, R Espinoza-Delgado, I Dorrance, C Takahashi, Y Igarashi, T Rezvani, K Lundqvist, A Barrett, AJ Childs, RW AF Savani, BN Srinivasan, R Espinoza-Delgado, I Dorrance, C Takahashi, Y Igarashi, T Rezvani, K Lundqvist, A Barrett, AJ Childs, RW TI Treatment of relapsed blast-phase Philadelphia-chromosome-positive leukaemia after non-myeloablative stem-cell transplantation with donor lymphocytes and imatinib SO LANCET ONCOLOGY LA English DT Article ID INFUSIONS; REMISSION; DISEASE C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Room 3-5330,10 Ctr Dr MSC 12, Bethesda, MD 20892 USA. EM childsr@nih.gov RI Takahashi, Yoshiyuki/I-1929-2012 NR 10 TC 9 Z9 10 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD OCT PY 2005 VL 6 IS 10 BP 809 EP 812 DI 10.1016/S1470-2045(05)70391-0 PG 4 WC Oncology SC Oncology GA 972WK UT WOS:000232483700033 PM 16198987 ER PT J AU Lehrnbecher, T Bernig, T Hanisch, M Koehl, U Behl, M Reinhardt, D Creutzig, U Klingebiel, T Chanock, S Schwabe, D AF Lehrnbecher, T Bernig, T Hanisch, M Koehl, U Behl, M Reinhardt, D Creutzig, U Klingebiel, T Chanock, S Schwabe, D TI Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia SO LEUKEMIA LA English DT Article DE polymorphism; infectious complication; child; acute myeloid leukemia ID HOST-DEFENSE; CANDIDATE GENES; HUMAN-DISEASE; POLYMORPHISMS; SUSCEPTIBILITY; CANCER; COMPLICATIONS; NEUTROPENIA; AML-BFM-93; IMMUNITY AB Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P = 0.026) and in patients with the H allele of CHIT (P = 0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations. C1 Univ Frankfurt, D-60590 Frankfurt, Germany. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Appl Sci, Frankfurt, Germany. Competence Ctr Stat & OR, Frankfurt, Germany. Hannover Med Sch, D-3000 Hannover, Germany. Univ Munster, D-4400 Munster, Germany. RP Lehrnbecher, T (reprint author), Univ Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM thomas_lehrnbecher@yahoo.com RI Reinhardt, Dirk/D-3939-2011; OI Reinhardt, Dirk/0000-0003-4313-9056; Koehl, Ulrike/0000-0002-8159-9160 NR 36 TC 43 Z9 45 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD OCT PY 2005 VL 19 IS 10 BP 1745 EP 1750 DI 10.1038/sj.leu.2403922 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 968ZU UT WOS:000232204000005 PM 16107886 ER PT J AU Terry, PD Shore, DL Rauscher, GH Sandler, DP AF Terry, PD Shore, DL Rauscher, GH Sandler, DP TI Occupation, hobbies, and acute leukemia in adults SO LEUKEMIA RESEARCH LA English DT Article DE occupation; hobbies; leukaemia; acute myeloid leukaemia; acute lymphocytic leukemia ID DRY-CLEANING WORKERS; HAIR DYE USE; MORTALITY RATIO ANALYSIS; ACUTE MYELOID-LEUKEMIA; CANCER-MORTALITY; RUBBER INDUSTRY; RISK-FACTORS; REINFORCED-PLASTICS; PETROLEUM REFINERY; MULTIPLE-MYELOMA AB Occupational and industrial exposures have been implicated in the etiology of leukemia, yet uncertainty remains regarding potential high risk occupations. We examined the associations between self-reported occupations and hobbies and acute leukemia risk using data from 811 cases and 637 controls participating in a case-control study in the U.S. and Canada. We found that several occupations may increase the risk of acute leukemia, particularly occupations related to petroleum products, rubber, nuclear energy, munitions, plastics, and electronics manufacturing. Differences were noted according to histological type. Other occupations and hobbies were not clearly associated with risk. Published by Elsevier Ltd. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. WESTAT Corp, Durham, NC 27703 USA. Univ Illinois, Div Epidemiol & Biostat, Chicago, IL 60612 USA. RP Terry, PD (reprint author), Emory Univ, Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM pdterry@sph.emory.edu OI Rauscher, Garth/0000-0003-0374-944X; Sandler, Dale/0000-0002-6776-0018 NR 94 TC 11 Z9 11 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD OCT PY 2005 VL 29 IS 10 BP 1117 EP 1130 DI 10.1016/j.leukres.2005.03.002 PG 14 WC Oncology; Hematology SC Oncology; Hematology GA 963EQ UT WOS:000231786800006 PM 16111530 ER PT J AU Allen, M Bulte, JWM Liepold, L Basu, G Zywicke, HA Frank, JA Young, M Douglas, T AF Allen, M Bulte, JWM Liepold, L Basu, G Zywicke, HA Frank, JA Young, M Douglas, T TI Paramagnetic viral nanoparticles as potential high-relaxivity magnetic resonance contrast agents SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE virus particles; FRET; MR contrast agent; relaxometry; gadolinium ID COWPEA MOSAIC-VIRUS; SUPRAMOLECULAR BUILDING-BLOCKS; METAL-BINDING; PROTEIN CAGES; HUMAN SERUM; IN-VITRO; GADOLINIUM; DENDRIMER; PEPTIDES; DELIVERY AB In order to compensate for the inherent high threshold of detectability of MR contrast agents, there has been an active interest in the development of paramagnetic nanoparticles incorporating high payloads of Gd3+ with high molecular relaxivities. Toward this end, the protein cage of Cowpea chlorotic mottle virus (CCMV), having 180 metal binding sites, is being explored. In vivo CCMV binds Ca2+ at specific metal binding sites; however, Gd3+ can also bind at these sites. Using fluorescence resonance energy transfer we have characterized the binding affinity of Gd3+ to the metal binding sites by competition experiments with Tb3+. The measured dissociation constant (K-d) for Gd3+ bound to the virus is 31 mu M. The T-1 and T-2 relaxivities of solvent water protons in the presence of Gd3+-bound CCMV were 202 and 376 mM(-1) s(-1), respectively, at 61 MHz Larmor frequency. The unusually high relaxivity values of the Gd3+-CCMV are largely a result of the nanoparticle virus size and the large number of Gd3+ ions bound to the virus. These preliminary results should encourage further investigations into the use of viral protein cages as a new platform for MR contrast agents. C1 Montana State Univ, Ctr Biolnspired Nanomat, Bozeman, MT 59717 USA. Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD USA. Bose Inst, Dept Biophys, Kolkata 700009, W Bengal, India. NIH, Ctr Clin, Expt Neuroimaging Sect, Bethesda, MD 20892 USA. Montana State Univ, Dept Plant Sci, Bozeman, MT 59717 USA. RP Young, M (reprint author), Montana State Univ, Ctr Biolnspired Nanomat, Bozeman, MT 59717 USA. EM myoung@montana.edu; tdouglas@chemistry.montana.edu RI Bulte, Jeff/A-3240-2008; Douglas, Trevor/F-2748-2011 OI Bulte, Jeff/0000-0003-1202-1610; FU NIBIB NIH HHS [R01 EB00432]; NIGMS NIH HHS [R01 GM61340] NR 35 TC 129 Z9 130 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2005 VL 54 IS 4 BP 807 EP 812 DI 10.1002/mrm.20614 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 970YJ UT WOS:000232348000008 PM 16155869 ER PT J AU Helm, PA Tseng, HJ Younes, L McVeigh, ER Winslow, RL AF Helm, PA Tseng, HJ Younes, L McVeigh, ER Winslow, RL TI Ex vivo 3D diffusion tensor imaging and quantification of cardiac laminar structure SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion tensor MRI; myocardial microstructure; anisotropic diffusion; myofiber laminar sheets; cardiac ID LEFT-VENTRICULAR MECHANICS; CANINE LEFT-VENTRICLE; FIBER-ORIENTATION; HISTOLOGICAL VALIDATION; MATHEMATICAL-MODEL; COLLAGEN NETWORK; SPIN-ECHO; MYOCARDIUM; HEART; ARCHITECTURE AB A three-dimensional (3D) diffusion-weighted imaging (DWI) method for measuring cardiac fiber structure at high spatial resolution is presented. The method was applied to the ex vivo reconstruction of the fiber architecture of seven canine hearts. A novel hypothesis-testing method was developed and used to show that distinct populations of secondary and tertiary eigenvalues may be distinguished at reasonable confidence levels (P <= 0.01) within the canine ventricle. Fiber inclination and sheet angles are reported as a function of transmural depth through the anterior, lateral, and posterior left ventricle (LV) free wall. Within anisotropic regions, two consistent and dominant orientations were identified, supporting published results from histological studies and providing strong evidence that the tertiary eigenvector of the diffusion tensor (DT) defines the sheet normal. C1 Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Ctr Cardiovasc Bioinformat & Modeling, Baltimore, MD 21218 USA. Johns Hopkins Univ, Ctr Imaging Sci, Baltimore, MD 21218 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Helm, PA (reprint author), Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Ctr Cardiovasc Bioinformat & Modeling, 202 Clark Hall,3400 N Charles St, Baltimore, MD 21218 USA. EM phelm@bme.jhu.edu RI Younes, E. Laurent/A-3349-2010 FU Intramural NIH HHS [Z01 HL004608-08]; NHLBI NIH HHS [HL52307, HL70894, R01 HL070894] NR 38 TC 125 Z9 129 U1 2 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2005 VL 54 IS 4 BP 850 EP 859 DI 10.1002/mrm.20622 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 970YJ UT WOS:000232348000013 PM 16149057 ER PT J AU Derbyshire, JA Herzka, DA McVeigh, ER AF Derbyshire, JA Herzka, DA McVeigh, ER TI (SFP)-F-5: Spectrally selective suppression with steady state free precession SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; steady-state; balanced SSFP; FISP; fat suppression ID MAGNETIZATION PREPARATION; TRUE-FISP; MRI; EQUILIBRIUM; SEQUENCES; RESONANCE AB A method is presented that employs the inherent spectral selectivity of the Steady-State Free Precession (SSFP) pulse sequence to provide a spectral band of suppression. At TE = TR/2, SSFP partitions the magnetization into two phase-opposed spectral components. Z-storing one of these components simultaneously further excites the other, which is then suppressed by gradient crushing and RF spoiling. The Spectrally Selective Suppression with SSFP ((SFP)-F-5) method is shown to provide significant attenuation of fat signals, while the water signals are essentially unaffected and provide the normal SSFP contrast. Fat suppression is achieved with relatively little temporal overhead (less than 10% reduction in temporal resolution). (SFP)-F-5 was validated using simulations, phantoms, and human studies. C1 NHLBI, Cardiac Energet Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Derbyshire, JA (reprint author), NHLBI, Cardiac Energet Lab, NIH, DHHS, Rm B1D,10 Ctr Dr, Bethesda, MD 20892 USA. EM jad11@nih.gov OI Herzka, Daniel/0000-0002-9400-7814 FU Intramural NIH HHS [Z01 HL004608-08] NR 28 TC 18 Z9 18 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2005 VL 54 IS 4 BP 918 EP 928 DI 10.1002/mrm.20633 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 970YJ UT WOS:000232348000021 PM 16155880 ER PT J AU Hu, ZL Dracheva, S Jang, WH Maglott, D Bastiaansen, J Rothschild, MF Reecy, JM AF Hu, ZL Dracheva, S Jang, WH Maglott, D Bastiaansen, J Rothschild, MF Reecy, JM TI A QTL resource and comparison tool for pigs: PigQTLDB SO MAMMALIAN GENOME LA English DT Article ID QUANTITATIVE TRAIT LOCI; INTRAMUSCULAR FAT-CONTENT; INFLUENCING ECONOMIC TRAITS; GENOME SCAN ANALYSIS; MEAT QUALITY TRAITS; BODY-COMPOSITION; CARCASS TRAITS; PORCINE CHROMOSOME-4; BACKFAT THICKNESS; MUSCLE MASS AB During the past decade, efforts to map quantitative trait loci (QTL) in pigs have resulted in hundreds of QTL being reported for growth, meat quality, reproduction, disease resistance, and other traits. It is a challenge to locate, interpret, and compare QTL results from different studies. We have developed a pig QTL database (PigQTLdb) that integrates available pig QTL data in the public domain, thus, facilitating the use of this QTL data in future studies. We also developed a pig trait classification system to standardize names of traits and to simplify organization and searching of the trait data. These steps made it possible to compare primary data from diverse sources and methods. We used existing pig map databases and other publicly available data resources (such as Pub-Med) to avoid redundant developmental work. The PigQTLdb was also designed to include data representing major genes and markers associated with a large effect on economically important traits. To date, over 790 QTL from 73 publications have been curated into the database. Those QTL cover more than 300 different traits. The data have been submitted to the Entrez Gene and the Map Viewer resources at NCBI, where the information about markers was matched to marker records in NCBI's UniSTS database. Having these data in a public resource like NCBI allows regularly updated automatic matching of markers to public sequence data by e-PCR. The submitted data, and the results of these calculations, are retrievable from NCBI via Entrez Gene, Map Viewer, and UniSTS. Efforts were undertaken to improve the integrated functional genomics resources for pigs. C1 Iowa State Univ, Ctr Integrated Anim Genom, Dept Anim Sci, Ames, IA 50011 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Sygen Int, Abingdon OX13 5FE, Oxon, England. RP Hu, ZL (reprint author), Iowa State Univ, Ctr Integrated Anim Genom, Dept Anim Sci, 2255 Kildee Hall, Ames, IA 50011 USA. EM zhu@iastate.edu; jreecy@iastate.edu RI Bastiaansen, John/A-5733-2010 OI Bastiaansen, John/0000-0002-6562-176X NR 49 TC 98 Z9 103 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD OCT PY 2005 VL 16 IS 10 BP 792 EP 800 DI 10.1007/s00335-005-0060-9 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 975VE UT WOS:000232691400006 PM 16261421 ER PT J AU Iser, WB Kim, D Bachman, E Wolkow, C AF Iser, WB Kim, D Bachman, E Wolkow, C TI Examination of the requirement for ucp-4, a putative homolog of mammalian uncoupling proteins, for stress tolerance and longevity in C-elegans SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Caenorhabditis elegans; mitochondria; oxidative stress; lifespan ID CAENORHABDITIS-ELEGANS; ENERGY-METABOLISM; SUPEROXIDE; GENE; MICE; ACTIVATION; DEFECT AB Reactive oxygen species (ROS) are generated by mitochondrial respiration and can react with and damage cellular components, According to the free radical theory of aging, oxidative damage from mitochondrial ROS is a major cause of cellular decline during aging, Mitochondrial uncoupling proteins (UCPs) uncouple ATP production from electron transport and can be stimulated by free radicals. suggesting UCPs may perform a cytoprotective function. The nematode, Caenorhabditis elegans. contains one UCP-like protein, encoded by the ucp-4 gene. We have investigated the genetic requirement for ucp-4 in normal aging and stress resistance. Consistent with the hypothesis that ucp-4 encodes a putative uncoupling protein, animals lacking ucp-4 function contained elevated ATP levels, However, the absence of ucp-4 function did not affect adult lifespan or survival in the presence of thermal or oxidative stress. Together, these results demonstrate that ucp-4 is a negative regulator of ATP production in C. elegans. but is not required for normal lifespan. Published by Elsevier Ireland Ltd. C1 NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Cheongju Univ, Dept Genet Engn, Cheongju 360764, South Korea. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. RP Wolkow, C (reprint author), NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. EM wolkowca@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000320-06, NIH0011061953] NR 18 TC 30 Z9 36 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD OCT PY 2005 VL 126 IS 10 BP 1090 EP 1096 DI 10.1016/j.mad.2005.04.002 PG 7 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 972HM UT WOS:000232444900010 PM 15893362 ER PT J AU Ruiz, MC Ayala, V Portero-Otin, M Requena, JR Barja, G Pamplona, R AF Ruiz, MC Ayala, V Portero-Otin, M Requena, JR Barja, G Pamplona, R TI Protein methionine content and MDA-lysine adducts are inversely related to maximum life span in the heart of mammals SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE aminoadipic semialdehyde; N-epsilon-(carboxyethyl)lysine; N-epsilon-(carboxymethyl)lysine; glutamic semialdehyde; Maillard reaction; N-epsilon-(malondialdehyde)lysine; maximum life span; peroxidizability index; protein oxidation ID FATTY-ACID UNSATURATION; FREE-RADICAL PRODUCTION; SHORT-LIVED RAT; OXIDATIVE DAMAGE; CALORIC RESTRICTION; SULFOXIDE REDUCTASE; LIPID-PEROXIDATION; FOOD RESTRICTION; TRANSGENIC MICE; DNA-DAMAGE AB Aging affects ail organisms and its basic mechanisms are expected to be conserved across species. Oxidation of proteins has been proposed to be one of the basic mechanisms linking oxygen radicals with the basic aging process. If oxidative damage to proteins is involved, in aging, long-lived animals (which age slowly) should show lower levels of markers of this kind of damage than short-lived ones. However, this possibility has not been investigated yet. In this study, steady-state levels of markers of different kinds of protein damage-oxidation (glutamic and aminoadipic semialdehydes), mixed glyco- and lipoxidation (carboxyrnethyl- and carboxyethyllysine). lipoxidation (malondialdehy-delysine) and amino acid composition - were measured in the heart of eight mammalian species ranging in maximum life span (MLSP) from 3.5 to 46 years. Oxidation markers were directly correlated with MLSP across species. Mixed glyco- and lipoxidation markers did not correlate with MLSP. However, the lipoxidation marker malondialdehydelysine was inversely correlated with MLSP (r(2) = 0.85, P < 0.001). The amino acid compositional analysis revealed that methionine is the only amino acid strongly correlated MLSP and that such correlation is negative (r(2) = 0.93; P < 0.001). This trait may contribute to lower steady-state levels of oxidized methionine residues in cellular proteins. These results reinforce the notion:that high longevity in homeothermic vertebrates is achieved in part by constitutively decreasing the sensitivity of both tissue proteins and lipids to oxidative damage. This is obtained by modifying the constituent structural components of proteins and lipids, selecting those less sensitive to oxidative modifications. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Univ Lleida, Dept Basic Med Sci, Lleida 25198, Spain. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Univ Complutense, Fac Biol Sci, Dept Anim Physiol 2, E-28040 Madrid, Spain. RP Pamplona, R (reprint author), Univ Lleida, Fac Med, Dept Ciencies Med Basiques, C Montserrat Roig,2, Lleida 25008, Spain. EM reinald.pamplona@cmb.udl.es RI Portero-Otin, Manuel/B-7122-2009; Gustavo, Barja/B-5591-2012; Ayala, Maria Victoria/A-7391-2010; Pamplona, Reinald/A-7359-2010 OI Portero-Otin, Manuel/0000-0002-1823-0299; Ayala, Maria Victoria/0000-0002-1496-966X; Pamplona, Reinald/0000-0003-4337-6107 NR 47 TC 32 Z9 35 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD OCT PY 2005 VL 126 IS 10 BP 1106 EP 1114 DI 10.1016/j.mad.2005.04.005 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 972HM UT WOS:000232444900012 PM 15955547 ER PT J AU Taaffe, DR Newman, AB Haggerty, CL Colbert, LH De Rekeneire, N Visser, M Goodpaster, BH Nevitt, MC Tylavsky, FA Harris, TB AF Taaffe, DR Newman, AB Haggerty, CL Colbert, LH De Rekeneire, N Visser, M Goodpaster, BH Nevitt, MC Tylavsky, FA Harris, TB TI Estrogen replacement, muscle composition, and physical function: The health ABC study SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE muscle density; muscle strength; computed tomography; Hounsfield units ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; SKELETAL-MUSCLE; ELDERLY-WOMEN; OLDER WOMEN; FAT MASS; THERAPY; STRENGTH; EXERCISE; MENOPAUSE AB Purpose: Although the beneficial effects of estrogen use on cardiovascular and cognitive function in postmenopausal women have been recently discredited, controversy remains regarding its usefulness for maintaining skeletal muscle mass or strength. Therefore, the purpose of this study was to determine whether estrogen use is associated with enhanced muscle composition and, if so, whether this translates into improved strength and physical function. Methods: Cross-sectional analysis of 840 well-functioning community-dwelling white women (current estrogen replacement therapy (ERT) users = 259, nonusers = 581) aged 70-79 yr participating in the Health, Aging and Body Composition Study. Muscle composition of the midthigh by computed tomography included cross-sectional area (CSA) of the quadriceps, hamstrings, intermuscular fat and subcutaneous fat, and muscle attenuation in Hounsfield units (HU) as a measure of muscle density. Isometric hand grip and isokinetic knee extensor strength were assessed by dynamometry. Physical function was assessed using a summary scale that included usual 6-m walk and narrow walk speed, repeated chair stands, and standing balance. Results: In analyses of covariance adjusted for relevant confounders. quadriceps muscle CSA and HU were greater in Current ERT than non-ERT women (P < 0.05). Grip strength was also greater (P < 0.05) in women taking ERT while knee extensor strength approached significance (P < 0.10). However, differences in muscle composition and strength were modest at <= 3.3%. There was no difference by ERT status for the hamstring, muscles. fat CSA. or for physical function. Conclusion: The associations between ERT and muscle composition and strength were minor and did not translate into improved physical function. Initiation of ERT for preservation of muscle composition and function may not be indicated. C1 Univ Queensland, Sch Human Movement Studies, Fac Hlth Sci, Brisbane, Qld 4072, Australia. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. NIA, Lab Epidemiol Biometry & Demog, Bethesda, MD 20892 USA. Vrije Univ Amsterdam, Inst Res Extramural Med, Amsterdam, Netherlands. Vrije Univ Amsterdam, Dept Nutr & Hlth, Amsterdam, Netherlands. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Univ Tennessee, Ctr Hlth Sci, Dept Epidemiol, Memphis, TN 38163 USA. RP Taaffe, DR (reprint author), Univ Queensland, Sch Human Movement Studies, Fac Hlth Sci, Brisbane, Qld 4072, Australia. EM dtaaffe@hms.uq.edu.au RI Newman, Anne B./C-6408-2013; OI Newman, Anne B./0000-0002-0106-1150; Haggerty, Catherine/0000-0002-9849-7865 FU NIA NIH HHS [N01-AG-6-2102, N01-AG-6-2106, N01-AG-6-2103] NR 37 TC 35 Z9 36 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD OCT PY 2005 VL 37 IS 10 BP 1741 EP 1747 DI 10.1249/01.mss.0000181678.28092.31 PG 7 WC Sport Sciences SC Sport Sciences GA 980XM UT WOS:000233051500014 PM 16260975 ER PT J AU Shia, J Klimstra, DS Li, AR Qin, J Saltz, L Teruya-Feldstein, J Akram, M Chung, KY Yao, D Paty, PB Gerald, W Chen, BY AF Shia, J Klimstra, DS Li, AR Qin, J Saltz, L Teruya-Feldstein, J Akram, M Chung, KY Yao, D Paty, PB Gerald, W Chen, BY TI Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study SO MODERN PATHOLOGY LA English DT Article; Proceedings Paper CT 94th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2005 CL San Antonio, TX SP US Canadian Acad Pathol DE cetuximab; anti-EGFR therapy; gene amplification ID TISSUE MICROARRAYS; BREAST-CANCER; EGFR; CETUXIMAB; VALIDATION; TUMORS; HER-2; SPECIMENS; THERAPY; TARGET AB Recent data suggest that detection of epidermal growth factor receptor protein by immunohistochemistry ( IHC) does not predict response to the antiepidermal growth factor receptor drug, cetuximab, in patients with colorectal carcinoma. In searching for foundation for further investigation to optimize patient selection for cetuximab therapy, this study sought to exploit the tissue microarray and chromogenic in situ hybridization techniques to evaluate the status of epidermal growth factor receptor gene amplification in colorectal cancer and its relationship with protein expression by IHC. The study included 158 primary or metastatic colorectal adenocarcinomas. Immunohistochemical results were scored as 0 - 3 + based on the intensity of membrane staining. The in situ hybridization signals were counted in 30 nuclei per tissue core. Overall, the rate of tissue loss was 7%, yielding 147 analyzable cases: 123 primary, 24 metastatic. Positive immunohistochemical staining of any intensity was detected in 85% ( 105/ 123) of primary and 79% ( 19/ 24) of metastatic tumors, whereas gene amplification ( 45 gene copies/ nucleus) was only seen in 12% ( 15/ 123) of primary and 8% ( 2/ 24) of metastatic tumors. Only 2/ 15 primary and 1/ 2 metastatic tumors that showed gene amplification were amplified at a high level ( 410 gene copies/ nucleus). Although a positive correlation was detected between the intensity of protein expression and the likelihood of gene amplification in both the primary ( P = 0.01) and the metastatic ( P = 0.05) tumors, IHC had a low specificity ( 17% in primary, 23% in metastatic) in predicting gene amplification. Conversely, all tumors that did not express the protein by IHC lacked gene amplification. Thus, this study shows that only a small fraction of epidermal growth factor receptor- positive colorectal carcinomas detected by IHC are associated with gene amplification. Additional studies are needed to determine whether epidermal growth factor receptor gene amplification bears any informative value in predicting response to cetuximabbased therapy. C1 Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. RP Shia, J (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. EM Shiaj@mskcc.org OI Shia, Jinru/0000-0002-4351-2511; Saltz, Leonard/0000-0001-8353-4670 FU NCI NIH HHS [2 P01 CA65930-05A2] NR 35 TC 95 Z9 98 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD OCT PY 2005 VL 18 IS 10 BP 1350 EP 1356 DI 10.1038/modpathol.3800417 PG 7 WC Pathology SC Pathology GA 968EV UT WOS:000232145600010 PM 15832190 ER PT J AU Rao, VA Fan, AM Meng, LH Doe, CF North, PS Hickson, ID Pommier, Y AF Rao, VA Fan, AM Meng, LH Doe, CF North, PS Hickson, ID Pommier, Y TI Phosphorylation of BLM, dissociation from topoisomerase III alpha, and colocalization with gamma-H2AX after topoisomerase I-Induced replication damage SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BLOOMS-SYNDROME HELICASE; MEDIATED DNA-DAMAGE; S-PHASE ARREST; DOUBLE-STRAND BREAKS; PML NUCLEAR-BODIES; SYNDROME PROTEIN; CLEAVAGE COMPLEXES; SYNDROME CELLS; HISTONE H2AX; RECQ HELICASES AB Topoisomerase I-associated DNA single-strand breaks selectively trapped by camptothecins are lethal after being converted to double-strand breaks by replication fork collisions. BLM (Bloom's syndrome protein), a RecQ DNA helicase, and topoisomerase III alpha (Top3 alpha) appear essential for the resolution of stalled replication forks (Holliday junctions). We investigated the involvement of BLM in the signaling response to Top1-mediated replication DNA damage. In BLM-complemented cells, BLM colocalized with promyelocytic leukemia protein (PML) nuclear bodies and Top3a. Fibroblasts without BLM showed an increased sensitivity to camptothecin, enhanced formation of Top1-DNA complexes, and delayed histone H2AX phosphorylation (gamma-H2AX). Camptothecin also induced nuclear relocalization of BLM, Top3 alpha, and PML protein and replication-dependent phosphorylation of BLM on threonine 99 (T99p-BLM). T99p-BLM was also observed following replication stress induced by hydroxyurea. Ataxia telangiectasia mutated (ATM) protein and AT- and Rad9-related protein kinases, but not DNA-dependent protein kinase, appeared to play a redundant role in phosphorylating BLM. Following camptothecin treatment, T99p-BLM colocalized with gamma-H2AX but not with Top3a or PML. Thus, BLM appears to dissociate from Top3 alpha and PML following its phosphorylation and facilitates H2AX phosphorylation in response to replication double-strand breaks induced by Top1. A defect in gamma-H2AX signaling in response to unrepaired replication-mediated double-strand breaks might, at least in part, explain the camptothecin-sensitivity of BLM-deficient cells. C1 NCI, NIH, Mol Pharmacol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Oxford, John Radcliffe Hosp, Canc Res UK Labs, Weatherall Inst Mol Med, Oxford OX3 9DS, England. RP Pommier, Y (reprint author), NCI, NIH, Mol Pharmacol Lab, Canc Res Ctr, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 75 TC 68 Z9 69 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2005 VL 25 IS 20 BP 8925 EP 8937 DI 10.1128/MCB.25.20.8925-8937.2005 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 972FU UT WOS:000232440400014 PM 16199871 ER PT J AU Chen, JG Archer, TK AF Chen, JG Archer, TK TI Regulating SWI/SNF subunit levels via protein-protein interactions and proteasomal degradation: BAF155 and BAF170 limit expression of BAF57 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHROMATIN-REMODELING COMPLEX; INI1 TUMOR-SUPPRESSOR; HUMAN BREAST-CANCER; GLUCOCORTICOID-RECEPTOR; BRG1 COMPLEX; SANT DOMAIN; DNA-BINDING; SWI-SNF; PROLIFERATION; ENZYMES AB The mammalian SWI/SNF chromatin remodeling complex, whose function is of critical importance in transcriptional regulation, contains approximately 10 protein components. The expression levels of the core SAI/SNF subunits, including BRG1/Brm, BAF155, BAF170, BAF60, hSNF/Ini1, and BAF57, are stoichiometric, with few to no unbound molecules in the cell. Here we report that exogenous expression of the wild type or certain deletion mutants of BAF57, a key subunit that mediates the interaction between the remodeling complex and transcription factors, results in diminished expression of endogenous BAF57. This down-regulation process is mediated by an increase in proteasome-dependent degradation of the BAF57 protein. Furthermore, the protein levels of BAF155/170 dictate the maximum cellular amount of BAF57. We mapped the domains responsible for the interaction between BAF57 and BAF155 and demonstrated that protein-protein interactions between them play an important role in this regulatory process. These findings provide insights into the physiological mechanisms responsible for maintaining the proper stoichiometric levels of the protein components comprising multimeric enzyme complexes. C1 NIEHS, Mol Carcinogenesis Lab, Chromatin & Gene Express Sect, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Mol Carcinogenesis Lab, Chromatin & Gene Express Sect, 111 Alexander Dr,POB 12233 MC C4-06, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov NR 37 TC 64 Z9 65 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2005 VL 25 IS 20 BP 9016 EP 9027 DI 10.1128/MCB.25.20.9016-9027.2005 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 972FU UT WOS:000232440400021 PM 16199878 ER PT J AU Eriksson, PR Mendiratta, G McLaughlin, NB Wolfsberg, TG Marino-Ramirez, L Pompa, TA Jainerin, M Landsman, D Shen, CH Clark, DJ AF Eriksson, PR Mendiratta, G McLaughlin, NB Wolfsberg, TG Marino-Ramirez, L Pompa, TA Jainerin, M Landsman, D Shen, CH Clark, DJ TI Global regulation by the yeast Spt10 protein is mediated through chromatin structure and the histone upstream activating sequence elements SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; IN-VIVO; GENE-EXPRESSION; CUP1 CHROMATIN; SPT21 GENES; CELL-CYCLE; TRANSCRIPTION; ACETYLTRANSFERASE; MUTATIONS; ROLES AB The yeast SPT10 gene encodes a putative histone acetyltransferase (HAT) implicated as a global transcription regulator acting through basal promoters. Here we address the mechanism of this global regulation. Although microarray analysis confirmed that Spt10p is a global regulator, Spt10p was not detected at any of the most strongly affected genes in vivo. In contrast, the presence of Spt10p at the core histone gene promoters in vivo was confirmed. Since Spt10p activates the core histone genes, a shortage of histones could occur in spt10 Delta cells, resulting in defective chromatin structure and a consequent activation of basal promoters. Consistent with this hypothesis, the spt10 Delta phenotype can be rescued by extra copies of the histone genes and chromatin is poorly assembled in spt10 Delta cells, as shown by irregular nucleosome spacing and reduced negative supercoiling of the endogenous 2 mu m plasmid. Furthermore, Spt10p binds specifically and highly cooperatively to pairs of upstream activating sequence elements in the core histone promoters [consensus sequence, (G/A)TTCCN6TTCNC], consistent with a direct role in histone gene regulation. No other high-affinity sites are predicted in the yeast genome. Thus, Spt10p is a sequence-specific activator of the histone genes, possessing a DNA-binding domain fused to a likely HAT domain. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. CUNY Coll Staten Isl, Dept Biol, Staten Isl, NY 10314 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6A,Room 2A14,6 Ctr Dr, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov RI Landsman, David/C-5923-2009; Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU Intramural NIH HHS [Z99 LM999999] NR 48 TC 34 Z9 35 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2005 VL 25 IS 20 BP 9127 EP 9137 DI 10.1128/MCB.25.20.9127-9137.2005 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 972FU UT WOS:000232440400031 PM 16199888 ER PT J AU Lee, S Comer, FI Sasaki, A McLeod, IX Duong, Y Okumura, K Yates, JR Parent, CA Firtel, RA AF Lee, S Comer, FI Sasaki, A McLeod, IX Duong, Y Okumura, K Yates, JR Parent, CA Firtel, RA TI TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PROTEIN-MEDIATED ACTIVATION; PLECKSTRIN HOMOLOGY DOMAIN; MYOSIN HEAVY-CHAIN; ADENYLYL-CYCLASE; ACTIN CYTOSKELETON; LEADING-EDGE; KINASE B; AKT/PKB; CHEMOATTRACTANT; POLARITY AB Dictyostelium cells form a multicellular organism through the aggregation of independent cells. This process requires both chemotaxis and signal relay in which the chemoattractant cAMP activates adenylyl cyclase through the G protein-coupled cAMP receptor cAR1. cAMP is produced and secreted and it activates receptors on neighboring cells, thereby relaying the chemoattractant signal to distant cells. Using coimmunoprecipitation and mass spectrometric analyses, we have identified a TOR-containing complex in Dictyostelium that is related to the TORC2 complex of Saccharomyces cerevisiae and regulates both chemotaxis and signal relay. We demonstrate that mutations in Dictyostelium LST8, RIP3, and Pia, orthologues of the yeast TORC2 components LST8, AVO1, and AVO3, exhibit a common set of phenotypes including reduced cell polarity, chemotaxis speed and directionality, phosphorylation of Akt/PKB and the related PKBR1, and activation of adenylyl cyclase. Further, we provide evidence for a role of Ras in the regulation of TORC2. We propose that, through the regulation of chemotaxis and signal relay, TORC2 plays an essential role in controlling aggregation by coordinating the two essential arms of the developmental pathway that leads to multicellularity in Dictyostelium. C1 Univ Calif San Diego, Div Biol Sci, Sect Cell & Dev Biol, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Mol Genet, La Jolla, CA 92093 USA. NCI, Cellular & Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. Univ Calif San Diego, Sch Med, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. RP Firtel, RA (reprint author), Univ Calif San Diego, Div Biol Sci, Sect Cell & Dev Biol, La Jolla, CA 92093 USA. EM rafirtel@ucsd.edu FU NCRR NIH HHS [P41 RR011823, RR11823-09]; NIGMS NIH HHS [GM37830, R01 GM037830] NR 45 TC 131 Z9 136 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2005 VL 16 IS 10 BP 4572 EP 4583 DI 10.1091/mbc.E05-04-0342 PG 12 WC Cell Biology SC Cell Biology GA 969TM UT WOS:000232257700010 PM 16079174 ER PT J AU Michishita, E Park, JY Burneskis, JM Barrett, JC Horikawa, I AF Michishita, E Park, JY Burneskis, JM Barrett, JC Horikawa, I TI Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CALORIE RESTRICTION; LIFE-SPAN; HUMAN-CELLS; SACCHAROMYCES-CEREVISIAE; ADP-RIBOSYLTRANSFERASE; DEPENDENT DEACETYLASE; TRANSCRIPTION FACTORS; SIR2-ALPHA PROTEIN; SIR2-LIKE PROTEINS; P53 AB Sir2 is a NAD(+)-dependent protein deacetylase that extends lifespan in yeast and worms. This study examines seven human proteins homologous to Sir2 (SIRT1 through SIRT7) for cellular localization, expression profiles, protein deacetylation activity, and effects on human cell lifespan. We found that: 1) three nuclear SIRT proteins (SIRT1, SIRT6, and SIRT7) show different subnuclear localizations: SIRT6 and SIRT7 are associated with heterochromatic regions and nucleoli, respectively, where yeast Sir2 functions; 2) SIRT3, SIRT4, and SIRT5 are localized in mitochondria, an organelle that links aging and energy metabolism; 3) cellular p53 is a major in vivo substrate of SIRT1 deacetylase, but not the other six SIRT proteins; 4) SIRT1, but not the other two nuclear SIRT proteins, shows an in vitro deacetylase activity on histone H4 and p53 peptides; and 5) overexpression of any one of the seven SIRT proteins does not extend cellular replicative lifespan in normal human fibroblasts or prostate epithelialcells. This study supports the notion that multiple human SIRT proteins have evolutionarily conserved and nonconseived functions at different cellular locations and reveals that the lifespan of normal human cells, in contrast to that of lower eukaryotes, cannot be manipulated by increased expression of a single SIRT protein. C1 NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Horikawa, I (reprint author), NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM horikawi@mail.nih.gov FU Intramural NIH HHS NR 50 TC 592 Z9 633 U1 3 U2 63 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2005 VL 16 IS 10 BP 4623 EP 4635 DI 10.1091/mbc.E05-01-0033 PG 13 WC Cell Biology SC Cell Biology GA 969TM UT WOS:000232257700014 PM 16079181 ER PT J AU Pogrlbny, I Koturbash, I Tryndyak, V Hudson, D Stevenson, SML Sedelnikova, O Bonner, W Kovalchuk, O AF Pogrlbny, I Koturbash, I Tryndyak, V Hudson, D Stevenson, SML Sedelnikova, O Bonner, W Kovalchuk, O TI Fractionated low-dose radiation exposure leads to accumulation of DNA damage and profound alterations in DNA and histone methylation in the murine thymus SO MOLECULAR CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; GENOMIC HYPOMETHYLATION; EPIGENETIC REGULATION; DEACETYLASE COMPLEX; CHILDHOOD LEUKEMIA; CANCER; CELLS; MOUSE; MICE; INSTABILITY AB Thymus, an important component of hematopoietic tissue, is a well-documented "target" of radiation carcinogenesis. Both acute and fractionated irradiation result in a high risk of leukemia and thymic lymphoma. However, the exact mechanisms underlying radiation-induced predisposition to leukemia and lymphoma are still unknown, and the contributions of genetic and epigenetic mechanisms in particular have yet to be defined. Global DNA hypomethylation is a well-known characteristic of cancer cells. Recent studies have also shown that tumor cells undergo prominent changes in histone methylation, particularly a substantial loss of trimethylation of histone H4-LyS(20) and demethylation of genomic DNA. These losses are considered a universal marker of malignant transformation. In the present study, we investigated the effect of low-dose radiation exposure on the accumulation of DNA lesions and alterations of DNA methylation and histone H4-LyS20 trimethylation in the thymus tissue using an in vivo murine model. For the first time, we show that fractionated whole-body application of 0.5 Gy X-ray leads to decrease in histone H4-LYS20 trimethylation in the thymus. The loss of histone H4-LYS20 trimethylation was accompanied by a significant decrease in global DNA methylation as well as the accumulation of DNA damage as monitored by persistence of histone gamma H2AX foci in the thymus tissue of mice exposed to fractionated irradiation. Altered DNA methylation was associated with reduced expression of maintenance (DNMT1) and, to a lesser extent, de novo DNA methyltransferase DNMT3a in exposed animals. Expression of another de novo DNA methyltransferase DNMT3b was decreased only in males. Irradiation also resulted in similar to 20% reduction in the levels of methyl-binding proteins MeCP2 and MBD2. Our results show the involvement of epigenetic alterations in radiation-induced responses in vivo. These changes may play a role in genome destabilization that ultimately leads to cancer. C1 Univ Lethbridge, Dept Biol Sci, Lethbridge, AB, Canada. Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kovalchuk, O (reprint author), Univ Lethbridge, Dept Biol Sci, 4401 Univ Dr,Lethbridge Dr, Lethbridge, AB, Canada. EM olga.kovalchuk@uleth.ca NR 54 TC 72 Z9 88 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD OCT PY 2005 VL 3 IS 10 BP 553 EP 561 DI 10.1158/1541-7786.MCR-05-0074 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 980OI UT WOS:000233027400003 PM 16254189 ER PT J AU Zhang, ZQ Yao, RS Jie, L Wang, Y Boone, CW Lubet, RA You, M AF Zhang, ZQ Yao, RS Jie, L Wang, Y Boone, CW Lubet, RA You, M TI Induction of invasive mouse skin carcinomas in transgenic mice with mutations in both H-ras and p53 SO MOLECULAR CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; SQUAMOUS-CELL CARCINOMAS; LI-FRAUMENI-SYNDROME; BREAST-CANCER; FAMILIAL SYNDROME; CARCINOGENESIS; EXPRESSION; SARCOMAS; TUMORIGENESIS; NEOPLASMS AB Synergistic interaction between H-ras and p53 were systematically examined during skin tumorigenesis. Concurrent expression of an activated H-ras gene and a mutant p53 gene was accomplished by crossing p53(Val135/wt) mice with TG(.)AC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone produced similar to 26% skin tumor incidence, whereas BaP treatment of p53(wt/wt) Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice produced a 75%, 77%, and 100% incidence of skin tumors, respectively. An average of 0.33 tumor per mouse was observed in wild-type (p53(wt/wt)Hras(wt/wt)) mice, whereas similar to 1.54, 1.96, and 3.08 tumors per mouse were seen in BaP-treated p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. The effects on total tumor volume were even more striking with 7-, 48-, and 588-fold increases in tumor volume compared with wild-type (p53(wt/wt)Hras(wt/wt)) in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. Histopathologically, all tumors from p53(wt/wt)Hras(wt/wt) mice were either papillomas or well-differentiated squamous cell carcinomas, whereas the tumors in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(VAL135/wt)Hras(TG.AC/wt) mice were principally squamous cell carcinomas with varying degree of invasiveness. Particularly, tumors in p(53Val135/wt)Hras(TG.AC/wt) mice exhibited the most rapid growth and the extreme form of tumor invasion. Microarray analysis revealed that dominant-negative p53 (Val(135)) and activated H-ras affected several cellular processes involved in tumorigenesis possibly through its effects on apoptosis, cell cycle arrest, and Ras-mitogen-activated protein kinase pathways. The present study provides the first in vivo evidence that a germ line p53 mutation and activated H-ras act synergistically to profoundly enhance tumor progression. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, 660 Euclid Ave,Box 8109, St Louis, MO 63110 USA. EM youm@msnotes.wustl.edu FU NCI NIH HHS [R01CA78797, R01CA58554] NR 35 TC 11 Z9 11 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD OCT PY 2005 VL 3 IS 10 BP 563 EP 574 DI 10.1158/1541-7786.MCR-05-0144 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 980OI UT WOS:000233027400004 PM 16254190 ER PT J AU Moon, Y Bottone, FG McEntee, MF Eling, TE AF Moon, Y Bottone, FG McEntee, MF Eling, TE TI Suppression of tumor cell invasion by cyclooxygenase inhibitors is mediated by thrombospondin-1 via the early growth response gene Egr-1 SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID TRANSCRIPTION FACTOR EGR-1; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLON CARCINOGENESIS; COLORECTAL-CANCER; LUNG-CANCER; EXPRESSION; APOPTOSIS; ANGIOGENESIS; SULINDAC; TRANSFORMATION AB Cyclooxygenase (COX) inhibitors have antitumongenic activity and increase the expression of the early growth response gene Egr-1, a tumor suppressor gene and transcription factor. In this study, we have investigated the gene regulatory and anti-invasive activity of two traditional nonsteroidal anti-inflammatory drugs (NSAID), sulindac sulfide and indomethacin. These compounds inhibited tumor cell invasion and induced Egr-1 expression in lung adenocarcinoma A549 cells. Overexpression of Egr-1 reduced cellular invasion in the Matrigel system, whereas suppression of Egr-1 by small interference RNA (siRNA) attenuated the inhibition of Matrigel invasion by these compounds, indicating that Egr-1 is responsible for the decrease in invasion reported following treatment with NSAIDs. Egr-1-overexpressing cells were analyzed for genes involved in invasion and metastasis. Thrombospondin-1 (TSP-1) an antiangiogenic and anti-invasion protein was up-regulated by Egr-1 overexpression, which was confirmed following treatment with sulindac sulfide. Furthermore, the induction of TSP-1 by sulindac sulfide was blocked by Egr-1 siRNA. When TSP-1 was sequestered by the addition of anti-TSP-1 antibody, the inhibition of invasion by sulindac sulfide was attenuated, indicating that TSP-1 is involved in the inhibition of invasion by NSAIDs. We used the Min mouse model to determine if sulindac sulfide would increase Egr-1 and TSP-1 in vivo, because this model is widely used to study the effects of NSAIDs on tumor formation. Treatment of Min mice with concentrations of sulindac sulfide that inhibit tumor formation increased the expression of Egr-1 and TSP-1 in colonic tissues and in the polyps of these mice. This is the first report suggesting that COX inhibitors suppress tumor cell invasion via TSP-1, which occurs downstream of Egr-1. C1 Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Eicosanoid Biochem Sect, NIH, Res Triangle Pk, NC 27709 USA. Univ Tennessee, Coll Vet Med, Dept Pathobiol, Knoxville, TN 37901 USA. RP Eling, TE (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Eicosanoid Biochem Sect, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov OI McEntee, Michael/0000-0002-1616-3715 FU Intramural NIH HHS NR 52 TC 33 Z9 37 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2005 VL 4 IS 10 BP 1551 EP 1558 DI 10.1158/1535-7163.MCT-05-0213 PG 8 WC Oncology SC Oncology GA 974AS UT WOS:000232564300012 PM 16227405 ER PT J AU Wallqvist, A Huang, R Covell, DG Roschke, AV Gelhaus, KS Kirsch, IR AF Wallqvist, A Huang, R Covell, DG Roschke, AV Gelhaus, KS Kirsch, IR TI Drugs aimed at targeting characteristic karyotypic phenotypes of cancer cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID TUMOR-SCREENING DATABASE; CHROMOSOMAL INSTABILITY; CYTOCHALASIN-B; ANTITUMOR-ACTIVITY; GENE-EXPRESSION; INHIBITOR; IDENTIFICATION; SEGREGATION; COMPLEXITY; INDUCTION AB The karyotypic features of cancer cells have not been a particular focus of anticancer drug targeting either as guidance for treatment or as specific drug targets themselves. Cancer cell lines typically have considerable, characteristic, and variable chromosomal aberrations. Here, we consider small-molecule screening data across the National Cancer Institute's 60 tumor cell line drug screening panel (NCI-60) analyzed for specific association with karyotypic variables (numerical and structural complexity and heterogeneity) determined for these same cell lines. This analysis is carried out with the aid of a self-organizing map allowing for a simultaneous assessment of all screened compounds, revealing an association between karyotypic variables and a unique part of the cytotoxic response space. Thirteen groups of compounds based on related specific chemical structural motifs are identified as possible leads for anticancer drug discovery. These compounds form distinct groups of molecules associated with relatively unexplored regions of the NCI-60 self-organizing map where anticancer agents currently standard in the clinic are not present. We suggest that compounds identified in this study may represent new classes of potential anticancer agents. C1 NCI, Sci Applicat Int Corp, Natl Canc Inst, Frederick, MD USA. NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD USA. NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM Ikirsch@amgen.com OI wallqvist, anders/0000-0002-9775-7469 FU NCI NIH HHS [N01-CO-12400] NR 34 TC 9 Z9 10 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2005 VL 4 IS 10 BP 1559 EP 1568 DI 10.1158/1535-7163.MCT-05-0224 PG 10 WC Oncology SC Oncology GA 974AS UT WOS:000232564300013 PM 16227406 ER PT J AU Kosakowska-Cholody, T Cholody, WM Monks, A Woynarowska, BA Michejda, CJ AF Kosakowska-Cholody, T Cholody, WM Monks, A Woynarowska, BA Michejda, CJ TI WMC-79, a potent agent against colon cancers, induces apoptosis through a p53-dependent pathway SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DNA-DAMAGE; PROTEIN-KINASES; TUMOR-CELLS; P53; ACTIVATION; COMPLEX; GENE; BISIMIDAZOACRIDONES; TARGET; GROWTH AB WMC-79 is a synthetic agent with potent activity against colon and hematopoietic tumors. In vitro, the agent is most potent against colon cancer cells that carry the wild-type p53 tumor suppressor gene (HCT116 and RKO cells: GI(50) < 1 nmol/L, LC50 similar to 40 nmol/L.. Growth arrest of HCT-116 and RKO cells occurs at the G, and G(2)-M check points at sublethal concentrations (10 nmol/L) but the entire cell population was killed at 100 nmol/L. WMC-79 is localized to the nucleus where it binds to DNA. We hypothesized that WMC-79 binding to DNA is recognized as an unrepairable damage in the tumor cells, which results in p53 activation. This triggers transcriptional up-regulation of p53-dependent genes involved in replication, cell cycle progression, growth arrest, and apoptosis as evidenced by DNA microarrays. The change in the transcriptional profile of HCT-116 cells is followed by a change in the levels of cell cycle regulatory proteins and apoptosis. The recruitment of the p53-dependent apoptosis pathway was suggested by the up-regulation of p53, p21, Bax, DR-4, DR-5, and p53 phosphorylated on Ser15; downregulation of Bcl-2; and activation of caspase-8, -9, -7, and -3 in cells treated with 100 nmol/L WMC-79. Apoptosis was also evident from the flow cytometric studies of drug-treated HCT-116 cells as well as from the appearance of nuclear fragmentation. However, whereas this pathway is important in wild-type p53 colon tumors, other pathways are also in operation because colon cancer cell lines in which the p53 gene is mutated are also affected by higher concentrations of WMC-79. C1 Natl Canc Inst, Canc Res Ctr, Struct Biophys Lab, Sci Applicat Int Corp, Frederick, MD 21702 USA. Natl Canc Inst, Screening Technol Branch, Lab Funct Genom, Sci Applicat Int Corp, Frederick, MD 21702 USA. Univ Texas, Hlth Sci Ctr, Dept Radiat Oncol, San Antonio, TX 78285 USA. RP Michejda, CJ (reprint author), Natl Canc Inst, Canc Res Ctr, Struct Biophys Lab, Sci Applicat Int Corp, Frederick, MD 21702 USA. EM michejda@ncifcrf.gov NR 51 TC 16 Z9 16 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2005 VL 4 IS 10 BP 1617 EP 1627 DI 10.1158/1535-7163.MCT-05-0170 PG 11 WC Oncology SC Oncology GA 974AS UT WOS:000232564300019 PM 16227412 ER PT J AU Margolis, RN Evans, RM O'Malley, BW AF Margolis, RN Evans, RM O'Malley, BW CA NURSA Atlas Consortium TI The nuclear receptor signaling atlas: Development of a functional atlas of nuclear receptors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID SUPERFAMILY; DIVERSITY; EVOLUTION; INSIGHTS; GENOME AB The Nuclear Receptor Signaling Atlas ( NURSA) was developed by the National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK), the National Institute on Aging ( NIA), and the National Cancer Institute (NCI) of the National Institutes of Health (NIH); the aim of NURSA is to utilize classical approaches to validate existing hypotheses and exploit new and emerging technologies to formulate and test new hypotheses that might elucidate the program of nuclear receptor (NR) structure, function, and role in disease. The means for carrying out this ambitious program required development of interactions among investigators and the combined application of new high-throughput technologies and existing approaches to allow for both mechanistic studies and accrual of large datasets in a discovery-based research effort, all leading to advances with implications for the missions of the NIDDK, NIA, and NCI. A team-based multidisciplinary approach has allowed for both objectives to proceed simultaneously, tied together via a central bioinformatics resource and one web-accessible venue ( www.nursa.org). The ultimate goals for the NURSA consortium are to: 1) establish the mechanistic principles of NR function, 2) characterize NR-coregulator complex formation and regulation, 3) map protein-protein interactions for coregulators, 4) identify candidate downstream target genes of NR action, 5) identify target tissue expression of NRs, 6) understand the regulation of NR expression and, 7) integrate existing and emerging information through NURSA bioinformatics tools. C1 NIDDKD, NIH, Dept Endocrinol, Bethesda, MD 20892 USA. Salk Inst Biol Studies, La Jolla, CA 92037 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Margolis, RN (reprint author), NIDDKD, NIH, Dept Endocrinol, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM rm76f@nih.gov OI Margolis, Ronald/0000-0002-8956-0455 FU NIDDK NIH HHS [U19DK062434] NR 10 TC 20 Z9 20 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD OCT PY 2005 VL 19 IS 10 BP 2433 EP 2436 DI 10.1210/me.2004-0461 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 967UO UT WOS:000232116900001 PM 16051673 ER PT J AU Shah, BH Baukal, AJ Shah, FB Catt, KJ AF Shah, BH Baukal, AJ Shah, FB Catt, KJ TI Mechanisms of extracellularly regulated kinases 1/2 activation in adrenal glomerulosa cells by lysophosphatidic acid and epidermal growth factor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID FACTOR RECEPTOR TRANSACTIVATION; GONADOTROPIN-RELEASING-HORMONE; PROTEIN-COUPLED RECEPTORS; SRC-DEPENDENT PHOSPHORYLATION; ANGIOTENSIN-II ACTIVATION; G-BETA-GAMMA; EGF RECEPTOR; SIGNALING PATHWAYS; PHOSPHOINOSITIDE 3-KINASE; MATRIX METALLOPROTEINASES AB The regulation of adrenal function, including aldosterone production from adrenal glomerulosa cells, is dependent on a variety of G protein-coupled receptors ( GPCRs) and receptor tyrosine kinases ( RTKs). In many cell types, GPCR-mediated MAPK activation is mediated through transactivation of RTKs, in particular the epidermal growth factor ( EGF) receptor ( EGF-R). However, the extent to which this cross-communication between GPCRs and RTKs is operative in the adrenal glomerulosa has not been defined. Bovine adrenal glomerulosa cells express receptors for lysophosphatidic acid ( LPA) and EGF. In cultured bovine adrenal glomerulosa cells, LPA, which is predominantly coupled to G(i) and partially to G(q)/protein kinase C alpha and is an element of, caused phosphorylation of Src ( at Tyr416), proline-rich tyrosine kinase ( Pyk2 at Tyr402), EGF-R, protein kinase B/Akt, extracellularly regulated signal kinases 1/2, and their dependent protein, p90 ribosomal S6 kinase. Overexpression of dominant negative mutants of Ras or EGF-R, and selective inhibition of EGF-R kinase with AG1478, significantly reduced LPA-induced ERK1/2 phosphorylation. However, this was not impaired by inhibition of matrix metalloproteinase (MMP) and heparin-binding EGF. LPA-induced ERK1/2 activation occurs predominantly through EGF-R transactivation by G(i)/Src and partly through activation of protein kinase C, which acts downstream of EGF-R and Ras. In contrast, LPA-induced phosphorylation of Shc and ERK1/2 in clonal hepatocytes ( C9 cells) was primarily mediated through MMP-dependent transactivation of the EGF-R. These observations in adrenal glomerulosa and hepatic cells demonstrate that LPA phosphorylates ERK1/2 through EGF-R transactivation in a MMP-dependent or -independent manner in individual target cells. This reflects the ability of GPCRs expressed in cell lines and neoplastic cells to utilize distinct signaling pathways that can elicit altered responses compared with those of native tissues. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Shah, BH (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A36, Bethesda, MD 20892 USA. EM shahb@mail.nih.gov NR 63 TC 41 Z9 43 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD OCT PY 2005 VL 19 IS 10 BP 2535 EP 2548 DI 10.1210/me.2005.0082 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 967UO UT WOS:000232116900010 PM 15928312 ER PT J AU Coss, D Thackray, VG Deng, CX Mellon, PL AF Coss, D Thackray, VG Deng, CX Mellon, PL TI Activin regulates luteinizing hormone beta-subunit gene expression through smad-binding and homeobox elements SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; CELL-SPECIFIC EXPRESSION; STEROIDOGENIC FACTOR-I; TGF-BETA; SIGNAL-TRANSDUCTION; TRANSCRIPTIONAL ACTIVATION; TARGETED DISRUPTION; GROWTH-FACTOR; PITUITARY; FOLLISTATIN AB LH beta-subunit ( LH beta), which is essential for ovulation and reproductive fitness, is synthesized specifically in pituitary gonadotropes. In this study, we show that LH beta gene expression is induced by activin in mouse primary pituitary cells if the cells are treated within 24 h after dispersion in culture. Furthermore, male mice deficient in Smad3, and therefore in activin signaling, have lower expression of both LH beta and FSH beta mRNAs compared with their wild-type littermates. Using the L beta T2 immortalized mouse gonadotrope cell line that endogenously expresses LH, we identify specific elements in the regulatory region of the rat LH beta gene necessary for its induction by activin. Activin responsiveness is conferred by a promoter-proximal region located -121/-86 from the transcriptional start site. Maximal LH beta induction by activin requires a homeobox element ( HB) and a 5'-early growth response (Egr) site found in this region of the promoter. Juxtaposed to the HB are three Smad- binding elements ( SBEs), which are essential for LH beta induction. Interestingly, two of the SBEs are also critical for basal expression of the LH beta gene. We demonstrate that Smad proteins are necessary and sufficient for activin induction of the LH beta gene. Furthermore, Smad proteins can bind one of the identified SBEs. In addition to binding this SBE, Smad proteins interact with pituitary homeobox 1 ( Ptx-1) and orthodenticle homeobox 1 ( Otx-1), which can bind the HB located close to the Smad- binding site. Thus, activin induction of LH beta gene expression requires a combination of several transcription factors, both basal and activin induced, as well as cooperation between multiple DNA elements. C1 Univ Calif San Diego, Ctr Reprod Sci & Med, Dept Reprod Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Reprod Sci & Med, Dept Neurosci, La Jolla, CA 92093 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Mellon, PL (reprint author), Univ Calif San Diego, Ctr Reprod Sci & Med, Dept Reprod Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM pmellon@ucsd.edu RI deng, chuxia/N-6713-2016 FU NCI NIH HHS [P30 CA23100, P30 CA023100]; NICHD NIH HHS [F32 HD041301, F32 HD41301, P50 HD012303, R01 HD020377, R01 HD020377-24, R01 HD020377-25, R01 HD057549, R01 HD057549-01A1, R01 HD057549-02, R03 HD054595, R03 HD054595-01A2, R03 HD054595-02, R21 HD058752, R21 HD058752-01A1, R37 HD020377, R37 HD20377, T32 HD007203, T32 HD007203-25, U54 HD012303, U54 HD012303-27, U54 HD012303-270011, U54 HD12303]; NIDDK NIH HHS [F32 DK065437] NR 45 TC 39 Z9 40 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD OCT PY 2005 VL 19 IS 10 BP 2610 EP 2623 DI 10.1210/me.2005-0047 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 967UO UT WOS:000232116900016 PM 15961509 ER PT J AU Wilson, SH Suk, WA AF Wilson, SH Suk, WA TI Framework for environmental exposure research: The disease-first approach SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID PARKINSONS-DISEASE; DOPAMINERGIC-NEURONS; DEFICIENT MICE; GLOBAL BURDEN; MODELS; ONSET; MPTP C1 NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 39 TC 1 Z9 2 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD OCT PY 2005 VL 5 IS 5 BP 262 EP 267 DI 10.1124/mi.5.5.1 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IN UT WOS:000232796800002 PM 16249520 ER PT J AU Mattson, MP Gleichmann, M AF Mattson, MP Gleichmann, M TI Modulating dopaminergic signaling and plasticity SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID PROSTATE APOPTOSIS RESPONSE-4; NF-KAPPA-B; MITOCHONDRIAL DYSFUNCTION; SYNAPTIC PLASTICITY; CELL-DEATH; NEURONAL DEGENERATION; EXCITOTOXIC INSULTS; AMYLOID-BETA; PAR-4; INVOLVEMENT C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov; gleichmannma@Grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 32 TC 9 Z9 11 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD OCT PY 2005 VL 5 IS 5 BP 278 EP 281 DI 10.1124/mi.5.5.6 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IN UT WOS:000232796800005 PM 16249523 ER PT J AU Banach-Orlowska, M Fijalkowska, IJ Schaaper, RM Jonczyk, P AF Banach-Orlowska, M Fijalkowska, IJ Schaaper, RM Jonczyk, P TI DNA polymerase II as a fidelity factor in chromosomal DNA synthesis in Escherichia coli SO MOLECULAR MICROBIOLOGY LA English DT Article ID SOS MUTATOR ACTIVITY; ADAPTIVE MUTATION; POL-IV; INDUCED MUTAGENESIS; IN-VIVO; ANTIMUTATOR ALLELES; REPLICATION; HOLOENZYME; STRAND; SUBUNIT AB Escherichia coli DNA polymerase III holoenzyme ( HE) is the main replicase responsible for replication of the bacterial chromosome. E. coli contains four additional polymerases, and it is a relevant question whether these might also contribute to chromosomal replication and its fidelity. Here, we have investigated the role of DNA polymerase II ( Pol II) ( polB gene product). Mismatch repair- defective strains containing the polBex1 allele - encoding a polymerase- proficient but exonucleolytically defective Pol II - displayed a mutator activity for four different chromosomal lac mutational markers. The mutator effect was dependent on the chromosomal orientation of the lacZ gene. The results indicate that Pol II plays a role in chromosomal replication and that its role is not equal in leading versus lagging- strand replication. In particular, the role of Pol II appeared larger in the lagging strand. When combined with dnaQ or dnaE mutator alleles, polBex1 showed strong, near multiplicative effects. The results fit a model in which Pol II acts as proofreader for HE- produced misinsertion errors. A second role of Pol II is to protect mismatched 3' termini against the mutagenic action of polymerase IV ( dinB product). Overall, Pol II may be considered a main player in the polymerase trafficking at the replication fork. C1 Polish Acad Sci, Inst Biochem & Biophys, Warsaw, Poland. Natl Inst Environm Hlth, Lab Mol Genet, Res Triangle Pk, NC 27709 USA. RP Jonczyk, P (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Pawinskiego 5A, Warsaw, Poland. EM piotrekj@ibb.waw.pl RI Fijalkowska, Iwona/I-7796-2016 NR 58 TC 39 Z9 39 U1 1 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2005 VL 58 IS 1 BP 61 EP 70 DI 10.1111/j.1365-2958.2005.04805.x PG 10 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 964VZ UT WOS:000231910400007 PM 16164549 ER PT J AU Yoshida, Y Ganguly, S Bush, CA Cisar, JO AF Yoshida, Y Ganguly, S Bush, CA Cisar, JO TI Carbohydrate engineering of the recognition motifs in streptococcal co-aggregation receptor polysaccharides SO MOLECULAR MICROBIOLOGY LA English DT Article ID VIRIDANS GROUP STREPTOCOCCI; CELL-WALL POLYSACCHARIDES; LACTIC-ACID BACTERIA; ACTINOMYCES-NAESLUNDII; ORAL ACTINOMYCES; GENETIC-TRANSFORMATION; LACTOCOCCUS-LACTIS; MITIS J22; PNEUMONIAE; BIOSYNTHESIS AB The cell wall polysaccharides of certain oral streptococci function as receptors for the lectin-like surface adhesins on other members of the oral biofilm community. Recognition of these receptor polysaccharides (RPS) depends on the presence of a host-like motif, either GalNAc beta 1-3Gal (Gn) or Gal beta 1-3GalNAc (G), within the oligosaccharide repeating units of different RPS structural types. Type 2Gn RPS of Streptococcus gordonii 38 and type 2G RPS of Streptococcus oralis J22 are composed of heptasaccharide repeats that are identical except for their host-like motifs. In the current investigation, the genes for the glycosyltransferases that synthesize these motifs were identified by high-resolution nuclear magnetic resonance (NMR) analysis of genetically altered polysaccharides. RPS production was switched from type 2Gn to 2G by replacing wefC and wefD in the type 2Gn gene cluster of S. gordonii 38 with wefF and wefG from the type 2G cluster of S. oralis J22. Disruption of either wefC or wefF abolished cell surface RPS production. In contrast, disruption of wefD in the type 2Gn cluster or wefG in the type 2G cluster eliminated beta-GalNAc from the Gn motif or beta-Gal from the G motif, resulting in mutant polysaccharides with hexa- rather than heptasaccharide subunits. The mutant polysaccharides reacted like wild-type RPS with rabbit antibodies against type 2Gn or 2G RPS but were inactive as co-aggregation receptors. Additional mutant polysaccharides with GalNAc beta 1-3GalNAc or Gal beta 1-3Gal recognition motifs were engineered by replacing wefC in the type 2Gn cluster with wefF or wefF in the type 2G cluster with wefC respectively. The reactions of these genetically modified polysaccharides as antigens and receptors provide further insight into the structural basis of RPS function. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Cisar, JO (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. EM john.cisar@nih.gov FU Intramural NIH HHS NR 36 TC 23 Z9 27 U1 1 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2005 VL 58 IS 1 BP 244 EP 256 DI 10.1111/j.1365-2958.2005.04820.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 964VZ UT WOS:000231910400020 PM 16164562 ER PT J AU Lee, CR Koo, BM Cho, SH Kim, YJ Yoon, MJ Peterkofsky, A Seok, YJ AF Lee, CR Koo, BM Cho, SH Kim, YJ Yoon, MJ Peterkofsky, A Seok, YJ TI Requirement of the dephospho-form of enzyme IIA(Ntr) for derepression of Escherichia coli K-12 ilvBN expression SO MOLECULAR MICROBIOLOGY LA English DT Article ID ACETOHYDROXY ACID SYNTHASE; GLOBAL REPRESSOR MLC; PHOSPHOTRANSFERASE SYSTEM; GLUCOSE-TRANSPORTER; GLYCOGEN-PHOSPHORYLASE; ALLOSTERIC REGULATION; NUCLEOTIDE-SEQUENCE; ILVIH OPERON; CYCLIC-AMP; RPON GENE AB While the proteins of the phosphoenolpyruvate:carbohydrate phosphotransferase system (carbohydrate PTS) have been shown to regulate numerous targets, little such information is available for the nitrogen-metabolic phosphotransferase system (nitrogen-metabolic PTS). To elucidate the physiological role of the nitrogen-metabolic PTS, we carried out phenotype microarray (PM) analysis with Escherichia coli K-12 strain MG1655 deleted for the ptsP gene encoding the first enzyme of the nitrogen-metabolic PTS. Together with the PM data, growth studies revealed that a ptsN (encoding enzyme IIA(Ntr)) mutant became extremely sensitive to leucine-containing peptides (LCPs), while both ptsP (encoding enzyme I-Ntr) and ptsO (encoding NPr) mutants were more resistant than wild type. The toxicity of LCPs was found to be due to leucine and the dephospho-form of enzyme IIA(Ntr) was found to be necessary to neutralize leucine toxicity. Further studies showed that the dephospho-form of enzyme IIA(Ntr) is required for derepression of the ilvBN operon encoding acetohydroxy acid synthase I catalysing the first step common to the biosynthesis of the branched-chain amino acids. C1 Seoul Natl Univ, Dept Biol Sci, Lab Macromol Interact, Seoul 151742, South Korea. Seoul Natl Univ, Inst Microbiol, Seoul 151742, South Korea. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Seok, YJ (reprint author), Seoul Natl Univ, Dept Biol Sci, Lab Macromol Interact, Seoul 151742, South Korea. EM yjseok@plaza.snu.ac.kr NR 44 TC 44 Z9 44 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2005 VL 58 IS 1 BP 334 EP 344 DI 10.1111/j.1365-2958.2005.04834.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 964VZ UT WOS:000231910400027 PM 16164569 ER PT J AU Bachmann, RF Schloesser, RJ Gould, TD Manji, HK AF Bachmann, RF Schloesser, RJ Gould, TD Manji, HK TI Mood stabilizers target cellular plasticity and resilience cascades - Implications for the development of novel therapeutics SO MOLECULAR NEUROBIOLOGY LA English DT Review DE mania; depression; manic-depressive illness; lithium; valproate; neurotrophic factors; pharmacology; bcl-2; neuroplasticity; mitochondria ID GLYCOGEN-SYNTHASE KINASE-3-BETA; PROTEIN-KINASE-C; LONG-TERM POTENTIATION; CENTRAL-NERVOUS-SYSTEM; RAT DENTATE GYRUS; AMYLOID-INDUCED NEURODEGENERATION; IMMORTALIZED HIPPOCAMPAL CELLS; HISTONE DEACETYLASE INHIBITION; NEUROTROPHIC FACTOR EXPRESSION; MEDIATED SIGNAL-TRANSDUCTION AB Bipolar disorder is a devastating disease with a lifetime incidence of about 1% in the general population. Suicide is the cause of death in 10 to 15% of patients and in addition to suicide, mood disorders are associated with many other harmful health effects. Mood stabilizers are medications used to treat bipolar disorder. In addition to their therapeutic effects for the treatment of acute manic episodes, mood stabilizers are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. The most established and investigated mood-stabilizing drugs are lithium and valproate but other anticonvulsants (such as carbamazepine and lamotrigine) and antipsychotics are also considered as mood stabilizers. Despite the efficacy of these diverse medications, their mechanisms of action remain, to a great extent, unknown. Lithium's inhibition of some enzymes, such as inositol monophosphatase and glycogen synthase kinase-3, probably results in its mood-stabilizing effects. Valproate may share its anticonvulsant target with its mood-stabilizing target or may act through other mechanisms. It has been shown that lithium, valproate, and/or carbamazepine regulate numerous factors involved in cell survival pathways, including cyclic adenine monophospate response element-binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen-activated protein kinases. These drugs have been suggested to have neurotrophic and neuroprotective properties that ameliorate impairments of cellular plasticity and resilience underlying the pathophysiology of mood disorders. This article also discusses approaches to develop novel treatments specifically for bipolar disorder. C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov FU Intramural NIH HHS NR 232 TC 110 Z9 111 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2005 VL 32 IS 2 BP 173 EP 202 DI 10.1385/MN:32:2:173 PG 30 WC Neurosciences SC Neurosciences & Neurology GA 975CM UT WOS:000232638600007 PM 16215281 ER PT J AU Acharya, MR Sparreboom, A Venitz, J Figg, WD AF Acharya, MR Sparreboom, A Venitz, J Figg, WD TI Rational development of histone deacetylase inhibitors as anticancer agents: A review SO MOLECULAR PHARMACOLOGY LA English DT Review ID SUBEROYLANILIDE HYDROXAMIC ACID; BREAST-CANCER CELLS; ACUTE MYELOID-LEUKEMIA; HUMAN PROSTATE-CANCER; HYPOXIA-INDUCED ANGIOGENESIS; P21/WAF1/CIP1 GENE PROMOTER; VIVO ANTITUMOR-ACTIVITY; TUMOR CONSORTIUM REPORT; TRICHOSTATIN-A; IN-VIVO AB The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy. C1 NCI, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Pharmaceut, Sch Pharm, Richmond, VA USA. RP Figg, WD (reprint author), NCI, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01,MSC1910, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 235 TC 164 Z9 174 U1 0 U2 21 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2005 VL 68 IS 4 BP 917 EP 932 DI 10.1124/mol.105.014167 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966EK UT WOS:000232002500001 PM 15955865 ER PT J AU Rivkin, E Eddy, EM Willis, WD Goulding, EH Suganuma, R Yanagimachi, R Kierszenbaum, AL AF Rivkin, E Eddy, EM Willis, WD Goulding, EH Suganuma, R Yanagimachi, R Kierszenbaum, AL TI Sperm tail abnormalities in mutant mice with neo(r) gene insertion into an intron of the keratin 9 gene SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE spermiogenesis; myosin Va; intramanchette transport; loss of heterozygocity; intraflagellar transport ID AMINO-ACID-SEQUENCE; MITOTIC RECOMBINATION; IN-VIVO; INTERMEDIATE-FILAMENTS; PERINUCLEAR RING; MOUSE; TRANSPORT; PROTEIN; HETEROZYGOSITY; MANCHETTE AB Keratin 9 (K9) is one of the components of the perinuclear ring of the manchette found in developing spermatids but is predominantly expressed in the epidermis of the footpad (palm and sole in human epidermis). As an initial step to determine the function of K9 protein in sperm development, we have generated a mutant mouse by homologous recombination of the targeting vector containing the disrupted K9 gene in which the neo(r) gene was inserted into the intron 6. This insertion resulted in the expression of two K9 mRNAs: a wild-type K9 mRNA, in which intron 6 with the neo(r) gene was completely spliced out, and a mutated form in which only a portion of the intron 6 between neo(r) gene and exon 7 was spliced out. While both heterozygous (K9(+/neo)) and homozygous (K9(neo/neo)) mutant mice expressed the wild-type form of K9 protein, the expression profile of the wild-type K9 in K9(neo/neo) mutants was modified. In addition, the open reading frame of the aberrant mRNA terminated at the exon 6/intron 6 splice site, resulting in a truncated K9 protein. Both K9(+neo) and K9(neo/neo) male mice displayed spermatids with ectopic manchette. Coiled tails were seen in maturing spermatids and epididymal sperm of mutant mice and sperm with deformed tails displayed forward motility. A predominant sperm anomaly was residual cytoplasm at the end of the mitochondria-containing middle piece tail segment. The residual cytoplasm displayed vesicles with random in situ motion, suggesting a transport impediment toward the distal end of the sperm tail. All mutant mice were fertile. Surprisingly, in oocyte nuclear injection experiments using K9(neo/neo) sperm donor, 76% of the resulting animals displayed a deletion of the neo(r) gene from the intron 6 of the mutated K9 allele. Results of this study support the view that intron 6 influences the transcriptional efficiency of the K9 gene by decreasing production of wild-type K9 and changing the expression of K9 proteins. C1 CUNY, Sch Med, Sophie Davis Sch Biomed Educ, Dept Cell Biol & Anat Sci, New York, NY 10021 USA. Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. Univ Hawaii, Inst Biogenesis Res, Honolulu, HI 96822 USA. RP Kierszenbaum, AL (reprint author), CUNY, Sch Med, Sophie Davis Sch Biomed Educ, Dept Cell Biol & Anat Sci, 138th St & Convent Ave,Harris Hall,Suite 306, New York, NY 10021 USA. EM kier@med.cuny.edu FU NICHD NIH HHS [HD 37282] NR 35 TC 8 Z9 10 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD OCT PY 2005 VL 72 IS 2 BP 259 EP 271 DI 10.1002/mrd.20335 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 951SH UT WOS:000230950600014 PM 16015579 ER PT J AU Torres, MS White, JE Bischoff, JF AF Torres, MS White, JE Bischoff, JF TI Cordyceps spegazzinii sp nov., a new species of the C. militaris group SO MYCOTAXON LA English DT Article DE Clavicipitales; taxonomy ID RDNA SEQUENCES; TELEOMORPHS; ALIGNMENT; NUCLEAR; MODEL; GENUS AB The proposed new species, Cordyceps spegazzinii sp nov., was collected on Barro Colorado Island, Panama. It is characterized by simple stromata with cylindrical to clavate heads, perithecia superficial to partially immersed, ascospores not fragmenting into part-spores and a Evlachovaea sp. anamorphic state. We compared C. spegazzinii to similar species in the C. militaris group. We determined that C. spegazzinii belongs to the C. militaris group, based on examination of morphological features and cultural characteristics, combined with phylogenetic analyses using LSU rDNA sequences. C1 Rutgers State Univ, Dept Plant Biol & Pathol, New Brunswick, NJ 08901 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Torres, MS (reprint author), Rutgers State Univ, Dept Plant Biol & Pathol, New Brunswick, NJ 08901 USA. EM jwhite@aesop.rutgers.edu RI White, James/C-2280-2009 NR 27 TC 5 Z9 7 U1 0 U2 5 PU MYCOTAXON LTD PI ITHACA PA PO BOX 264, ITHACA, NY 14851-0264 USA SN 0093-4666 J9 MYCOTAXON JI Mycotaxon PD OCT-DEC PY 2005 VL 94 BP 253 EP 263 PG 11 WC Mycology SC Mycology GA 044JX UT WOS:000237669600031 ER PT J AU Jia, ST Kobayashi, R Grewal, SIS AF Jia, ST Kobayashi, R Grewal, SIS TI Ubiquitin ligase component Cul4 associates with Clr4 histone methyltransferase to assemble heterochromatin SO NATURE CELL BIOLOGY LA English DT Article ID DNA-BINDING PROTEIN; FISSION YEAST; EPIGENETIC CONTROL; METHYLATION; CHROMATIN; GENOME; DAMAGE; H2B; H3; ESTABLISHMENT AB In eukaryotes, heterochromatin mediates diverse processes including gene silencing and regulation of long-range chromatin interactions(1,2). The formation of heterochromatin involves a conserved array of histone modifications; in particular, methylation of histone H3 at Lys 9 (H3K9me) is essential for recruiting HP1/Swi6 proteins(3). In fission yeast, the Clr4 methyltransferase is responsible for H3K9me across all heterochromatic domains(4,5). However, the mechanism of Clr4 recruitment to these loci is poorly understood. We show that Clr4 associates with Cul4, a cullin family protein that serves as a scaffold for assembling ubiquitin ligases. Mutations in Cul4 result in defective localization of Clr4 and loss of silencing at heterochromatic loci. This is accompanied by a severe reduction in H3K9me and Swi6 levels, and accumulation of transcripts corresponding to naturally silenced repeat elements within heterochromatic domains. Moreover, heterochromatin defects in Cul4 mutants could not be rescued by expression of Cul4 protein lacking Nedd8 modification, which is essential for its ubiquitin ligase activity. Rik1, a protein related to DNA damage binding protein DDB1 and required for H3K9me(4,6), also interacts with Cul4, the association of which might serve to target Clr4 to heterochromatic loci. These analyses uncover a role for Cul4-based protein ubiquitination in regulating H3K9me and heterochromatin formation. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA. RP Grewal, SIS (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov FU Intramural NIH HHS NR 35 TC 132 Z9 140 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD OCT PY 2005 VL 7 IS 10 BP 1007 EP U113 DI 10.1038/ncb1300 PG 11 WC Cell Biology SC Cell Biology GA 971BM UT WOS:000232356100016 PM 16127433 ER PT J AU Park, YG Zhao, XH Lesueur, F Lowy, DR Lancaster, M Pharoah, P Qian, XL Hunter, KW AF Park, YG Zhao, XH Lesueur, F Lowy, DR Lancaster, M Pharoah, P Qian, XL Hunter, KW TI Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1 SO NATURE GENETICS LA English DT Article ID GTPASE-ACTIVATING PROTEIN; GENE-EXPRESSION; BREAST-CANCER; MAMMARY-TUMOR; IMPORTANT DETERMINANT; RAP1 ACTIVATION; SUPPRESSOR GENE; MULTIPLE CROSS; NEW-GENERATION; CELL-ADHESION AB We previously identified loci in the mouse genome that substantially influence the metastatic efficiency of mammary tumors. Here, we present data supporting the idea that the signal transduction molecule, Sipa1, is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes identified a nonsynonymous amino acid polymorphism in Sipa1 that affects the Sipa1 Rap-GAP function. Spontaneous metastasis assays using cells ectopically expressing Sipa1 or cells with knocked-down Sipa1 expression showed that metastatic capacity was correlated with cellular Sipa1 levels. We examined human expression data and found that they were consistent with the idea that Sipa1 concentration has a role in metastasis. Taken together, these data suggest that the Sipa1 polymorphism is one of the genetic polymorphisms underlying the Mtes1 locus. This report is also the first demonstration, to our knowledge, of a constitutional genetic polymorphism affecting tumor metastasis. C1 NCI, Lab Populat Genet, Bethesda, MD 20892 USA. Univ Cambridge, Hutchinson MRC Res Ctr, Dept Oncol, Cambridge CB2 2XZ, England. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Lab Populat Genet, Bldg 41,Room 702,41 Lib Dr, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 CP010146-06] NR 49 TC 115 Z9 121 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2005 VL 37 IS 10 BP 1055 EP 1062 DI 10.1038/ng1635 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 968TP UT WOS:000232185600016 PM 16142231 ER PT J AU Maitra, A Arking, DE Shivapurkar, N Ikeda, M Stastny, V Kassauei, K Sui, GP Cutler, DJ Liu, Y Brimble, SN Noaksson, K Hyllner, J Schulz, TC Zeng, XM Freed, WJ Crook, J Abraham, S Colman, A Sartipy, P Matsui, SI Carpenter, M Gazdar, AF Rao, M Chakravarti, A AF Maitra, A Arking, DE Shivapurkar, N Ikeda, M Stastny, V Kassauei, K Sui, GP Cutler, DJ Liu, Y Brimble, SN Noaksson, K Hyllner, J Schulz, TC Zeng, XM Freed, WJ Crook, J Abraham, S Colman, A Sartipy, P Matsui, SI Carpenter, M Gazdar, AF Rao, M Chakravarti, A TI Genomic alterations in cultured human embryonic stem cells SO NATURE GENETICS LA English DT Article ID EPIGENETIC INACTIVATION; METHYLATION; CANCER; GENE; AMPLIFICATION; TUMORIGENESIS; MUTATIONS; PHENOTYPE; FREQUENT; TUMORS AB Cultured human embryonic stem cell (hESC) lines are an invaluable resource because they provide a uniform and stable genetic system for functional analyses and therapeutic applications. Nevertheless, these dividing cells, like other cells, probably undergo spontaneous mutation at a rate of 10(-9) per nucleotide. Because each mutant has only a few progeny, the overall biological properties of the cell culture are not altered unless a mutation provides a survival or growth advantage. Clonal evolution that leads to emergence of a dominant mutant genotype may potentially affect cellular phenotype as well. We assessed the genomic fidelity of paired early- and late-passage hESC lines in the course of tissue culture. Relative to early-passage lines, eight of nine late-passage hESC lines had one or more genomic alterations commonly observed in human cancers, including aberrations in copy number (45%), mitochondrial DNA sequence (22%) and gene promoter methylation (90%), although the latter was essentially restricted to 2 of 14 promoters examined. The observation that hESC lines maintained in vitro develop genetic and epigenetic alterations implies that periodic monitoring of these lines will be required before they are used in in vivo applications and that some late-passage hESC lines may be unusable for therapeutic purposes. C1 Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Oncol, Baltimore, MD 21205 USA. Univ Texas, Hamon Ctr Therapeut Oncol Res, Dallas, TX USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. BresaGen Inc, Athens, GA USA. Cellartis AB, Gothenburg, Sweden. NIDA, Cellular Neurobiol Branch, Baltimore, MD USA. ES Cell Int, Singapore, Singapore. SUNY Buffalo, Roswell Pk Canc Inst, Buffalo, NY 14260 USA. Robarts Res Inst, London, ON N6A 5C1, Canada. RP Chakravarti, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, 733 N Broadway Res Bldg, Baltimore, MD 21205 USA. EM raomah@grc.nia.nih.gov; aravinda@jhmi.edu NR 26 TC 395 Z9 419 U1 4 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2005 VL 37 IS 10 BP 1099 EP 1103 DI 10.1038/ng1631 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 968TP UT WOS:000232185600021 PM 16142235 ER PT J AU Leikina, E Delanoe-Ayari, H Melikov, K Cho, MS Chen, A Waring, AJ Wang, W Xie, YM Loo, JA Lehrer, RI Chernomordik, LV AF Leikina, E Delanoe-Ayari, H Melikov, K Cho, MS Chen, A Waring, AJ Wang, W Xie, YM Loo, JA Lehrer, RI Chernomordik, LV TI Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins SO NATURE IMMUNOLOGY LA English DT Article ID SEMLIKI-FOREST-VIRUS; INFLUENZA-A VIRUS; BIOLOGICAL-MEMBRANES; THETA-DEFENSINS; EARLY-STAGE; HEMAGGLUTININ; CELLS; PH; PROTEIN; LECTIN AB Defensins are peptides that protect the host against microorganisms. Here we show that the theta-defensin retrocyclin 2 (RC2) inhibited influenza virus infection by blocking membrane fusion mediated by the viral hemagglutinin. RC2 was effective even after hemagglutinin attained a fusogenic conformation or had induced membrane hemifusion. RC2, a multivalent lectin, prevented hemagglutinin-mediated fusion by erecting a network of crosslinked and immobilized surface glycoproteins. RC2 also inhibited fusion mediated by Sindbis virus and baculovirus. Human beta-defensin 3 and mannan-binding lectin also blocked viral fusion by creating a protective barricade of immobilized surface proteins. This general mechanism might explain the broad-spectrum antiviral activity of many multivalent lectins of the innate immune system. C1 NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Biochem & Chem, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Chernomordik, LV (reprint author), NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. EM chernoml@mail.nih.gov RI Melikov, Kamran/A-6604-2009 FU Intramural NIH HHS; NCRR NIH HHS [RR 20004]; NIAID NIH HHS [AI056921] NR 50 TC 145 Z9 161 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2005 VL 6 IS 10 BP 995 EP 1001 DI 10.1038/ni1248 PG 7 WC Immunology SC Immunology GA 966NR UT WOS:000232027200018 PM 16155572 ER PT J AU Deng, GM Zheng, LX Chan, FKM Lenardo, M AF Deng, GM Zheng, LX Chan, FKM Lenardo, M TI Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors SO NATURE MEDICINE LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; RHEUMATOID-ARTHRITIS; FACTOR-ALPHA; THERAPEUTIC TARGET; BACTERIAL-DNA; CPG MOTIFS; IN-VIVO; TNF; MICE; JOINT AB Tumor necrosis factor (TNF)-alpha has an important role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid and septic arthritis. The biological effects of TNF-alpha are mediated by binding to TNF receptors TNFR1 ( also known as P60) or TNFR2 ( also known as P80). The pre-ligand assembly domain (PLAD) is a portion of the extracellular region of TNFRs that mediates receptor-chain association essential for signaling. We found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-alpha in vitro and potently inhibit arthritis in animal models. Thus, targeting the PLAD may have clinical value in the treatment of human arthritis and other disorders involving receptors of the TNFR superfamily. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. RP Lenardo, M (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM lenardo@nih.gov 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 Intramural NIH HHS NR 34 TC 63 Z9 71 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2005 VL 11 IS 10 BP 1066 EP 1072 DI 10.1038/nm1304 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 972ZM UT WOS:000232492500027 PM 16170321 ER PT J AU Chattopadhyay, PK Yu, J Roederer, M AF Chattopadhyay, PK Yu, J Roederer, M TI A live-cell assay to detect antigen-specific CD4(+) T cells with diverse cytokine profiles SO NATURE MEDICINE LA English DT Article ID CD40 LIGAND; IMMUNE-RESPONSES; FLOW-CYTOMETRY; EXPRESSION; IDENTIFICATION; ACTIVATION; MOLECULES; MICE AB Recently activated, but not resting, CD4(+) T cells express CD154, providing costimulatory signals to B cells and antigen-presenting cells (APCs). Therefore, de novo CD154 expression after stimulation identifies antigen-specific CD4+ T cells. Previous assays were limited by the transient nature of surface CD154 expression; we overcame this by including fluorescently conjugated CD154-specific antibody during stimulation. Our assay is fully compatible with intracellular cytokine staining, and can be used for stimulations as long as 24 h. Notably, it is nonlethal, providing a means to purify viable antigen-specific CD4+ T cells for further analysis. Using this assay, we found that stimulated cells expressing tumor necrosis factor (TNF)-alpha, interleukin (IL)-2 or interferon (IFN)-alpha were predominantly CD154(+). Furthermore, some cells expressing none of these cytokines also expressed CD154, suggesting that CD154 marks cells with other effector functions. For vaccine- or pathogen-specific responses, we found substantial heterogeneity in expression of CD154 and cytokines, suggesting previously unrecognized diversity in abilities of responding cells to stimulate APCs through CD40. C1 NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. EM roederer@nih.gov RI Chattopadhyay, Pratip/B-9227-2008; Roederer, Mario/G-1887-2011; OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural NIH HHS [Z99 AI999999] NR 21 TC 177 Z9 180 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2005 VL 11 IS 10 BP 1113 EP 1117 DI 10.1038/nm1293 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 972ZM UT WOS:000232492500034 PM 16186817 ER PT J AU Xiao, Y Telford, WG Ball, JC Locascio, LE Barker, PE AF Xiao, Y Telford, WG Ball, JC Locascio, LE Barker, PE TI Semiconductor nanocrystal conjugates, FISH and pH SO NATURE METHODS LA English DT Letter ID PROBES C1 NIST, DNA Technol Grp, Div Biotechnol, Gaithersburg, MD 20899 USA. NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, MOl Spectrometry & Microfluid Methods Grp, Analyt Chem Div, Gaithersburg, MD 20899 USA. RP Xiao, Y (reprint author), NIST, DNA Technol Grp, Div Biotechnol, Gaithersburg, MD 20899 USA. EM peter.barker@nist.gov NR 3 TC 26 Z9 28 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD OCT PY 2005 VL 2 IS 10 BP 723 EP 723 DI 10.1038/nmeth1005-723 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 980FC UT WOS:000232998600002 PM 16179915 ER PT J AU Baker, SC Bauer, SR Beyer, RP Brenton, JD Bromley, B Burrill, J Causton, H Conley, MP Elespuru, R Fero, M Foy, C Fuscoe, J Gao, XL Gerhold, DL Gilles, P Goodsaid, F Guo, X Hackett, J Hockett, RD Ikonomi, P Irizarry, RA Kawasaki, ES Kaysser-Kranich, T Kerr, K Kiser, G Koch, WH Lee, KY Liu, CM Liu, ZL Lucas, A Manohar, CF Miyada, G Modrusan, Z Parkes, H Puri, RK Reid, L Ryder, TB Salit, M Samaha, RR Scherf, U Sendera, TJ Setterquist, RA Shi, LM Shippy, R Soriano, JV Wagar, EA Warrington, JA Williams, M Wilmer, F Wilson, M Wolber, PK Wu, XN Zadro, R AF Baker, SC Bauer, SR Beyer, RP Brenton, JD Bromley, B Burrill, J Causton, H Conley, MP Elespuru, R Fero, M Foy, C Fuscoe, J Gao, XL Gerhold, DL Gilles, P Goodsaid, F Guo, X Hackett, J Hockett, RD Ikonomi, P Irizarry, RA Kawasaki, ES Kaysser-Kranich, T Kerr, K Kiser, G Koch, WH Lee, KY Liu, CM Liu, ZL Lucas, A Manohar, CF Miyada, G Modrusan, Z Parkes, H Puri, RK Reid, L Ryder, TB Salit, M Samaha, RR Scherf, U Sendera, TJ Setterquist, RA Shi, LM Shippy, R Soriano, JV Wagar, EA Warrington, JA Williams, M Wilmer, F Wilson, M Wolber, PK Wu, XN Zadro, R CA External RNA Controls Consortium TI The external RNA controls consortium: a progress report SO NATURE METHODS LA English DT Editorial Material ID DNA AMPLIFICATION; PCR AB Standard controls and best practice guidelines advance acceptance of data from research, preclinical and clinical Laboratories by providing a means for evaluating data quality. The External RNA Controls Consortium (ERCC) is developing commonly agreed-upon and tested controls for use in expression assays, a true industry-wide standard control. C1 Affymetrix Inc, Santa Clara, CA 95051 USA. Illumina Inc, San Diego, CA 92121 USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. Univ Washington, Seattle, WA 98105 USA. Univ Cambridge, CIMR, Addenbrookes Hosp, Cambridge CB2 2XY, England. ViaLogy Corp, Altadena, CA 91001 USA. Appl Biosyst Inc, Foster City, CA 94404 USA. Univ London Imperial Coll, London SW7 2AZ, England. Enzo Life Sci Inc, Farmingdale, NY 11735 USA. US FDA, Ctr Devices & Radiol Hlth, Fed Labs White Oak, Silver Spring, MD 20903 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Lab Govt Chemist, Bio Mol Innovat, Teddington TW11 0LY, Middx, England. US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. Atactic Technol Inc, Houston, TX 77054 USA. Merck Sharp Labs, Dept Mol Profiling, West Point, PA 19486 USA. Invitrogen Corp, Carlsbad, CA 92008 USA. US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20852 USA. Affymetrix Inc, Santa Clara, CA 95051 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20850 USA. Eli Lilly & Co, Lilly Res Lab, Lilly Corp Ctr, Indianapolis, IN 46285 USA. Amer Type Culture Collect, Manassas, VA 20110 USA. NCI, Ctr Adv Technol, NIH, Baltimore, MD 21205 USA. GE Healthcare, Chandler, AZ 85248 USA. Roche Mol Syst, Pleasanton, CA 94588 USA. USDA, Peoria, IL 61604 USA. Agilent Technol Inc, Santa Clara, CA 95051 USA. Lawrence Livermore Natl Lab Microarray Ctr, Livermore, CA 94550 USA. Genentech Inc, San Francisco, CA 94080 USA. US FDA, NIH, Bethesda, MD 20892 USA. Express Anal, Durham, NC 27713 USA. NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. US FDA, Off In Vitro Diagnost Device Evaluat & Safety, Rockville, MD 20850 USA. Ambion Inc, Austin, TX 78744 USA. Amer Type Culture Collect, Manassas, VA 20110 USA. Univ Calif Los Angeles, Clin Labs, Los Angeles, CA 90095 USA. Qiagen Inc, D-40727 Hilden, Germany. Univ Zagreb, Sch Med, Zagreb 10000, Croatia. RP Warrington, JA (reprint author), Affymetrix Inc, 3380 Cent Expressway, Santa Clara, CA 95051 USA. EM janet_warrington@affymetrix.com RI Bauer, Steven/G-5559-2012; Kiser, Gretchen/A-3228-2013; OI Brenton, James/0000-0002-5738-6683; Bauer, Steven/0000-0003-2831-846X NR 8 TC 128 Z9 130 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD OCT PY 2005 VL 2 IS 10 BP 731 EP 734 DI 10.1038/nmeth1005-731 PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 980FC UT WOS:000232998600009 PM 16179916 ER PT J AU Keng, VW Yae, K Hayakawa, T Mizuno, S Uno, Y Yusa, K Kokubu, C Kinoshita, T Akagi, K Jenkins, NA Copeland, NG Horie, K Takeda, J AF Keng, VW Yae, K Hayakawa, T Mizuno, S Uno, Y Yusa, K Kokubu, C Kinoshita, T Akagi, K Jenkins, NA Copeland, NG Horie, K Takeda, J TI Region-specific saturation germline mutagenesis in mice using the Sleeping Beauty transposon system SO NATURE METHODS LA English DT Article ID HUMAN TRANSCRIPTOME MAP; IBMP RECEPTOR BMPRIB; CHROMOSOMAL TRANSPOSITION; EXPRESSED GENES; MOUSE; GENOME; DOMAINS; CELLS; FISH AB Recent consolidation of the whole-genome sequence with genome-wide transcriptome profiting revealed the existence of functional units within the genome in specific chromosomal regions, as seen in the coordinated expression of gene clusters and colocatization of functionally related genes. An efficient region-specific mutagenesis screen would greatly facilitate research in addressing the importance of these clusters. Here we use the 'local hopping' phenomenon of a DNA-type transposon, Sleeping Beauty (SB), for region-specific saturation mutagenesis. A transgenic mouse containing both transposon (acts as a mutagen) and transposase (recognizes and mobilizes the transposon) was bred for germ-cell transposition events, allowing us to generate many mutant mice. ALL genes within a 4-Mb region of the original donor site were mutated by SB, indicating the potential of this system for functional genomic studies within a specific chromosomal region. C1 Osaka Univ, Ctr Adv Sci & Innovat, Suita, Osaka 5650871, Japan. Osaka Univ, Dept Social & Environm Med, Grad Sch Med, Suita, Osaka 5650871, Japan. Osaka Univ, Res Inst Microbial Dis, Suita, Osaka 5650871, Japan. NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Takeda, J (reprint author), Osaka Univ, Ctr Adv Sci & Innovat, 2-1 Yamadaoka, Suita, Osaka 5650871, Japan. EM takeda@mr-envi.med.osaka-u.ac.jp RI Kinoshita, Taroh/C-7353-2009; OI Keng, Vincent/0000-0003-3473-0653 NR 30 TC 81 Z9 88 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD OCT PY 2005 VL 2 IS 10 BP 763 EP 769 DI 10.1038/NMETH795 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 980FC UT WOS:000232998600016 PM 16179923 ER PT J AU Kwong, AD Rao, BG Jeang, KT AF Kwong, AD Rao, BG Jeang, KT TI Viral and cellular RNA helicases as antiviral targets SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID HEPATITIS-C-VIRUS; DEAD-BOX PROTEINS; CRYSTAL-STRUCTURE; NS3 HELICASE; SACCHAROMYCES-CEREVISIAE; PROTEASE INHIBITOR; ATPASE ACTIVITY; BINDING-SITES; DUPLEX RNA; IN-VITRO AB Although there has been considerable progress in the development of antiviral agents in recent years, there is still a pressing need for new drugs both to improve on the properties of existing agents and to combat the problem of viral resistance. Helicases, both viral and human, have recently emerged as novel targets for the treatment of viral infections. Here, we discuss the role of these enzymes, factors affecting their potential as drug targets and progress in the development of agents that inhibit their activity using the hepatitis C virus-encoded helicase NS3 and the cellular helicase DDX3 adopted for use by HIV-1 as examples. C1 NIAID, Bethesda, MD 20892 USA. Vertex Pharmaceut Inc, Cambridge, MA 02139 USA. RP Jeang, KT (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 90 TC 114 Z9 116 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD OCT PY 2005 VL 4 IS 10 BP 845 EP 853 DI 10.1038/nrd1853 PG 9 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 973TS UT WOS:000232546100023 PM 16184083 ER PT J AU Di Prospero, NA Fischbeck, KH AF Di Prospero, NA Fischbeck, KH TI Therapeutics development for triplet repeat expansion diseases SO NATURE REVIEWS GENETICS LA English DT Review ID FRAGILE-X-SYNDROME; TRANSGENIC MOUSE MODEL; HISTONE DEACETYLASE INHIBITORS; EARLY HUNTINGTONS-DISEASE; CREB-BINDING PROTEIN; WILD-TYPE HUNTINGTIN; LONG-TERM TREATMENT; POLYGLUTAMINE AGGREGATION; FRIEDREICHS-ATAXIA; RAT MODEL AB The underlying genetic mutations for many inherited neurodegenerative disorders have been identified in recent years. One frequent type of mutation is trinucleotide repeat expansion. Depending on the location of the repeat expansion, the mutation might result in a loss of function of the disease gene, a toxic gain of function or both. Disease gene identification has led to the development of model systems for investigating disease mechanisms and evaluating treatments. Examination of experimental findings reveals similarities in disease mechanisms as well as possibilities for treatment. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Di Prospero, NA (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM DiProsperN@ninds.nih.gov FU Intramural NIH HHS NR 134 TC 97 Z9 98 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD OCT PY 2005 VL 6 IS 10 BP 756 EP 765 DI 10.1038/nrg1690 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 970NL UT WOS:000232316800012 PM 16205715 ER PT J AU Moll, J Zahn, R de Oliveira-Souza, R Krueger, F Grafman, J AF Moll, J Zahn, R de Oliveira-Souza, R Krueger, F Grafman, J TI The neural basis of human moral cognition SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID VENTROMEDIAL PREFRONTAL CORTEX; FRONTAL-LOBE DAMAGE; ANTISOCIAL PERSONALITY-DISORDER; SCRIPT-DRIVEN IMAGERY; DECISION-MAKING; FRONTOTEMPORAL DEMENTIA; ORBITOFRONTAL CORTEX; CRIMINAL PSYCHOPATHS; CONCEPTUAL KNOWLEDGE; SOCIAL-PERCEPTION AB Moral cognitive neuroscience is an emerging field of research that focuses on the neural basis of uniquely human forms of social cognition and behaviour. Recent functional imaging and clinical evidence indicates that a remarkably consistent network of brain regions is involved in moral cognition. These findings are fostering new interpretations of social behavioural impairments in patients with brain dysfunction, and require new approaches to enable us to understand the complex links between individuals and society. Here, we propose a cognitive neuroscience view of how cultural and context-dependent knowledge, semantic social knowledge and motivational states can be integrated to explain complex aspects of human moral cognition. C1 Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. LABS DOr Hosp Network, Cognit & Behav Neurosci Unit, BR-22281080 Rio De Janeiro, Brazil. RP Grafman, J (reprint author), Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov RI Zahn, Roland/C-4665-2008; Moll, Jorge/B-2654-2013; OI Zahn, Roland/0000-0002-8447-1453; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS NR 153 TC 396 Z9 409 U1 20 U2 119 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD OCT PY 2005 VL 6 IS 10 BP 799 EP 809 DI 10.1038/nrn1768 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 970NV UT WOS:000232317800016 PM 16276356 ER PT J AU Hinnebusch, AG AF Hinnebusch, AG TI eIF2 alpha kinases provide a new solution to the puzzle of substrate specificity SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID DOUBLE-STRANDED-RNA; CRYSTAL-STRUCTURE; PROTEIN-KINASES; STRUCTURAL BASIS; ACTIVATION LOOP; PKR; GCN2; TRANSLATION; DIMERIZATION; BINDING AB The stress-activated protein kinases PKR and GCN2 regulate protein synthesis by phosphorylating the a subunit of translation initiation factor 2. Three recent studies reveal the molecular basis for the exquisite substrate specificity of this family of kinases and address the role of interlobe flexibility in kinase activation. C1 NICHHD, Lab Gene Regulat & Dev, US NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, US NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov NR 26 TC 19 Z9 19 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD OCT PY 2005 VL 12 IS 10 BP 835 EP 838 DI 10.1038/nsmb1005-835 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 971BJ UT WOS:000232355800007 PM 16205706 ER PT J AU Bradley, CM Ronning, DR Ghirlando, R Craigie, R Dyda, F AF Bradley, CM Ronning, DR Ghirlando, R Craigie, R Dyda, F TI Structural basis for DNA bridging by barrier-to-autointegration factor SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID PREINTEGRATION COMPLEXES; RETROVIRAL DNA; INTEGRATION; BAF; GLYCOSYLASE; PROTEIN; ROLES AB The ability of barrier-to-autointegration factor (BAF) to bind and bridge DNA in a sequence-independent manner is crucial for its role in retroviral integration and a variety of cellular processes. To better understand this behavior, we solved the crystal structure of BAF bound to DNA. The structure reveals that BAF bridges DNA using two pairs of helix-hairpin-helix motifs located on opposite surfaces of the BAF dimer without changing its conformation. C1 NIDDKD, Mol Biol Lab, US NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDKD, Mol Biol Lab, US NIH, 5 Ctr Dr, Bethesda, MD 20892 USA. EM fred.dyda@nih.gov RI Ghirlando, Rodolfo/A-8880-2009 FU Intramural NIH HHS NR 16 TC 56 Z9 56 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD OCT PY 2005 VL 12 IS 10 BP 935 EP 936 DI 10.1038/nsmb989 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 971BJ UT WOS:000232355800023 PM 16155580 ER PT J AU Proescholdt, MA Mayer, C Kubitza, M Schubert, T Liao, SY Stanbridge, EJ Ivanov, S Oldfield, EH Brawanski, A Merrill, MJ AF Proescholdt, MA Mayer, C Kubitza, M Schubert, T Liao, SY Stanbridge, EJ Ivanov, S Oldfield, EH Brawanski, A Merrill, MJ TI Expression of hypoxia-inducible carbonic anhydrases in brain tumors SO NEURO-ONCOLOGY LA English DT Article DE pH regulation; carbonic anhydrase; glioma; hypoxia ID POSITRON EMISSION TOMOGRAPHY; MN/CA IX; DIAGNOSTIC BIOMARKER; INVIVO MEASUREMENT; CELL CARCINOMA; TYROSINE PHOSPHATASE; OXYGEN-TENSION; REGIONAL BRAIN; HUMAN GLIOMAS; RAT-BRAIN AB Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel-Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-let staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Regensburg, Dept Neurosurg, D-8400 Regensburg, Germany. Univ Regensburg, Inst Pathol, D-8400 Regensburg, Germany. Univ Calif Irvine, Coll Med, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. SAIC Frederick Inc, Basic Res Program, Immunobiol Lab, NCI, Frederick, MD 21702 USA. RP Merrill, MJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 5D37,10 Ctr Dr, Bethesda, MD 20892 USA. EM merrillm@ninds.nih.gov OI Ivanov, Sergey/0000-0001-9770-7237 NR 56 TC 37 Z9 38 U1 0 U2 5 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2005 VL 7 IS 4 BP 465 EP 475 DI 10.1215/S1152851705000025 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 973HX UT WOS:000232514600005 PM 16212811 ER PT J AU Bendel, A Watterson, J Ries, L Bleyer, A AF Bendel, A Watterson, J Ries, L Bleyer, A TI Epidemiology and outcome of CNS germ cell tumors in the United States, SEER, 1975-2000, a disease of adolescents and young adults (AYA) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 2nd International Symposium on Central Nervous System Germ Cell Tumors CY NOV 18-21, 2005 CL Los Angeles, CA C1 Childrens Hosp & Clin, Minneapolis, MN USA. Natl Canc Inst, Bethesda, MD USA. St Charles Hosp, Bend, OR USA. Childrens Oncol Grp, Arcadia, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2005 VL 7 IS 4 BP 516 EP 516 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 973HX UT WOS:000232514600020 ER PT J AU Balis, FM AF Balis, FM TI Current approaches in the management of leptomeningeal diseases: Potential applications to CNS germ cell tumors SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 2nd International Symposium on Central Nervous System Germ Cell Tumors CY NOV 18-21, 2005 CL Los Angeles, CA C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2005 VL 7 IS 4 BP 523 EP 523 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 973HX UT WOS:000232514600047 ER PT J AU Depboylu, C Schafer, MKH Schwaeble, WJ Reinhart, TA Maeda, H Mitsuya, H Damadzic, R Rausch, DM Eiden, LE Weihe, E AF Depboylu, C Schafer, MKH Schwaeble, WJ Reinhart, TA Maeda, H Mitsuya, H Damadzic, R Rausch, DM Eiden, LE Weihe, E TI Increase of C1q biosynthesis in brain microglia and macrophages during lentivirus infection in the rhesus macaque is sensitive to antiretroviral treatment with 6-chloro-2',3'-dideoxyguanosine SO NEUROBIOLOGY OF DISEASE LA English DT Article; Proceedings Paper CT 31st Annual Meeting of the Society-for-Neuroscience CY NOV 10-15, 2001 CL SAN DIEGO, CA SP Soc Neurosci DE complement; microglia; neuro-AIDS; antiretroviral treatment; blood-brain barrier; cell proliferation ID SIMIAN IMMUNODEFICIENCY VIRUS; ANTIBODY-DEPENDENT ENHANCEMENT; MULTINUCLEATED GIANT-CELLS; IMMUNE-DEFICIENCY-SYNDROME; CEREBROSPINAL-FLUID; COMPLEMENT-SYSTEM; HIV-1 INFECTION; ALZHEIMERS-DISEASE; IN-VITRO; 6-CHLORO-2',3'-DIDEOXYGUANOSINE 6-CL-DDG AB Complement activation in the brain contributes to the pathology of neuroinflammatory and neurodegenerative diseases such as neuro-AIDS. Using semiquantitative in situ hybridization and immunohistochemistry, we observed an early and sustained increase in the expression of C1q, the initial recognition subcomponent of the classical complement cascade, in the CNS during simian immunodeficiency virus (SIV) infection of rhesus macaques. Cells of the microglial/ macrophage lineage were the sources for C1q protein and transcripts. C1q expression was observed in proliferating and infiltrating cells in SIV-encephalitic brains. All SIV-positive cells were also C1q-positive. Treatment with the CNS-permeant antiretroviral agent 6-chloro-2',3'- dideoxyguanosine decreased C1q synthesis along with SIV burden and focal inflammatory reactions in the brains of AIDS-symptomatic monkeys. Thus, activation of the classical complement arm of innate immunity is an early event in neuro-AIDS and a possible target for intervention. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Marburg, Dept Mol Neurosci, Inst Anat & Cell Biol, D-35033 Marburg, Germany. Univ Marburg, Dept Neurol, Ctr Nervous Dis, D-35033 Marburg, Germany. Univ Leicester, Dept Infect Immun & Inflammat, Leicester, Leics, England. Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA 15260 USA. NCI, Div Canc Treatment, NIH, Bethesda, MD 20892 USA. NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. NIMH, Div Mental Disorders Behav Res & AIDS, NIH, Bethesda, MD 20892 USA. RP Weihe, E (reprint author), Univ Marburg, Dept Mol Neurosci, Inst Anat & Cell Biol, Robert Koch Str 8, D-35033 Marburg, Germany. EM weihe@staff.uni-marburg.de OI Eiden, Lee/0000-0001-7524-944X NR 78 TC 18 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2005 VL 20 IS 1 BP 12 EP 26 DI 10.1016/j.nbd.2005.01.30 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 965IX UT WOS:000231945000002 PM 16137563 ER PT J AU Kim, SY Marekov, L Bubber, P Browne, S Stavrovskaya, I Lee, J Steinert, PM Blass, JP Beal, MF Gibson, GE Cooper, AJL AF Kim, SY Marekov, L Bubber, P Browne, S Stavrovskaya, I Lee, J Steinert, PM Blass, JP Beal, MF Gibson, GE Cooper, AJL TI Mitochondrial aconitase is a transglutaminase 2 substrate: Transglutamination is a probable mechanism contributing to high-molecular-weight aggregates of aconitase and loss of aconitase activity in Huntington disease brain SO NEUROCHEMICAL RESEARCH LA English DT Article DE Huntington disease; mitochondrial aconitase; non-synaptosomal mitochondria; transglutaminase ID TISSUE TRANSGLUTAMINASE; ALZHEIMERS-DISEASE; CROSS-LINKING; PARKINSONS-DISEASE; MESSENGER-RNA; PROTEIN; EXPRESSION; MODEL; NEURODEGENERATION; INCREASES AB Transglutaminase activity was found to be present in highly purified non-synaptosomal rat brain mitochondria. A 78-kDa protein in these organelles was shown to be a transglutaminase 2 substrate, and incubation of a non-synaptosomal mitochondrial lysate with transglutaminase 2 yielded high-M-r proteins. The 78-kDa protein was identified as mitochondrial aconitase by MALDI-TOF analysis. Aconitase activity was decreased in a dose-dependent manner when non-synaptosomal rat brain mitochondria were incubated with transglutaminase 2. Transglutaminase activity is increased about 2-fold in the mitochondrial fraction of HD caudate. Moreover, Western blotting of the mitochondrial fraction revealed that most of the mitochondrial aconitase in HD caudate is present as high-M-r aggregates. Aconitase activity was previously shown to be decreased in Huntington disease (HD) caudate (a region severely damaged by the disease). The present findings suggest that an increase of transglutaminase activity in HD caudate may contribute to mitochondrial dysfunction by incorporating aconitase into inactive polymers. C1 Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA. Burke Med Res Inst, White Plains, NY 10605 USA. NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, SY (reprint author), Natl Canc Ctr, Div Basic Sci, 809 Madu Dong, Goyang 410351, South Korea. RI Cooper, Arthur/H-5171-2016 FU NIA NIH HHS [AG19589, P01 AG14930]; NIMH NIH HHS [R24-MH 068855] NR 44 TC 27 Z9 31 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD OCT PY 2005 VL 30 IS 10 BP 1245 EP 1255 DI 10.1007/s11064-005-8796-x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 992EI UT WOS:000233866800006 PM 16341586 ER PT J AU Wu, CWH van Gelderen, P Hanakawa, T Yaseen, Z Cohen, LG AF Wu, CWH van Gelderen, P Hanakawa, T Yaseen, Z Cohen, LG TI Enduring representational plasticity after somatosensory stimulation SO NEUROIMAGE LA English DT Article DE somatosensory; motor cortex; premotor; fMRI; reorganization; nerve stimulation ID CEREBRAL-BLOOD-FLOW; MEDIAN NERVE-STIMULATION; HUMAN MOTOR CORTEX; POSTERIOR PARIETAL CORTEX; PAIRED ASSOCIATIVE STIMULATION; POSITRON EMISSION TOMOGRAPHY; MAGNETIC-RESONANCE; PREMOTOR CORTEX; STROKE PATIENTS; CORTICAL REORGANIZATION AB Somatosensory stimulation (SS), leading to increases in motor cortical excitability, influences motor performance in patients with brain lesions like stroke. The mechanisms by which SS modulates motor function are incompletely understood. Here, we used functional magnetic resonance imaging (fMRI, blood-oxygenation-level-dependent (BOLD), and perfusion imagings simultaneously acquired in a 3 T magnet) to assess the effects of SS on thumb-movement-related activation in three regions of interest (ROI) in the motor network: primary motor cortex (M1), primary somatosensory cortex (SI), and dorsal premotor cortex (PMd) in healthy volunteers. Scans were obtained in different sessions before and after 2-h electrical stimulation applied to the median nerve at the wrist (MNS), to the skin overlying the shoulder deltoid muscle (DMS), and in the absence of stimulation (NOSTIM) in a counterbalanced design. We found that baseline perfusion intensity was comparable within and across sessions. MNS but not DMS nor NOSTIM led to an increase in signal intensity and number of voxels activated by performance of median nerve-innervated thumb movements in M1, S1 and PMd for up to 60 min. Task-related fMRI activation changes were most prominent in M1 followed by S1 and to a lesser extent in PMd. MNS elicited a displacement of the center of gravity for the thumb movement representation towards the other finger representations within S1. These results indicate that MNS leads to an expansion of the thumb representation towards other finger representations within S1, a form of plasticity that may underlie the influence of SS on motor cortical function, possibly supporting beneficial effects on motor control. Published by Elsevier Inc. C1 Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. RP Wu, CWH (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room B1D728, Bethesda, MD 20892 USA. EM wuwh@ninds.nih.gov; cohenl@ninds.nih.gov NR 89 TC 56 Z9 59 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2005 VL 27 IS 4 BP 872 EP 884 DI 10.1016/j.neuroimage.2005.05.055 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 968DD UT WOS:000232141200016 PM 16084740 ER PT J AU Bramon, E McDonald, C Croft, RJ Landau, S Filbey, F Gruzelier, JH Sham, PC Frangou, S Murray, RM AF Bramon, E McDonald, C Croft, RJ Landau, S Filbey, F Gruzelier, JH Sham, PC Frangou, S Murray, RM TI Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study SO NEUROIMAGE LA English DT Article DE P300; meta-analysis; endophenotype; schizophrenia; psychosis; genetic ID EVENT-RELATED POTENTIALS; AFFECTIVE-DISORDERS; GENE POLYMORPHISM; ASSOCIATION; RISK; ABNORMALITIES; RELATIVES; CHILDREN; SAMPLE; PHENOTYPES AB We assessed the usefulness of the P300 wave as endophenotype for schizophrenia by means of a meta-analysis of the literature as well as our own family study. Method: Meta-analysis: We conducted a systematic search for articles published between 1983 and 2003 that reported P300 measures in nonpsychotic relatives of schizophrenic patients and in healthy controls. Meta-regression analyses were performed using a random effects procedure. The pooled standardized effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation. Local study: We examined the P300 wave with a standard two-tone oddball paradigm in 30 patients with schizophrenia, 40 non-psychotic relatives, and 40 controls using linear mixed models. Results: Meta-analysis: We pooled 472 relatives and 513 controls. The P300 amplitude was significantly reduced in relatives (PSES = 0.61; 95% Cl: 0.30 to 0.91; P < 0.001). The P300 latency was significantly delayed in relatives (PSES of-0.50; 95% Cl: -0.88 to -0.13; P=0.009]. Local study: The patients showed a trend for amplitude reductions (P = 0.06) and significant latency delays (P < 0.01). The relatives displayed normal amplitude but had significant latency delays (P = 0.01). The P300 amplitude and especially the P300 latency are promising alternative phenotypes for genetic research into schizophrenia. (C) 2005 Elsevier Inc. All rights reserved. C1 Inst Psychiat, London SE5 8AF, England. Swinburne Univ Technol, Brain Sci Inst, Hawthorn, Vic 3122, Australia. NIMH, Bethesda, MD 20892 USA. Univ London Imperial Coll Sci Technol & Med, Div Neurosci & Psychol Med, London W6 8RF, England. RP Bramon, E (reprint author), Inst Psychiat, POB 63,De Crespigny Pk, London SE5 8AF, England. EM e.bramon@iop.kcl.ac.uk RI Bramon, Elvira/A-9463-2011; Landau, Sabine/B-9354-2011; Frangou, Sophia/A-2672-2013; McDonald, Colm/C-1430-2009; Murray, Robin/F-8658-2012 OI Murray, Robin/0000-0003-0829-0519 FU Department of Health [PDA/02/06/016]; Wellcome Trust NR 53 TC 120 Z9 125 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2005 VL 27 IS 4 BP 960 EP 968 DI 10.1016/j.neuroimage.2005.05.022 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 968DD UT WOS:000232141200024 PM 16009570 ER PT J AU Muntoni, F Mercuri, E Bonne, G Goldfarb, L Richard, P Recan, D Sewry, CA Brown, SC AF Muntoni, F Mercuri, E Bonne, G Goldfarb, L Richard, P Recan, D Sewry, CA Brown, SC TI Double lamin-emerin and lamin-desmin trouble SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 10th International Congress of the World-Muscle-Society CY SEP 28-OCT 10, 2005 CL Iguassu Falls, BRAZIL SP World Muscle Soc C1 Dubowitz Neuromuscular Ctr, London, England. INSERM UR582, Paris, France. Natl Inst Neurol Disorders, Bethesda, MD USA. Ctr Inherited neuromuscular Disorders, Oswestry, Shrops, England. RI Nicholas, Janet/C-6674-2008 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 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2005 VL 15 IS 9-10 BP 677 EP 677 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969GJ UT WOS:000232221900017 ER PT J AU Olive, M Goldfarb, L Shatunov, A Fischer, D Ferrer, I AF Olive, M Goldfarb, L Shatunov, A Fischer, D Ferrer, I TI Myotilinopathy: refining the clinical and myopathological phenotype SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 10th International Congress of the World-Muscle-Society CY SEP 28-OCT 10, 2005 CL Iguassu Falls, BRAZIL SP World Muscle Soc C1 Bellvitge Hosp, IDIBELL, Inst Neuropathol, Barcelona, Spain. NINDS, NIH, Bethesda, MD 20892 USA. Univ Bonn, Dept Neurol, D-5300 Bonn, Germany. RI Shatunov, Aleksey/E-6946-2011 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 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2005 VL 15 IS 9-10 BP 679 EP 679 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969GJ UT WOS:000232221900024 ER PT J AU Zhu, Y Li, X McVie-Wylie, A Jiang, C Thurberg, BL Raben, N Mattaliano, RJ Cheng, SH AF Zhu, Y Li, X McVie-Wylie, A Jiang, C Thurberg, BL Raben, N Mattaliano, RJ Cheng, SH TI Carbohydrate-remodeled acid alpha-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 10th International Congress of the World-Muscle-Society CY SEP 28-OCT 10, 2005 CL Iguassu Falls, BRAZIL SP World Muscle Soc C1 Genzyme Corp, Framingham, MA USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2005 VL 15 IS 9-10 BP 712 EP 713 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969GJ UT WOS:000232221900151 ER PT J AU Ziegler, RJ Bercury, S Armentaro, D Raben, N Cheng, SH AF Ziegler, RJ Bercury, S Armentaro, D Raben, N Cheng, SH TI AAV-mediated gene therapy of Pompe disease SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 10th International Congress of the World-Muscle-Society CY SEP 28-OCT 10, 2005 CL Iguassu Falls, BRAZIL SP World Muscle Soc C1 NIH, Bethesda, MD 20892 USA. Genzyme Corp, Framingham, MA 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 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2005 VL 15 IS 9-10 BP 713 EP 713 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969GJ UT WOS:000232221900152 ER PT J AU Pine, DS Costello, J Masten, A AF Pine, DS Costello, J Masten, A TI Trauma, proximity, and developmental psychopathology: The effects of war and terrorism on children SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE trauma; children; psychobiology; terrorism ID POSTTRAUMATIC-STRESS-DISORDER; DISASTER VICTIMS SPEAK; AMYGDALA RESPONSE; FOLLOW-UP; ADOLESCENT DEVELOPMENT; FACIAL EXPRESSIONS; DOMESTIC VIOLENCE; ANXIETY DISORDERS; BEHAVIOR PROBLEMS; REFUGEE CHILDREN AB This report summarizes recent literature relevant to the effects of terrorism on children's mental health. The paper addresses three aspects of this topic. In the first section of the paper, data are reviewed concerning the relationships among stress, trauma, and developmental psychopathology. A particular emphasis is placed on associations with indirect forms of trauma, given that terrorism involves high levels of indirect trauma. Second, the paper delineates a set of key principles to be considered when considering ways in which the effects of terrorism on children's mental health can be minimized. Third, data are reviewed from studies in developmental psychobiology. These data are designed to illustrate the mechanisms through which children exhibit unique effects in the wake of traumatic circumstances. C1 NIMH, Sect Dev & Affect Neurosci, Intramural Res Program, Bethesda, MD 20817 USA. Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Dev Epidemiol Program, Durham, NC USA. Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. RP Pine, DS (reprint author), NIMH, Sect Dev & Affect Neurosci, Intramural Res Program, Bldg 15-K,Room 110,MSC-2670, Bethesda, MD 20817 USA. EM daniel.pine@nih.gov RI Masten, Ann/E-7091-2011; OI Masten, Ann/0000-0003-2871-7508 NR 110 TC 59 Z9 59 U1 15 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2005 VL 30 IS 10 BP 1781 EP 1792 DI 10.1038/sj.npp.1300814 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 965VJ UT WOS:000231978200002 PM 16012537 ER PT J AU Rubinow, DR Roca, CA Schmidt, PJ Danaceau, MA Putnam, K Cizza, G Chrousos, G Nieman, L AF Rubinow, DR Roca, CA Schmidt, PJ Danaceau, MA Putnam, K Cizza, G Chrousos, G Nieman, L TI Testosterone suppression of CRH-stimulated cortisol in men SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE testosterone; cortisol; HPA axis; ACTH; CRH; men ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING HORMONE; SEX-DIFFERENCES; CHRONIC ESTROGEN; FEMALE RATS; CORTICOSTERONE SECRETION; PARAVENTRICULAR NUCLEUS; PSYCHOLOGICAL STRESS; PSYCHOSOCIAL STRESS; INDUCED ACTIVATION AB Despite observations of age-dependent sexual dimorphisms in hypothalamic - pituitary - adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men ( ages 18 - 45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p<0.05, 0.005, and 0.01, respectively) during testosterone replacement compared with the induced hypogonadal condition ( leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p<0.1). Paradoxically, CRH-stimulated corticotropin ( ACTH) was increased significantly during testosterone replacement (p<0.05). The cortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p<0.1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral ( adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. NIDDKD, Clin Endocrinol Branch, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Rubinow, DR (reprint author), NIMH, Behav Endocrinol Branch, Bldg 10-CRC,Room 6-5340 SE,10 Ctr Dr MSC 1276, Bethesda, MD 20892 USA. EM rubinowd@mail.nih.gov FU NIMH NIH HHS [Z01 MH002765-09] NR 51 TC 56 Z9 57 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2005 VL 30 IS 10 BP 1906 EP 1912 DI 10.1038/sj.npp.1300742 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 965VJ UT WOS:000231978200013 PM 15841103 ER PT J AU Lonser, RR Oldfield, EH AF Lonser, Russell R. Oldfield, Edward H. TI MICROSURGICAL RESECTION OF SPINAL CORD HEMANGIOBLASTOMAS SO NEUROSURGERY LA English DT Article DE Hemangioblastoma; Microsurgery; Spinal cord; Surgery; Technique; von Hippel-Lindau disease AB HEMANGIOBLASTOMAS ARE NOT uncommon intramedullary spinal cord neoplasms. They are highly vascular, benign tumors that occur either sporadically or in the presence of von Hippel-Lindau disease. Despite their exceptionally vascular nature, these lesions can consistently be resected completely and safely with minimal blood loss. We describe a microsurgical method for removal of these tumors from the spinal cord. C1 [Lonser, Russell R.; Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM eo10D@nih.gov NR 10 TC 27 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X EI 1524-4040 J9 NEUROSURGERY JI Neurosurgery PD OCT PY 2005 VL 57 IS 4 SU 4 BP 372 EP 376 AR ONS372 DI 10.1227/01.NEU.0000176849.76663.E4 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA V21LL UT WOS:000208209000041 PM 16234688 ER PT J AU Seth, P Major, EO AF Seth, P Major, EO TI Human brain derived cell culture models of HIV-1 infection SO NEUROTOXICITY RESEARCH LA English DT Article DE HIV-1; infection; lymphocytes; microglia; astrocytes; cell culture systems; neuropathogenesis; Aids dementia complex; HIV associated dementia; encephalopathy ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CENTRAL-NERVOUS-SYSTEM; IMMUNE-DEFICIENCY-SYNDROME; CHEMOKINE RECEPTOR CXCR4; NEURAL PROGENITOR CELLS; AIDS DEMENTIA COMPLEX; HUMAN FETAL MICROGLIA; COAT PROTEIN GP120; HIPPOCAMPAL-NEURONS AB During the clinical course of acquired immune deflciency syndrome, infection of the CNS by human immunodeficiency virus-1 (HIV-1) may ultimately result in the impairment of cognitive, behavioral and motor functions. Viral neuropathogenesis involves inflammatory molecules and neurotoxins produced from infected and immune-activated lymphocytes, microglial cells and astrocytes. Here, we discuss the current understanding of HIV-1 infection of the CNS and various cell culture systems from the developing human brain in order to study the neurobiology of HIV-1 infection, the mechanisms contributing to HIV-1 infection, and disease progression. C1 Natl Inst Neurol Disorders & Stroke, NIH, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. Natl Brain Res Ctr, Manesar, India. RP Major, EO (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. EM major@ninds.nih.gov NR 88 TC 5 Z9 5 U1 0 U2 0 PU F P GRAHAM PUBLISHING CO PI MOUNTAIN HOME PA PO BOX 370, MOUNTAIN HOME, TN 37684 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD OCT PY 2005 VL 8 IS 1-2 BP 83 EP 89 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 019AT UT WOS:000235808700005 PM 16260387 ER PT J AU Li, W Galey, D Mattson, MP Nath, A AF Li, W Galey, D Mattson, MP Nath, A TI Molecular and cellular mechanisms of neuronal cell death in HIV dementia SO NEUROTOXICITY RESEARCH LA English DT Review DE HIV; dementia; astrocytes; endothelial cells; apoptosis; Tat; gp120; cytokines; chemokines; excitotoxins; proteases ID HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR-NECROSIS-FACTOR; ENVELOPE PROTEIN GP120; NERVE GROWTH-FACTOR; PLATELET-ACTIVATING-FACTOR; NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; TYPE-1 TAT PROTEIN; RECEPTOR-MEDIATED NEUROTOXICITY; MICROVASCULAR ENDOTHELIAL-CELLS AB The deaths of neurons, astrocytes and endothelial cells have been described in patients with HIV (human immunodeficiency virus) dementia. HIV-1 does not infect neurons; instead, neurotoxic substances shed by infected glia and macrophages can induce a form of programmed cell death called apoptosis in neurons. These neurotoxins include the HIV-1 proteins Tat and gp120, as well as pro-inflammatory cytokines, chemokines, excitotoxins and proteases. In this article we review the evidence for apoptosis of various cell types within the brain of HIV-infected patients, and describe in vitro and in vivo experimental studies that have elucidated the mechanisms by which HIV causes apoptosis of brain cells. C1 Johns Hopkins Univ, Dept Neurol, RT Johnson Div Neuroimmunol & Neurol Infect, Baltimore, MD 21287 USA. NIA, Intramural Res Program, Natl Inst Aging, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Nath, A (reprint author), Johns Hopkins Univ, Dept Neurol, RT Johnson Div Neuroimmunol & Neurol Infect, 600 N Wolfe St, Baltimore, MD 21287 USA. EM anath1@jhmi.edu RI Mattson, Mark/F-6038-2012 NR 230 TC 52 Z9 53 U1 0 U2 3 PU F P GRAHAM PUBLISHING CO PI MOUNTAIN HOME PA PO BOX 370, MOUNTAIN HOME, TN 37684 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD OCT PY 2005 VL 8 IS 1-2 BP 119 EP 134 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 019AT UT WOS:000235808700008 PM 16260390 ER PT J AU Berlin, I Covey, LS Jiang, HP Hamer, D AF Berlin, I Covey, LS Jiang, HP Hamer, D TI Lack of effect of D2 dopamine receptor TaqI A polymorphism on smoking cessation SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID GENETIC RISK FACTOR; GENOTYPE; TRIAL AB One previous report (Cinciripini et al., [2004] Nicotine & Tobacco Research, 6, 229-239) found that the D2 dopamine receptor (DRD2) TaqI A polymorphism was associated with smoking cessation: Carriers of the Al allele were less likely to quit than were those who were not carriers. If confirmed, this finding would allow one to use precessation genotyping to predict the likelihood of successful quitting. The present study reports on results of a similar smoking cessation study and uses the same methods and data analysis in a larger number of smokers. It fails to replicate the effect of DRD2 TaqI A polymorphism on smoking cessation. C1 GHU Pitie Salpetriere, Dept Pharmacol, F-75013 Paris, France. Columbia Univ, New York State Psychiat Inst, Smoking Cessat Clin, New York, NY USA. NIH, Biochem Lab, NCI, Bethesda, MD 20892 USA. RP Berlin, I (reprint author), GHU Pitie Salpetriere, Dept Pharmacol, 47 Bd Hop, F-75013 Paris, France. EM ivan.berlin@pst.ap-hop-paris.fr FU NIDA NIH HHS [DA13490] NR 11 TC 22 Z9 23 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2005 VL 7 IS 5 BP 725 EP 728 DI 10.1080/14622200500259176 PG 4 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 982CD UT WOS:000233134600003 PM 16191743 ER PT J AU Parascandola, M AF Parascandola, M TI Lessons from the history of tobacco harm reduction: The National Cancer Institute's Smoking and Health Program and the "less hazardous cigarette" SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE; SMOKERS; RISK AB Scientists and public health practitioners are sharply divided today over the risks and benefits of tobacco harm-reduction strategies. At the same time, a range of novel tobacco products is being marketed with claims of reduced exposure or risk. Current scientific efforts to study tobacco products and harm reduction should be informed by past experience. During the 1960s and 1970s, there was substantial support within government and academia, as well as among voluntary health organizations, for efforts to modify tobacco products to reduce harm. This paper analyzes the former National Cancer Institute (NCI) Smoking and Health Program, which, between 1968 and 1980, pursued the development of "less hazardous" cigarettes as its primary goal. During this period, the program spent over $50 million on contract research, of which 74% went toward biological and chemical analysis of modified cigarettes, 9.6% to epidemiological studies of risk factors, and only 1.4% to studies evaluating smoking cessation or prevention programs. NCI officials predicted during the mid-1970s that new "low-tar" cigarette brands would substantially reduce smoking-related mortality, but by 1978 the research agenda began to change in response to a reorganization of NO research activities, modification of government antismoking efforts, and an emerging understanding of nicotine addiction that challenged key scientific assumptions. In retrospect, the program suffered from significant weaknesses that severely limited the likelihood that it would generate knowledge beneficial to public health, including a research agenda that failed to include surveillance and behavioral research, tobacco industry influence of the research agenda, and a lack of access to information about the characteristics of products on the market. There exists today a need for a public health-oriented research agenda on tobacco products and harm reduction, but current efforts should include input from a diverse range of disciplines, collect data on users' behavior, and limit the involvement of industry scientists. C1 NCI, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NCI, 6130 Execut Blvd,Room 4309, Bethesda, MD 20892 USA. EM paramark@mail.nih.gov NR 93 TC 19 Z9 19 U1 0 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2005 VL 7 IS 5 BP 779 EP 789 DI 10.1080/14622200500262584 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 982CD UT WOS:000233134600009 PM 16191749 ER PT J AU Arbab, AS Wilson, LB Ashari, P Jordan, EK Lewis, BK Frank, JA AF Arbab, AS Wilson, LB Ashari, P Jordan, EK Lewis, BK Frank, JA TI A model of lysosomal metabolism of dextran coated superparamagnetic iron oxide (SPIO) nanoparticles: implications for cellular magnetic resonance imaging SO NMR IN BIOMEDICINE LA English DT Article DE ferumoxides; SPIO; endosome/lysosome; poly-L-lysine; labeled cells ID MR CONTRAST AGENTS; TRANSFECTION AGENT; SODIUM-CITRATE; STEM-CELLS; IN-VITRO; MECHANISMS; FERUMOXIDES; PHARMACOKINETICS; ENHANCEMENT; TRAFFICKING AB Ferumoxides, dextran-coated superparamagnetic iron oxide (SPIO) particles, form ferumoxide-transfection agent (FE-TA) complexes that are internalized into endosornes/lysosomes and have been used to label cells for in vivo MRI tracking and localization studies. A better understanding of the physical state of the FE-TA complexes during endocytosis could improve their use. The purpose of this study was to measure the rate of the degradation of iron particles under varying physiological conditions. FE-TA complexes were incubated in seven different buffers containing different chelates with different pH. Reducible iron concentrations, T, relaxation rates and gradient echo (GRE) magnetic resonance images (MRI) were obtained from each condition immediately after incubation and at 6, 24, 48, 72 and 96 h and days 7, 14 and 21. The dynamics of FE-TA in the endosome/lysomes within the cells were visualized with electron microscopy. Sodium citrate buffer at pH 4.5 rapidly dissolved FE-TA complexes. However, FE-TA complexes were less soluble in the same buffer at pH 5.5. Similarly, FE-TA complexes were not readily soluble in any of the other buffers with or without chelates, regardless of pH. Electron microscopic images showed degraded FE-TA in some intracellular endosome/lysosomes between days 3 and 5. In the cellular environment, some of the FE-TA-containing endosomes were found to fuse with lysosomes, causing rapid dissociation at low pH and exposing the iron core to chelates that resulted in soluble Fe(III) within the lysosomes. The studies presented represent a first step in identifying the important cellular environmental parameters affecting the integrity of FE-TA complexes. Published in 2005 by John Wiley & Sons, Ltd. C1 NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Arbab, AS (reprint author), Henry Ford Hlth Syst, 1 Ford Pl, Box 82, Detroit, MI 48202 USA. EM Saali@rad.hfh.edu NR 33 TC 198 Z9 217 U1 9 U2 53 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD OCT PY 2005 VL 18 IS 6 BP 383 EP 389 DI 10.1002/nbm.970 PG 7 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 971HW UT WOS:000232375800005 PM 16013087 ER PT J AU Schmidt, KC Smith, CB AF Schmidt, KC Smith, CB TI Resolution, sensitivity and precision with autoradiography and small animal positron emission tomography: implications for functional brain imaging in animal research SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE positron emission tomography; cerebral blood flow; cerebral glucose utilization; cerebral protein synthesis ID CEREBRAL-BLOOD-FLOW; HEAD-MOUNTED PET; GLUCOSE-UTILIZATION; PROTEIN-SYNTHESIS; HETEROGENEOUS TISSUES; ANESTHETIZED RAT; AMINO-ACIDS; AWAKE CAT; ANESTHESIA; MODELS AB Quantitative autoradiographic methods for in vivo measurement of regional rates of cerebral blood flow, glucose metabolism, and protein synthesis contribute significantly to our understanding of phsysiological and biochemical responses of the brain to changes in the environment. A disadvantage of these autoradiographic methods is that experimental animals can be studied only once. With the advent of small animal positron emission tomography (PET) and with increases in the sensitivity and spatial resolution of scanners it is now possible to use adaptations of these methods in experimental animals with PET. These developments allow repeated studies of the same animal, including studies of the same animal under different conditions, and longitudinal studies. In this review we summarize the tradeoffs between the use of autoradiography and small animal PET for functional brain imaging studies in animal research. (c) 2005 Elsevier Inc. All rights reserved. C1 NIMH, Unit Neuroadaptat & Prot Metab, Lab Cerebral Metab, Bethesda, MD 20892 USA. RP Schmidt, KC (reprint author), NIMH, Unit Neuroadaptat & Prot Metab, Lab Cerebral Metab, Bethesda, MD 20892 USA. EM schmidtk@intra.nimh.nih.gov NR 42 TC 29 Z9 29 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD OCT PY 2005 VL 32 IS 7 BP 719 EP 725 DI 10.1016/j.nucmedbio.2005.04.020 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 982QS UT WOS:000233177300009 PM 16243647 ER PT J AU Svec, MA Ward, MH Dosemeci, M Checkoway, H De Roos, AJ AF Svec, MA Ward, MH Dosemeci, M Checkoway, H De Roos, AJ TI Risk of lymphatic or haematopoietic cancer mortality with occupational exposure to animals or the public SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID NON-HODGKINS-LYMPHOMA; HEPATITIS-C VIRUS; HAIRY-CELL LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; 24-STATE DEATH CERTIFICATE; MULTIPLE-MYELOMA; UNITED-STATES; MEAT INDUSTRY; ANTIGENIC-STIMULATION; PESTICIDE EXPOSURE AB Background: Occupational exposure to animals or the public could result in exposure to infectious agents, which may play a role in the aetiology of lymphohaematopoietic (LH) cancers. Aims: To conduct a population based, case-control study of death certificate data from 1984 to 1998 in 24 US states in order to evaluate the risk of mortality from LH neoplasms associated with occupational exposure to animals or the public. Methods: Cases were selected as those with an underlying cause of death of non-Hodgkin's lymphoma (NHL, n = 72 589), Hodgkin's disease (HD, n = 5479), multiple myeloma ( n = 35 857), or leukaemia ( n = 68 598); 912 615 controls were randomly selected from all remaining deaths, frequency matched on age, sex, race, and geographic region. Results: Occupational exposure to animals was associated with modest increased risks of mortality from all four LH cancers; these associations varied by region. Occupational exposure to the public was associated with only negligible increased risk with LH cancer outcomes. Occupations involving animal exposure were predominantly agricultural, and the risks associated with employment in the livestock industry exceeded the corresponding risks associated with the crop industry for all outcomes except HD. Conclusions: Increased risks of NHL, HD, multiple myeloma, and leukaemia were associated with occupations that involved animal exposure. Regional differences in risk imply that the risks may be associated with exposure to specific livestock or farming practices. However, these associations may be confounded by other farming related exposures, such as pesticides. Because the use of death certificates to classify occupation may result in misclassification during aetiologically relevant time periods, these hypotheses should be further explored in studies with detailed information on lifetime occupation. C1 Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP De Roos, AJ (reprint author), 1100 Fairview Ave N,M4-B874,POB 19024, Seattle, WA 98109 USA. EM deroos@u.washington.edu NR 90 TC 30 Z9 33 U1 1 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD OCT PY 2005 VL 62 IS 10 BP 726 EP 735 DI 10.1136/oem.2005.021550 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 965OO UT WOS:000231960200011 PM 16169919 ER PT J AU Mickelsen, SR Ashikaga, H Desilva, R Raval, AN McVeigh, E Kusumoto, F AF Mickelsen, SR Ashikaga, H Desilva, R Raval, AN McVeigh, E Kusumoto, F TI Transvenous access to the pericardial space: An approach to epicardial lead implantation for cardiac resynchronization therapy SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE pacing; epicardial; transvenous; technique; resynchronization; pericardial ID CONSTRICTIVE PERICARDITIS; TRANSATRIAL ACCESS; PLACEMENT AB Background: Percutaneous access to the pericardial space (PS) may be useful for a number of therapeutic modalities including implantation of epicardial pacing leads. We have developed a catheter-based transvenous method to access the PS for implanting chronic medical devices. Methods: In eight pigs, a transseptal Mullins sheath and Brockenbrough needle were introduced into the right atrium (RA) from the jugular vein under fluoroscopic guidance. The PS was entered through a controlled puncture of the terminal anterior superior vena cava (SVC) (n = 7) or right atria] appendage (n = 1). A guidewire was advanced through the transseptal sheath, which was then removed leaving the wire in PS. The guidewire was used to direct both passive and active fixation pacing leads into the PS. Pacing was attempted and lead position was confirmed by cine fluoroscopy. Animals were sacrificed acutely and at 2 and 6 weeks. Results: All animals survived the procedure. Pericardial effusion (PE) during the procedure was hemodynamically significant in four of the eight animals. At necropsy, lead exit sites appeared to heal without complication at 2 and 6 weeks, Volume of pericardial fluid was 10.8 +/- 6.2 mL and appeared normal in four of the six chronic animals. Moderate fibrinous deposition was observed in two animals, which had exhibited significant over-procedurol PE. Conclusions: Access to the PS via a transvenous approach is feasible. Pacing leads can be negotiated into this region. The puncture site heals with the lead in place. Further development should focus on eliminating PE and performing this technique in appropriate heart failure models. C1 NHLBI, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. Mayo Clin, Electrophysiol & Pacing Serv, Div Cardiol, Jacksonville, FL 32224 USA. RP Mickelsen, SR (reprint author), NHLBI, Lab Cardiac Energet, NIH, Bldg 10 Rm B1D412 10 Ctr Dr, Bethesda, MD 20892 USA. EM smickelsen@salud.unm.edu OI Ashikaga, Hiroshi/0000-0003-3689-6892 FU Intramural NIH HHS [Z01 HL004609-08] NR 21 TC 9 Z9 9 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD OCT PY 2005 VL 28 IS 10 BP 1018 EP 1024 DI 10.1111/j.1540-8159.2005.00236.x PG 7 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 976JS UT WOS:000232730300002 PM 16221257 ER PT J AU Dougherty, ER Hua, JP Xiong, ZX Chen, YD AF Dougherty, ER Hua, JP Xiong, ZX Chen, YD TI Optimal robust classifiers SO PATTERN RECOGNITION LA English DT Article DE classification; feature set; optimal classifier; pattern recognition; robust filter ID GENE-EXPRESSION PROFILES; NOISE INJECTION; CLASSIFICATION; FILTERS; CANCER AB `Qualitatively, a filter is said to be "robust" if its performance degradation is acceptable for distributions close to the one for which it is optimal, that is, the one for which it has been designed. This paper adapts the signal-processing theory of optimal robust filters to classifiers. The distribution (class conditional distributions) to which the classifier is to be applied is parameterized by a state vector and the principle issue is to choose a design state that is optimal in comparison to all other states relative to some measure of robustness. A minimax robust classifier is one whose worst performance over all states is better than the worst performances of the other classifiers (defined at the other states). A Bayesian robust classifier is one whose expected performance is better than the expected performances of the other classifiers. The state corresponding to the Bayesian robust classifier is called the maximally robust state. Minimax robust classifiers tend to give too much weight to states for which classification is very difficult and therefore our effort is focused on Bayesian robust classifiers. Whereas the signal-processing theory of robust filtering concentrates on design with full distributional knowledge and a fixed number of observation variables (features), design via training from sample data and feature selection are so important for classification that robustness optimality must be considered from these perspectives-in particular, for small samples. In this context, for a given sample size, we will be concerned with the maximally robust state-feature pair All definitions are independent of the classification rule; however, applications are only considered for linear and quadratic discriminant analysis, for which there are parametric forms for the optimal discriminants. (c) 2005 Pattern Recognition Society. Published by Elsevier Ltd. All rights reserved. C1 Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Dougherty, ER (reprint author), Texas A&M Univ, Dept Elect Engn, 3128 TAMU, College Stn, TX 77843 USA. EM e.dougherty@tamu.edu NR 29 TC 9 Z9 9 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-3203 J9 PATTERN RECOGN JI Pattern Recognit. PD OCT PY 2005 VL 38 IS 10 BP 1520 EP 1532 DI 10.1016/j.patcog.2005.01.019 PG 13 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 956HX UT WOS:000231291900005 ER PT J AU Pannaraj, PS Walsh, TJ Baker, CJ AF Pannaraj, PS Walsh, TJ Baker, CJ TI Advances in antifungal therapy SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Editorial Material ID CASPOFUNGIN; INFECTIONS; EXPERIENCE C1 NCI, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Pannaraj, PS (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 10 TC 11 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2005 VL 24 IS 10 BP 921 EP 922 DI 10.1097/01.inf0000181742.93963.bb PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 976IS UT WOS:000232727500012 PM 16220093 ER PT J AU Ray, PE Soler-Garcia, AA Xu, L Soderland, C Blumenthal, R Puri, A AF Ray, PE Soler-Garcia, AA Xu, L Soderland, C Blumenthal, R Puri, A TI Fusion of HIV-1 envelope-expressing cells to human glomerular endothelial cells through an CXCR4-mediated mechanism SO PEDIATRIC NEPHROLOGY LA English DT Article DE kidney; human glomerular endothelial cells; HIV-1 co-receptors; fusion; hemolytic uremic syndrome ID IMMUNODEFICIENCY-VIRUS TYPE-1; HEMOLYTIC-UREMIC SYNDROME; FIBROBLAST-GROWTH-FACTOR; CHEMOKINE RECEPTOR CCR5; INTERCELLULAR-ADHESION MOLECULE-1; RENAL EPITHELIAL-CELLS; FETAL MESANGIAL CELLS; THROMBOTIC MICROANGIOPATHY; ANGIOTENSIN-II; INFECTION AB A central question in the pathogenesis of HIV-associated thrombotic microangiopathic (HIV-TMA) lesions is whether the HIV-1 envelope glycoprotein (HIV-1 Env) can interact directly with human glomerular endothelial cells (HGECs) through specific HIV-1 co-receptors. The goal of this study was to determine whether cultured primary HGECs express significant levels of the major HIV-1 co-receptors CD4, CXCR4, and/or CCR5 to allow fusion interactions with HIV-1. The expression of CD4, CXCR-4 and CCR-5 was assessed in cultured HGECs by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry using specific antibodies. The HIV-1 Env-mediated membrane fusion of target glomerular cells was evaluated by a fluorescent dye transfer-based cell-cell fusion microscopic method. HGECs express CXCR4 mRNA and protein as determined by RT-PCR and immunostaining with phycoerythrin-conjugated anti-CXCR4 Mab 12G5. CD4 and CCR5 were not detected in HGECs, either by RT-PCR or by surface immunostaining with specific antibodies. Incubation of HGECs with cells expressing a CD4-independent envelope strain (HIV-1(IIIB)-8x) and the CD4-dependent envelope strain (HIV-1(IIIB)) resulted in transfer of fluorescent dyes of approximately 20% after 8-16 h incubation at 37 degrees C. Incubation in the presence of inhibitors (C34, which blocks six-helix bundle formation, and AMD3100, which interacts with CXCR4) reduced dye transfer by 60%-80%, confirming that the dye transfer was specific with respect to gp120-gp41-mediated fusion. Cultured primary HGECs express CXCR4 but not CD4 or CCR5. The ability of HGECs to promote fusion by a CD4-independent HIV-1 envelope glycoprotein suggests that these cells may become a potential direct target of certain HIV-1 isolates. C1 Childrens Natl Med Ctr, Div Nephrol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Childrens Res Inst, Ctr Med Genet, Washington, DC 20010 USA. George Washington Univ, Dept Pediat, Washington, DC 20052 USA. Appl Cell Biol Res Inst, Seattle, WA USA. NCI, Sect Membrane Struct & Funct, Lab Expt & Computat Biol, NIH, Frederick, MD 21701 USA. RP Ray, PE (reprint author), Childrens Natl Med Ctr, Div Nephrol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM Pray@cnmc.org FU NHLBI NIH HHS [R0-1 HL 55605]; NIDDK NIH HHS [R0-1 DK 49419] NR 53 TC 8 Z9 8 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD OCT PY 2005 VL 20 IS 10 BP 1401 EP 1409 DI 10.1007/s00467-005-1950-5 PG 9 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 965ID UT WOS:000231942900006 PM 16047221 ER PT J AU Llanos, A Lin, YH Mena, P Salem, N Uauy, R AF Llanos, A Lin, YH Mena, P Salem, N Uauy, R TI Infants with intrauterine growth restriction have impaired formation of docosahexaenoic acid in early neonatal life: A stable isotope study SO PEDIATRIC RESEARCH LA English DT Article ID COACTIVATOR-1 GENE-EXPRESSION; POLYUNSATURATED FATTY-ACIDS; RAT SKELETAL-MUSCLE; LOW-BIRTH-WEIGHT; PRETERM INFANTS; GESTATIONAL-AGE; RETARDATION; METABOLISM; TISSUES; LIPIDS AB This study evaluated the arachidonic acid (AA) and docosahexaenoic acid (DHA) formation from d5-labeled linoleic acid (d5-LA) and a-linolenic acid (d5-LNA) precursors in infants with intrauterine growth restriction (IUGR) compared with control groups matched by gestational age (GA) or birth weight. We compared DHA and AA formation from deuterated precursors d5-LA and d5-LNA in 11 infants with IUGR with 13 and 25 control subjects who were appropriate for GA and matched by GA and by birth weight, respectively. After an enteral administration of d5-LA and d5-LNA, we determined unlabeled and d5-labeled fatty acids at 24, 48, and 96 h in plasma. Absolute concentrations and area under the curve (AUC) over the 96-h study were used for analysis. Absolute concentration of d5-DHA and the product/precursor ratio of the d5-labeled AUCs indicated a less active DHA formation from LNA in infants with IUGR compared with their GA-matched (2-fold) and birth weight-matched (3-fold) control subjects. The ratios of eicosapentaenoic and n-3 docosapentaenoic acid to DHA were also affected. Similar evaluation for the n-6 series was not significant. DHA metabolism is affected in infants with IUGR; the restricted DPA to DHA conversion step seems to be principally responsible for this finding. C1 Inst Nutr & Food Technol, Santiago, Chile. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Hosp Dr Sotero del Rio, Neonatol Unit, Santiago 8207257, Chile. London Sch Hyg & Trop Med, London WC1E 7HT, England. RP Llanos, A (reprint author), U Chile Macul, INTA, Santiago 5540, Chile. EM allanos@inta.cl NR 33 TC 23 Z9 25 U1 0 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2005 VL 58 IS 4 BP 735 EP 740 DI 10.1203/01.PDR.0000180542.68526.A2 PG 6 WC Pediatrics SC Pediatrics GA 968OU UT WOS:000232172600020 PM 16189202 ER PT J AU Lim, SY Hoshiba, J Moriguchi, T Salem, N AF Lim, SY Hoshiba, J Moriguchi, T Salem, N TI N-3 fatty acid deficiency induced by a modified artificial rearing method leads to poorer performance in spatial learning tasks SO PEDIATRIC RESEARCH LA English DT Article ID ALPHA-LINOLENIC ACID; DOCOSAHEXAENOIC ACID; GUINEA-PIG; AUTOMATIC FEEDER; RHESUS-MONKEYS; RAT-BRAIN; PLUS-MAZE; RETINA; LIVER; FORMULA AB Docosahexaenoic acid (DHA) is a major structural component of the nervous system, and depletion may lead to losses in neural function. Our objective was to demonstrate a deficit in spatial task performance in rats with low brain DHA due to a low n-3 fatty acid intake using a first-generational artificial rearing technique. Newborn rat pups were separated on d 2 and assigned to two artificial rearing groups or a dam-reared control group. Pups were hand fed artificial milk via custom-designed nursing bottles containing either 0.02% (n-3 Def) or 3.1 % (n-3 Adq) of total fatty acids as LNA. At d 21, rats were weaned to either n-3 Def or n-3 Adq pelleted diets and several behavioral tasks were evaluated at 9 wk of age. Brain DHA was lower (58% and 61%, p < 0.001) in n-3 Def in comparison to n-3 Adq and dam-reared rats, respectively. At adulthood, the n-3 fatty acid-deficient rats had a significantly greater moving time than the dam-reared group (p < 0.05), but there were no differences among the three groups in the elevated plus maze test. The n-3 fatty acid deficient rats exhibited a longer escape latency (p < 0.05) and poorer memory retention in the Morris water maze compared with n-3 fatty acid adequate and dam-reared rats. We concluded that artificial rearing can be used to produce n-3 fatty acid deficiency in the first generation. This deficiency was associated with significantly reduced spatial learning. Adequate brain DHA levels are required for optimal spatial learning. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. Korea Maritime Univ, Pusan 600791, South Korea. Okayama Univ, Adv Sci Res Ctr, Dept Anim Resources, Okayama 7008558, Japan. RP NIAAA, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Ln,Room 3N-07, Bethesda, MD 20892 USA. EM nsalem@niaaa.nih.gov NR 69 TC 58 Z9 59 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2005 VL 58 IS 4 BP 741 EP 748 DI 10.1203/01.PDR.0000180547.46725.CC PG 8 WC Pediatrics SC Pediatrics GA 968OU UT WOS:000232172600021 PM 16189203 ER PT J AU Rouzaud, F Hearing, VJ AF Rouzaud, F Hearing, VJ TI Regulatory elements of the melanocortin 1 receptor SO PEPTIDES LA English DT Review DE melanocortin 1 receptor (MC1R); promoter; alpha-MSH; pigmentation; melanocyte ID STIMULATING-HORMONE-RECEPTOR; BACTERIAL ARTIFICIAL CHROMOSOMES; AGOUTI SIGNALING PROTEIN; CCAAT/ENHANCER-BINDING-PROTEINS; CULTURED HUMAN MELANOCYTES; ULTRAVIOLET-B IRRADIATION; TRANSCRIPTION FACTOR MITF; FRENCH CATTLE BREEDS; AUG INITIATOR CODON; TATA-LESS PROMOTER AB Among more than 120 genes that are now known to regulate mammalian pigmentation, one of the key genes is MC1R, which encodes the melanocortin I receptor, a seven transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Since the monoexonic sequence of the gene was cloned and characterized more than a decade ago, tremendous efforts have been dedicated to the extensive genotyping of mostly red-haired populations all around the world, thus providing allelic variants that may or may not account for melanoma susceptibility in the presence or absence of ultraviolet (UV) exposure. Soluble factors, such as proopiomelanocortin (POMC) derivatives, agouti signal protein (ASP) and others, regulate MC1R expression, leading to improved photoprotection via increased eumelanin synthesis or in contrast, inducing the switch to pheomelanin. However, there is an obvious lack of knowledge regarding the numerous and complex regulatory mechanisms that govern the expression of MC1R at the intra-cellular level, from gene transcription in response to an external stimulus to the expression of the mature receptor on the melanocyte surface. Published by Elsevier Inc. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132, Bethesda, MD 20892 USA. EM hearingv@nih.gov NR 177 TC 17 Z9 20 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD OCT PY 2005 VL 26 IS 10 BP 1858 EP 1870 DI 10.1016/j.peptides.2004.11.041 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 974TH UT WOS:000232613800021 PM 16005546 ER PT J AU Putney, JW AF Putney, JW TI Physiological mechanisms of TRPC activation SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review DE ion channels; TRPC channels; calcium signaling; signal transduction; phospholipase C; diacylglycerol; store-operated channels ID CAPACITATIVE CA2+ ENTRY; CA2+-PERMEABLE CATION CHANNEL; SMOOTH-MUSCLE-CELLS; PROTEIN-KINASE-C; CALCIUM-STORE DEPLETION; OPERATED HTRP3 CHANNELS; SALIVARY-GLAND CELLS; PORTAL-VEIN MYOCYTES; TRANSIENT RECEPTOR; FUNCTIONAL EXPRESSION AB TRPC (canonical transient receptor potential) channels are vertebrate homologs of the Drosophila photoreceptor channel, TRP. Considerable research has been brought to bear on the seven members of this family, especially with regard to their possible role in calcium entry. Unfortunately, the current literature presents a confusing picture, with different laboratories producing widely differing results and interpretations. It appears that ectopically expressed TRPC channels can be activated by phospholipase C products (generally, diacylglycerols), by stimulation of trafficking to the plasma membrane, or by depletion of intracellular Ca2+ stores. Here, I discuss the possibility that these diverse experimental findings arise because TRPC channels can, under both experimental as well as physiological conditions, be activated in three distinct ways, possibly depending on their subunit composition and/or signaling complex environment. The TRPCs may be unique among ion-channel subunit families in being able to participate in the assembly and function of multiple types of physiologically important ion channels. C1 NIEHS, US Dept HHS, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, US Dept HHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov NR 84 TC 71 Z9 75 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD OCT PY 2005 VL 451 IS 1 BP 29 EP 34 DI 10.1007/s00424-005-1416-4 PG 6 WC Physiology SC Physiology GA 971GS UT WOS:000232372800004 PM 16133266 ER PT J AU Qian, F Noben-Trauth, K AF Qian, F Noben-Trauth, K TI Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2) SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review DE mucolipin; polycystin; mucolipidosis; polycystic kidney disease; transient-potential-receptor cation channel ID SEA-URCHIN SPERM; KIDNEY-DISEASE; CATION CHANNEL; CAENORHABDITIS-ELEGANS; CULTURED FIBROBLASTS; ACROSOMAL REGION; PLASMA-MEMBRANE; MALE-FERTILITY; GENE; IV AB Mucolipins ( transient receptor potential mucolipin, TRPML) and polycystin-2 proteins ( transient receptor potential polycystin, TRPP) constitute two small families of cation channels with motif and sequence similarities to the transient receptor potential (TRP) class of non-selective cation channels. Genetic defects in TRPML1 and TRPML3 in humans and in animal models cause the accumulation of large vacuoles, leading to a variety of cellular phenotypes including neurological and neurosensory deficiencies. TRPML1 is a Ca2+-, K+-, and Na+- permeable cation channel sensitive to pH changes, and regulates a critical step in the maturation of late endosomes to lysosomes. Mutations of TRPP2 in humans result in autosomal dominant polycystic kidney disease. Molecular studies have demonstrated that TRPP2 and TRPP3 proteins function as Ca2+- regulated, non-selective cation channels. During embryogenesis TRPP2 is active in node monocilia and plays a role in the establishment of left-right asymmetry. Recent results have indicated that TRPP2 interacts with polycystin-1 and that their interaction is important for their function as mechanosensitive channels at the primary cilium of renal epithelial cells. The interaction of polycystin family members appears to be conserved and is critical for fertilization and mating behavior. An emerging concept from the studies of the polycystin family is that they function as cation-influx based devices for sensing extracellular signals on ciliated structures. Here we review the function of TRPML1 and TRPP2 as representative members of these families, focusing on the genetics, physiology, and biochemistry. C1 Johns Hopkins Univ, Sch Med, Div Nephrol, Baltimore, MD 21205 USA. Natl Inst Deafness & Commun Deafness, Neurogenet Sect, Mol Biol Lab, NIH, Rockville, MD 20855 USA. RP Qian, F (reprint author), Johns Hopkins Univ, Sch Med, Div Nephrol, Baltimore, MD 21205 USA. EM fqjhupkd@jhmi.edu; nobentk@nidcd.nih.gov FU NIDDK NIH HHS [R01 DK062199] NR 72 TC 32 Z9 34 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD OCT PY 2005 VL 451 IS 1 BP 277 EP 285 DI 10.1007/s00424-005-1469-4 PG 9 WC Physiology SC Physiology GA 971GS UT WOS:000232372800032 PM 15971078 ER PT J AU Mackenzie, PI Bock, KW Burchell, B Guillemette, C Ikushiro, S Iyanagi, T Miners, JO Owens, IS Nebert, DW AF Mackenzie, PI Bock, KW Burchell, B Guillemette, C Ikushiro, S Iyanagi, T Miners, JO Owens, IS Nebert, DW TI Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily SO PHARMACOGENETICS AND GENOMICS LA English DT Review DE gene names; glucuronosyltransferase; UDP ID GLUCURONOSYLTRANSFERASE; CLONING; GLUCURONIDATION; LOCUS; MOUSE AB Several novel UDP glycosyltransferase (UGT) genes, mainly UDP glucuronosyltransferases, have been identified in the human, mouse and rat genomes and in other mammalian species. This review provides an update of the UGT nomenclature to include these new genes and prevent the confusion that arises when the same gene is given different names. The new genes are named following previously established recommendations, taking into consideration evolutionary relatedness and the names already in general usage in the literature. The mammalian UGT gene superfamily currently has 117 members that can be divided into four families, UGT1, UGT2, UGT3 and UGT8. The 5-exon genes of the UGT1 family each contain a unique first exon, plus four exons that are shared between the genes; the exons 1 appear to have evolved by a process of duplication, leading to the synthesis of proteins with identical carboxyl-terminal and variable amino-terminal domains. Exon-sharing is also seen with the 6-exon UGT2A1 and UGT2A2 genes. However, UGT2A3 and those of the UGT2B (six exons), UGT3 (seven exons) and UGT8 gene families (five or six exons) do not share exons and most likely were derived by a process of duplication of all exons in the gene. Most UGT1 and UGT8 enzymes have been characterized in detail; however, the catalytic functions of the UGT3A enzymes and several UGT2 enzymes remain to be characterized. C1 Flinders Univ Sch Med, Flinders Med Ctr, Dept Clin Pharmacol, Bedford Pk, SA 5050, Australia. Univ Tubingen, Inst Pharmacol & Toxicol, Dept Toxicol, Tubingen, Germany. Univ Dundee, Ninewells Hosp & Med Sch, Div Pathol & Neurosci, Dundee DD1 9SY, Scotland. Univ Laval, Fac Pharm, CHUL Res Ctr,Mol Endocrinol & Oncol Res Ctr, Pharmacogenom Lab, Quebec City, PQ G1K 7P4, Canada. Toyama Prefectural Univ, Fac Engn, Biotechnol Res Ctr, Toyama, Japan. RIKEN, Harima Inst, Biomet Sci Lab, Mikazuki, Hyogo, Japan. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. Univ Cincinnati, Med Ctr, Ctr Environm Genet, Cincinnati, OH 45267 USA. RP Mackenzie, PI (reprint author), Flinders Univ Sch Med, Flinders Med Ctr, Dept Clin Pharmacol, Bedford Pk, SA 5050, Australia. EM peter.mackenzie@flinders.edu.au RI Guillemette, Chantal/J-6463-2012; OI Guillemette, Chantal/0000-0002-1113-1212 FU NIEHS NIH HHS [P30 ES06096] NR 17 TC 475 Z9 497 U1 3 U2 43 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD OCT PY 2005 VL 15 IS 10 BP 677 EP 685 DI 10.1097/01.fpc.0000173483.13689.56 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 972IC UT WOS:000232446500001 PM 16141793 ER PT J AU Freebern, WJ Haggerty, CM Montano, I McNutt, MC Collins, I Graham, A Chandramouli, GVR Stewart, DH Biebuyck, HA Taub, DD Gardner, K AF Freebern, WJ Haggerty, CM Montano, I McNutt, MC Collins, I Graham, A Chandramouli, GVR Stewart, DH Biebuyck, HA Taub, DD Gardner, K TI Pharmacologic profiling of transcriptional targets deciphers promoter logic SO PHARMACOGENOMICS JOURNAL LA English DT Article DE transcription regulation; signal transduction; transcriptional profiling; IGF-1; multivariate analysis; promoter structure; cyclosporin A ID T-CELL-ACTIVATION; NF-KAPPA-B; CD28 RESPONSE ELEMENT; GENE-EXPRESSION; GROWTH-FACTOR; IL-2 PROMOTER; SIGNALING PATHWAYS; ANTIGEN RECEPTOR; IGF-1 RECEPTOR; C-JUN AB The blueprint for cellular diversity and response to environmental change is encoded in the cis- acting regulatory sequences of most genes. Deciphering this ' cis- regulatory code' requires multivariate data sets that examine how these regions coordinate transcription in response to diverse environmental stimuli and therapeutic treatments. We describe a transcriptional approach that profiles the activation of multiple transcriptional targets against combinatorial arrays of therapeutic and signal transducing agents. Application of this approach demonstrates how cis- element composition and promoter context combine to influence transcription downstream of mitogen-induced signaling networks. Computational dissection of these transcriptional profiles in activated T cells uncovers a novel regulatory synergy between IGF- 1 and CD28 costimulation that modulates NF- kappa B and AP1 pathways through signaling cascades sensitive to cyclosporin A and wortmannin. This approach provides a broader view of the hierarchical signal integration governing gene expression and will facilitate a practical design of combinatorial therapeutic strategies for exploiting critical control points in transcriptional regulation. C1 NCI, Lab Receptor Biol & Gene Express, Ctr Adv Technol, Bethesda, MD 20892 USA. Meso Scale Discovery, Gaithersburg, MD USA. NIA, Clin Immunol Sect, Immunol Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Gardner, K (reprint author), NCI, Lab Receptor Biol & Gene Express, Ctr Adv Technol, Room 133,8717 Grovemeont Circle, Bethesda, MD 20892 USA. EM gardnerk@mail.nih.gov NR 69 TC 8 Z9 8 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. PD OCT PY 2005 VL 5 IS 5 BP 305 EP 323 DI 10.1038/sj.tpj.6500325 PG 19 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 968FK UT WOS:000232147100004 PM 16044165 ER PT J AU Volkow, ND Li, TK AF Volkow, ND Li, TK TI Drugs and alcohol: Treating and preventing abuse, addiction and their medical consequences SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE addiction; dopamine; prevention; treatment; mental illness; adolescence ID PRENATAL COCAINE EXPOSURE; SUBSTANCE USE DISORDERS; GAMMA-VINYL GABA; UNITED-STATES; HUMAN BRAIN; FOLLOW-UP; CONTINGENCY MANAGEMENT; OUTPATIENT TREATMENT; COST-EFFECTIVENESS; NONHUMAN-PRIMATES AB Recent advances in the fields of genetics, molecular biology, behavioral neuropharmacology, and brain imaging have dramatically changed our understanding of the addictive process and why relapse occurs even in the face of catastrophic consequences. Addiction is now recognized as a chronic brain disease that involves complex interactions between repeated exposure to drugs, biological (i.e., genetic and developmental), and environmental (i.e., drug availability, social, and economic variables) factors. Its treatment, therefore, requires, in general, not only a long-term intervention but also a multipronged approach that addresses the psychiatric, medical, legal, and social consequences of addiction. Also, because addiction usually starts in adolescence or early adulthood and is frequently comorbid with mental illness, we need to expand our treatment interventions in this age group both for substance abuse and psychiatric disorders. Published by Elsevier Inc. C1 NIDA, NIH, Bethesda, MD 20892 USA. NIAAA, NIH, Bethesda, MD USA. RP Volkow, ND (reprint author), 6001 Executive Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 125 TC 93 Z9 98 U1 8 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD OCT PY 2005 VL 108 IS 1 BP 3 EP 17 DI 10.1016/j.pharmthera.2005.06.021 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 974KB UT WOS:000232589200002 PM 16098597 ER PT J AU O'Brien, CP Gardner, EL AF O'Brien, CP Gardner, EL TI Critical assessment of how to study addiction and its treatment: Human and non-human animal models SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE addiction; dependence; relapse; dopamine; norepinephrine; serotonin; limbic system; reward system; nucleus accumbens; ventral pallidum; cocaine; heroin; alcohol; nicotine; amphetamine ID GAMMA-VINYL-GABA; VENTRAL TEGMENTAL AREA; DOPAMINE D-3 RECEPTOR; CONDITIONED PLACE PREFERENCE; COCAINE-SEEKING BEHAVIOR; NUCLEUS-ACCUMBENS DOPAMINE; SELF-ADMINISTRATION BEHAVIOR; PROGRESSIVE-RATIO SCHEDULES; BRAIN-STIMULATION REWARD; FREELY-MOVING RATS AB Laboratory models, both animal and human, have made enormous contributions to our understanding of addiction. For addictive disorders, animal models have the great advantage of possessing both face validity and a significant degree of predictive validity, already demonstrated. Another important advantage to this field is the ability of reciprocal interplay between preclinical and clinical experiments. These models have made important contributions to the development of medications to treat addictive disorders and will likely result in even more advances in the future. Human laboratory models have gone beyond data obtained from patient histories and enabled investigators to make direct observations of human drug self-administration and test the effects of putative medications on this behavior. This review examines in detail some animal and human models that have led not only to important theories of addiction mechanisms but also to medications shown to be effective in the clinic. Published by Elsevier Inc. C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. VA Med Ctr, Mental Illness Res & Educ Ctr, Philadelphia, PA 19104 USA. NIDA, Neuropsychopharmacol Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP O'Brien, CP (reprint author), Univ Penn, Sch Med, Dept Psychiat, 3900 Chestnut St, Philadelphia, PA 19104 USA. FU PHS HHS [P60-5186] NR 470 TC 104 Z9 107 U1 12 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD OCT PY 2005 VL 108 IS 1 BP 18 EP 58 DI 10.1016/j.pharmthera.2005.06.018 PG 41 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 974KB UT WOS:000232589200003 PM 16183393 ER PT J AU Vocci, F Ling, W AF Vocci, F Ling, W TI Medications development: Successes and challenges SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE medications; opiate; cocaine; methamphetamine; marijuana; cannabis ID CORTICOTROPIN-RELEASING-FACTOR; COCAINE-SEEKING BEHAVIOR; PLACEBO-CONTROLLED TRIAL; STRESS-INDUCED RELAPSE; DOPAMINE AUTORECEPTOR ANTAGONIST; FACTOR-RECEPTOR SUBTYPE-1; BETA-HYDROXYLASE ACTIVITY; RAT NUCLEUS-ACCUMBENS; MARIJUANA DEPENDENCE; EXTRACELLULAR DOPAMINE AB The National Institute on Drug Abuse has funded a medications program that has concentrated on the development of medications for opiate and cocaine dependence. Levomethadyl acetate (LAAM) and buprenorphine and buprenorphine/naloxone sublingual tablets were developed in conjunction with pharmaceutical partners and approved by the Food and Drug Administration. The remaining challenges for medications development for opiate dependence involves Phase IV studies in special populations, for example, pregnant opiate-dependent patients, and to translate neuroscience-based findings into treatments. Several marketed medications have shown initial efficacy to reduce cocaine use in well-controlled clinical trials. Disulfiram has been shown to reduce cocaine use in several clinical trials, while baclofen, modafinil, naltrexone, ondansetron, tiagabine, and topiramate have shown preliminary efficacy in initial clinical studies. Confirmatory studies of many of these medications is underway. More recently, the NIDA medications program has evaluated medications for their ability to reduce methamphetamine use. To date, no medications tested have shown efficacy to reduce methamphetamine use. Both marketed medications and investigational agents will be tested. Finally, NIDA has begun to test medications for efficacy to reduce cannabis use. Initial studies are underway. Both agonist and antagonist approaches will be evaluated. Additionally, medications will be tested in cannabis-dependent patients for the management of insomnia, withdrawal, and concurrent depression. (c) 2005 Elsevier Inc. All rights reserved. C1 NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Integrated Subst Abuse Programs, Los Angeles, CA 90025 USA. RP Vocci, F (reprint author), NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, 6001 Executive Blvd,Ste 4123,MSC 9551, Bethesda, MD 20892 USA. EM fv6k@nih.gov NR 141 TC 88 Z9 88 U1 14 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD OCT PY 2005 VL 108 IS 1 BP 94 EP 108 DI 10.1016/j.pharmthera.2005.06.010 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 974KB UT WOS:000232589200008 PM 16083966 ER PT J AU Lee, CR North, KE Bray, MS Couper, DJ Heiss, G Zeldin, DC AF Lee, CR North, KE Bray, MS Couper, DJ Heiss, G Zeldin, DC TI Genetic variation in cycolooxygenase-1 (PTGS1) and risk of ischemic stroke: an atherosclerosis risk in communities (ARIC) study. SO PHARMACOTHERAPY LA English DT Meeting Abstract CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 23-26, 2005 CL San Francisco, CA SP Amer Coll Clin Pharm C1 Univ N Carolina, Chapel Hill, NC USA. Baylor Univ, Houston, TX 77030 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD OCT PY 2005 VL 25 IS 10 BP 1479 EP 1479 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 971BP UT WOS:000232356400202 ER PT J AU Lee, CR North, KE Bray, MS Avery, CL Mosher, MJ Couper, DJ Heiss, G Zeldin, DC AF Lee, CR North, KE Bray, MS Avery, CL Mosher, MJ Couper, DJ Heiss, G Zeldin, DC TI Genetic variation in endothelial nitric oxide synthase (NOS3) and risk of coronary heart disease in Caucasians: an atherosclerosis risk in communities (ARIC) study. SO PHARMACOTHERAPY LA English DT Meeting Abstract CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 23-26, 2005 CL San Francisco, CA SP Amer Coll Clin Pharm C1 Univ N Carolina, Chapel Hill, NC USA. Baylor Univ, Houston, TX 77030 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD OCT PY 2005 VL 25 IS 10 BP 1479 EP 1479 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 971BP UT WOS:000232356400201 ER PT J AU Sissung, TM Danesi, R Price, DK Steinberg, SM De Wit, R Cox, MC Dahut, W Figg, W Sparreboom, A AF Sissung, TM Danesi, R Price, DK Steinberg, SM De Wit, R Cox, MC Dahut, W Figg, W Sparreboom, A TI Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel. SO PHARMACOTHERAPY LA English DT Meeting Abstract CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 23-26, 2005 CL San Francisco, CA SP Amer Coll Clin Pharmacy C1 NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. Univ Pisa, Dept Oncol Transplants & Adv Technol Med, Pisa, Italy. NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Dr Daniel Denhoed Canc Ctr, Erasmus Med Ctr, Rotterdam, Netherlands. NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD OCT PY 2005 VL 25 IS 10 BP 1479 EP 1479 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 971BP UT WOS:000232356400200 ER PT J AU Scripture, CD Sissung, TM Permenter, MG Price, DK Swain, SM Sparreboom, A Figg, WD AF Scripture, CD Sissung, TM Permenter, MG Price, DK Swain, SM Sparreboom, A Figg, WD TI Association of genetic variants in ABCB1 and CYP3A4/5 with the pharmacokinetics of erlotinib. SO PHARMACOTHERAPY LA English DT Meeting Abstract CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 23-26, 2005 CL San Francisco, CA SP Amer Coll Clin Pharmacy C1 NCI, Clin Pharmacol Res Core, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD OCT PY 2005 VL 25 IS 10 BP 1480 EP 1480 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 971BP UT WOS:000232356400204 ER PT J AU Bismuth, K Maric, D Arnheiter, H AF Bismuth, K Maric, D Arnheiter, H TI MITF and cell proliferation: the role of alternative splice forms SO PIGMENT CELL RESEARCH LA English DT Article DE melanocyte; transcription regulation; post-translational regulation; cell cycle ID MICROPHTHALMIA TRANSCRIPTION FACTOR; MELANOCYTE DEVELOPMENT; MOUSE; LOCUS; DIFFERENTIATION; MUTATIONS; HELIX; TBX2; RECOGNITION; SUMOYLATION AB Recent studies show that the melanocyte transcription factor MITF not only activates differentiation genes but also genes involved in the regulation of the cell cycle, suggesting that it provides a link between cell proliferation and differentiation. MITF, however, comes in a variety of splice isoforms with potentially distinct biological activities. In particular, there are two isoforms, (-) and (+) MITF, that differ in six residues located upstream of the DNA binding basic domain and show slight differences in the efficiency with which they bind to target DNA. Using in vitro BrdU incorporation assays and FACS analysis in transiently transfected cells, we show that (+) MITF has a strong inhibitory effect on DNA synthesis while (-) MITF has none or only a mild one. The strong inhibitory activity of (+) MITF is not influenced by a number of mutations that modulate MITF's transcriptional activities and is independent of the protein's carboxyl terminus but dependent on its aminoterminus. A further dissection of the molecule points to the importance of an aminoterminal serine, serine-73, which in both isoforms is phosphorylated to comparable degrees. The results suggest that one or several aminoterminal domains cooperate with the alternatively spliced hexapeptide to render MITF anti-proliferative in a way that does not depend on direct E box binding. C1 NINDS, Mammalian Dev Sect, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Arnheiter, H (reprint author), NINDS, Mammalian Dev Sect, NIH, Bethesda, MD 20892 USA. EM ha3p@nih.gov FU NINDS NIH HHS [Z01 NS002790-17] NR 38 TC 33 Z9 34 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD OCT PY 2005 VL 18 IS 5 BP 349 EP 359 DI 10.1111/j.1600-0749.2005.00249.x PG 11 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 963JU UT WOS:000231801400004 PM 16162175 ER PT J AU Berens, W Van Den Bossche, K Yoon, TJ Westbroek, W Valencia, JC Out, CJ Naeyaert, JM Hearing, VJ Lambert, J AF Berens, W Van Den Bossche, K Yoon, TJ Westbroek, W Valencia, JC Out, CJ Naeyaert, JM Hearing, VJ Lambert, J TI Different approaches for assaying melanosome transfer SO PIGMENT CELL RESEARCH LA English DT Article DE melanin; transfer; pigmentation; melanocyte; keratinocyte; GFP; thiouracil ID GREEN FLUORESCENT PROTEIN; IN-VITRO MODEL; HUMAN MELANOCYTES; ENDOPLASMIC-RETICULUM; GRISCELLI-SYNDROME; MOUSE MELANOCYTES; LIVING CELLS; TYROSINASE; KERATINOCYTES; SKIN AB Many approaches have been tried to establish assays for melanosome transfer to keratinocytes. In this report, we describe and summarize various novel attempts to label melanosomes in search of a reliable, specific, reproducible and quantitative assay system. We tried to fluorescently label melanosomes by transfection of GFP-labeled melanosomal proteins and by incubation of melanocytes with fluorescent melanin intermediates or homologues. In most cases a weak cytoplasmic fluorescence was perceived, which was probably because of incorrect sorting or deficient incorporation of the fluorescent protein and different localization. We were able to label melanosomes via incorporation of C-14-thiouracil into melanin. Consequently, we tried to develop an assay to separate keratinocytes with transferred radioactivity from melanocytes after co-culture. Differential trypsinization and different magnetic bead separation techniques were tested with unsatisfactory results. An attempt was also made to incorporate fluorescent thiouracil, since this would allow cells to be separated by FACS. In conclusion, different methods to measure pigment transfer between donor melanocytes and acceptor keratinocytes were thoroughly examined. This information could give other researchers a head start in the search for a melanosome transfer assay with said qualities to better understand pigment transfer. C1 State Univ Ghent Hosp, Dept Dermatol, B-9000 Ghent, Belgium. NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Leiden Univ, Med Ctr, Dept Dermatol, NL-2300 RC Leiden, Netherlands. Gyeongsang Natl Univ Hosp, Dept Dermatol, Chinju, South Korea. RP Lambert, J (reprint author), State Univ Ghent Hosp, Dept Dermatol, De Pintelaan 185, B-9000 Ghent, Belgium. EM jo.lambert@ugent.be FU NCI NIH HHS [Z01 BC009100-20] NR 54 TC 20 Z9 23 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD OCT PY 2005 VL 18 IS 5 BP 370 EP 381 DI 10.1111/j.1600-0749.2005.00263.x PG 12 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 963JU UT WOS:000231801400006 PM 16162177 ER PT J AU Mu, JB Awadalla, P Duan, JH McGee, KM Joy, DA McVean, GAT Su, XZ AF Mu, JB Awadalla, P Duan, JH McGee, KM Joy, DA McVean, GAT Su, XZ TI Recombination hotspots and population structure in Plasmodium falciparum SO PLOS BIOLOGY LA English DT Article ID GLOBIN GENE-CLUSTER; LINKAGE DISEQUILIBRIUM; MALARIA PARASITES; NONUNIFORM RECOMBINATION; MEIOTIC RECOMBINATION; HUMAN GENOME; RESISTANCE; CHLOROQUINE; COALESCENT; DIVERSITY AB Understanding the influences of population structure, selection, and recombination on polymorphism and linkage disequilibrium (LD) is integral to mapping genes contributing to drug resistance or virulence in Plasmodium falciparum. The parasite's short generation time, coupled with a high cross-over rate, can cause rapid LD break-down. However, observations of low genetic variation have led to suggestions of effective clonality: selfing, population admixture, and selection may preserve LD in populations. Indeed, extensive LD surrounding drug-resistant genes has been observed, indicating that recombination and selection play important roles in shaping recent parasite genome evolution. These studies, however, provide only limited information about haplotype variation at local scales. Here we describe the first ( to our knowledge) chromosome-wide SNP haplotype and population recombination maps for a global collection of malaria parasites, including the 3D7 isolate, whose genome has been sequenced previously. The parasites are clustered according to continental origin, but alternative groupings were obtained using SNPs at 37 putative transporter genes that are potentially under selection. Geographic isolation and highly variable multiple infection rates are the major factors affecting haplotype structure. Variation in effective recombination rates is high, both among populations and along the chromosome, with recombination hotspots conserved among populations at chromosome ends. This study supports the feasibility of genome-wide association studies in some parasite populations. C1 N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA. NIH, Lab Malaria & Vector Res, Rockville, MD USA. Univ Oxford, Dept Stat, Oxford OX1 3TG, England. RP Awadalla, P (reprint author), N Carolina State Univ, Dept Genet, Box 7614, Raleigh, NC 27695 USA. EM pawadalla@ncsu.edu; xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU Wellcome Trust NR 42 TC 120 Z9 124 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD OCT PY 2005 VL 3 IS 10 BP 1734 EP 1741 AR e335 DI 10.1371/journal.pbio.0030335 PG 8 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 971SJ UT WOS:000232404600008 PM 16144426 ER PT J AU Zhang, JH Wheeler, DA Yakub, I Wei, S Sood, R Rowe, W Liu, PP Gibbs, RA Buetow, KH AF Zhang, JH Wheeler, DA Yakub, I Wei, S Sood, R Rowe, W Liu, PP Gibbs, RA Buetow, KH TI SNPdetector: A software tool for sensitive and accurate SNP detection SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID LABORATORY MOUSE GENOME; SEQUENCE VARIATION; MAP; DISCOVERY; PATTERNS; PROJECT; GENES AB Identification of single nucleotide polymorphisms (SNPs) and mutations is important for the discovery of genetic predisposition to complex diseases. PCR resequencing is the method of choice for de novo SNP discovery. However, manual curation of putative SNPs has been a major bottleneck in the application of this method to high-throughput screening. Therefore it is critical to develop a more sensitive and accurate computational method for automated SNP detection. We developed a software tool, SNPdetector, for automated identification of SNPs and mutations in fluorescence-based resequencing reads. SNPdetector was designed to model the process of human visual inspection and has a very low false positive and false negative rate. We demonstrate the superior performance of SNPdetector in SNP and mutation analysis by comparing its results with those derived by human inspection, PolyPhred (a popular SNP detection tool), and independent genotype assays in three large-scale investigations. The first study identified and validated inter- and intra-subspecies variations in 4,650 traces of 25 inbred mouse strains that belong to either the Mus musculus species or the M. spretus species. Unexpected heterozgyosity in CAST/Ei strain was observed in two out of 1,167 mouse SNPs. The second study identified 11,241 candidate SNPs in five ENCODE regions of the human genome covering 2.5 Mb of genomic sequence. Approximately 50% of the candidate SNPs were selected for experimental genotyping; the validation rate exceeded 95%. The third study detected ENU-induced mutations (at 0.04% allele frequency) in 64,896 traces of 1,236 zebra fish. Our analysis of three large and diverse test datasets demonstrated that SNPdetector is an effective tool for genome-scale research and for large-sample clinical studies. SNPdetector runs on Unix/Linux platform and is available publicly (http://Ipg.nci.nih.gov). C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX USA. Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD USA. RP Zhang, JH (reprint author), NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. EM jinghuiz@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU Intramural NIH HHS NR 23 TC 79 Z9 81 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2005 VL 1 IS 5 BP 395 EP 404 AR e53 DI 10.1371/journal.pcbi.0010053 PG 10 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 003WQ UT WOS:000234713100006 PM 16261194 ER PT J AU Dauter, Z AF Dauter, Z TI Efficient use of synchrotron radiation for macromolecular diffraction data collection SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE synchrotron radiation; diffraction data collection; macromolecular crystals ID DAMAGE; CRYSTALLOGRAPHY; QUALITY AB In recent years, number of X-ray synchrotron beam lines dedicated to collecting diffraction data from macromolecular crystals has exceeded 50. Indeed, today most protein and nucleic acid crystal structures are solved and refined based on the synchrotron data. Collecting diffraction data on a synchrotron beam line involves many technical points, but it is not a mere technicality. Even though the available hardware and software have become more advanced and user-friendly, it is always beneficial if the experimenter is aware of the problems involved in the data collection process and can make informed decisions leading to the highest possible quality of the acquired diffraction data. Various factors, important for the success of data collection experiments and their relevance for different kinds of applications, are discussed. (c) 2004 Elsevier Ltd. All rights reserved. C1 Brookhaven Natl Lab, Synchrotron Radiat Res Sect, MCL, Natl Canc Inst, Upton, NY 11973 USA. RP Dauter, Z (reprint author), Brookhaven Natl Lab, Synchrotron Radiat Res Sect, MCL, Natl Canc Inst, Bldg 725A-X9, Upton, NY 11973 USA. EM dauter@anl.gov NR 22 TC 13 Z9 16 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD OCT PY 2005 VL 89 IS 2 BP 153 EP 172 DI 10.1016/j.pbiomolbio.2004.09.004 PG 20 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 940OL UT WOS:000230153700003 PM 15910916 ER PT J AU Paruszewski, R Strupinska, M Rostafinska-Suchar, G Stables, JP AF Paruszewski, R Strupinska, M Rostafinska-Suchar, G Stables, JP TI New derivatives of picolinic acid and nicotinic acid with anticonvulsant activity SO PROTEIN AND PEPTIDE LETTERS LA English DT Article DE anticonvulsant; activity; neurotoxicity; time of action; picolinic acid; nicotinic acid AB Previously obtained Pic-BZA is a potent anticonvulsant with low neurotoxicity, but its half-time of action is only about 15 min. In search for equally effective anticonvulsants but with a longer time of action fourteen Pic-BZA analogs were obtained. The compounds were evaluated in the Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Picolinic acid 2-fluorobenzylamide (Pic-2-F-BZA, 7) appeared to be the most effective compound of the series. C1 Med Univ, Dept Drug Chem, PL-02097 Warsaw, Poland. Natl Inst Neurol Disorders & Stroke, Epilepsy Branch, Rockville, MD 20852 USA. RP Paruszewski, R (reprint author), Med Univ, Dept Drug Chem, PL-02097 Warsaw, Poland. EM rpbw@farm.amwaw.edu.pl NR 7 TC 7 Z9 7 U1 1 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8665 J9 PROTEIN PEPTIDE LETT JI Protein Pept. Lett. PD OCT PY 2005 VL 12 IS 7 BP 701 EP 704 DI 10.2174/0929866054696046 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 965OB UT WOS:000231958900016 PM 16522187 ER PT J AU Yeliseev, AA Wong, KK Soubias, O Gawrisch, K AF Yeliseev, AA Wong, KK Soubias, O Gawrisch, K TI Expression of human peripheral cannabinoid receptor for structural studies SO PROTEIN SCIENCE LA English DT Article DE cannabinoid receptor; CB2; E. coli; NMR; GPCR; anodic aluminum oxide ID ESCHERICHIA-COLI; SIGNAL-TRANSDUCTION; MEMBRANE-PROTEIN; CB2 RECEPTORS; PURIFICATION; NEUROTENSIN; PHARMACOLOGY; TRYPTOPHAN; LIGANDS AB Human peripheral-type cannabinoid receptor (CB2) was expressed in Escherichia coli as a fusion with the maltose-binding protein, thioredoxin, and a deca-histidine tag. Functional activity and structural integrity of the receptor in bacterial protoplast membranes was confirmed by extensive binding studies with a variety of natural and synthetic cannabinoid ligands. E. coli membranes expressing CB2 also activated cognate G-proteins in an in vitro coupled assay. Detergent-solubilized receptor was purified to 80%-90% homogeneity by affinity chromatography followed by ion-exchange chromatography. By high-resolution NMR on the receptor in DPC micelles, it was determined that purified CB2 forms 1:1 complexes with the ligands CP-55,940 and anandamide. The receptor was successfully reconstituted into phosphatidylcholine bilayers and the membranes were deposited into a porous Substrate as tubular lipid bilayers for structural studies by NMR and scattering techniques. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Yeliseev, AA (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM yeliseeva@mail.nih.gov; gawrisch@helix.nih.gov RI Yeliseev, Alexei/B-3143-2009 FU Intramural NIH HHS NR 31 TC 57 Z9 58 U1 2 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2005 VL 14 IS 10 BP 2638 EP 2653 DI 10.1110/ps.051550305 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 969KQ UT WOS:000232233400014 PM 16195551 ER PT J AU Phan, J Austin, BP Waugh, DS AF Phan, J Austin, BP Waugh, DS TI Crystal structure of the Yersinia type III secretion protein YscE SO PROTEIN SCIENCE LA English DT Article DE Yersinia pestis; plague; type III secretion; YscE; crystal structure ID PROGRAM; SYSTEM AB The plague-causing bacterium Yersinia pestis utilizes a contact-dependent (type III) secretion system (T3SS) to transport virulence factors from the bacterial cytosol directly into the interior of mammalian cells where they interfere with signal transduction pathways that mediate phagocytosis and the inflammatory response. The type III secretion apparatus is composed of 20-25 different Yersinia secretion (Ysc) proteins. We report here the structure of YscE, the smallest Ysc protein, which is a dimer in solution. The probable mode of oligomerization is discussed. C1 Natl Canc Inst Frederick, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), Natl Canc Inst Frederick, Ctr Canc Res, Macromol Crystallog Lab, POB B, Frederick, MD 21702 USA. EM waughd@ncifcrf.gov NR 14 TC 13 Z9 13 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2005 VL 14 IS 10 BP 2759 EP 2763 DI 10.1110/ps.051706105 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 969KQ UT WOS:000232233400027 PM 16195558 ER PT J AU Mintz, S Shulman-Peleg, A Wolfson, HJ Nussinov, R AF Mintz, S Shulman-Peleg, A Wolfson, HJ Nussinov, R TI Generation and analysis of a protein-protein interface data set with similar chemical and spatial patterns of interactions SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE protein-protein interactions; protein binding sites; data set of protein-protein interfaces; structural comparison of binding sites; alignment of interfaces; physicochemical properties ID SEARCHING STRUCTURAL DATABASES; 3D COORDINATE TEMPLATES; BINDING-SITES; HOT-SPOTS; STATISTICAL-ANALYSIS; RECOGNITION SITES; FUNCTIONAL SITES; ACTIVE-SITES; SEQUENCE; ALGORITHM AB Protein-protein interfaces are regions between 2 polypeptide chains that are not covalently connected. Here, we have created a non redundant interface data set generated from all 2-chain interfaces in the Protein Data Bank. This data set is unique, since it contains clusters of interfaces with similar shapes and spatial organization of chemical functional groups. The data set allows statistical investigation of similar interfaces, as well as the identification and analysis of the chemical forces that account for the protein-protein associations. Toward this goal, we have developed I2I-SiteEngine (Interface-to-Interface SiteEngine) [Data set available at http:H bioinfo3d.cs.tau.ac.il/Interfaces; Web server: http:// bioinfo3d.cs.tau.ac.il/I21-SiteEnginel. The algorithm recognizes similarities between protein-protein binding surfaces. I2I-SiteEngine is independent of the sequence or the fold of the proteins that comprise the interfaces. In addition to geometry, the method takes into account both the backbone and the side-chain physicochemical properties of the interacting atom groups. Its high efficiency makes it suitable for large-scale database searches and classifications. Below, we briefly describe the I2I-SiteEngine method. We focus on the classification process and the obtained nonredundant proteinprotein interface data set. In particular, we analyze the biological significance of the clusters and present examples which illustrate that given constellations of chemical groups in protein-protein binding sites may be preferred, and are observed in proteins with different structures and different functions. We expect that these would yield further information regarding the forces stabilizing protein-protein interactions. C1 SAIC Frederick Inc, Basic Res Program, Lab Expt & Computat Biol, Frederick, MD USA. Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Bldg 469,Rm 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 63 TC 36 Z9 37 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD OCT 1 PY 2005 VL 61 IS 1 BP 6 EP 20 DI 10.1002/prot.20580 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 961TA UT WOS:000231683500002 PM 16184518 ER PT J AU Wheatley, T Haidt, J AF Wheatley, T Haidt, J TI Hypnotic disgust makes moral judgments more severe SO PSYCHOLOGICAL SCIENCE LA English DT Article ID AFFECTIVE STATES; MOOD AB Highly hypnotizable participants were given a posthypnotic suggestion to feel a flash of disgust whenever they read an arbitrary word. They were then asked to rate moral transgressions described in vignettes that either did or did not include the disgust-inducing word. Two studies show that moral judgments can be made more severe by the presence of a flash of disgust. These findings suggest that moral judgments may be grounded in affectively laden moral intuitions. C1 NIH, Bethesda, MD 20892 USA. Univ Virginia, Charlottesville, VA 22903 USA. RP Wheatley, T (reprint author), NIH, 10 Ctr Dr,MSC 1366, Bethesda, MD 20892 USA. EM wheatley@nih.gov RI sarinopoulos, isidoros/B-5453-2010; Henrich, Joseph/A-2403-2009; Haidt, Jonathan/B-2835-2013 FU NIDA NIH HHS [1-RO3-DA12606-01] NR 16 TC 341 Z9 351 U1 9 U2 76 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD OCT PY 2005 VL 16 IS 10 BP 780 EP 784 DI 10.1111/j.1467-9280.2005.01614.x PG 5 WC Psychology, Multidisciplinary SC Psychology GA 967OQ UT WOS:000232101200007 PM 16181440 ER PT J AU Elmer, GI Pieper, JO Levy, J Rubinstein, M Low, MJ Grandy, DK Wise, RA AF Elmer, GI Pieper, JO Levy, J Rubinstein, M Low, MJ Grandy, DK Wise, RA TI Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice SO PSYCHOPHARMACOLOGY LA English DT Article DE amphetamine; reinforcement; knockout; depolarization; mice; opioid; ICSS; addiction; neuroleptic ID VENTRAL TEGMENTAL AREA; INTRACRANIAL SELF-STIMULATION; PIMOZIDE-INDUCED EXTINCTION; NUCLEUS-ACCUMBENS DOPAMINE; KNOCK-OUT MICE; LOCOMOTOR-ACTIVITY; COCAINE REINFORCEMENT; INVIVO MICRODIALYSIS; PREPULSE INHIBITION; CHOLINERGIC NEURONS AB Rationale: The rewarding effects of lateral hypothalamic brain stimulation, various natural rewards, and several drugs of abuse are attenuated by D1 or D2 dopamine receptor (D1R or D2R) antagonists. Much of the evidence for dopaminergic involvement in rewards is based on pharmacological agents with limited or "relative" selectivity for dopamine receptor subtypes. Genetically engineered animal models provide a complementary approach to pharmacological investigations. Objectives: In the present study, we explored the contribution of dopamine D2Rs to (1) brain stimulation reward (BSR) and (2) the potentiation of this behavior by morphine and amphetamine using D2R-deficient mice. Methods: Wild-type (D2Rwt), heterozygous (D2Rhet), and D2R knockout (D2Rko) mice were trained to turn a wheel for rewarding brain stimulation. Once equivalent rate-frequency curves were established, morphine-induced (0, 1.0, 3.0, and 5.6 mg/kg s.c.) and amphetamine-induced (0, 1.0, 2.0, and 4.0 mg/kg i.p.) potentiations of BSR were determined. Results: The D2Rko mice required approximately 50% more stimulation than the D2Rwt mice did. With the equi-rewarding levels of stimulation current, amphetamine potentiated BSR equally across the three genotypes. In contrast, morphine potentiated rewarding stimulation in the D2Rwt, had no effect in the D2Rhet, and antagonized rewarding stimulation in the D2Rko mice. Conclusions: D2R elimination decreases, but does not eliminate, the rewarding effects of lateral hypothalamic stimulation. After compensation for this deficit, amphetamine continues to potentiate BSR, while morphine does not. C1 Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. NIDA, IRP, NIH, Baltimore, MD 21224 USA. Univ Buenos Aires, INGEBI, Buenos Aires, DF, Argentina. Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97239 USA. Oregon Hlth Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. Oregon Hlth Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 USA. RP Elmer, GI (reprint author), Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Maple & Locust St, Catonsville, MD 21228 USA. EM gelmer@mprc.umaryland.edu RI Wise, Roy/A-6465-2012; OI Levy, Jamey/0000-0002-7434-7213 NR 94 TC 27 Z9 27 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2005 VL 182 IS 1 BP 33 EP 44 DI 10.1007/s00213-005-0051-2 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 979YH UT WOS:000232980600004 PM 16136297 ER PT J AU Yasar, S Gaal, J Justinova, Z Bergman, J AF Yasar, S Gaal, J Justinova, Z Bergman, J TI Discriminative stimulus and reinforcing effects of p-fluoro-L-deprenyl in monkeys SO PSYCHOPHARMACOLOGY LA English DT Article DE amphetamine; cocaine; deprenyl; drug discrimination; methamphetamine; p-fluoro-L-deprenyl; self-administration; squirrel monkey ID MONOAMINE-OXIDASE INHIBITION; DRUG-SEEKING BEHAVIOR; MAO-B INHIBITORS; ALZHEIMERS-DISEASE; MALE-RATS; SUPEROXIDE-DISMUTASE; 2ND-ORDER SCHEDULES; CONTROLLED TRIAL; DOUBLE-BLIND; SELEGILINE AB Rationale: para-Fluoro-L-deprenyl (Fludepryl), a halogenated derivative of L-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. Objectives: p-Fluoro-L-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. Methods: One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5min schedule with FR10 components. Results: Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-L-deprenyl. L-Deprenyl and the metabolites of p-fluoro-L-deprenyl, p-fluoro-L-amphetamine, and p-fluoro-L-methylamphetamine were more potent, producing full generalization at doses of 1.0 - 3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-L-deprenyl up to 1.0 mg/kg. However, p-fluoro-L-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-L-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or D-amphetamine. Conclusions: p-Fluoro-L-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, L-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine. C1 Harvard Univ, Sch Med, ADARC, McLean Hosp,Dept Psychiat, Belmont, MA 02478 USA. Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Res Branch,NIH, Dept Hlth & Human Serv,Intramural Res Program, Baltimore, MD 21224 USA. MegaPharma Ltd, Budapest, Hungary. RP Bergman, J (reprint author), Harvard Univ, Sch Med, ADARC, McLean Hosp,Dept Psychiat, 115 Mill St, Belmont, MA 02478 USA. EM jbergman@hms.harvard.edu RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 FU Intramural NIH HHS NR 58 TC 5 Z9 5 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2005 VL 182 IS 1 BP 95 EP 103 DI 10.1007/s00213-005-0063-y PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 979YH UT WOS:000232980600011 PM 15990999 ER PT J AU Bazinet, RP Rao, JS Chang, L Rapoport, SI Lee, HJ AF Bazinet, RP Rao, JS Chang, L Rapoport, SI Lee, HJ TI Chronic valproate does not alter the kinetics of docosahexaenoic acid within brain phospholipids of the unanesthetized rat SO PSYCHOPHARMACOLOGY LA English DT Article DE valproate; arachidonic acid; docosahexaenoic acid; brain; bipolar disorder; mood stabilizer; anti-epileptic; lithium; mania; turnover; metabolism; kinetics ID CENTRAL-NERVOUS-SYSTEM; ARACHIDONIC-ACID; BIPOLAR DISORDER; CHRONIC LITHIUM; FATTY-ACID; LINOLEATE DEFICIENCY; METABOLISM; COA; TURNOVER; EXPRESSION AB Rationale: It has been reported that each of three drugs effective in treating bipolar disorder (lithium, carbamazepine, and valproate) decreases the turnover of arachidonic acid (AA, 20:4n-6) in brain phospholipids of the awake rat. It is also known that lithium and carbamazepine do so without decreasing the turnover of docosahexaenoic acid (DHA, 22:6n-3). Objective: The aim of this study was to see whether valproate also specifically targets the turnover of AA but not of DHA in brain phospholipids. Methods: Valproate was administered (200 mg kg(-1), i.p.) to rats for 30 days to produce a therapeutically relevant plasma concentration and then determine its effect compared with that of vehicle on incorporation and turnover rates of DHA in brain phospholipids. In unanesthetized rats that had received valproate or vehicle, [1-C-14] DHA was infused intravenously, and arterial blood plasma was sampled until the animal was killed at 5 min; and its brain, after being microwaved, was subjected to chemical and radiotracer analysis. Results: Using equations derived from our fatty acid model, it was found that chronic valproate compared with vehicle did not alter the rate of incorporation or turnover of DHA in brain phospholipids. Valproate-treated animals had higher concentrations of linoleic acid (18:2n-6) in several brain phospholipids, supporting the hypothesis that it alters brain n-6 fatty acid metabolism. Conclusions: The results, comparable to published findings following chronic administration of lithium and carbamazepine to rats, support the hypothesis that drugs are effective against mania in bipolar disorder act by down-regulating incorporation and turnover of AA, but not of DHA, in brain phospholipids. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Lee, HJ (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 1S 128, Bethesda, MD 20892 USA. EM hojoolee@mail.nih.gov RI Rao, Jagadeesh/C-1250-2009 NR 49 TC 36 Z9 37 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2005 VL 182 IS 1 BP 180 EP 185 DI 10.1007/s00213-005-0059-7 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 979YH UT WOS:000232980600020 PM 15986187 ER PT J AU Siesser, WB Cheng, SY McDonald, MP AF Siesser, WB Cheng, SY McDonald, MP TI Hyperactivity, impaired learning on a vigilance task, and a differential response to methylphenidate in the TR beta PV knock-in mouse SO PSYCHOPHARMACOLOGY LA English DT Article DE thyroid hormone; attention deficit-hyperactivity disorder; methylphenidate; mouse; locomotor activity; vigilance; response acquisition ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; TRANSGENIC MICE BEARING; THYROID-HORMONE ACTION; CONGENITAL HYPOTHYROIDISM; TYROSINE-HYDROXYLASE; SUSTAINED ATTENTION; DEFICIT DISORDER; VISUAL-ATTENTION; SEX-DIFFERENCES; RECEPTOR GENE AB Rationale: The thyroid hormones (T3 and T4) play a critical role in brain development, and thyroid abnormalities have been linked to a variety of psychiatric and neuropsychological disorders. Among patients with the rare genetic syndrome resistance to thyroid hormone (RTH), 40-70% meet the diagnostic criteria for attention deficit-hyperactivity disorder (ADHD). RTH is caused by a mutation in the thyroid receptor beta (Thrb) gene that results in reduced binding of T3 to its receptor and elevated concentrations of T3, T4, and thyroid-stimulating hormone. Objectives: We tested a knock-in (KI) mouse expressing a mutant TR beta allele (TR beta PV) for the behavioral features of ADHD and their response to methylphenidate (MPH). Methods: The locomotor activity of the TR beta PV KI mice was measured in activity monitors over multiple sessions. Sustained attention and the effects of MPH on attention were assessed using a vigilance task. Results: The TR beta PV KI mice are hyperactive and have learning deficits on a vigilance task. Doses of MPH that impair the vigilance performance of wild-type mice do not affect the performance of the TR beta PV KI mice. Conclusions: The TR beta PV KI mice provide a tool for studying the underlying neural deficits that contribute to thyroid-related neurological disorders, hyperactivity, and altered responsiveness to MPH. C1 Vanderbilt Univ, Program Neurosci, Nashville, TN 37232 USA. NCI, Gene Regulat Sect, Mol Biol Lab, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. Vanderbilt Univ, John F Kennedy Ctr Res Human Dev, Nashville, TN 37232 USA. RP McDonald, MP (reprint author), Vanderbilt Univ, Program Neurosci, 221 Kirkland Hall, Nashville, TN 37232 USA. EM Mike.McDonald@Vanderbilt.edu OI McDonald, Michael P./0000-0002-9642-964X NR 55 TC 34 Z9 36 U1 4 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2005 VL 181 IS 4 BP 653 EP 663 DI 10.1007/s00213-005-0024-5 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 975KL UT WOS:000232661300003 PM 15983791 ER PT J AU Silvera, SAN Rohan, TE Jain, M Terry, PD Howe, GR Miller, AB AF Silvera, SAN Rohan, TE Jain, M Terry, PD Howe, GR Miller, AB TI Glycaemic index, glycaemic load and risk of endometrial cancer: a prospective cohort study SO PUBLIC HEALTH NUTRITION LA English DT Article DE glycaemic index; glycaemic load; endometrial neoplasms; prospective cohort; National Breast Screening Study ID COLORECTAL-CANCER; PLASMA-INSULIN; WOMEN; QUESTIONNAIRE; DISEASE; OBESITY; HEALTH; FOODS; DIET AB Objective: High-glycaemic-load diets may increase endometrial cancer risk by increasing circulating insulin levels and, as a consequence, circulating oestrogen levels. Given the paucity of epidemiological data regarding the relationship between dietary glycaemic index and glycaemic load and endometrial cancer risk, we sought to examine these associations using data from a prospective cohort study. Design, setting and subjects: We examined the association between dietary glycaemic load and endometrial cancer risk in a cohort of 49 613 Canadian women aged between 40 and 59 years at baseline who completed self-administered food-frequency questionnaires between 1982 and 1985. Linkages to national mortality and cancer databases yielded data on deaths and cancer incidence, with follow-up ending between 1998 and 2000. Results: During a mean of 16.4 years of follow-up, we observed 426 incident cases of endometrial cancer. Hazard ratios for the highest versus the lowest quartile level of overall glycaemic index and glycaemic load were 1.47 (95% confidence interval (CI)=0.90-2.41; P for trend=0.14) and 1.36 (95% CI=1.01-1.84; P for trend=0.21), respectively. No association was observed between total carbohydrate or total sugar consumption and endometrial cancer risk. Among obese women (body mass index > 30 kg m(-2)) the hazard ratio for the highest versus the lowest quartile level of glycaemic load was 1.88 (95% CI=1.08-3.29; P for trend=0.54) and there was a 55% increased risk for the highest versus the lowest quartile level of glycaemic load among premenopausal women. There was also evidence to support a positive association between glycaemic load and endometrial cancer risk among postmenopausal women who had used hormone replacement therapy. Conclusions: Our data suggest that diets with high glycaemic index or high glycaemic load may be associated with endometrial cancer risk overall, and particularly among obese women, premenopausal women and postmenopausal women who use hormone replacement therapy. C1 Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. NIEHS, NIH, Dept Hlth & Human Sci, Res Triangle Pk, NC 27709 USA. Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Silvera, SAN (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave,Room 1301, Bronx, NY 10461 USA. EM ssilvera@aecom.yu.edu NR 37 TC 33 Z9 34 U1 1 U2 5 PU CABI PUBLISHING PI WALLINGFORD PA C/O PUBLISHING DIVISION, NOSWORTHY WAY, WALLINGFORD OX10 8DE, OXON, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD OCT PY 2005 VL 8 IS 7 BP 912 EP 919 DI 10.1079/PHN2005741 PG 8 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 981OD UT WOS:000233097000015 PM 16277808 ER PT J AU Patsalides, AD Atac, G Hedge, U Janik, J Grant, N Jaffe, ES Dwyer, A Patronas, NJ Wilson, WH AF Patsalides, AD Atac, G Hedge, U Janik, J Grant, N Jaffe, ES Dwyer, A Patronas, NJ Wilson, WH TI Lymphomatoid granulomatosis: Abnormalities of the brain at MR imaging SO RADIOLOGY LA English DT Article; Proceedings Paper CT 87th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 25-30, 2001 CL CHICAGO, IL SP Radiol Soc N Amer ID CENTRAL-NERVOUS-SYSTEM; BARR-VIRUS INFECTION; CNS; CT; LESIONS; CHEMOTHERAPY AB PURPOSE: To retrospectively evaluate the magnetic resonance (MR) imaging features of lymphomatoid granulomatosis in the brain. MATERIALS AND METHODS: The study, including retrospective analysis of data, was approved by the institutional review board of the National Cancer Institute and complied with Health Insurance Portability and Accountability Act. All patients gave written informed consent. Thirty-one patients with pathologically confirmed lymphomatoid granulornatosis were enrolled in a natural history and treatment study at the National Institutes of Health. Twenty-five patients (median age, 50 years; range, 18-62 years; 18 men, seven women) were evaluated with MR imaging of the brain at study entry for the presence of brain lesions and enhancing characteristics. Patients with abnormal findings were reexamined at intervals ranging from 2 to 19 months, as medically indicated. Cytologic analysis and flow cytometry of cerebrospinal fluid (CSF) were performed. Statistical analysis was performed to compare neurologic and CSF findings in patients with brain MR imaging abnormalities and in patients without abnormalities. The sensitivity of brain MR imaging was compared with that of CSF studies. RESULTS: Thirteen (52%) of 25 patients evaluated with MR imaging had a variety of brain abnormalities. Multiple focal intraparenchymal lesions, which exhibited T2 prolongation and commonly punctate or linear enhancement, were the most frequent abnormalities, and they were encountered in seven patients. The second most common finding was involvement of leptomeninges and cranial nerves, which manifested as abnormal enhancement on MR images obtained after contrast agent administration. This abnormality was seen in six patients. Involvement of dura mater was noted in another. Four patients had brain masses. Two had abnormal engorgement and intense enhancement of the choroid plexus. Most lesions resolved after treatment, but seven resulted in lacunar infarctions. Abnormal B cells were detected in the CSF with either cytologic techniques or flow cytometry in five patients. CONCLUSION: Lymphomatoid granulomatosis has a high rate of central nervous system involvement and a variable spectrum of lesions at MR imaging. Findings in this study suggest that MR imaging is more sensitive than CSF cytologic analysis or flow cytometry for detection of central nervous system involvement from lymphomatoid granulonnatosis. (c) RSNA, 2005. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Washington, DC 20007 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Patsalides, AD (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Room 1C660,9000 Rockville Pike, Bethesda, MD 20892 USA. EM apatsalides@cc.nih.gov NR 29 TC 38 Z9 40 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 OCT PY 2005 VL 237 IS 1 BP 265 EP 273 DI 10.1148/radiol.2371041087 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 965RM UT WOS:000231968000036 PM 16100084 ER PT J AU Lodde, BM Sankar, V Kok, MR Leakan, RA Tak, PP Pillemer, SR AF Lodde, BM Sankar, V Kok, MR Leakan, RA Tak, PP Pillemer, SR TI Adult heart block is associated with disease activity in primary Sjogren's syndrome SO SCANDINAVIAN JOURNAL OF RHEUMATOLOGY LA English DT Article ID RHEUMATOID-ARTHRITIS; FOLLOW-UP; ANTIBODIES; AUTOANTIBODIES; PATIENT; RO AB Objectives: Congenital heart block occurring in the foetus and neonate may be associated with maternal anti-SS-A/anti-SS-B autoantibodies (anti-SSA/anti-SSB). The adult atrioventricular node is generally thought to be resistant to the damaging effects of anti-SSA/anti-SSB. However, case reports suggest that heart block developing in adult Sjogren's syndrome (SS) patients may be associated with these autoantibodies. Therefore, we investigated the relationship between serum antibodies and heart block in adult SS patients. Methods: We abstracted data from clinic patient records. Diagnosis of primary SS was based on American European classification criteria. Electrocardiograms (EKGs), laboratory immunology parameters, lipid profiles, and focus scores from labial salivary gland biopsies were available for 51 SS patients. Fifteen patients had follow-up EKGs. PR interval >= 200 ms was considered to be first-degree heart block. Results: Five patients showed prolonged PR intervals; the presence of heart block was not related to the presence of anti-SSA antibodies. However, significant differences between patients with prolonged and normal PR intervals were seen for mean focus scores (p<0.0001), anti-cardiolipin immunoglobulin IgG (p=0.0009), age (p=0.01), IgG (p=0.02), anti-SSB antibodies (p=0.02), and high density lipoprotein (HDL) cholesterol levels (p=0.03). These parameters correlated with prolonged PR intervals. Conclusions: These results suggest an association between disease activity, the presence of anti-SSB antibodies, and the occurrence of first-degree heart block in adults with primary SS. C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. RP Lodde, BM (reprint author), NIDCR, GTTB, NIH, 10 Ctr Dr,Room 1N114,MSC 1190, Bethesda, MD 20892 USA. EM blodde@mail.nih.gov NR 23 TC 11 Z9 14 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA PO BOX 12 POSTHUSET, NO-0051 OSLO, NORWAY SN 0300-9742 J9 SCAND J RHEUMATOL JI Scand. J. Rheumatol. PD OCT PY 2005 VL 34 IS 5 BP 383 EP 386 DI 10.1080/03009740510026661 PG 4 WC Rheumatology SC Rheumatology GA 974RX UT WOS:000232610200008 PM 16234186 ER PT J AU Resnik, DB AF Resnik, DB TI Using electronic discussion boards to teach responsible conduct of research SO SCIENCE AND ENGINEERING ETHICS LA English DT Article DE discussion boards; ethics; online education; responsible conduct of research AB This study presents the results of a survey of student satisfaction with electronic discussion boards in a course on the responsible conduct of research (RCR). On a 1-5 scale, the respondents stated that the use of the electronic discussion board was an effective teaching tool (4.71), that it enabled them to get feedback from their peers (4.43), that it helped promote discussion and debate (4.3 6), that it helped them learn how to analyze ethical dilemmas in research (4.36), and that they would consider using an electronic discussion board, if they ever taught a course themselves (4.76). In their written comments, the respondents indicated that electronic discussion boards are a convenient way of promoting debate and in-depth discussion. These results suggest, but do not prove, that discussion boards can promote debate and discussion in courses on research ethics. Instructors who teach RCR should consider using electronic discussion boards in regular or online courses, and they should consider studying the effectiveness of electronic discussion boards in research ethics education. Although electronic discussion boards cannot replace the face-to-face interaction that occurs in a classroom setting, they may provide a useful medium for the exchange of ideas and opinions online. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop NH 06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 23 TC 7 Z9 7 U1 0 U2 6 PU OPRAGEN PUBLICATIONS PI GUILDFORD PA PO BOX 54, GUILDFORD GU1 2YF, SURREY, ENGLAND SN 1353-3452 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD OCT PY 2005 VL 11 IS 4 BP 617 EP 630 DI 10.1007/s11948-005-0029-9 PG 14 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA 984PB UT WOS:000233315700008 PM 16279758 ER PT J AU Kleinman, HK Martin, GR AF Kleinman, HK Martin, GR TI Matrigel: Basement membrane matrix with biological activity SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE basement membrane; extracellular matrix; differentiation; laminin; matrigel ID HEPARAN-SULFATE PROTEOGLYCAN; STEM-CELL DIFFERENTIATION; LAMININ-A CHAIN; EXTRACELLULAR-MATRIX; MURINE TUMOR; ACINAR DIFFERENTIATION; EPITHELIAL-CELLS; GENE-EXPRESSION; BINDING-SITES; GROWTH-FACTOR AB The basement membrane extracellular matrix contacts epithelial, endothelial, fat and smooth muscle cells. Because this extracellular matrix is so thin, it had been hard to study its composition, structure, and function. An extract of a tumor was found to contain all of the components present in basement and to be very biologically active. This extract, termed Matrigel, Cultrex, or EHS matrix, promotes cell differentiation, and is used to measure the invasive activity of tumor cells. In vivo, it is used for measuring angiogenic inhibitors and stimulators, to improve graft survival, repair damaged tissues, and increase tumor growth. Published by Elsevier Ltd. C1 NIDCR, NIH, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), NIDCR, NIH, 30-433,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov NR 55 TC 536 Z9 549 U1 10 U2 123 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD OCT PY 2005 VL 15 IS 5 BP 378 EP 386 DI 10.1016/j.semcancer.2005.05.004 PG 9 WC Oncology SC Oncology GA 966KO UT WOS:000232018800006 PM 15975825 ER PT J AU Murgo, AJ AF Murgo, AJ TI Innovative approaches to the clinical development of DNA methylation inhibitors as epigenetic remodeling drugs SO SEMINARS IN ONCOLOGY LA English DT Review ID RECEPTOR GENE-EXPRESSION; CANCER TESTIS ANTIGENS; CELL LUNG-CANCER; PHASE-I TRIAL; RETINOIC ACID; 5-AZA-2'-DEOXYCYTIDINE DECITABINE; MYELODYSPLASTIC SYNDROME; HYPOMETHYLATING AGENT; PROMOTER REGION; BREAST-CANCER C1 NCI, Div Canc Treatment & Diagnost, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD 20852 USA. RP Murgo, AJ (reprint author), NCI, Div Canc Treatment & Diagnost, Canc Therapy Evaluat Program, Invest Drug Branch, 6130 Execut Blvd,7131, Bethesda, MD 20852 USA. EM murgoa@mail.nih.gov NR 87 TC 19 Z9 19 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2005 VL 32 IS 5 BP 458 EP 464 DI 10.1053/j.seminoncol.2005.07.004 PG 7 WC Oncology SC Oncology GA 973SZ UT WOS:000232544200005 PM 16210086 ER PT J AU Schrump, DS Nguyen, DM AF Schrump, DS Nguyen, DM TI Targeting the epigenome for the treatment and prevention of lung cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID HISTONE DEACETYLASE INHIBITORS; DEPSIPEPTIDE-MEDIATED APOPTOSIS; MESSENGER-RNA EXPRESSION; BINDING PROTEIN MECP2; TUMOR-SUPPRESSOR GENE; CELL-CYCLE PROTEINS; PHASE-II TRIAL; DNA METHYLATION; PROMOTER HYPERMETHYLATION; MELANOMA ANTIGEN C1 NCI, Ctr Canc Res, Thorac Oncol Sect, Surg Branch,NIH, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Ctr Canc Res, Thorac Oncol Sect, Surg Branch,NIH, Bldg 10,4-3940 10 Ctr Dr, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov NR 168 TC 27 Z9 28 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2005 VL 32 IS 5 BP 488 EP 502 DI 10.1053/j.seminoncol.2005.07.007 PG 15 WC Oncology SC Oncology GA 973SZ UT WOS:000232544200009 PM 16210090 ER PT J AU Cizza, G Skarulis, M Mignot, E AF Cizza, G Skarulis, M Mignot, E TI A link between short sleep and obesity: Building the evidence for causation SO SLEEP LA English DT Editorial Material ID BODY-MASS INDEX; ENVIRONMENTAL-FACTORS; RISK-FACTORS; DURATION; POPULATION; RESTRICTION; OVERWEIGHT; CHILDHOOD; LEPTIN; COHORT C1 Stanford Univ, Sch Med, Ctr Narcolepsy, Palo Alto, CA 94304 USA. NIDDK, Clin Endocrine Sect, NIH, Bethesda, MD USA. RP Mignot, E (reprint author), Stanford Univ, Sch Med, Ctr Narcolepsy, 701-B Welch Rd,Room 146, Palo Alto, CA 94304 USA. EM mignot@stanford.edu RI Loureiro, Nuno/I-6400-2012 OI Loureiro, Nuno/0000-0002-1166-3219 FU Intramural NIH HHS; NIMH NIH HHS [MH-073435] NR 31 TC 56 Z9 57 U1 0 U2 7 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 PD OCT 1 PY 2005 VL 28 IS 10 BP 1217 EP 1220 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 972NT UT WOS:000232461200004 PM 16295203 ER PT J AU Nabel, EG AF Nabel, EG TI Fostering the independence of new investigators SO SLEEP LA English DT Editorial Material C1 NHLBI, Off Director, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Off Director, Bldg 31,Room 5A52,31 Ctr Dr MSC 2486, 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 PD OCT 1 PY 2005 VL 28 IS 10 BP 1221 EP 1222 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 972NT UT WOS:000232461200005 PM 16295204 ER PT J AU Schwartz, CM Spivak, CE Baker, SC McDaniel, TK Loring, JF Nguyen, C Chrest, FJ Wersto, R Arenas, E Zeng, XM Freed, WJ Rao, MS AF Schwartz, CM Spivak, CE Baker, SC McDaniel, TK Loring, JF Nguyen, C Chrest, FJ Wersto, R Arenas, E Zeng, XM Freed, WJ Rao, MS TI NTera2: A model system to study dopaminergic differentiation of human embryonic stem cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID IN-VITRO; NEURONAL DIFFERENTIATION; CARCINOMA-CELLS; RETINOIC ACID; TERATOCARCINOMA CELLS; TYROSINE-HYDROXYLASE; SURFACE-ANTIGENS; HNT NEURONS; ES CELLS; HUMAN BLASTOCYSTS AB NTera2, a human embryonal carcinoma (EC) stem cell line, shares many characteristics with human embryonic stem cells (hESCs). To determine whether NTera2 can serve as a useful surrogate for hESCs, we compared global gene expression between undifferentiated NTera2, multiple undifferentiated hESC cell lines, and their differentiated derivatives, and we showed that NTera2 cells share multiple markers with hESCs. Similar to hESCs, NTera2 cells differentiated into TH-positive cells that express dopaminergic markers including AADC, DAT, Nurr1, TrkB, TrkC, and GFRA1 when co-cultured with PA6 cells. Flow cytometry analysis showed that tyrosine hydroxylase (TH) and neural cell adhesion molecule (NCAM) expression increased, whereas SSEA4 expression decreased as cells differentiated. Medium conditioned by PA6 cells stimulated differentiation of NTera2 cells to generate TH-positive cells that expressed dopaminergic markers. Flow cytometry selected polysialylated (PSA-NCAM) cells responded to medium conditioned by PA6 cells by differentiating into TH- positive cells and expressed dopaminergic markers. Sorted cells differentiated for 4 weeks in PA6 cell conditioned media included functional neurons that responded to neurotransmitters and exhibited electronic excitability. Therefore, NTera2 cell dopaminergic neuronal differentiation and PSA- NCAM enrichment provides a useful system for the future study of hESCs. C1 NIA, Stem Cell Biol Unit, Neurosci Lab, Gerontol Res Ctr,Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. NIA, DDHS, Flow Cytometry Unit,Intramural Res Program, Cent Lab Serv Sect,Res Resources Branch,NIH, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Cellular Neurobiol Branch, DHHS, NIH, Baltimore, MD 21224 USA. Illumina Inc, San Diego, CA 92121 USA. Burnham Inst, Program Stem Cells & Regenerat, La Jolla, CA 92037 USA. Karolinska Inst, Retzius Lab, Mol Neurobiol Lab, S-17177 Stockholm, Sweden. RP Schwartz, CM (reprint author), NIA, Stem Cell Biol Unit, Neurosci Lab, Gerontol Res Ctr,Dept Hlth & Human Serv,NIH, 333 Cassell Hlth, Baltimore, MD 21224 USA. EM schwartzc@mail.nih.gov NR 60 TC 40 Z9 45 U1 4 U2 9 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD OCT PY 2005 VL 14 IS 5 BP 517 EP 534 DI 10.1089/scd.2005.14.517 PG 18 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 992SO UT WOS:000233904500007 PM 16305337 ER PT J AU Sulima, A Prisinzano, TE Spande, T Deschamps, JR Whittaker, N Hochberg, Z Jacobson, AE Rice, KC AF Sulima, A Prisinzano, TE Spande, T Deschamps, JR Whittaker, N Hochberg, Z Jacobson, AE Rice, KC TI A concise method for the preparation of deuterium-labeled cortisone: Synthesis of [6,7-H-2]cortisone SO STEROIDS LA English DT Article DE cortisone; cortisol; deuterium-label; 11 beta-HSD; [6,7-H-2]cortisone ID HOMOGENEOUS CATALYTIC HYDROGENATION; MAGNETIC-RESONANCE SPECTROSCOPY; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; MASS-SPECTROMETRY; STEROIDS; C-13; CORTICOSTEROIDS; REDUCTION AB A method is described for the synthesis of isotopically labeled cortisone from commercially available cortisone acetate through a Delta(4.6)-dieneone. Direct deuteration of the dienone acetate with various catalysts in different solvent systems failed to give an isolable product. Initial hydrolysis of the side-chain ester of the Delta(4.6)-dieneone and subsequent derivatization gave the key intermediate, 17 alpha,20;20,21-bismethylenedioxy-pregna-4,6-diene-3,11-dione, which could be satisfactorily deuterated to the desired product. The availability of [6,7-H-2]cortisone will provide a tool for the future study of the metabolism of cortisone in human tissues. (c) 2005 Elsevier Inc. All rights reserved. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. Meyer Childrens Hosp, Div Endocrinol, IL-31096 Haifa, Israel. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, Bldg 8,Room BI-23,8 Ctr Dr MSC 0815, Bethesda, MD 20892 USA. EM kr21f@nih.gov RI Prisinzano, Thomas/B-7877-2010; OI Deschamps, Jeffrey/0000-0001-5845-0010 NR 27 TC 4 Z9 4 U1 2 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 OCT PY 2005 VL 70 IS 11 BP 763 EP 769 DI 10.1016/j.steroids.2005.04.006 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 965EO UT WOS:000231933300004 PM 16005918 ER PT J AU Hall, TMT AF Hall, TMT TI Structure and function of argonaute proteins SO STRUCTURE LA English DT Review ID CRYSTAL-STRUCTURE; MICRORNA TARGETS; PAZ DOMAIN; RNA INTERFERENCE; SLICER ACTIVITY; PIWI PROTEIN; RECOGNITION; DROSOPHILA; RISC; INSIGHTS AB Argonaute (Ago) family proteins are multidomain proteins expressed in prokaryotic and eukaryotic organisms. In eukaryotes, Ago proteins are most well known for their roles in RNA silencing. In prokaryotes, the functions of Ago proteins are unknown, but based on their similarity to eukaryotic Ago proteins, they could be involved in nucleic acid-directed regulatory pathways related to RNA silencing. Recent structural and biochemical studies have shed new light on the function of this family of proteins. These studies reveal how these proteins recognize and cleave RNA and suggest a function for prokaryotic family members. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM hall4@niehs.nih.gov NR 37 TC 67 Z9 72 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT PY 2005 VL 13 IS 10 BP 1403 EP 1408 DI 10.1016/j.str.2005.08.005 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 977EQ UT WOS:000232785600005 PM 16216572 ER PT J AU Gan, JH Tropea, JE Austin, BP Court, DL Waugh, DS Ji, XH AF Gan, JH Tropea, JE Austin, BP Court, DL Waugh, DS Ji, XH TI Intermediate states of ribonuclease III in complex with double-stranded RNA SO STRUCTURE LA English DT Article ID ESCHERICHIA-COLI; PROCESSING ACTIVITY; BINDING DOMAIN; DSRNA-BINDING; PROTEIN; MECHANISM; CLEAVAGE; INTERFERENCE; MOLSCRIPT; MODELS AB Bacterial ribonuclease III (RNase 111) can affect RNA structure and gene expression in either of two ways: as a processing enzyme that cleaves double-stranded (ds) RNA, or as a binding protein that binds but does not cleave dsRNA. We previously proposed a model of the catalytic complex of RNase III with dsRNA based on three crystal structures, including the endonuclease domain of RNase III with and without bound metal ions and a dsRNA binding protein complexed with dsRNA. We also reported a noncatalytic assembly observed in the crystal structure of an RNase III mutant, which binds but does not cleave dsRNA, complexed with dsRNA. We hypothesize that the RNase III(.)dsRNA complex can exist in two functional forms, a catalytic complex and a noncatalytic assembly, and that in between the two forms there may be intermediate states. Here, we present four crystal structures of RNase III complexed with dsRNA, representing possible intermediates. C1 NCI, Canc Res Ctr, NIH, Frederick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Canc Res Ctr, NIH, Frederick, MD 21702 USA. EM jix@ncifcrf.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 38 TC 37 Z9 38 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT PY 2005 VL 13 IS 10 BP 1435 EP 1442 DI 10.1016/j.str.2005.06.014 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 977EQ UT WOS:000232785600008 PM 16216575 ER PT J AU Pascale, P Oddo, M Pacher, P Augsburger, M Liaudet, L AF Pascale, Patrizio Oddo, Mauro Pacher, Pal Augsburger, Marc Liaudet, Lucas TI Severe rhabdomyolysis following venlafaxine overdose SO THERAPEUTIC DRUG MONITORING LA English DT Article DE venlafaxine; rhabdomyolysis; toxicity; overdose; serotoninergic drug ID CREATINE-KINASE; TOXICITY; ANTIDEPRESSANTS; SEIZURE; DRUGS AB Venlafaxine is a recently developed serotoninergic antidepressant whose reported toxicity at overdose levels includes central nervous system depression, seizures, and cardiovascular toxicity. The authors now present a case of venlafaxine overdose in a young woman complicated by a rise in plasma creatine kinase activity up to 52,600 U/L. Immediate therapy with intravenous fluids, bicarbonate, and furosemide was administered, and there were no further complications, notably no renal failure. This case supports the notion that venlafaxine can induce direct skeletal muscle toxicity leading to severe rhabdomyolysis. Therefore, clinicians should monitor muscle enzymes in patients with venlafaxine overdose to detect the development of rhabdomyolysis at an early stage and to initiate appropriate therapy rapidly. C1 Univ Hosp, Div Crit Care, Dept Internal Med, CH-1011 Lausanne, Switzerland. NIAAA, NIH, Sect Neuroendocrinol, Lab Phys Studies, Bethesda, MD 20892 USA. Univ Lausanne, Inst Forens Med, Lab Forens Toxicol & Chem, CH-1011 Lausanne, Switzerland. RP Liaudet, L (reprint author), Univ Hosp, Div Crit Care, Dept Internal Med, BH 10-982, CH-1011 Lausanne, Switzerland. EM Lucas.Liaudet@chuv.hospvd.ch RI Pacher, Pal/B-6378-2008; Oddo, Mauro/R-3370-2016; Liaudet, Lucas/E-1322-2017 OI Pacher, Pal/0000-0001-7036-8108; Oddo, Mauro/0000-0002-6155-2525; Liaudet, Lucas/0000-0003-2670-4930 FU Intramural NIH HHS [Z99 AA999999] NR 21 TC 9 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD OCT PY 2005 VL 27 IS 5 BP 562 EP 564 PG 3 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 155YX UT WOS:000245615900003 PM 16175126 ER PT J AU Kumamoto, K Sugano, K Hoshino, M Utsumi, Y Suzuki, S Takenoshita, S AF Kumamoto, K Sugano, K Hoshino, M Utsumi, Y Suzuki, S Takenoshita, S TI Cavernous hemangioma of the thyroid SO THYROID LA English DT Article C1 Ohara Gen Hosp, Dept Surg, Fukushima 9608611, Japan. Ohara Gen Hosp, Dept Pathol, Fukushima 9608611, Japan. Fukushima Med Univ, Dept Surg 2, Fukushima 9601295, Japan. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Kumamoto, K (reprint author), Ohara Gen Hosp, Dept Surg, 6-11 Omachi, Fukushima 9608611, Japan. EM fwiy_4465@mb.infoweb.ne.jp NR 2 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD OCT PY 2005 VL 15 IS 10 BP 1199 EP 1201 DI 10.1089/thy.2005.15.1199 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 987AX UT WOS:000233491900016 PM 16279857 ER PT J AU Carreon, JD Martin, MP Hildesheim, A Gao, X Schiffman, M Herrero, R Bratti, MC Sherman, ME Zaino, RJ Carrington, M Wang, SS AF Carreon, JD Martin, MP Hildesheim, A Gao, X Schiffman, M Herrero, R Bratti, MC Sherman, ME Zaino, RJ Carrington, M Wang, SS TI Human leukocyte antigen class I and II haplotypes and risk of cervical cancer SO TISSUE ANTIGENS LA English DT Article DE cancer; cervix; haplotype; human leukocyte antigen ID NEOPLASIA; ALLELES AB Human leukocyte antigen (HLA) variations may affect immune response to human papillomavirus infection and subsequent cervical neoplasia risk. We investigated the frequency and relationship between HLA-A-B and HLA-A-B-DR haplotypes among women with cervical cancer/high-grade lesions (n = 365) and cytologically normal population controls (n = 681) within three cervical neoplasia studies in the US and Costa Rica. Notable differences in haplotype frequencies were observed; the HLA-A*01-B*08 haplotype occurred in > 5% of US Caucasians but in < 1% of Costa Ricans. The most prevalent HLA-A*24-B*40-DR*04 haplotype in Costa Rica (5%) was found in < 1% of US Caucasians. No HLA haplotype was significantly associated with cervical neoplasia, suggesting that individual allele associations reported to date (e.g. HLA-DR*13) are not likely explained by underlying haplotypes. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Basic Res Program, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. Proyecto Epidemiol Guanacaste, Guanacaste, Costa Rica. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. RP Carreon, JD (reprint author), NCI, DCEG, 6120 Execut Blvd, Rockville, MD 20852 USA. NR 8 TC 17 Z9 18 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD OCT PY 2005 VL 66 IS 4 BP 321 EP 324 DI 10.1111/j.1399-0039.2005.00478.x PG 4 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 966VO UT WOS:000232050800010 PM 16185329 ER PT J AU Rastogi, T Jha, P Reddy, KS Prabhakaran, D Spiegelman, D Stampfer, MJ Willett, WC Ascherio, A AF Rastogi, T Jha, P Reddy, KS Prabhakaran, D Spiegelman, D Stampfer, MJ Willett, WC Ascherio, A TI Bidi and cigarette smoking and risk of acute myocardial infarction among males in urban India SO TOBACCO CONTROL LA English DT Article ID MORTALITY AB Death from myocardial infarction (MI) in India is exacerbated by smoking of bidis or cigarettes. Smoking among 309 men with incident MI was compared to 618 age matched controls; 56% of the individuals with MI and 26% of controls were current smokers. Current smokers had a relative risk of 4.7 (95% confidence interval (CI) 3.2 to 6.9) compared to never smokers. Relative risks for smoking more than 10 cigarettes or 10 bidis daily were 9.1 (95% CI 4.7 to 17.7) and 8.1 (95% CI 4.3 to 15.3), respectively. It is estimated that smoking may cause 53% (95% CI 47% to 64%) of MIs among urban males in India. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Univ Toronto, Toronto, ON, Canada. All India Inst Med Sci, New Delhi, India. Harvard Univ, Sch Publ Hlth, Dept Biostat & Epidemiol, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. RP Rastogi, T (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 6120 Execut Blvd,EPS 320, Rockville, MD 20852 USA. EM TRASTOGI@post.harvard.edu OI Prabhakaran, Dorairaj/0000-0002-3172-834X FU FIC NIH HHS [R01 TW05991-01] NR 13 TC 11 Z9 13 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD OCT PY 2005 VL 14 IS 5 BP 356 EP 358 DI 10.1136/tc.2005.011965 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 967CP UT WOS:000232069400019 PM 16183987 ER PT J AU Sander, M Cadet, J Casciano, DA Galloway, SM Marnett, LJ Novak, RF Pettit, SD Preston, RJ Skare, JA Williams, GM Van Houten, B Gollapudi, BB AF Sander, M Cadet, J Casciano, DA Galloway, SM Marnett, LJ Novak, RF Pettit, SD Preston, RJ Skare, JA Williams, GM Van Houten, B Gollapudi, BB TI Proceedings of a workshop on DNA adducts: Biological significance and applications to risk assessment Washington, DC, April 13-14, 2004 SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE risk assessment; DNA; DNA adducts; DNA damage; workshop report ID ENVIRONMENTAL-POLLUTANT 3-NITROBENZANTHRONE; TANDEM MASS-SPECTROMETRY; A/J MOUSE LUNG; ETHYLENE-OXIDE; IN-VIVO; GENOME REARRANGEMENTS; CARCINOGENIC RISK; SOMATIC MUTATIONS; LIVER-CANCER; HUMAN-CELLS AB In April 2004, the Health and Environmental Sciences Institute, a branch of the International Life Sciences Institute, with support from the National Institute of Environmental Health Sciences, organized a workshop to discuss the biological significance of DNA adducts. Workshop speakers and attendees included leading international experts from government, academia, and industry in the field of adduct detection and interpretation. The workshop initially examined the relationship between measured adduct levels in the context of exposure and dose. This was followed by a discussion on the complex response of cells to deal with genotoxic insult in complex, interconnected, and interdependent repair pathways. One of the major objectives of the workshop was to address the recurring question about the mechanistic and toxicological relevance of low-concentration measured adducts and the presentations in the session entitled "Can low levels of DNA adducts predict adverse outcomes?" served as catalysts for further discussions on this subject during the course of the workshop. Speakers representing the regulatory community and industry reviewed the value, current practices, and limitations of utilizing DNA adduct data in risk assessment and addressed a number of practical questions pertaining to these issues. While no consensus statement emerged on the biological significance of low levels of DNA adducts, the workshop concluded by identifying the need for more experimental data to address this important question. One of the recommendations stemming from this workshop was the need to develop an interim "decision-logic" or framework to guide the integration of DNA adduct data in the risk assessment process. HESI has recently formed a subcommittee consisting of experts in the field and other key stakeholders to address this recommendation as well as to identify specific research projects that could help advance the understanding of the biological significance of low levels of DNA adducts. (c) 2005 Elsevier Inc. All rights reserved. C1 ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA. Page 1 Editorial Serv, Durham, NC 27707 USA. French Atom Energy Comiss, F-38054 Grenoble, France. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. Merck Res Labs, West Point, PA 19486 USA. Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37235 USA. Wayne State Univ, Inst Chem Toxicol, Detroit, MI 48201 USA. US EPA, Res Triangle Pk, NC 27711 USA. Procter & Gamble Co, Cent Product Safety, Cincinnati, OH 45217 USA. New York Med Coll, Dept Toxicol & Pathol, Valhalla, NY 10595 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. RP Pettit, SD (reprint author), ILSI Hlth & Environm Sci Inst, 1 Thomas Circle,9th Floor NW, Washington, DC 20005 USA. EM spettit@ilsi.org NR 77 TC 15 Z9 15 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 1 PY 2005 VL 208 IS 1 BP 1 EP 20 DI 10.1016/j.taap.2004.12.012 PG 20 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 972TT UT WOS:000232476800001 PM 16164957 ER PT J AU de Gramont, A Cohen-Fix, O AF de Gramont, A Cohen-Fix, O TI The many phases of anaphase SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID SISTER-CHROMATID SEPARATION; APC-DEPENDENT PROTEOLYSIS; CONTROLLING MITOTIC EXIT; CELL-CYCLE REGULATION; COHESIN SUBUNIT SCC1; BUDDING YEAST; SACCHAROMYCES-CEREVISIAE; CDC14 PHOSPHATASE; FISSION YEAST; PROMOTING COMPLEX AB Anaphase is the stage of the cell cycle in which duplicated chromosomes separate and move towards opposite poles of the cell. Although its chromosome movements have always been viewed as majestic, until recently anaphase lacked obvious landmarks of regulation. The picture has changed with numerous recent studies that have highlighted the raison d'etre of anaphase. It is now known to be associated with a series of regulatory pathways that promote a switch from high to low cycl in-dependent kinase activity - an essential feature for proper mitotic exit. The balance between protein phosphorylation and protein dephosphorylation drives and coordinates diverse processes such as chromosome movement, spindle dynamics and cleavage furrow formation. This well-ordered sequence of events is central to successful mitosis. C1 NIDDKD, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. RP de Gramont, A (reprint author), NIDDKD, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. EM degramonta@niddk.nih.gov; ornacf@helix.nih.gov FU Intramural NIH HHS NR 100 TC 13 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 2005 VL 30 IS 10 BP 559 EP 568 DI 10.1016/j.tibs.2005.08.008 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 975ZU UT WOS:000232703400005 PM 16126387 ER PT J AU Panyutin, IG Neumann, RD AF Panyutin, IG Neumann, RD TI The potential for gene-targeted radiation therapy of cancers SO TRENDS IN BIOTECHNOLOGY LA English DT Editorial Material ID TRIPLEX-FORMING OLIGONUCLEOTIDES; PEPTIDE NUCLEIC-ACIDS; MESSENGER-RNA; ANTIGENE RADIOTHERAPY; MAMMALIAN-CELLS; AUGER ELECTRONS; STRAND BREAKS; MOUSE MODEL; IN-VITRO; DNA AB Targeted cancer therapy is the mantra now chanted by oncologists of all types. Everyone hopes that the rapid expansion in the knowledge of cancer cell genetics, signaling, regulatory factors and other changes that underlie malignant transformation and metastasis will lead to innovative approaches for the treatment of cancers. To date, successful targeted therapies have been derived from pharmaceutical chemistry - designing chemical compounds intended to disrupt a crucial pathway for malignant cells to survive, grow and metastasize. Radiotherapy also has a goal of more-selective targeting of therapeutic radiation effects to only tumor cells. In this review, we describe our efforts to create a form of gene-targeted radiation therapy by using the unique radiation effects of radionuclides that decay by the Auger process attached to oligonucleotide carrier-molecules that are capable of forming triplex DNA structures with target sequences in the genome of the human cancer cell. C1 NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. EM igorp@helix.nih.gov NR 46 TC 9 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD OCT PY 2005 VL 23 IS 10 BP 492 EP 496 DI 10.1016/j.tibtech.2005.08.001 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 974QG UT WOS:000232605900004 PM 16125814 ER PT J AU Hallenbeck, JM Hansson, GK Becker, KJ AF Hallenbeck, JM Hansson, GK Becker, KJ TI Immunology of ischemic vascular disease: plaque to attack SO TRENDS IN IMMUNOLOGY LA English DT Review ID LOW-DENSITY-LIPOPROTEIN; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; CELLS AGGRAVATES ATHEROSCLEROSIS; ACUTE MYOCARDIAL-INFARCTION; CEREBRAL-ARTERY OCCLUSION; SPINAL-CORD INJURY; TOLL-LIKE RECEPTOR; E KNOCKOUT MICE; CD4(+) T-CELLS AB Interest and studies focused on the role of immune and inflammatory mechanisms in vascular disease have advanced in synchrony with the advances in the understanding of innate immune system regulation and the interplay between innate and adaptive immunity. Clinical studies have implicated immune and inflammatory mechanisms in stroke and acute coronary syndromes. Analyses of genetically modified mice and in vitro and in vivo preclinical ischemia models have yielded insights into pathobiological mechanisms. Deciphering the role of innate immune mechanisms that confer tolerance to ischemia might guide translation of more effective therapies. Antigen-targeted and other forms of focused immunomodulation that can suppress vessel activation and protect ischemic tissue might ultimately find a niche in the prevention and treatment of vascular disease. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Karolinska Hosp, Ctr Mol Med, SE-17176 Stockholm, Sweden. Univ Washington, Sch Med, Harborview Med Ctr, Dept Neurol, Seattle, WA 98104 USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, Bldg 49,Rm 2A10,49 Convent Dr, Bethesda, MD 20892 USA. EM hallenbj@ninds.nih.gov RI Hansson, Goran/B-7423-2012 NR 72 TC 47 Z9 49 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD OCT PY 2005 VL 26 IS 10 BP 550 EP 556 DI 10.1016/j.it.2005.08.007 PG 7 WC Immunology SC Immunology GA 972UB UT WOS:000232477600010 PM 16109503 ER PT J AU Hasko, G Pacher, P Vizi, ES Illes, P AF Hasko, G Pacher, P Vizi, ES Illes, P TI Adenosine receptor signaling in the brain immune system SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE PRODUCTION; RAT HIPPOCAMPAL SLICES; MULTIPLE-SCLEROSIS; EXTRACELLULAR ADENOSINE; GROWTH-FACTOR; REACTIVE ASTROGLIOSIS; PRIMARY ASTROCYTES; DIFFERENT ROLES; A(3) RECEPTOR AB The brain immune system, which consists mainly of astrocytes, microglia and infiltrating immune cells, is quiescent normally, but it is activated in response to pathophysiological events such as ischemia, trauma, inflammation and infection. Adenosine is an endogenous purine nucleoside that is generated at sites that are subjected to these 'stressful' conditions. Adenosine interacts with specific G-protein-coupled receptors on astrocytes, microglia and infiltrating immune cells to regulate the function of the immune system in the brain. Although many of the effects of adenosine on immune-competent cells in the brain protect neuronal integrity, adenosine might also aggravate neuronal injury by promoting inflammatory processes. A more complete understanding of adenosine receptor function in the brain immune system should help develop novel therapeutic ways to treat brain disorders that are associated with a dysfunctional immune response. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, H-1450 Budapest, Hungary. NIAAA, NIH, Bethesda, MD 20892 USA. Univ Leipzig, Rudolf Boehm Inst Pharmacol & Toxicol, D-04107 Leipzig, Germany. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS [Z01 AA000375-02]; NIGMS NIH HHS [R56 GM066189, GM 66189, R01 GM066189, R01 GM066189-01] NR 70 TC 108 Z9 113 U1 1 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD OCT PY 2005 VL 26 IS 10 BP 511 EP 516 DI 10.1016/j.tips.2005.08.004 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 974QJ UT WOS:000232606200005 PM 16125796 ER PT J AU Bischoff, C Graakjaer, J Petersen, HC Jeune, B Bohr, VA Koelvraa, S Christensen, K AF Bischoff, C Graakjaer, J Petersen, HC Jeune, B Bohr, VA Koelvraa, S Christensen, K TI Telomere length among the elderly and oldest-old SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Article ID HUMAN-LYMPHOCYTES; CELLS; LONGEVITY; CENTENARIANS; MORTALITY; TRF2; END; CHROMOSOME-7; MONOSOMY-7; LEUKOCYTES AB Human chromosomes terminate in a number of repeats of the sequence TTAGGG. At birth, each chromosome end is equipped with approximately 15 kb of telomere sequence, but this sequence is shortened during each cell division. In cell cultures telomere shortening is associated with senescence, a phenomenon that has also been observed in normal adult tissues, indicating that telomere loss is associated with organismal ageing. Previous work has established that the rate of telomere loss in humans is age dependent, and recent work shows a sex-specific difference in telomere length and shortening in individuals over the age span of 20 to 75 years. Here, terminal restriction fragment lengths on DNA purified from whole blood were measured to examine the mean telomere length in a cross-sectional cohort of 816 Danish individuals of age 73 to 101 years. In this age group, females show a linear correlation between telomere length and age, whereas the pattern tends to be nonlinear (quadratic in age) for males. This difference in telomere length dynamics between the 2 sexes may be caused by several different mechanisms, including differences in selection by mortality, differences in leukocyte population or different telomerase expression pattern. C1 Univ So Denmark, Inst Publ Hlth, Danish Twin Registry, DK-5000 Odense, Denmark. Aarhus Univ, Inst Human Genet, DK-8000 Aarhus, Denmark. Univ So Denmark, Dept Stat, Odense, Denmark. Univ So Denmark, Inst Publ Hlth, Aging Res Ctr, Odense, Denmark. NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. Cty Hosp Vejle, Dept Clin Genet, Vejle, Denmark. RP Christensen, K (reprint author), Univ So Denmark, Inst Publ Hlth, Danish Twin Registry, JB Winslows Vej 9B, DK-5000 Odense, Denmark. EM KChristensen@health.sdu.dk RI Christensen, Kaare/C-2360-2009; Jeune, Bernard/P-6866-2015 OI Christensen, Kaare/0000-0002-5429-5292; FU NIA NIH HHS [P01-AG08761] NR 41 TC 20 Z9 21 U1 0 U2 2 PU AUSTRALIAN ACAD PRESS PI BOWEN HILLS PA 32 JEAYS ST, BOWEN HILLS, QLD 4006, AUSTRALIA SN 1832-4274 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD OCT PY 2005 VL 8 IS 5 BP 425 EP 432 DI 10.1375/183242705774310079 PG 8 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 974LH UT WOS:000232592500001 PM 16212831 ER PT J AU Bischoff, C Graakjaer, J Petersen, HC Hjelmborg, JV Vaupel, JW Bohr, V Koelvraa, S Christensen, K AF Bischoff, C Graakjaer, J Petersen, HC Hjelmborg, JV Vaupel, JW Bohr, V Koelvraa, S Christensen, K TI The heritability of telomere length among the elderly and oldest-old SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Article ID HUMAN-LYMPHOCYTES; CHROMOSOME; CELLS; PROTEIN; HUMANS; TWIN; DNA; MONOSOMY-7; LOCUS; TRF2 AB A tight link exists between telomere length and both population doublings of a cell culture and age of a given organism. The more population doublings of the cell culture or the higher the age of the organism, the shorter the telomeres. The proposed model for telomere shortening, called the end replication problem, explains why the telomere erodes at each cellular turnover. Telomere length is regulated by a number of associated proteins through a number of different signaling pathways. The determinants of telomere length were studied using whole blood samples from 287 twin pairs aged 73 to 95 years. Structural equation models revealed that a model including additive genetic effects and nonshared environment was the best fitting model and that telomere length was moderately heritable, with an estimate that was sensitive to the telomere length standardization procedure. Sex-specific analyses showed lower heritability in males, although not statistically significant, which is in line with our earlier finding of a sex difference in telomere dynamics among the elderly and oldest-old. C1 Univ So Denmark, Inst Publ Hlth, Danish Twin Registry, DK-5000 Odense, Denmark. Aarhus Univ, Inst Human Genet, DK-8000 Aarhus, Denmark. Univ So Denmark, Dept Stat, Odense, Denmark. NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. Vejle Hosp, Dept Clin Genet, Vejle, Denmark. RP Christensen, K (reprint author), Univ So Denmark, Inst Publ Hlth, Danish Twin Registry, JB Winslows Vej 9B, DK-5000 Odense, Denmark. EM KChristensen@health.sdu.dk RI Christensen, Kaare/C-2360-2009 OI Christensen, Kaare/0000-0002-5429-5292 FU NIA NIH HHS [P01-AG-08761] NR 33 TC 43 Z9 43 U1 0 U2 2 PU AUSTRALIAN ACAD PRESS PI BOWEN HILLS PA 32 JEAYS ST, BOWEN HILLS, QLD 4006, AUSTRALIA SN 1832-4274 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD OCT PY 2005 VL 8 IS 5 BP 433 EP 439 DI 10.1375/183242705774310141 PG 7 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 974LH UT WOS:000232592500002 PM 16212832 ER PT J AU Kaplan, B Martin, BM Boykov, O Gal, R Pras, M Shechtman, I Saute, M Kramer, MR AF Kaplan, B Martin, BM Boykov, O Gal, R Pras, M Shechtman, I Saute, M Kramer, MR TI Co-deposition of amyloidogenic immunoglobulin light and heavy chains in localized pulmonary amyloidosis SO VIRCHOWS ARCHIV LA English DT Article DE amyloid; pulmonary amyloidosis; immunoglobulin light and heavy chains; microtechniques ID B-CELL LYMPHOMA; CHEMICAL-CHARACTERIZATION; DEPOSITION DISEASE; CONSTANT-REGION; PROTEINS; PATIENT; TISSUE; FEATURES; NODULES; DOMAIN AB Localized pulmonary amyloidosis is a rare condition whose pathogenesis is insufficiently understood. In the present study, we report a case of localized pulmonary amyloidosis associated with lung-restricted lymphoplasmacytoid lymphoma, monoclonal for immunoglobulin (Ig) G lambda (lambda). Biochemical microtechniques have been applied for extraction, purification, and characterization of amyloid proteins. Surprisingly, chemical analysis of these proteins revealed a not-previously-described case of combined deposits containing Ig fragments of gamma heavy chain (variable domain) and lambda light chain (constant domain). In view of the absence of circulating monoclonal Ig, this case supports the hypothesis that localized amyloid is formed by local plasmacytoid cells. C1 Chaim Sheba Med Ctr, Heller Inst Med Res, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Sch Med, Tel Hashomer, Israel. NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. Rabin Med Ctr, Dept Pathol, Petah Tiqwa, Israel. Rabin Med Ctr, Dept Thorac Surg, Petah Tiqwa, Israel. Rabin Med Ctr, Pulm Inst, Petah Tiqwa, Israel. RP Kaplan, B (reprint author), Chaim Sheba Med Ctr, Heller Inst Med Res, IL-52621 Tel Hashomer, Israel. EM kaplanb@sheba.health.gov.il NR 36 TC 13 Z9 15 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD OCT PY 2005 VL 447 IS 4 BP 756 EP 761 DI 10.1007/s00428-005-0009-0 PG 6 WC Pathology SC Pathology GA 980MQ UT WOS:000233023000012 PM 16021505 ER PT J AU Chen, LJ Lebetkin, EH Burka, LT AF Chen, LJ Lebetkin, EH Burka, LT TI Metabolism and disposition of juglone in male F344 rats SO XENOBIOTICA LA English DT Article DE juglone; disposition; metabolism; rat; kidney ID DT-DIAPHORASE; DERIVATIVES; TOXICOLOGY; EXCRETION AB The metabolism and disposition of C-14-labelled juglone in male F344 rats following oral, intravenous and dermal administration were studied. Approximately 40-50% of an oral dose (0.1 to 10 mg kg(-1)) and less than 20% of the dermal dose (4 mg kg(-1)) were absorbed within 24 h. Most of the oral dose was excreted in faeces and urine within 24 h and only 1-3% remained in the tissues. High concentrations of juglone-derived radioactivity were found in kidney for all three dosing routes. The accumulation in kidney can be attributed to covalent binding of juglone and/or metabolites to cytosolic protein. Five metabolites were identified in the urine of rats treated with an oral dose: 1,4,5-trihydroxynaphthalene di-glucuronide, 1,4,5-trihydroxynaphthalene mono-glucuronide mono-sulfate, 2-sulfo-2,3-dihydrojuglone, 4,8-dihydroxy-1-tetralone mono-glucuronide and 1,4,5-trihydroxynaphthalene mono-glucuronide. Liver microsomal incubations of juglone in the presence of NAD(P)H and UDP-glucuronic acid gave rise to two 1,4,5-trihydroxynaphthalene mono-glucuronides. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Chen, LJ (reprint author), NIEHS, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. EM ferguso2@niehs.nih.gov NR 18 TC 7 Z9 7 U1 1 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD OCT-NOV PY 2005 VL 35 IS 10-11 BP 1019 EP 1034 DI 10.1080/00498250500356621 PG 16 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 999YH UT WOS:000234427600007 PM 16393859 ER PT J AU McLeod, CJ Aziz, A Hoyt, RF McCoy, JP Sack, MN AF McLeod, CJ Aziz, A Hoyt, RF McCoy, JP Sack, MN TI Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ISCHEMIA/REPERFUSION INJURY; TRANSGENIC MICE; PROTON LEAK; RAT-HEART; SUPEROXIDE; MITOCHONDRIA; OVEREXPRESSION; ANTIOXIDANTS; ACTIVATION; UCP2 AB Transient cardiac ischemia activates cell survival signaling, conferring subsequent ischemia tolerance to the heart. This biological phenomenon, termed ischemic preconditioning, results in improved clinical outcome and attenuated infarct size following myocardial infarction. To explore genomic modifications underpinning this ischemia tolerance, we delineated the regulation and function of the cardiac enriched mitochondrial uncoupling proteins 2 and 3 during delayed ischemic preconditioning in the rat. Cardiac transcripts of genes encoding uncoupling proteins 2 and 3 are upregulated in parallel with infarct size reduction in preconditioned hearts. Mitochondria isolated from preconditioned hearts exhibit an augmented inducible proton leak. In parallel, following anoxia-reoxygenation these mitochondria generate less hydrogen peroxide compared with non-preconditioned mitochondria. Preconditioning in rat cardiac derived myoblasts is abolished following uncoupling protein-2 depletion by RNA-interference. RNAi of uncoupling protein-3 partially attenuates the capacity to precondition these cells. Functional characterization of anoxia and reoxygenation tolerance following uncoupling protein 2 or 3 and combined 2 and 3 RNAi shows the largest reduction in viability follows depletion of both homologues. Uncoupling protein-2 depletion alone significantly attenuates anoxia-reoxygenation tolerance but uncoupling protein-3 depletion does not reduce anoxia tolerance. In parallel combined uncoupling protein depletion and isolated uncoupling protein-2 depletion augments ROS production in viable cardiomyocytes following anoxia-reoxygenation. Concurrent antioxidant administration ameliorates the uncoupling protein-depleted anoxia-susceptible phenotype. In conclusion, mitochondrial uncoupling proteins are necessary components of ischemia tolerance and function as components of the cellular antioxidant defense program. In the cytoprotective hierarchy, uncoupling protein-2 appears to play a greater role than uncoupling protein-3 in modulating ischemia/anoxia tolerance in heart-derived cells. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. NHLBI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10 CRC,Rm 5-3150,10 Ctr Dr, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov FU Intramural NIH HHS NR 38 TC 97 Z9 102 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 SEP 30 PY 2005 VL 280 IS 39 BP 33470 EP 33476 DI 10.1074/jbc.M505258200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 966YG UT WOS:000232058100046 PM 16079144 ER PT J AU Zhou, Z Huang, YZ Bai, YW AF Zhou, Z Huang, YZ Bai, YW TI An on-pathway hidden intermediate and the early rate-limiting transition state of Rd-apocytochrome b(562) characterized by protein engineering SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein engineering; rate-limiting transition state; partially unfolded intermediate; on-pathway hidden intermediate ID PHI-VALUE ANALYSIS; 4-HELIX BUNDLE PROTEIN; CHYMOTRYPSIN INHIBITOR-2; MOLECULAR-DYNAMICS; HYDROGEN-EXCHANGE; FOLDING PATHWAY; PSI-ANALYSIS; STABILITY; BARNASE; ENERGY AB The folding pathway of Rd-apocytochrome b(562) a four-helix bundle protein, was characterized using Trp and Ala /Gly pair mutations. We found that the Trp mutants (F65W) of both the fully folded Rd-apocytochrome b(562) and a partially unfolded intermediate with the N-terminal helix (helix I) unfolded, fold with identical folding rates, providing direct evidence for the conclusion that the rate-limiting transition state folds before the partially unfolded intermediate; and that this hidden intermediate is an on-pathway intermediate. We further characterized the helical structures formed in the rate-limiting transition state by measuring the folding/ unfolding rates for Ala/Gly pair mutations at solvent-exposed positions. Little change in folding rates occurred for the Ala/ Gly pair mutations at positions in helix I and the C-terminal regions of helix II and IV. In contrast, a significant difference in folding rates was observed for the Ala/Gly pair mutations in helix III and the N-terminal regions of helix II and IV, suggesting that helix III and the N-terminal regions of helix II and IV are formed in the rate-limiting transition state. These results complement those obtained from earlier studies and help to define the folding pathway of Rd-apocytochrome b (562) in more detail. Published by Elsevier Ltd.The folding pathway of Rd-apocytochrome b(562) a four-helix bundle protein, was characterized using Trp and Ala /Gly pair mutations. We found that the Trp mutants (F65W) of both the fully folded Rd-apocytochrome b(562) and a partially unfolded intermediate with the N-terminal helix (helix I) unfolded, fold with identical folding rates, providing direct evidence for the conclusion that the rate-limiting transition state folds before the partially unfolded intermediate; and that this hidden intermediate is an on-pathway intermediate. We further characterized the helical structures formed in the rate-limiting transition state by measuring the folding/ unfolding rates for Ala/Gly pair mutations at solvent-exposed positions. Little change in folding rates occurred for the Ala/ Gly pair mutations at positions in helix I and the C-terminal regions of helix II and IV. In contrast, a significant difference in folding rates was observed for the Ala/Gly pair mutations in helix III and the N-terminal regions of helix II and IV, suggesting that helix III and the N-terminal regions of helix II and IV are formed in the rate-limiting transition state. These results complement those obtained from earlier studies and help to define the folding pathway of Rd-apocytochrome b(562) in more detail. Published by Elsevier Ltd.The folding pathway of Rd-apocytochrome b(562), a four-helix bundle protein, was characterized using Trp and Ala/Gly pair mutations. We found that the Trp mutants (F65W) of both the fully folded Rd-apocytochrome b(562) and a partially unfolded intermediate with the N-terminal helix (helix I) unfolded, fold with identical folding rates, providing direct evidence for the conclusion that the rate-limiting transition state folds before the partially unfolded intermediate; and that this hidden intermediate is an on-pathway intermediate. We further characterized the helical structures formed in the rate-limiting transition state by measuring the folding/ unfolding rates for Ala/Gly pair mutations at solvent-exposed positions. Little change in folding rates occurred for the Ala/Gly pair mutations at positions in helix I and the C-terminal regions of helix II and IV. In contrat, a significant difference in folding rates was observed for the Ala/Gly pair mutations in helix III and the N-terminal regions of helix II and IV, suggesting that helix III and the N-terminal regions of helix II and IV are formed in the rate-limiting transition state. These results complement those obtained from earlier studies and help to define the folding pathway of Rd-apocytochrome b(562) in more detail. Published by Elsevier Ltd. C1 NCI, Biochem Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, Canc Res Ctr, NIH, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov FU Intramural NIH HHS NR 28 TC 13 Z9 13 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 30 PY 2005 VL 352 IS 4 BP 757 EP 764 DI 10.1016/j.jmb.2005.07.057 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 968UN UT WOS:000232188100001 PM 16125200 ER PT J AU Puhlmann, M Weinreich, DM Farma, JM Carroll, NM Turner, EM Alexander, HR AF Puhlmann, M Weinreich, DM Farma, JM Carroll, NM Turner, EM Alexander, HR TI Interleukin-1 beta induced vascular permeability is dependent on induction of endothelial Tissue Factor (TF) activity SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA; PROCOAGULANT ACTIVITY; RECEPTOR BLOCKADE; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; CELLS; INHIBITION; CHEMOTHERAPY; ANTAGONIST AB IL-1 beta is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1 beta are mediated through induction of tissue factor (TF) but its alterations on vascular permeability are not well characterized. We found that IL-1 beta induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs) under routine culture conditions. However, IL-1 beta caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1 beta induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM markus.puhlmann@verizon.net; dmw4@columbia.edu; j.farma@temple.edu; carrollnm@upmc.edu; ewa_turner@nih.gov; richard_alexander@nih.gov NR 29 TC 25 Z9 27 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 30 PY 2005 VL 3 AR 37 DI 10.1186/1479-5876-3-37 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 979ZD UT WOS:000232982800001 PM 16197553 ER PT J AU Kornyshev, AA Lee, DJ Leikin, S Wynveen, A Zimmerman, SB AF Kornyshev, AA Lee, DJ Leikin, S Wynveen, A Zimmerman, SB TI Direct observation of azimuthal correlations between DNA in hydrated aggregates SO PHYSICAL REVIEW LETTERS LA English DT Article ID X-RAY-DIFFRACTION; ELECTROSTATIC INTERACTION; HELICAL MACROMOLECULES; LIQUID-CRYSTALS; B-DNA; PARAMETERS; FIBERS; PHASE; TWIST AB This study revisits the classical x-ray diffraction patterns from hydrated, noncrystalline fibers originally used to establish the helical structure of DNA. We argue that changes in these diffraction patterns with DNA packing density reveal strong azimuthally dependent interactions between adjacent molecules up to similar to 40 A interaxial or similar to 20 A surface-to-surface separations. These interactions appear to force significant torsional "straightening" of DNA and strong azimuthal alignment of nearest neighbor molecules. The results are in good agreement with the predictions of recent theoretical models relating DNA-DNA interactions to the helical symmetry of their surface charge patterns. C1 Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England. NICHD, Sect Phys Biochem, DHHS, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, DHHS, NIH, Bethesda, MD 20892 USA. RP Leikin, S (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England. EM leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008; Kornyshev, Alexei/C-3404-2008 OI Leikin, Sergey/0000-0001-7095-0739; NR 37 TC 20 Z9 20 U1 0 U2 2 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD SEP 30 PY 2005 VL 95 IS 14 AR 148102 DI 10.1103/PhysRevLett.95.148102 PG 4 WC Physics, Multidisciplinary SC Physics GA 969JG UT WOS:000232229800064 PM 16241694 ER PT J AU Berger, VW AF Berger, VW TI The reverse propensity score to detect selection bias and correct for baseline imbalances SO STATISTICS IN MEDICINE LA English DT Article DE allocation concealment; balancing score; covariate adjustment; randomized clinical trials ID CLINICAL-TRIALS; RANDOMIZED-TRIALS; BREAST-CANCER; MAMMOGRAPHY; DESIGN AB The propensity score has been proposed, and for the most part accepted, as a tool to allow for the evaluation of medical interventions in the presence of baseline imbalances arising in the context of observational studies. The lack of an analogous tool to allow for the evaluation of medical interventions in the presence of potentially systematic baseline imbalances in randomized trials has required the use of ad hoc methods. This, in turn, leads to challenges to the conclusions. For example, much of the controversy surrounding recommendations for or against mammography for some age groups stems from the fact that all the randomized trials to study mammography had baseline imbalances, to some extent, in important prognostic covariates. While some of these trials used cluster randomization, baseline imbalances are prevalent also in individually randomized trials. We provide a systematic approach for evaluating medical interventions in the presence of potentially systematic baseline imbalances in individually randomized trials with allocation concealment. Specifically, we define the reverse propensity score as the probability, conditional on all previous allocations and the allocation procedure (restrictions on the randomization), that a given patient will receive a given treatment. We demonstrate how the reverse propensity score allows for both detection of and correction for selection bias, or systematic baseline imbalances. Published in 2005 by John Wiley & Sons, Ltd. C1 NCI, Div Canc Prevent, EPN, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. RP Berger, VW (reprint author), NCI, Div Canc Prevent, EPN, 6130 Execut Blvd,Suite 3131,MSC-7354, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 26 TC 13 Z9 13 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 30 PY 2005 VL 24 IS 18 BP 2777 EP 2787 DI 10.1002/sim.2141 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 967VG UT WOS:000232118700003 PM 15981305 ER PT J AU Kapadia, SU Rose, JK Lamirande, E Vogel, L Subbarao, K Roberts, A AF Kapadia, SU Rose, JK Lamirande, E Vogel, L Subbarao, K Roberts, A TI Long-term protection from SARS coronavirus infection conferred by a single immunization with an attenuated VSV-based vaccine SO VIROLOGY LA English DT Article DE intranasal; neutralizing antibodies; protective immunity; spike ID ACUTE RESPIRATORY SYNDROME; VESICULAR STOMATITIS-VIRUS; SPIKE PROTEIN; NEUTRALIZING ANTIBODIES; RECEPTOR-BINDING; BALB/C MICE; CHALLENGE; GLYCOPROTEIN; HEPATITIS; IMMUNITY AB Although the recent SARS coronavirus (SARS-CoV) that appeared in 2002 has now been contained, the possibility of re-emergence of SARS-CoV remains. Due to the threat of re-emergence, the overall fatality rate of similar to 10%, and the rapid dispersion of the virus via international travel, viable vaccine candidates providing protection from SARS are clearly needed. We developed an attenuated VSV recombinant (VSV-S) expressing the SARS coronavirus (SARS-CoV) spike (S) protein. In cells infected with this recombinant, S protein was synthesized, glycosylated at approximately 17 Asn residues, and transported via the Golgi to the cell surface. Mice vaccinated with VSV-S developed SARS-neutralizing antibody and were able to control a challenge with SARS-CoV performed at I month or 4 months after a single vaccination. We also demonstrated, by passive antibody transfer, that the antibody response induced by the vaccine was sufficient for controlling SARS-CoV infection. A VSV-vectored SARS vaccine could have significant advantages over other SARS vaccine candidates described to date. (c) 2005 Published by Elsevier Inc. C1 Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Rose, JK (reprint author), Yale Univ, Sch Med, Dept Pathol, 310 Cedar St,LH 315, New Haven, CT 06510 USA. EM john.rose@yale.edu FU NIAID NIH HHS [AI057158] NR 42 TC 82 Z9 86 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2005 VL 340 IS 2 BP 174 EP 182 DI 10.1016/j.virol.2005.06.016 PG 9 WC Virology SC Virology GA 969FB UT WOS:000232217800002 PM 16043204 ER PT J AU Koch, M Frazier, J Sodroski, J Wyatt, R AF Koch, M Frazier, J Sodroski, J Wyatt, R TI Characterization of antibody responses to purified HIV-1 gp120 glycoproteins fused with the molecular adjuvant C3d SO VIROLOGY LA English DT Article DE HIV-1; glycoprotein; molecular adjuvant ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; NEUTRALIZING ANTIBODIES; PARTIAL DELETION; RECEPTOR; TRIMERS; IMMUNOGENICITY; FUSION; INFECTION; VACCINE AB The HIV-1 exterior envelope glycoprotein gp120 binds receptor (CD4) and co-receptors (CCR5/CXCR4) and is a major target for neutralizing antibodies. The two functionally conserved regions of gp120 involved in receptor binding are conformational in nature. It is likely that the elicitation of neutralizing antibodies to these targets will benefit by presentation of these sites to the humoral immune system under physiologic conditions. Initially, we investigated the ability of the molecular adjuvant C3d to enhance antibody responses to variant gp120 glycoproteins in phosphate-buffered saline (PBS). We utilized a gp120 variant glycoprotein deleted of N- and C-terminal sequences (gp120 Delta C1/C5) originally designed to eliminate immunodominant, non-neutralizing epitopes and characterized this protein when fused to two C3d elements (gp120 Delta C1/C5(C3d)2). In PBS, the gp120 Delta C1/C5(C3d)2 proteins are able to elicit gp120 binding antibodies more efficiently than gp120 lacking C3d moieties. We then asked if we could observe C3d-enhanced immunogenicity of gp120 in the presence of the classical oil-in-water adjuvant, Ribi. In the presence of the Ribi, which contains the TLR-4 agonist monophospholipid A (MPL), antibodies elicited by the gp120 Delta C1/C5(C3d)2 were of higher titer than those elicited by the identical protein in PBS. To determine if the elicited secondary response was due to a synergy between the C3d repeats and the Ribi, we then inoculated gp120 Delta C1/C5 protein in Ribi and observed that similar titers of anti-gp120 antibodies were elicited in comparison to the gp120 Delta C1/C5(C3d)2 protein also inoculated in Ribi adjuvant. In Ribi, there was a small but consistent increase in gp120-specific antibody titer of a gp120 Delta C1/C5(C3d)2 prime followed by two gp120 Delta C1/C5 boosts compared to three inoculations of either the gp120 Delta C1/C5 proteins or the-gp120 Delta C1/C5(C3d)2 proteins alone. We conclude that the molecular adjuvant C3d demonstrates utility in conditions where physiologic presentation of native protein structures is desired, but may have less benefit in the context of a relatively potent protein adjuvant such as Ribi. C1 NIAID, Vaccine Res Ctr, NIH, Struct Virol Sect, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Max Planck Inst Infect Biol, Dept Immunol, D-10117 Berlin, Germany. RP Wyatt, R (reprint author), NIAID, Vaccine Res Ctr, NIH, Struct Virol Sect, 40 Convent Dr,Bldg 40, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov FU NIAID NIH HHS [AI42719-02] NR 36 TC 11 Z9 12 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2005 VL 340 IS 2 BP 277 EP 284 DI 10.1016/j.virol.2005.06.034 PG 8 WC Virology SC Virology GA 969FB UT WOS:000232217800011 PM 16051303 ER PT J AU Feder, N AF Feder, N TI Public disclosure could deter conflicts of interest SO NATURE LA English DT Letter C1 NIH, Bethesda, MD 20817 USA. RP Feder, N (reprint author), NIH, 2 Democracy Plaza, Bethesda, MD 20817 USA. NR 1 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 29 PY 2005 VL 437 IS 7059 BP 630 EP 630 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 968JD UT WOS:000232157900023 ER PT J AU Beigel, H Farrar, H Han, AM Hayden, FG Hyer, R de Jong, MD Lochindarat, S Tien, NTK Hien, NT Hien, TT Nicoll, A Touch, S Yuen, KY AF Beigel, H Farrar, H Han, AM Hayden, FG Hyer, R de Jong, MD Lochindarat, S Tien, NTK Hien, NT Hien, TT Nicoll, A Touch, S Yuen, KY CA WHO Consultation Human Influenza TI Current concepts - Avian influenza A (H5N1) infection in humans SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; HEALTH-CARE WORKERS; HONG-KONG; VIRUS-INFECTION; HUMAN-DISEASE; MF59-ADJUVANTED INFLUENZA; NEURAMINIDASE INHIBITORS; OSELTAMIVIR PHOSPHATE; IN-VITRO; TRANSMISSION C1 Univ Virginia, Hlth Sci Ctr, Dept Internal Med, Charlottesville, VA 22908 USA. NIAID, NIH, Bethesda, MD 20892 USA. Hosp Trop Dis, Ho Chi Minh City, Vietnam. Inst Med, Dept Child Hlth, Yangon, Myanmar. World Hlth Org, Geneva, Switzerland. Queen Sirikit Natl Inst Child Hlth, Bangkok, Thailand. Inst Pasteur, Ho Chi Minh City, Vietnam. Natl Inst Hyg & Epidemiol, Hanoi, Vietnam. Hlth Protect Agcy, London, England. Minist Hlth, Phnom Penh, Cambodia. Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. RP Hayden, FG (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Internal Med, POB 800473, Charlottesville, VA 22908 USA. EM vgh@virginia.edu RI Han, Aye/J-3814-2012 NR 71 TC 606 Z9 667 U1 15 U2 67 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 29 PY 2005 VL 353 IS 13 BP 1374 EP 1385 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 968FB UT WOS:000232146200009 PM 16192482 ER PT J AU Hale, DA Dhanireddy, K Bruno, D Kirk, AD AF Hale, DA Dhanireddy, K Bruno, D Kirk, AD TI Induction of transplantation tolerance in non-human primate preclinical models SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE cynomolgus; rhesus; tolerance; transplantation; chimerism; costimulation ID TOTAL LYMPHOID IRRADIATION; RENAL-ALLOGRAFT TOLERANCE; LONG-TERM SURVIVAL; DONOR BONE-MARROW; MONKEYS MACACA MULATTA; HUMANIZED MONOCLONAL-ANTIBODIES; MIXED HEMATOPOIETIC CHIMERISM; INTRAHEPATIC ISLET ALLOGRAFTS; T-CELL-ACTIVATION; RHESUS-MONKEYS AB Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application. C1 NIDDKD, Transplantat Branch, NIH, Bethesda, MD 20892 USA. RP Hale, DA (reprint author), NIDDKD, Transplantat Branch, NIH, Bethesda, MD 20892 USA. EM douglash@intra.niddk.nih.gov RI Kirk, Allan/B-6905-2012 NR 142 TC 13 Z9 13 U1 0 U2 0 PU ROYAL SOCIETY PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD SEP 29 PY 2005 VL 360 IS 1461 BP 1723 EP 1737 DI 10.1098/rstb.2005.1703 PG 15 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 965UP UT WOS:000231976200011 PM 16147537 ER PT J AU Horton, JK Stefanick, DF Wilson, SH AF Horton, JK Stefanick, DF Wilson, SH TI Involvement of poly(ADP-ribose) polymerase activity in regulating Chk1-dependent apoptotic cell death SO DNA REPAIR LA English DT Article DE DNA polymerase; base excision repair; Poly(ADP-ribose) polymerase; PARP inhibitor; apoptosis; DNA methylation; methyl methanesulfonate ID BASE-EXCISION-REPAIR; DNA-DAMAGE; CYCLE ARREST; INDUCED CYTOTOXICITY; INHIBITOR; TEMOZOLOMIDE; CHECKPOINT; BETA; INCREASES; INDOLOCARBAZOLE AB The activity of poly(ADP-ribose) polymerase (PARP) is highly stimulated following DNA damage resulting in formation of DNA nicks and strand breaks. This leads to modification of numerous proteins, including itself, using NAD(+) as substrate and to exhaustion of intracellular ATP. A highly cytotoxic concentration of the DNA methylating agent methyl methanesulfonate (MMS) results in cellular ATP depletion and cell death primarily by necrosis in both wild-type and DNA polymerase P null mouse fibroblasts. The loss of ATP can be prevented by the PARP inhibitor 4-amino-1,8-naphthalimide (4-AN), and now cells die by an energy-dependent apoptotic pathway. We find that inhibition of PARP activity transforms a sub-lethal exposure to MMS into a highly cytotoxic event. Under this condition, ATP is not depleted and cell death is by apoptosis. The caspase inhibitor, Z-VAD, shifts the mechanism of cell death to necrosis indicating a caspase-dependent component of the apoptotic cell death. Co-exposure to the Chk1 inhibitor UCN-01 also produces a decrease in apoptotic cell death, but now there is an increase in viable cells and an enhancement in long-term survival. Taken together, our results suggest that inhibition of PARP activity, induced as a result of low dose MMS exposure, signals via a Chk1-dependent pathway for cell death by apoptosis. Published by Elsevier B.V. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 30 TC 24 Z9 26 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD SEP 28 PY 2005 VL 4 IS 10 BP 1111 EP 1120 DI 10.1016/j.dnarep.2005.05.011 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 972BP UT WOS:000232429100007 PM 16002346 ER PT J AU Poltoratsky, V Horton, JK Prasad, R Wilson, SH AF Poltoratsky, V Horton, JK Prasad, R Wilson, SH TI REV1 mediated mutagenesis in base excision repair deficient mouse fibroblast SO DNA REPAIR LA English DT Article DE MMS-induced mutagenesis; REV1; Pol beta; mouse fibroblasts ID DNA-POLYMERASE; ABASIC SITES; SACCHAROMYCES-CEREVISIAE; CELLS; MUTATIONS; PROTEIN; DAMAGE; 3-METHYLADENINE; HOMOLOG; BYPASS AB The DNA polymerase beta (Pol beta) null background renders mouse embryonic fibroblast (MEF) cells base excision repair deficient and hypermutagenic upon treatment with the monofunctional alkylating agent, methyl methanesulfonate (MMS). This effect involves an increase in all types of base substitutions, with a modest predominance of G to A transitions. In the present study, we examined the hypothesis that the MMS-induced mutagenesis in the Pol beta null MEF system is due to a lesion bypass mechanism. We studied the effect of RNAi mediated down-regulation of the lesion bypass factor REV1. The steady-state level of REV1 protein was reduced by more than 95% using stable expression of a siRNA construct in a Pol P null cell line. We found that REV1 expression is required for the MMS-induced mutagenesis phenotype of Pol P null MEF cells. In contrast, cell survival after MMS treatment is not reduced in the absence of REV1. Published by Elsevier B.V. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 26 TC 20 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD SEP 28 PY 2005 VL 4 IS 10 BP 1182 EP 1188 DI 10.1016/j.dnarep.2005.05.002 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 972BP UT WOS:000232429100014 PM 15950550 ER PT J AU Soubias, O Gawrisch, K AF Soubias, O Gawrisch, K TI Probing specific lipid-protein interaction by saturation transfer difference NMR spectroscopy SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TRANSDUCIN BINDING; RHODOPSIN; RECEPTOR; BILAYER; OPTIMIZATION; ENHANCEMENT; SELECTIVITY; RESONANCE; LIGAND C1 NIAAA, NIH, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. RP Gawrisch, K (reprint author), NIAAA, NIH, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. EM gawrisch@helix.nih.gov FU Intramural NIH HHS NR 16 TC 45 Z9 46 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 28 PY 2005 VL 127 IS 38 BP 13110 EP 13111 DI 10.1021/ja0538942 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 968OC UT WOS:000232170800015 PM 16173715 ER PT J AU Stroncek, DF Shankar, RA Skubitz, KM AF Stroncek, DF Shankar, RA Skubitz, KM TI The subcellular distribution of myeloid-related protein 8 (MRP8) and MRP14 in human neutrophils SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID CALCIUM-BINDING PROTEINS; MONOCLONAL-ANTIBODY; ENDOTHELIAL-CELLS; MYELOID DIFFERENTIATION; RHEUMATOID-ARTHRITIS; PLASMA-MEMBRANE; S100 FAMILY; MONOCYTES; CALPROTECTIN; COMPLEX AB Background: Myeloid-related protein 8 (MRP8) and MRP14 are S100 family calcium binding proteins that form a heterodimer known as calprotectin or MRP8/14 that is present in the cytosol of neutrophils and monocytes. MRP8/14 becomes associated with endothelium at sites of monocyte and neutrophil adhesion and transmigration and induces a thrombogenic and inflammatory response by increasing the endothelial transcription of proinflamatory chemokines and adhesion molecules. The distribution of MRP8/MRP14 among neutrophil granules and plasma membranes is unclear and was investigated to better understand the role of this molecule in acute inflammation. Study design: Three monoclonal antibodies specific for MRP8 and MRP14 were characterized and used in immunoblotting assays of neutrophil whole cell extracts, and isolated plasma membranes, primary granules, secondary granules and cytosol. Results: MRP8 and MRP14 were detected in neutrophil cytosol, plasma membrane, primary granule and secondary granule fractions. MRP8/14 demonstrated a calcium-dependent adherence to plasma membranes and primary granules and could be removed by washing with EGTA in a high ionic strength buffer. In contrast, MRP8/14 was found within the contents of the secondary granules. Activated neutrophils released secondary granules and MRP8/14. Conclusion: MRP8/14 is located in neutrophil cytosol and secondary granule fractions and is loosely associated with plasma membranes. MRP8/14 released with secondary granules by activated neutrophils likely binds to endothelium and plays an important role in acute inflammation. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. 3M Corp, St Paul, MN USA. Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. Mason Canc Ctr, Minneapolis, MN 55455 USA. RP Stroncek, DF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov; rashankar@mmm.com; skubi001@umn.edu NR 30 TC 19 Z9 21 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 28 PY 2005 VL 3 BP 1 EP 9 AR 36 DI 10.1186/1479-5876-3-36 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 973GV UT WOS:000232511800001 PM 16191197 ER PT J AU Webster, JI Sternberg, EM AF Webster, JI Sternberg, EM TI Anthrax lethal toxin represses glucocorticoid receptor (GR) transactivation by inhibiting GR-DNA binding in vivo SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE glucocorticoid; receptor; anthrax; lethal factor; lethal toxin; nuclear hormone receptors; repression ID NF-KAPPA-B; BACILLUS-ANTHRACIS; DEPENDENT TRANSCRIPTION; GENE-EXPRESSION; STEROID-RECEPTORS; KINASE-KINASE; CELL-LINES; TNF-ALPHA; MACROPHAGES; ACTIVATION AB Anthrax lethal factor (LF) is a non-competitive repressor of glucocorticoid (GR) and progesterone receptor (PR) transactivation. This repression was shown to be specific and selective and was dependent on promoter context and receptor subtype. Anthrax lethal toxin (LeTx) selectively repressed GR-mediated transactivation but not transrepression. The DNA binding region of GR was required for repression by LeTx and LeTx prevented GR-DNA binding in vivo, which had downstream consequences on polymerase II binding and histone acetylation. In addition, LeTx also prevented the accessory protein C/EBP from binding to a GR-responsive promoter. We hypothesize that LeTx may remove/inactivate one of the many co-factors or accessory proteins that are required to stabilize the GR-DNA complex. These findings enhance the current knowledge of the molecular mechanism by which the anthrax lethal factor represses nuclear hormone receptors and could provide an approach to overcome some of LeTx's effects. Published by Elsevier Ireland Ltd. C1 NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Dept Hlth & Human Serv, 5625 Fishers Lane,Rm 4N14,MSC 9401, Bethesda, MD 20892 USA. EM jeanettewebster@mail.nih.gov; sternbee@mail.nih.gov RI Webster Marketon, Jeanette/H-5613-2011 OI Webster Marketon, Jeanette/0000-0002-3627-1094 NR 60 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD SEP 28 PY 2005 VL 241 IS 1-2 BP 21 EP 31 DI 10.1016/j.mce.2005.03.011 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 972FN UT WOS:000232439700003 PM 15964137 ER PT J AU Duh, FM Dirks, C Lerman, MI Miller, AD AF Duh, FM Dirks, C Lerman, MI Miller, AD TI Amino acid residues that are important for Hyal2 function as a receptor for jaagsiekte sheep retrovirus SO RETROVIROLOGY LA English DT Article ID CELL-SURFACE RECEPTOR; NASAL TUMOR-VIRUS; ONCOGENIC TRANSFORMATION; LEUKEMIA-VIRUS; IDENTIFICATION; GLYCOSYLATION; SELECTION; SITES; ENTRY AB Background: Infection by jaagsiekte sheep retrovirus ( JSRV) and by enzootic nasal tumor virus (ENTV) depends on cell-surface expression of the virus entry receptor, hyaluronidase 2 (Hyal2). Human Hyal2 binds the envelope (Env) proteins of these viruses and is functional as a receptor, but Hyal2 from mice does not bind Env nor does it mediate entry of either virus. Here we have explored the amino acid determinants that account for the difference in receptor function. Results: Analysis of human-mouse Hyal2 chimeric proteins showed that amino acid differences responsible for the difference in Hyal2 receptor activity were localized to the central third of Hyal2. Human Hyal2 mutants containing single or double amino acid replacements with the respective mouse amino acids were generated across this region and were assayed for activity. None of the single or double mutation reduced the receptor activity of human Hyal2 by more than 10-fold, whereas mouse Hyal2 activity is reduced 1,000-fold from that of human Hyal2. While the 3-dimensional structures of mammalian Hyal2 proteins are unknown, bee venom hyaluronidase shows significant amino acid similarity to human and mouse Hyal2 and its structure has been determined. Many mutations having the largest negative effects on human Hyal2 function mapped to a small region of the bee venom hyaluronidase close to but not overlapping the active site of the enzyme, suggesting that this site represents the binding site for Env. Analysis of synonymous and non-synonymous nucleotide substitutions in the coding sequences of multiple mammalian Hyal2 proteins shows that the proteins are undergoing strong selection for amino acid conservation. We found no evidence for positive selection of amino acid changes that might reflect evolution of mammalian hosts to resist JSRV or ENTV infection. Conclusion: These results show that the greatly reduced receptor activity of mouse Hyal2 in comparison to that of human Hyal2 is determined by multiple amino acid changes acting in concert. In particular, no one amino acid change blocks infection. However, the most important amino acids map to a small patch on a predicted 3-dimensional Hyal2 structure, which may represent the binding site for Env. C1 Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Miller, AD (reprint author), Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. EM duh@mail.ncifcrf.gov; cdirks@u.washington.edu; lerman@ncifcrf.gov; dmiller@fhcrc.org OI Miller, Dusty/0000-0002-3736-3660 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-56000, N01-CO-12400, N01CO12400]; NHLBI NIH HHS [HL66947, P01 HL036444, U01 HL066947, HL36444]; NIDDK NIH HHS [P30 DK047754, DK47754] NR 24 TC 12 Z9 13 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 28 PY 2005 VL 2 AR 59 DI 10.1186/1742-4690-2-59 PG 11 WC Virology SC Virology GA 033NV UT WOS:000236856500001 PM 16191204 ER PT J AU Meunier, S Hallett, M AF Meunier, S Hallett, M TI Endophenotyping - A window to the pathophysiology of dystonia SO NEUROLOGY LA English DT Editorial Material ID MUTATION; CARRIERS C1 Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. UPMC, INSERM, U731, Paris, France. RP Meunier, S (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, 10 Ctr Dr,Bldg 10,Room 5N240, Bethesda, MD 20892 USA. EM meuniers@ninds.nih.gov RI meunier, sabine/G-7622-2014 OI meunier, sabine/0000-0002-6167-4602 FU Intramural NIH HHS NR 10 TC 13 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 27 PY 2005 VL 65 IS 6 BP 792 EP 793 DI 10.1212/01.wnl.0000177919.02950.4a PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 967RV UT WOS:000232109800003 PM 16186515 ER PT J AU Kaplan, RC Tirschwell, DL Longstreth, WT Manolio, TA Heckbert, SR Lefkowitz, D El-Saed, A Psaty, BM AF Kaplan, RC Tirschwell, DL Longstreth, WT Manolio, TA Heckbert, SR Lefkowitz, D El-Saed, A Psaty, BM TI Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly SO NEUROLOGY LA English DT Article ID CARDIOVASCULAR HEALTH; SEX-DIFFERENCES; POPULATION; RECURRENCE; RISK; DISEASE; MANAGEMENT; HYPERTENSION; INDIVIDUALS; COMMUNITY AB Background: The authors studied mortality, vascular events, and preventive therapies following ischemic stroke among adults aged >= 65 years. Methods: The authors identified 546 subjects with first ischemic stroke during 1989 to 2001 among Cardiovascular Health Study participants. Deaths, recurrent strokes, and coronary heart disease (CHD) events were identified over 3.2 years ( median) follow-up. Results: During the first year of follow-up, rates were 105.4/1,000 for recurrent stroke and 59.3/1,000 for CHD. After the first year, the stroke rate was 52.0/1,000 and the CHD rate was 46.5/1,000. Cardioembolic strokes had the highest mortality (185.4/1,000) and recurrence rates (86.6/1,000). Lacunar strokes had the lowest mortality (119.3/1,000) and recurrence rates (43.0/1,000). Age and male sex predicted death and CHD, but not recurrence. Outcomes did not differ by race. Following stroke, 47.8% used aspirin and 13.5% used other antiplatelet agents; 52.6% of patients with atrial fibrillation used warfarin; 31.3% of hyperlipidemic subjects, 57.0% of diabetic patients, and 81.5% of hypertensive patients were drug-treated; and 40.0% of hypertensive patients had blood pressure ( BP) < 140/90 mm Hg. Older subjects were less likely to use lipid-lowering therapy, women were less likely to have BP < 140/90 mm Hg, and low- income subjects were less likely to use diabetes medications. Conclusions: Recurrent strokes were nearly twice as frequent as coronary heart disease ( CHD) events during the first year after initial stroke, but stroke and CHD rates were similar after the first year. Preventive drug therapies were underused, which may reflect clinical uncertainty due to the lack of clinical trials among the elderly. Utilization was lower among the oldest patients, women, and low-income individuals. C1 Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. NHLBI, Epidemiol & Biometry Program, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Neurol, Winston Salem, NC 27109 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA USA. RP Kaplan, RC (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Belfer BldgRoom 1303A,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM rkaplan@aecom.yu.edu RI Kaplan, Robert/A-2526-2011 FU NHLBI NIH HHS [N01 HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85086]; NIA NIH HHS [5R01AG009556-08] NR 35 TC 76 Z9 81 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 27 PY 2005 VL 65 IS 6 BP 835 EP 842 DI 10.1212/01.wnl.0000176058.09848.bb PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 967RV UT WOS:000232109800012 PM 16186519 ER PT J AU Herbeuval, JP Hardy, AW Boasso, A Anderson, SA Dolan, MJ Dy, M Shearer, GM AF Herbeuval, JP Hardy, AW Boasso, A Anderson, SA Dolan, MJ Dy, M Shearer, GM TI Regulation of TNF-related apoptosis-inducing ligand on primary CD4(+) T cells by HIV-1: Role of type IIFN-producing plasmacytoid dendritic cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INTERFERON-PRODUCING CELLS; ANTIRETROVIRAL THERAPY; INFECTION; ALPHA; TRAIL; ACTIVATION; INDUCTION; PROTEINS; RECEPTOR AB TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, was suggested to contribute to HIV-1 pathogenesis by inducing CD4(+) T cell death characteristic of AIDS. We previously reported HIV-1-mediated, TRAIL-induced apoptosis in primary CD4+ T cells in vitro and observed elevated levels of plasma TRAIL in HIV-1-infected patients. The present study elucidates the unresolved mechanism by which HIV-1 induces TRAIL expression on primary CD4(+) T cells. We demonstrate that the expression of TRAIL by primary CD4+ T cells is regulated by IFN-alpha that is produced by HIV-1-stimulated plasmacytoid dendritic cells (pDCs). We also found that IFN-induced TRAIL is mediated by signal transducers and activators of transcription 1 and 2. We show that IFN-a production by HIV-1-activated pDCs is blocked by an early viral entry inhibitor of CD4-gp120 binding, but not by inhibitors of viral coreceptor binding. Our in vitro data are supported by the demonstration that anti-IFN-alpha and -beta Abs inhibit apoptosis and TRAIL expression in CD4+ T cells from HIV-1-infected patients. Our findings suggest a potential unique role of pDCs in the immunopathogenesis of HIV-1 infection by inducing the death molecule TRAIL. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Fac Med Rene Descartes, CNRS, UMR 8147, F-75270 Paris, France. Wilford Hall USAF Med Ctr, Henry M Jackson Fdn, Lackland AFB, TX 78236 USA. Wilford Hall USAF Med Ctr, Infect Dis Serv, Lackland AFB, TX 78236 USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM gene_shearer@nih.gov OI Boasso, Adriano/0000-0001-9673-6319 NR 40 TC 114 Z9 119 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2005 VL 102 IS 39 BP 13974 EP 13979 DI 10.1073/pnas.0505251102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969KB UT WOS:000232231900048 PM 16174727 ER PT J AU Oseroff, C Kos, F Bui, HH Peters, B Pasquetto, V Glenn, J Palmore, T Sidney, J Tscharke, DC Bennink, JR Southwood, S Grey, HM Yewdell, JW Sette, A AF Oseroff, C Kos, F Bui, HH Peters, B Pasquetto, V Glenn, J Palmore, T Sidney, J Tscharke, DC Bennink, JR Southwood, S Grey, HM Yewdell, JW Sette, A TI HLA class I-restricted responses to vaccinia recognize a broad array of proteins mainly involved in virulence and viral gene regulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunodominance; smallpox vaccination; virulence factors ID T-CELL RESPONSES; SMALLPOX VACCINES; IMMUNE-RESPONSE; ANTIGEN; EPITOPES; IDENTIFICATION; VIRUSES; LYMPHOCYTES; PROTECTION; MOLECULES AB We have analyzed by ex vivo ELISPOT the anti-vaccinia cytotoxic T lymphocyte responses of peripheral blood mononuclear cells from humans vaccinated with Dryvax vaccine. More than 6,000 pepticles from 258 putative vaccinia ORFs predicted to bind the common molecules of the HLA A1, A2, A3, A24, B7, and B44 supertypes were screened with peripheral blood mononuclear cells of 31 vaccinees. A total of 48 epitopes derived from 35 different vaccinia antigens were identified, some of which (B8R, D1R, D5R, C101L, C19L, C7L, F12, and O1L) were recognized by multiple donors and contain multiple epitopes recognized in the context of different HLA types. The antigens recognized tend to be >100 residues in length and are expressed predominantly in the early phases of infection, although some late antigens were also recognized. Viral genome regulation and virulence factor were recognized most frequently, whereas few structural proteins were immunogenic. Finally, most epitopes were highly conserved among vaccinia virus Western Reserve, variola major and modified vaccinia Ankara, supporting their potential use in vaccine and diagnostic applications. C1 La Jolla Inst Allergy & Immunol, San Diego, CA 92109 USA. Epimmune, San Diego, CA 92121 USA. NIH, Viral Dis Lab, Bethesda, MD 20892 USA. Queensland Inst Med Res, Div Infect Dis & Immunol, Brisbane, Qld 4029, Australia. RP Grey, HM (reprint author), La Jolla Inst Allergy & Immunol, 3030 Bunker Hill St,Suite 326, San Diego, CA 92109 USA. EM hgrey@liai.org; alex@liai.org RI yewdell, jyewdell@nih.gov/A-1702-2012; Tscharke, David/C-9133-2009 OI Tscharke, David/0000-0001-6825-9172 FU NIAID NIH HHS [R01 AI056268, R01-AI-56268] NR 33 TC 95 Z9 96 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2005 VL 102 IS 39 BP 13980 EP 13985 DI 10.1073/pnas.0506768102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969KB UT WOS:000232231900049 PM 16172378 ER PT J AU Miura, Y Miura, M Gronthos, S Allen, MR Cao, CZ Uveges, TE Bi, YM Ehirchiou, D Kortesidis, A Shi, ST Zhang, L AF Miura, Y Miura, M Gronthos, S Allen, MR Cao, CZ Uveges, TE Bi, YM Ehirchiou, D Kortesidis, A Shi, ST Zhang, L TI Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE integrin; leukocyte adhesion deficiency; bone ID HUMAN BONE-MARROW; HEMATOPOIETIC PROGENITOR CELLS; MONOCLONAL-ANTIBODY; GENE-TRANSFER; NULL MICE; IN-VITRO; DIFFERENTIATION; IDENTIFICATION; PRECURSORS; EXPRESSION AB osteogenesis by the bone marrow stromal stem cells (BMSSCs) supports continuous bone formation and the homeostasis of the bone marrow microenvironment. The mechanism that controls the proliferation and differentiation of BMSSCs is not fully understood. Here, we report that CD18, a surface protein present primarily on hematopoietic cells, but not on differentiated mesenchymal cells, is expressed by the stromal stem cells and plays a critical role in the osteogenic process. Constitutive expression of CD18 on BMSSCs using a retroviral promoter significantly enhances bone formation in vivo, whereas genetic inactivation of CD18 in mice leads to defective osteogenesis due to decreased expression of the osteogenic master regulator Runx2/Cbfa1. The defective osteogenesis of the CD18-null BMSSCs can be restored by expressing full-length, but not cytoplasmic domain-truncated, CD18. Radiographic analyses with dual-energy x-ray absorptiometry and 3D microcomputed tomography show that mice lacking CD18 have decreased bone mineral density and exhibit certain features of osteoporosis. Altogether, this work demonstrates that CD18 functions critically in the osteogenesis of BMSSCs, and thus lack of CD18 expression in the leukocyte adhesion deficiency patients may predispose them to osteoporosis. C1 Univ Maryland, Sch Med, Dept Physiol, Rockville, MD 20855 USA. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NICHHD, NIH, Bethesda, MD 20892 USA. NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. Inst Med & Vet Sci, Div Haematol, Mesenchymal Stem Cell Grp, Div Haematol, Adelaide, SA 5000, Australia. Indiana Univ, Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA. RP Shi, ST (reprint author), Univ Maryland, Sch Med, Dept Physiol, Rockville, MD 20855 USA. EM sshi@mail.nih.gov; lizhang@som.umaryland.edu RI Allen, Matthew/A-8799-2015 OI Allen, Matthew/0000-0002-1174-9004 FU NHLBI NIH HHS [R01 HL61589-01, P01 HL054710, R01 HL061589] NR 31 TC 47 Z9 54 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2005 VL 102 IS 39 BP 14022 EP 14027 DI 10.1073/pnas.0409397102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969KB UT WOS:000232231900056 PM 16172402 ER PT J AU Simonsen, L Reichert, TA Viboud, C Blackwelder, WC Taylor, RJ Miller, MA AF Simonsen, L Reichert, TA Viboud, C Blackwelder, WC Taylor, RJ Miller, MA TI Influenza vaccination among the elderly in the United States - Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID MORTALITY C1 NIAID, Off Global Affairs, NIH, Bethesda, MD 20892 USA. RP Simonsen, L (reprint author), NIAID, Off Global Affairs, NIH, 6610 Rockledge Dr,Room 2033, Bethesda, MD 20892 USA. EM Lsimonsen@niaid.nih.gov NR 6 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 26 PY 2005 VL 165 IS 17 BP 2039 EP 2040 DI 10.1001/archinte.165.17.2039 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 967SZ UT WOS:000232112800019 ER PT J AU Ingerman, E Perkins, EM Marino, M Mears, JA McCaffery, JM Hinshaw, JE Nunnari, J AF Ingerman, E Perkins, EM Marino, M Mears, JA McCaffery, JM Hinshaw, JE Nunnari, J TI Dnm1 forms spirals that are structurally tailored to fit mitochondria SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; GTPASE EFFECTOR DOMAIN; DYNAMIN-RELATED GTPASE; RATE-LIMITING STEP; WD REPEAT PROTEIN; IN-VIVO; FISSION; DIVISION; YEAST; CONSTRICTION AB Dynamin-related proteins (DRPs) are large self-assembling GTPases whose common function is to regulate membrane dynamics in a variety of cellular processes. Dnm1, which is a yeast DRP (Drp1/Dlp1 in humans), is required for mitochondrial division, but its mechanism is unknown. We provide evidence that Dnm1 likely functions through self-assembly to drive the membrane constriction event that is associated with mitochondrial division. Two regulatory features of Dnm1 self-assembly were also identified. Dnm1 self-assembly proceeded through a rate-limiting nucleation step, and nucleotide hydrolysis by assembled Dnm1 structures was highly cooperative with respect to GTP. Dnm1 formed extended spirals, which possessed diameters greater than those of dynamin-1 spirals but whose sizes, remarkably, were equal to those of mitochondrial constriction sites in vivo. These data suggest that Dnm1 has evolved to form structures that fit the dimensions of mitochondria. C1 Univ Calif Davis, Ctr Genet & Dev, Dept Mol & Cellular Biol, Davis, CA 95616 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Integrated Imaging Ctr, Baltimore, MD 21218 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Hinshaw, JE (reprint author), Univ Calif Davis, Ctr Genet & Dev, Dept Mol & Cellular Biol, Davis, CA 95616 USA. EM jennyh@helix.nih.gov; jmnunnari@ucdavis.edu RI Perkins, Edward/B-8276-2009; OI Perkins, Edward/0000-0002-3077-7422 FU NCRR NIH HHS [S10 RR019409-01]; NEI NIH HHS [1R01EY015924, R01 EY015924]; NIGMS NIH HHS [R01 GM062942, 5R01GM062942, 5T32GM007377, T32 GM007377] NR 40 TC 282 Z9 287 U1 2 U2 17 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 26 PY 2005 VL 170 IS 7 BP 1021 EP 1027 DI 10.1083/jcb.200506078 PG 7 WC Cell Biology SC Cell Biology GA 967WA UT WOS:000232120700003 PM 16186251 ER PT J AU Pastrana, DV Hanson, AJ Knisely, J Bu, GJ Fitzgerald, DJ AF Pastrana, DV Hanson, AJ Knisely, J Bu, GJ Fitzgerald, DJ TI LRP1B functions as a receptor for Pseudomonas Exotoxin SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE toxin; receptor; LRP1; LRP1B; pseudomonas; ADP-ribosylation ID DENSITY-LIPOPROTEIN RECEPTOR; MUTATIONAL ANALYSIS; GENE FAMILY; PROTEIN RAP; BINDING; MEMBERS; CELLS; TOXIN; INTERNALIZES; ACTIVATION AB Pseudomonas aeruginosa is an opportunistic pathogen that produces several virulence factors, among them Pseudomonas Exotoxin A (PE). Previously, low-density lipoprotein receptor-related protein 1 (LRP1) was shown to be the primary receptor for PE. In this report, we show that a close family member, LRP1B, can also function as a receptor. Published by Elsevier B.V. C1 NCI, LMB, CCR, Biotherapy Sect, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. RP Fitzgerald, DJ (reprint author), NCI, LMB, CCR, Biotherapy Sect, 37-5124,37 Covent Dr,MSC 4264, Bethesda, MD 20892 USA. EM djpf@helix.nih.gov NR 29 TC 16 Z9 19 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD SEP 25 PY 2005 VL 1741 IS 3 BP 234 EP 239 DI 10.1016/j.bbadis.2005.06.007 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 972NS UT WOS:000232461100003 PM 16095885 ER PT J AU Lalezari, J Thompson, M Kumar, P Piliero, P Davey, R Patterson, K Shachoy-Clark, A Adkison, K Demarest, J Lou, Y Berrey, M Piscitelli, S AF Lalezari, J Thompson, M Kumar, P Piliero, P Davey, R Patterson, K Shachoy-Clark, A Adkison, K Demarest, J Lou, Y Berrey, M Piscitelli, S TI Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults SO AIDS LA English DT Article DE CCR5; 873140; HIV infection; tropism; pharmacokinetics ID DRUG-RESISTANCE; INHIBITOR; TRIAL AB Objective: 873140 is a spirodiketopiperazine CCR5 antagonist with prolonged receptor binding and potent antiviral activity in vitro. This study evaluated plasma HIV RNA, safety, and pharmacokinetics following short-term monotherapy in HIV-infected adults. Design: Double-blind, randomized, placebo-controlled multi-center trial. Methods: Treatment-naive or experienced HIV-infected subjects with R5-tropic virus, CD4 cell count nadir > 200 x 10(6) cells/I, viral load > 5000 copies/ml and not receiving antiretroviral therapy for the preceding 12 weeks were enrolled. Forty subjects were randomized to one of four cohorts (200 mg QD, 200 mg BID, 400 mg QD, 600 mg BID) with 10 subjects (eight active, two placebo) in each cohort, and received treatment for 10 days. Serial HIV RNA, pharmacokinetics, and safety evaluations were performed through day 24. Results: Of the 40 subjects, 21 were treatment-experienced; 35 were male, 20 were non-white, and eight were coinfected with hepatitis C virus. Median baseline HIV RNA ranged from 4.26 log(10) to 4.46 log(10). 873140 was generally well tolerated with no drug-related discontinuations. The most common adverse events were grade 1 gastrointestinal complaints that generally resolved within 1 - 3 days on therapy. No clinically significant abnormalities were observed on electrocardiogram or in laboratory parameters. Mean log changes in HIV RNA at nadir, and the percentage of subjects with > 1 log(10) decrease were -0.12 (0%) for placebo, -0.46 (17%) for 200 mg once daily, -1.23 (75%) for 200 mg twice daily, -1.03 (63%) for 400 mg once daily, and -1.66 (100%) for 600mg twice daily. An E-max,, relationship was observed between the area under the 873140 plasma concentration-time curve and change in HIV RNA. C1 GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA. Quest Clin Res, San Francisco, CA USA. ARCA, Atlanta, GA USA. Georgetown Univ, Washington, DC USA. Albany Med Coll, Albany, NY 12208 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. RP Piscitelli, S (reprint author), GlaxoSmithKline Inc, 5 Moore Dr, Res Triangle Pk, NC 27709 USA. EM stephen.c.piscitelli@gsk.com NR 11 TC 80 Z9 85 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 23 PY 2005 VL 19 IS 14 BP 1443 EP 1448 DI 10.1097/01.aids.0000183633.06580.8a PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 970MN UT WOS:000232314400001 PM 16135896 ER PT J AU Lund, N Branch, DR Sakac, D Lingwood, CA Siatskas, C Robinson, CJ Brady, RO Medin, JA AF Lund, N Branch, DR Sakac, D Lingwood, CA Siatskas, C Robinson, CJ Brady, RO Medin, JA TI Lack of susceptibility of cells from patients with Fabry disease to productive infection with R5 human immunodeficiency virus SO AIDS LA English DT Article ID HIV-1 ENTRY; ENDOPLASMIC-RETICULUM; RETROGRADE TRANSPORT; GANGLIOSIDE GM3; RECEPTOR; GP120; GLYCOSPHINGOLIPIDS; MEMBRANE; FUSION; MICRODOMAINS AB A lack of viral replication after HIV-1(Ba-L) (R5) but not HIV-1I(IIB) (X4) infection was found using in-vitro activated peripheral blood-derived mononuclear cells from patients with Fabry disease, who have a defect in the catabolism of globotriaosylceramide. CCR5, but not CD4 or CXCR4 expression levels, were lower and the surface expression of globotriaosylceramide was negligible on activated patients' cells. Our findings suggest a novel resistance mechanism to productive infection with R5 HIV-1 that potentially involves abnormal globotriaosylceramide, catabolism. C1 Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. Univ Toronto, Dept Med, Toronto, ON, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. Univ Toronto, Dept Biochem, Toronto, ON, Canada. Canadian Blood Serv Res & Dev, Toronto, ON, Canada. Toronto Gen Res Inst, Div Cell & Mol Biol, Toronto, ON, Canada. Univ Hlth Network, Ontario Canc Inst, Toronto, ON, Canada. Hosp Sick Children, Res Inst, Toronto, ON M5G 1X8, Canada. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Lund, N (reprint author), Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. FU NHLBI NIH HHS [HL 070569] NR 23 TC 24 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 23 PY 2005 VL 19 IS 14 BP 1543 EP 1546 DI 10.1097/01.aids.0000183521.90878.79 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 970MN UT WOS:000232314400015 PM 16135910 ER PT J AU Dar, AC Dever, TE Sicheri, F AF Dar, AC Dever, TE Sicheri, F TI Higher-order substrate recognition of elF2 alpha by the RNA-dependent protein kinase PKR SO CELL LA English DT Article ID DOUBLE-STRANDED-RNA; INITIATION-FACTOR 2-ALPHA; CRYSTAL-STRUCTURE; PEPTIDE SUBSTRATE; ALPHA-SUBUNIT; EIF2 ALPHA; TRANSLATION; EIF2-ALPHA; ACTIVATION; BINDING AB In response to binding viral double-stranded RNA by products within a cell, the RNA-dependent protein kinase PKR phosphorylates the a subunit of the translation initiation factor eIF2 on a regulatory site, Ser51. This triggers the general shutdown of protein synthesis and inhibition of viral propagation. To understand the basis for substrate recognition by and the regulation of PKR, we determined X-ray crystal structures of the catalytic domain of PKR in complex with eIF2 alpha. The structures reveal that eIF2a binds to the C-terminal catalytic lobe while catalytic-domain dimerization is mediated by the N-terminal lobe. In addition to inducing a local unfolding of the Ser51 acceptor site in eIF2 alpha, its mode of binding to PKR affords the Ser51 site full access to the catalytic cleft of PKR. The generality and implications of the structural mechanisms uncovered for PKR to the larger family of four human eIF2 alpha protein kinases are discussed. C1 Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Program Mol Biol & Canc, Toronto, ON M5G 1X5, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Sicheri, F (reprint author), Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Program Mol Biol & Canc, 600 Univ Ave, Toronto, ON M5G 1X5, Canada. EM sicheri@mshri.on.ca RI Sicheri, Frank/F-8856-2013 FU Intramural NIH HHS NR 36 TC 207 Z9 216 U1 3 U2 10 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD SEP 23 PY 2005 VL 122 IS 6 BP 887 EP 900 DI 10.1016/j.cell.2005.06.044 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 967ZL UT WOS:000232130200013 PM 16179258 ER PT J AU Dey, M Cao, C Dar, AC Tamura, T Ozato, K Sicheri, F Dever, TE AF Dey, M Cao, C Dar, AC Tamura, T Ozato, K Sicheri, F Dever, TE TI Mechanistic link between PKR dimerization, autophosphorylation, and elF2 alpha substrate recognition SO CELL LA English DT Article ID DOUBLE-STRANDED-RNA; PROTEIN-KINASE PKR; TRANSLATION INITIATION; CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; FUNCTIONALLY SUBSTITUTE; INTERFERON ACTION; ACTIVATION LOOP; ALPHA-SUBUNIT; IN-VIVO AB The antiviral protein kinase PKR inhibits protein synthesis by phosphorylating the translation initiation factor eIF2 alpha on Ser51. Binding of double-stranded RNA to the regulatory domains of PKR promotes dimerization, autophosphorylation, and the functional activation of the kinase. Herein, we identify mutations that activate PKR in the absence of its regulatory domains and map the mutations to a recently identified dimerization surface on the kinase catalytic domain. Mutations of other residues on this surface block PKR autophosphorylation and eIF2 alpha phosphorylation, while mutating Thr446, an autophosphorylation site within the catalytic-domain activation segment, impairs eIF2 alpha phosphorylation and viral pseudosubstrate binding. Mutational analysis of catalytic-domain residues preferentially conserved in the eIF2 alpha kinase family identifies helix alpha G as critical for the specific recognition of eIF2 alpha. We propose an ordered mechanism of PKR activation in which catalytic-domain climerization triggers Thr446 autophosphorylation and specific eIF2 alpha substrate recognition. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mol Growth & Regulat, NIH, Bethesda, MD 20892 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Program Mol Biol & Canc, Toronto, ON M5G 1X5, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada. RP Dever, TE (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM tdever@nih.gov RI Sicheri, Frank/F-8856-2013 FU Intramural NIH HHS NR 30 TC 177 Z9 181 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD SEP 23 PY 2005 VL 122 IS 6 BP 901 EP 913 DI 10.1016/j.cell.2005.06.041 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 967ZL UT WOS:000232130200014 PM 16179259 ER PT J AU Liu, YY Kvaratskhelia, M Hess, S Qu, YX Zou, Y AF Liu, YY Kvaratskhelia, M Hess, S Qu, YX Zou, Y TI Modulation of replication protein A function by its hyperphosphorylation-induced conformational change involving DNA binding domain B SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; MASS-SPECTROMETRY; P34 SUBUNIT; INDUCED PHOSPHORYLATION; CHEMICAL-MODIFICATION; RPA PHOSPHORYLATION; IONIZING-RADIATION; SURFACE-TOPOLOGY; KINASE-ACTIVITY; HUMAN-CELLS AB Human replication protein A (RPA), composed of RPA70, RPA32, and RPA14 subunits, undergoes hyperphosphorylation in cells in response to DNA damage. Hyperphosphorylation that occurs predominately in the N-terminal region of RPA32 is believed to play a role in modulating the cellular activities of RPA essential for almost all DNA metabolic pathways. To understand how the hyperphosphorylation modulates the functions of RPA, we compared the structural characteristics of full-length native and hyper-phosphorylated RPAs using mass spectrometric protein footprinting, fluorescence spectroscopy, and limited proteolysis. Our mass spectrometric data showed that of 24 lysines and 18 arginines readily susceptible to small chemical reagent modification in native RPA, the three residues Lys-343, Arg-335, and Arg-382, located in DNA binding domain B (DBD- B) of RPA70, were significantly shielded in the hyperphosphorylated protein. Tryptophan fluorescence studies indicated significant quenching of Trp-361, located in the DBD- B domain, induced by hyperphosphorylation of RPA. Consistently, DBD- B became more resistant to the limited proteolysis by chymotrypsin after RPA hyperphosphorylation. Taken together, our results indicate that upon hyperphosphorylation of RPA32 N terminus ( RPA32N), RPA undergoes a conformational change involving the single-stranded DNA binding cleft of DBD- B. Comparison of the interactions of native and hyperphosphorylated RPAs with short single-stranded oligonucleotides or partial DNA duplexes with a short 5 ' or 3 ' single-stranded DNA tails showed reduced affinity for the latter protein. We propose that the hyperphosphorylation may play a role in modulating the cellular pathways by altering the DBD-B-mediated RPA-DNA and RPA-protein interactions, hypothetically via the interaction of hyperphosphorylated RPA32N with DBD- B. C1 E Tennessee State Univ, James H Quillen Coll Med, Dept Biochem & Mol Biol, Johnson City, TN 37614 USA. Ohio State Univ, Hlth Sci Ctr, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. Ctr Comprehens Canc, Columbus, OH 43210 USA. NIDDK, Prote & Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA. RP Zou, Y (reprint author), E Tennessee State Univ, James H Quillen Coll Med, Dept Biochem & Mol Biol, Johnson City, TN 37614 USA. EM zouy@etsu.edu RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 FU NCI NIH HHS [CA86927, R01 CA086927, R56 CA086927] NR 64 TC 41 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 SEP 23 PY 2005 VL 280 IS 38 BP 32775 EP 32783 DI 10.1074/jbc.M505705200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 964ZU UT WOS:000231920300029 PM 16006651 ER PT J AU Mandal, AK Ray, R Zhang, ZJ Chowdhury, B Pattabiraman, N Mukherjee, AB AF Mandal, AK Ray, R Zhang, ZJ Chowdhury, B Pattabiraman, N Mukherjee, AB TI Uteroglobin inhibits prostaglandin F-2 alpha receptor-mediated expression of genes critical for the production of pro-inflammatory lipid mediators SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; RECOMBINANT HUMAN UTEROGLOBIN; CYTOSOLIC PHOSPHOLIPASE A(2); ENDOPEROXIDE-H SYNTHASE-1; INVITRO CHARACTERIZATION; PROSTANOID RECEPTOR; HUMAN MYOMETRIUM; BINDING-PROTEIN; AMNIOTIC-FLUID; NUCLEAR-FACTOR AB Prematurity is one of the leading causes of infant mortality. It may result from intrauterine infection, which mediates premature labor by stimulating the production of inflammatory lipid mediators such as prostaglandin F-2 alpha (PGF2(alpha)). The biological effects of PGF(2 alpha) are mediated via the G protein-coupled receptor FP; however, the molecular mechanism(s) of FP signaling that mediates inflammatory lipid mediator production remains unclear. We reported previously that in the human uterus, a composite organ in which fibroblast, epithelial, and smooth muscle cells are the major constituents, an inverse relationship exists between the levels of PGF(2 alpha) and a steroid-inducible anti-inflammatory protein, uteroglobin. Here we report that, in NIH 3T3 fibroblasts and human uterine smooth muscle cells, FP signaling is mediated via multi-kinase pathways in a cell type-specific manner to activate NF-kappa B, thus stimulating the expression of cyclooxygenase-2. Cyclooxygenase-2 is a critical enzyme for the production of prostaglandins from arachidonic acid, which is released from membrane phospholipids by phospholipase A(2), the expression of which is also stimulated by PGF(2 alpha). Most importantly, uteroglobin inhibits FP-mediated NF-kappa B activation and cyclooxygenase- 2 gene expression by binding and most likely by sequestering PGF(2 alpha) into its central hydrophobic cavity, thereby preventing FP-PGF(2 alpha) interaction and suppressing the production of inflammatory lipid mediators. We propose that uteroglobin plays important roles in maintaining homeostasis in organs that are vulnerable to inadvertent stimulation of FP-mediated inflammatory response. C1 NICHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Dept Oncol, Washington, DC 20057 USA. RP Mukherjee, AB (reprint author), NICHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov NR 58 TC 11 Z9 12 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 23 PY 2005 VL 280 IS 38 BP 32897 EP 32904 DI 10.1074/jbc.M502375200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 964ZU UT WOS:000231920300044 PM 16061484 ER PT J AU Xie, C Prahl, A Ericksen, B Wu, ZB Zeng, PY Li, XQ Lu, WY Lubkowski, J Lu, WY AF Xie, C Prahl, A Ericksen, B Wu, ZB Zeng, PY Li, XQ Lu, WY Lubkowski, J Lu, WY TI Reconstruction of the conserved beta-bulge in mammalian defensins using D-amino acids SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN ALPHA-DEFENSINS; ANTIMICROBIAL PEPTIDES; MEMBRANE PERMEABILIZATION; NEUTROPHIL DEFENSINS; DENDRITIC CELLS; PROTEIN; DESIGN; BETA-DEFENSIN-2; SPECIFICITY; DESTABILIZATION AB Defensins are cationic antimicrobial mini-proteins that play important roles in the innate immune defense against microbial infection. Six invariant Cys residues in each defensin form three structurally indispensable intramolecular disulfide bridges. The only other residue invariant in all known mammalian defensins is a Gly. Structural studies indicate that the invariant Gly residue is located in an atypical, classic-type beta-bulge with the backbone torsion angles ( phi, psi) disallowed for L-amino acids but permissible for D-enantiomers. We replaced the invariant Gly(17) residue in human neutrophil alpha-defensin 2 (HNP2) by L-Ala or one of the D-amino acids Ala, Glu, Phe, Arg, Thr, Val, or Tyr. Although L-Ala(17)-HNP2 could not be folded, resulting in massive aggregation, all of the D-amino acid-substituted analogs folded with high efficiency. The high resolution x-ray crystal structures of dimeric D-Ala(17)-HNP2 were determined in three different crystal forms, showing a well preserved beta-bulge identical to those found in other defensins. The seven D-analogs of HNP2 exhibited highly variable bactericidal activity against Gram-positive and Gram-negative test strains, consistent with the premise that interplay between charge and hydrophobicity dictates how amphiphilic defensins kill. Further, the bactericidal activity of these D-amino acid analogs of HNP2 correlated well with their ability to induce leakage from large unilamellar vesicles, supporting membrane permeabilization as the lethal event in microbial killing by HNP2. Our findings identify a conformational prerequisite in the beta-bulge of defensins essential for correct folding and native structure, thereby explaining the molecular basis of the Gly-Xaa-Cys motif conserved in all mammalian defensins. C1 NCI, Macromol Assembly Struct & Cell Signaling Sect, NIH, Frederick, MD 21702 USA. Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. Fudan Univ, Sch Pharm, Fudan PharmCo Drug Target Res Ctr, Shanghai 200032, Peoples R China. RP Lubkowski, J (reprint author), NCI, Macromol Assembly Struct & Cell Signaling Sect, NIH, Frederick, MD 21702 USA. EM jacek@ncifcrf.gov; luw@umbi.umd.edu RI Lu, Wuyuan/B-2268-2010; Ericksen, Bryan/F-9047-2012; Lu, Weiyue/E-7938-2010; Prahl, Adam/H-7654-2014; OI Ericksen, Bryan/0000-0002-8016-8289 FU NIAID NIH HHS [AI061482, AI056264] NR 64 TC 51 Z9 55 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 23 PY 2005 VL 280 IS 38 BP 32921 EP 32929 DI 10.1074/jbc.M503084200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 964ZU UT WOS:000231920300047 PM 15894545 ER PT J AU Banks, WA Kumar, VB Franko, MW Bess, JW Arthur, LO AF Banks, WA Kumar, VB Franko, MW Bess, JW Arthur, LO TI Evidence that the species barrier of human immunodeficiency virus-1 does not extend to uptake by the blood-brain barrier: Comparison of mouse and human brain microvessels SO LIFE SCIENCES LA English DT Article DE HIV-1; blood-brain barrier; mouse; AIDS; gp120; microarray ID ENDOTHELIAL-CELLS; IN-VITRO; ADSORPTIVE ENDOCYTOSIS; HIV-1; INFECTION; INHIBITORS; MIGRATION; TRANSPORT; PROTEINS; STRAIN AB HIV-1 within the CNS produces a neuroAlDS syndrome and may act as a reservoir for reinfection of the peripheral tissues. Study of how HIV-1 crosses the blood-brain barrier (BBB) has been hampered by the lack of nonprimate animal models. However, BBB transport of HIV-1 does not involve any of the known steps conferring species specificity, including binding to CD4 receptors. In vivo and in vitro studies show that HIV-1 and its glycoprotein coat, gp 120, are taken up and transported across the BBB of the mouse. Here, we compared the ability of gp 120 and HIV-1 to be taken up by isolated brain microvessels (IBM) freshly isolated from mice, from post-mortem human brain, and from mice that had been treated in a manner analogous to the human material (mouse post-mortem). Freshly isolated mouse IBM took up more gp 120 and HIV-1 than the human or mouse post-mortem cells. We found no difference between the ability of mouse post-mortem and human IBM to take up either gp 120 or HIV-1 . Wheatgerm agglutinin has been previously shown to stimulate gp 120 and HIV-1 uptake by the BBB; here, it stimulated the uptake of gp 120 and of HIV-1 by both mouse post-mortem and human IBM, although stimulated uptake was greatest for fresh mouse IBM. These results show that the mouse can be used to study the initial phases of HIV-1 uptake by the BBB. Published by Elsevier Inc. C1 Vet Affairs Med Ctr, GRECC, St Louis, MO 63106 USA. St Louis Univ, Sch Med, Dept Internal Med, Div Geriatr, St Louis, MO 63106 USA. Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC, Frederick, MD 21702 USA. RP Banks, WA (reprint author), Vet Affairs Med Ctr, GRECC, 915 N Grand Blvd, St Louis, MO 63106 USA. EM bankswa@slu.edu RI Bess, Jr., Julian/B-5343-2012 FU NCI NIH HHS [N01-CO-12400]; NINDS NIH HHS [R01 NS41863] NR 25 TC 4 Z9 5 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD SEP 23 PY 2005 VL 77 IS 19 BP 2361 EP 2368 DI 10.1016/j.lfs.2004.11.041 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 963FF UT WOS:000231788400003 PM 15946698 ER PT J AU Sriraman, S Kevrekidis, IG Hummer, G AF Sriraman, S Kevrekidis, IG Hummer, G TI Coarse nonlinear dynamics and metastability of filling-emptying transitions: Water in carbon nanotubes SO PHYSICAL REVIEW LETTERS LA English DT Article ID MOLECULAR-DYNAMICS; MONTE-CARLO; FREE-ENERGY; SIMULATIONS; BIFURCATION; EQUATION; KINETICS AB Using a coarse-grained molecular dynamics ( CMD) approach we study the apparent nonlinear dynamics of water molecules filling or emptying carbon nanotubes as a function of system parameters. Different levels of the pore hydrophobicity give rise to tubes that are empty, water-filled, or fluctuate between these two long-lived metastable states. The corresponding coarse-grained free-energy surfaces and their hysteretic parameter dependence are explored by linking MD to continuum fixed point and bifurcation algorithms. The results are validated through equilibrium MD simulations. C1 Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. Princeton Univ, PACM, Princeton, NJ 08544 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Sriraman, S (reprint author), Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. EM rudram@princeton.edu; yannis@princeton.edu; gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS NR 20 TC 36 Z9 36 U1 1 U2 12 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD SEP 23 PY 2005 VL 95 IS 13 AR 130603 DI 10.1103/PhysRevLett.95.130603 PG 4 WC Physics, Multidisciplinary SC Physics GA 966ZA UT WOS:000232060100007 PM 16197128 ER PT J AU Nguyen, TL McGrath, C Hermone, AR Burnett, JC Zaharevitz, DW Day, BW Wipf, P Hamel, E Gussio, R AF Nguyen, TL McGrath, C Hermone, AR Burnett, JC Zaharevitz, DW Day, BW Wipf, P Hamel, E Gussio, R TI A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NATURAL-PRODUCT CURACIN; CANCER-CELL-CULTURES; TUBULIN POLYMERIZATION; BIOLOGICAL EVALUATION; ANTIMITOTIC AGENT; ANTITUMOR AGENTS; BINDING-SITE; ANALOGS; POTENT; 2-METHOXYESTRADIOL AB Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site. C1 NCI, Dev Therapeut Program, Target Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Ctr Chem Methodol & Lib Dev, Pittsburgh, PA 15260 USA. NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Screening Technol Branch, Frederick, MD 21702 USA. RP Nguyen, TL (reprint author), NCI, Dev Therapeut Program, Target Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. EM nguyent@ncifcrf.gov; gussio@ncifcrf.gov NR 40 TC 197 Z9 207 U1 0 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 22 PY 2005 VL 48 IS 19 BP 6107 EP 6116 DI 10.1021/jm050502t PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 967GS UT WOS:000232080200022 PM 16162011 ER PT J AU Guiotto, A Calderan, A Ruzza, P Osler, A Rubini, C Jo, DG Mattson, MP Borin, G AF Guiotto, A Calderan, A Ruzza, P Osler, A Rubini, C Jo, DG Mattson, MP Borin, G TI Synthesis and evaluation of neuroprotective alpha,beta-unsaturated aldehyde scavenger histidyl-containing analogues of carnosine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID LIPID-PEROXIDATION PRODUCTS; 4-HYDROXYNONENAL PROTEIN; OXIDATIVE STRESS; CROSS-LINKING; ADDUCTS; DISEASE; MALONDIALDEHYDE; IDENTIFICATION; MALONALDEHYDE; INVOLVEMENT AB The synthesis, scavenging activity, and cytoprotective profiles of histidyl-containing carnosine analogues bearing hydrazide or 1,2-diol moieties is reported. Some compounds have demonstrated higher aldehyde-sequestering efficiency than carnosine and were also efficient in protecting SH-SY5Y neuroblastoma cells and rat hippocampal neurons from 4-hydroxy-trans-2,3-nonenal (HNE)-mediated death. The cytoprotective efficacy of these compounds suggests their potential use as therapeutic agents for disorders that involve excessive membrane lipids peroxidation and HNE-mediated neuronal toxicity. C1 CNR, Inst Biomol Chem, Padova Unit, I-35131 Padua, Italy. NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Guiotto, A (reprint author), CNR, Inst Biomol Chem, Padova Unit, Via F Marzolo 1, I-35131 Padua, Italy. EM andrea.guiotto@unipd.it RI Guiotto, Andrea/A-4720-2009; Mattson, Mark/F-6038-2012; Ruzza, Paolo/N-6030-2015; OI Ruzza, Paolo/0000-0002-5596-9295; CALDERAN, ANDREA/0000-0003-4763-0782 NR 23 TC 25 Z9 25 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 22 PY 2005 VL 48 IS 19 BP 6156 EP 6161 DI 10.1021/jm050507q PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 967GS UT WOS:000232080200026 PM 16162015 ER PT J AU Kaur, N Lu, XP Gershengorn, MC Jain, R AF Kaur, N Lu, XP Gershengorn, MC Jain, R TI Thyrotropin-releasing hormone (TRH) analogues that exhibit selectivity to TRH receptor subtype 2 SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CLONING; HISTIDINE; BINDING AB Thyrotropin-releasing hormone (TRH) analogues in which the C-2 position of the imidazole ring of the centrally placed histidine residue is substituted with various alkyl groups were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRHR2). Several analogues were found to be selective agonists for TRH-R2 exhibiting no activation of TRH-R1. For example, analogue 4 (R = c-C3H5) was found to activate TRH-R2 with a potency (EC50) of 0.41 mu M but did not activate TRH-R1 (potency > 100 mu M). This study describes the first discovery of TRH-R2-specific agonists and provides impetus to design predominately CNS-effective TRH peptides. C1 Natl Inst Pharmaceut Educ & Res, Dept Med Chem, Sector 67, Nagar 160062, Punjab, India. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Jain, R (reprint author), Natl Inst Pharmaceut Educ & Res, Dept Med Chem, Sector 67, Nagar 160062, Punjab, India. EM rahuljain@niper.ac.in OI Kaur, Navneet/0000-0002-0012-6151 NR 25 TC 37 Z9 37 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 22 PY 2005 VL 48 IS 19 BP 6162 EP 6165 DI 10.1021/jm0505462 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 967GS UT WOS:000232080200027 PM 16162016 ER PT J AU Gopich, IV Szabo, A AF Gopich, IV Szabo, A TI Photon counting histograms for diffusing fluorophores SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID FLUORESCENCE FLUCTUATION SPECTROSCOPY; MOLECULAR BRIGHTNESS; EXCITATION; HETEROGENEITY AB The theory of photon counting histograms for fluorescent molecules diffusing through a laser spot is presented. Analytic expressions for the factorial cumulants of photon counts are obtained. For an arbitrary counting time window, it is shown how the exact histograms can be obtained by solving an appropriate reaction-diffusion equation. Our formalism reduces correctly when the molecules are immobile. The approximation used in fluorescence intensity multiple distribution analysis (FIMDA) is tested against the exact numerical solution of the problem. FIMDA works very well for a wide range of parameters except for small concentrations and long time windows. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gopich, IV (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM gopich@nih.gov RI Szabo, Attila/H-3867-2012 NR 19 TC 16 Z9 16 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD SEP 22 PY 2005 VL 109 IS 37 BP 17683 EP 17688 DI 10.1021/jp052345f PG 6 WC Chemistry, Physical SC Chemistry GA 964ZZ UT WOS:000231920800048 PM 16853263 ER PT J AU Cai, HX Manoussaki, D Chadwick, R AF Cai, HX Manoussaki, D Chadwick, R TI Effects of coiling on the micromechanics of the mammalian cochlea SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE cochlear curvature; cochlear micromechanics; shear gain; organ of Corti; fluid-structure interaction ID TECTORIAL MEMBRANE; BASILAR-MEMBRANE; INNER-EAR; MODEL; MOTION; MECHANICS AB The cochlea transduces sound-induced vibrations in the inner ear into electrical signals in the auditory nerve via complex fluid-structure interactions. The mammalian cochlea is a spiral-shaped organ, which is often uncoiled for cochlear modelling. In those few studies where coiling has been considered, the cochlear partition was often reduced to the basilar membrane only. Here, we extend our recently developed hybrid analytical/numerical micromechanics model to include curvature effects, which were previously ignored. We also use a realistic cross-section geometry, including the tectorial membrane and cellular structures of the organ of Corti, to model the apical and basal regions of a guinea-pig cochlea. We formulate the governing equations of the fluid and solid domains in a curvilinear coordinate system. The WKB perturbation method is used to treat the propagation of travelling waves along the coiled cochlear duct, and the O(1) system of the governing equations is solved in the transverse plane using finite-clement analysis. We find that the curvature of the cochlear geometry has an important functional significance; at the apex, it greatly increases the shear gain of the cochlear partition, which is a measure of the bending efficiency of the outer hair cell stereocilia. C1 NIDCD, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Math, Nashville, TN 37240 USA. RP Chadwick, R (reprint author), NIDCD, Sect Auditory Mech, NIH, Bldg 10,Room 5D49, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov NR 24 TC 21 Z9 21 U1 1 U2 4 PU ROYAL SOCIETY PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J ROY SOC INTERFACE JI J. R. Soc. Interface PD SEP 22 PY 2005 VL 2 IS 4 BP 341 EP 348 DI 10.1098/rsif.2005.0049 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998TH UT WOS:000234342000008 PM 16849192 ER PT J AU Varela, I Cadinanos, J Pendas, AM Gutierrez-Fernandez, A Folgueras, AR Sanchez, LM Zhou, ZJ Rodriguez, FJ Stewart, CL Vega, JA Tryggvason, K Freije, JMP Lopez-Otin, C AF Varela, I Cadinanos, J Pendas, AM Gutierrez-Fernandez, A Folgueras, AR Sanchez, LM Zhou, ZJ Rodriguez, FJ Stewart, CL Vega, JA Tryggvason, K Freije, JMP Lopez-Otin, C TI Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation SO NATURE LA English DT Article ID A-TYPE LAMINS; HUTCHINSON-GILFORD PROGERIA; LIFE-SPAN; IN-VIVO; METALLOPROTEINASE; SENESCENCE; PHENOTYPES; MUTATIONS; CANCER; CELLS AB Zmpste24 ( also called FACE- 1) is a metalloproteinase involved in the maturation of lamin A ( Lmna), an essential component of the nuclear envelope(1 - 3). Both Zmpste24- and Lmna- deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process(1,2,4,5). Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes(6 - 10). To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24- deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24 (-/-) Lmna (+/-) mice and partially reversed in Zmpste24 (-/-) p53 (-/-) mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing(11). C1 Inst Univ Oncol, Fac Med, Dept Bioquim & Biol Mol, Oviedo, Spain. Univ Oviedo, Dept Morfol & Biol Celular, E-33006 Oviedo, Spain. Karolinska Inst, Dept Biochem & Biophys, Div Matrix Biol, S-17177 Stockholm, Sweden. NCI, Frederick, MD 21702 USA. RP Lopez-Otin, C (reprint author), Inst Univ Oncol, Fac Med, Dept Bioquim & Biol Mol, Oviedo, Spain. EM clo@uniovi.es RI Freije, Jose M.P./A-6535-2008; zhou, zhongjun/D-4818-2012; Pendas, Alberto/L-1017-2014; Varela, Ignacio/G-1699-2016; Lopez-Otin, Carlos/C-6657-2013; Folgueras, Alicia/B-3281-2017; OI Freije, Jose M.P./0000-0002-4688-8266; Gutierrez-Fernandez, Ana/0000-0002-9287-8843; Varela, Ignacio/0000-0002-0969-506X; Lopez-Otin, Carlos/0000-0001-6964-1904; Folgueras, Alicia/0000-0003-3426-9502; Pendas, Alberto M/0000-0001-9264-3721 NR 30 TC 245 Z9 259 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 22 PY 2005 VL 437 IS 7058 BP 564 EP 568 DI 10.1038/nature04019 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 966FF UT WOS:000232004800053 PM 16079796 ER PT J AU Lieberman, JA Stroup, TS McEvoy, JP Swartz, MS Rosenheck, RA Perkins, DO Keefe, RSE Davis, SM Davis, CE Lebowitz, BD Severe, J Hsiao, JK AF Lieberman, JA Stroup, TS McEvoy, JP Swartz, MS Rosenheck, RA Perkins, DO Keefe, RSE Davis, SM Davis, CE Lebowitz, BD Severe, J Hsiao, JK CA CATIE Investigators TI Effectiveness of antipsychotic drugs in patients with chronic schizophrenia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTERVENTION EFFECTIVENESS CATIE; NEW-GENERATION ANTIPSYCHOTICS; 2ND-GENERATION ANTIPSYCHOTICS; RANDOMIZED-TRIALS; CONVENTIONAL ANTIPSYCHOTICS; ATYPICAL ANTIPSYCHOTICS; CLINICAL-TRIALS; DOUBLE-BLIND; METAANALYSIS; HALOPERIDOL AB BACKGROUND: The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. METHODS: A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. RESULTS: Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. CONCLUSIONS: The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism. C1 Columbia Univ, New York State Psychiat Inst, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Quintiles, Res Triangle Pk, NC USA. John Umstead Hosp, Dept Biol Psychiat, Butner, NC USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. RP Lieberman, JA (reprint author), Columbia Univ, New York State Psychiat Inst, Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA. EM jlieberman@columbia.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NIMH NIH HHS [N01 MH90001] NR 37 TC 3079 Z9 3202 U1 55 U2 390 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 22 PY 2005 VL 353 IS 12 BP 1209 EP 1223 DI 10.1056/NEJMoa051688 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 966DS UT WOS:000232000400005 PM 16172203 ER PT J AU Paik, S Tang, G AF Paik, S Tang, G TI Molecular prediction of recurrence of breast cancer - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID REPRODUCIBILITY; INTEROBSERVER; CARCINOMA; GRADE C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. RP Paik, S (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. EM spaik.nejm@nsabp.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 22 PY 2005 VL 353 IS 12 BP 1300 EP 1300 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 966DS UT WOS:000232000400032 ER PT J AU Sebastian, T Malik, R Thomas, S Sage, J Johnson, PF AF Sebastian, T Malik, R Thomas, S Sage, J Johnson, PF TI C/EBP beta cooperates with RB : E2F to implement Ras(V12)-induced cellular senescence SO EMBO JOURNAL LA English DT Article DE C/EBP beta; cell cycle arrest; cellular senescence; oncogenic Ras; RB : E2F ID BINDING-PROTEIN-BETA; TRANSCRIPTIONAL ACTIVATOR PROTEIN; RETINOBLASTOMA PROTEIN; GROWTH ARREST; ADIPOCYTE DIFFERENTIATION; HEPATOCYTE PROLIFERATION; REPLICATIVE SENESCENCE; PREMATURE SENESCENCE; TARGETED DISRUPTION; TUMOR SUPPRESSION AB In primary cells, overexpression of oncogenes such as Ras(V12) induces premature senescence rather than transformation. Senescence is an irreversible form of G(1) arrest that requires the p19(ARF)/p53 and p16(INK4a)/pRB pathways and may suppress tumorigenesis in vivo. Here we show that the transcription factor C/EBP beta is required for Ras(V12)-induced senescence. C/EBP beta(-/-) mouse embryo fibroblasts (MEFs) expressing Ras(V12) continued to proliferate despite unimpaired induction of p19(ARF) and p53, and lacked morphological features of senescent fibroblasts. Enforced C/EBP beta expression inhibited proliferation of wild-type MEFs and also slowed proliferation of p19(Arf-/-) and p53(-/-) cells, indicating that C/EBP beta acts downstream or independently of p19(ARF)/p53 to suppress growth. C/EBP beta was unable to inhibit proliferation of MEFs lacking all three RB family proteins or wild-type cells expressing dominant negative E2F-1 and, instead, stimulated their growth. C/EBP beta decreased expression of several E2F target genes and was associated with their promoters in chromatin immunoprecipitation assays, suggesting that C/EBP beta functions by repressing genes required for cell cycle progression. C/EBP beta is therefore a novel component of the RB: E2F-dependent senescence program activated by oncogenic stress in primary cells. C1 NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Johnson, PF (reprint author), NCI, Lab Prot Dynam & Signaling, Bldg 539,Room 122,7th Mil St, Frederick, MD 21702 USA. EM johnsopf@ncifcrf.gov RI Johnson, Peter/A-1940-2012; Malik, Radek/G-3578-2014 OI Johnson, Peter/0000-0002-4145-4725; FU Intramural NIH HHS NR 61 TC 85 Z9 84 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 21 PY 2005 VL 24 IS 18 BP 3301 EP 3312 DI 10.1038/sj.emboj.7600789 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973VV UT WOS:000232551600014 PM 16107878 ER PT J AU Bao, TH Guynet, C Ronning, DR Cointin-Marty, B Dyda, F Chandler, M AF Bao, TH Guynet, C Ronning, DR Cointin-Marty, B Dyda, F Chandler, M TI Transposition of ISHp608, member of an unusual family of bacterial insertion sequences SO EMBO JOURNAL LA English DT Article DE excision; in vitro; in vivo; integration; transposase activity ID ROLLING-CIRCLE REPLICATION; HELICOBACTER-PYLORI; FUNCTIONAL-ORGANIZATION; SUPERCOILED DNA; IS91; IS200; SPECIFICITY; SALMONELLA; ELEMENTS; GENE AB ISHp608 from Helicobacter pylori is active in Escherichia coli and represents a recently recognised group of insertion sequences. Its transposase and organisation suggest that it transposes using a different mechanism to that of other known transposons. The IS was shown to excise as a circular form, which is accompanied by the formation of a resealed donor plasmid backbone. We also demonstrate that TnpA, which is less than half the length of other transposases, is responsible for this and for ISHp608 transposition. Transposition was shown to be site specific: both insertion and transposon excision require a conserved target, 5'TTAC. Deletion analysis suggested that potential secondary structures at the left and right ends are important for transposition. In vitro TnpA bound both ends, showed a strong preference for a specific single-stranded DNA and introduced a single-strand break on the same strand at each end. Although many of the characteristics of ISHp608 appear similar to rolling-circle transposons, there are differences suggesting that, overall, transposition occurs by a different mechanism. The results have permitted the formulation of several related models. C1 LMGM, CNRS, UMR5100, F-31062 Toulouse, France. NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Chandler, M (reprint author), LMGM, CNRS, UMR5100, 118 Route Narbonne, F-31062 Toulouse, France. EM mike@ibcg.biotoul.fr RI Guynet, Catherine/A-4815-2011; OI Chandler, Michael/0000-0002-0292-6662 NR 36 TC 13 Z9 13 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 21 PY 2005 VL 24 IS 18 BP 3325 EP 3338 DI 10.1038/sj.emboj.7600787 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973VV UT WOS:000232551600016 ER PT J AU Zerhouni, EA AF Zerhouni, EA TI US biomedical research - Basic, translational, and clinical sciences SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID EBOLA-VIRUS GLYCOPROTEIN; SMALLPOX VACCINE; MICE AB The National Institutes of Health (NIH) is the world's largest biomedical research agency, with a 75-year record of responding to the nation's key medical challenges. Today, medical science is entering a revolutionary period marked by a shift in focus from acute to chronic diseases, rapidly escalating health care costs, a torrent of biological data generated by the sequencing of the human genome, and the development of advanced high-throughput technologies that allow for the study of vast molecular networks in health and disease. This unique period offers the unprecedented opportunity to identify individuals at risk of disease based on precise molecular knowledge, and the chance to intervene to preempt disease before it strikes. Conceptually, this represents the core scientific challenge of the coming century. The NIH is committed to the discoveries that will change the practice of medicine as we know it in order to meet this challenge. The NIH Roadmap constitutes an important vehicle for generating change-a most critical element of this plan is the reengineering of the national clinical research enterprise. This reinvention will call for the transformation of translational clinical science and for novel interdisciplinary approaches that will advance science and enhance the health of the nation. C1 NIH, Bethesda, MD 20892 USA. RP Zerhouni, EA (reprint author), NIH, 1 Ctr Dr,Bldg 1,Room 126, Bethesda, MD 20892 USA. EM zerhoune@od.nih.gov NR 39 TC 154 Z9 159 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 SEP 21 PY 2005 VL 294 IS 11 BP 1352 EP 1358 DI 10.1001/jama.294.11.1352 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 965YW UT WOS:000231987800008 PM 16174693 ER PT J AU Guttmacher, AE Collins, FS AF Guttmacher, AE Collins, FS TI Realizing the promise of genomics in biomedical research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID INTERNATIONAL HAPMAP PROJECT; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; FAMILY-HISTORY; LUNG-CANCER; MUTATIONS; GENETICS; HAPLOTYPES; GEFITINIB; SEQUENCE C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Guttmacher, AE (reprint author), NHGRI, NIH, Room 4B09,31 Ctr Dr, Bethesda, MD 20892 USA. EM guttmach@mail.nih.gov NR 39 TC 84 Z9 87 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 21 PY 2005 VL 294 IS 11 BP 1399 EP 1402 DI 10.1001/jama.294.11.1399 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 965YW UT WOS:000231987800016 PM 16174701 ER PT J AU Pinn, VW AF Pinn, VW TI Research on women's health - Progress and opportunities SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; SYSTEMIC-LUPUS-ERYTHEMATOSUS; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; INFECTIOUS-DISEASES; PRIMARY PREVENTION; VITAMIN-E; CANCER; ATHEROSCLEROSIS; ESTROGEN C1 NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, Bldg 1,Room 201, Bethesda, MD 20892 USA. EM vivian.pinn@nih.gov NR 36 TC 14 Z9 14 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 21 PY 2005 VL 294 IS 11 BP 1407 EP 1410 DI 10.1001/jama.294.11.1407 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 965YW UT WOS:000231987800018 PM 16174703 ER PT J AU Rezai-Zadeh, K Shytle, D Sun, N Mori, T Hou, HY Jeanniton, D Ehrhart, J Townsend, K Zeng, J Morgan, D Hardy, J Town, T Tan, J AF Rezai-Zadeh, K Shytle, D Sun, N Mori, T Hou, HY Jeanniton, D Ehrhart, J Townsend, K Zeng, J Morgan, D Hardy, J Town, T Tan, J TI Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE aging; Alzheimer's disease; beta-amyloid; green tea; PKC; protease ID ALPHA-CONVERTING-ENZYME; CANCER PREVENTION; KINASE-C; DISEASE; SECRETASE; GALLATE; POLYPHENOLS; MECHANISMS; EXPRESSION; INHIBITION AB Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid ( A beta) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate ( EGCG), the main polyphenolic constituent of green tea, reduces A beta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APP(sw) line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-alpha. These cleavage events are associated with elevated alpha-secretase activity and enhanced hydrolysis of tumor necrosis factor alpha-converting enzyme, a primary candidate alpha-secretase. As a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing A beta with EGCG and found decreased A beta levels and plaques associated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD. C1 Univ S Florida, Dept Psychiat & Behav Med, Neuroimmunol Lab, Silver Child Dev Ctr, Tampa, FL 33613 USA. Univ S Florida, Ctr Excellence Aging & Brain Repair, Dept Neurosurg, Tampa, FL 33613 USA. Univ S Florida, Dept Pharmacol, Alzheimers Dis Res Lab, Tampa, FL 33613 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06519 USA. RP Tan, J (reprint author), Univ S Florida, Dept Psychiat, Neuroimmunol Lab, 3515 E Fletcher Ave, Tampa, FL 33613 USA. EM jtan@hsc.usf.edu RI Hardy, John/C-2451-2009; Morgan, David/J-5989-2012; Tan, Jun/I-5339-2012; Shytle, Roland/J-4249-2012 NR 37 TC 330 Z9 350 U1 6 U2 50 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 21 PY 2005 VL 25 IS 38 BP 8807 EP 8814 DI 10.1523/JNEUROSCI.1521-05.2005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 966OD UT WOS:000232028500025 PM 16177050 ER PT J AU Yu, XM Shen, G Neckers, L Blake, H Holzbeierlein, J Cronk, B Blagg, BSJ AF Yu, XM Shen, G Neckers, L Blake, H Holzbeierlein, J Cronk, B Blagg, BSJ TI Hsp90 inhibitors identified from a library of novobiocin analogues SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHAPERONE; BINDING; CANCER C1 Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. Univ Kansas, Ctr Prot Struct & Funct, Lawrence, KS 66045 USA. NCI, Urol Oncol Branch, NIH, Rockville, MD 20850 USA. Univ Kansas, Med Ctr, Dept Urol, Kansas City, KS 66103 USA. RP Blagg, BSJ (reprint author), Univ Kansas, Dept Med Chem, 1251 Wescoe Hall Dr,Malott 4070, Lawrence, KS 66045 USA. EM bblagg@ku.edu FU NCRR NIH HHS [RR017708] NR 11 TC 121 Z9 127 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 21 PY 2005 VL 127 IS 37 BP 12778 EP 12779 DI 10.1021/ja0535864 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 965CY UT WOS:000231928800015 PM 16159253 ER PT J AU Travis, LB Fossa, SD Schonfeld, SJ McMaster, ML Lynch, CF Storm, H Hall, P Holowaty, E Andersen, A Pukkala, E Andersson, M Kaijser, M Gospodarowicz, M Joensuu, T Cohen, RJ Boice, JD Dores, GM Gilbert, ES AF Travis, LB Fossa, SD Schonfeld, SJ McMaster, ML Lynch, CF Storm, H Hall, P Holowaty, E Andersen, A Pukkala, E Andersson, M Kaijser, M Gospodarowicz, M Joensuu, T Cohen, RJ Boice, JD Dores, GM Gilbert, ES TI Second cancers among 40576 testicular cancer patients: Focus on long-term survivors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GERM-CELL TUMORS; MEDICAL-RESEARCH-COUNCIL; LUNG-CANCER; HODGKINS-DISEASE; MALIGNANT NEOPLASMS; BREAST-CANCER; EUROPEAN ORGANIZATION; RADIATION-EXPOSURE; RANDOMIZED-TRIAL; POOLED ANALYSIS AB Background: Although second primary cancers are a leading cause of death among men with testicular cancer, few studies have quantified risks among long-term survivors. Methods: Within 14 population-based tumor registries in Europe and North America (1943-2001), we identified 40576 1-year survivors of testicular cancer and ascertained data on any new incident solid tumors among these patients. We used Poisson regression analysis to model relative risks (RRs) and excess absolute risks (EARs) of second solid cancers. All statistical tests were two-sided. Results: A total of 2285 second solid cancers were reported in the cohort. The relative risk and EAR decreased with increasing age at testicular cancer diagnosis (P<.001); the EAR increased with attained age (P<.001) but the excess RR decreased. Among 10-year survivors diagnosed with testicular cancer at age 35 years, the risk of developing a second solid tumor was increased (RR = 1.9, 95% confidence interval [CI] = 1.8 to 2.1). Risk remained statistically significantly elevated for 35 years (RR = 1.7, 95% CI = 1.5 to 2.0; P<.001). We observed statistically significantly elevated risks, for the first time, for cancers of the pleura (malignant mesothelioma; RR = 3.4, 95% Cl = 1.7 to 5.9) and esophagus (RR = 1.7, 95% CI = 1.0 to 2.6). Cancers of the lung (RR = 1.5, 95% CI = 1.2 to 1.7), colon (RR = 2.0, 95% CI = 1.7 to 2.5), bladder (RR = 2.7, 95% CI = 2.2 to 3.1), pancreas (RR = 3.6, 95% CI = 2.8 to 4.6), and stomach (RR = 4.0, 95% CI = 3.2 to 4.8) accounted for almost 60% of the total excess. Overall patterns were similar for seminoma and nonseminoma patients, with lower risks observed for nonseminoma patients treated after 1975. Statistically significantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% Cl = 1.9 to 2.2), chemotherapy alone (RR = 1.8,95% CI = 1.3 to 2.5), and both (RR = 2.9,95% CI = 1.9 to 4.2). For patients diagnosed with seminomas or nonseminomatous tumors at age 35 years, cumulative risks of solid cancer 40 years later (i.e., to age 75 years) were 36% and 31%, respectively, compared with 23% for the general population. Conclusions: Testicular cancer survivors are at statistically significantly increased risk of solid tumors for at least 35 years after treatment. Young patients may experience high levels of risk as they reach older ages. The statistically significantly increased risk of malignant mesothelioma in testicular cancer survivors has, to our knowledge, not been observed previously in a cohort of patients treated with radiotherapy. C1 NCI, US Dept HHS, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Norwegian Radium Hosp, N-0310 Oslo, Norway. Univ Iowa, Iowa City, IA USA. Danish Canc Soc, Copenhagen, Denmark. Karolinska Inst, Stockholm, Sweden. Canc Care Ontario, Toronto, ON, Canada. Canc Registry Norway, Oslo, Norway. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Univ Helsinki, Cent Hosp, Helsinki, Finland. Howard Hughes Med Inst, Chevy Chase, MD USA. Int Epidemiol Inst, Rockville, MD USA. Vanderbilt Univ, Ctr Canc, Nashville, TN USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Travis, LB (reprint author), NCI, US Dept HHS, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Ste 7086, Bethesda, MD 20892 USA. EM travisl@mail.nih.gov OI Storm, Hans/0000-0001-7223-8198 FU Intramural NIH HHS NR 73 TC 397 Z9 405 U1 0 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 21 PY 2005 VL 97 IS 18 BP 1354 EP 1365 DI 10.1093/jnci/dji278 PG 12 WC Oncology SC Oncology GA 969YV UT WOS:000232273000010 PM 16174857 ER PT J AU Pawliczak, R Logun, C Madara, P Barb, J Suffredini, AF Munson, PJ Danner, RL Shelhamer, JH AF Pawliczak, R Logun, C Madara, P Barb, J Suffredini, AF Munson, PJ Danner, RL Shelhamer, JH TI Influence of IFN-gamma on gene expression in normal human bronchial epithelial cells: modulation of IFN-gamma effects by dexamethasone SO PHYSIOLOGICAL GENOMICS LA English DT Article DE interferon; inflammation; cytokines; lung cells; corticosteroids; transcriptional regulation ID NF-KAPPA-B; INTERFERON-GAMMA; MICROARRAY ANALYSIS; TYROSINE KINASE; CHEMOKINE EXPRESSION; T-CELLS; ACTIVATION; RECEPTOR; PATHWAYS; ALPHA AB Interferon gamma (IFN-gamma) plays a role in a variety of lung inflammatory responses, and corticosteroids are frequently employed as a treatment in these conditions. Therefore, the effect of IFN-gamma, of the corticosteroid dexamethasone (Dex), or of both on gene expression was studied in normal human bronchial epithelial ( NHBE) cells. NHBE cells were exposed to medium alone, IFN-gamma (300 U/ ml), Dex (10 (-7) M), or both IFN-gamma and Dex for 8 or 24 h. Gene expression was examined using oligonucleotide microarrays. A principal components analysis demonstrated that the IFN-gamma treatment effect was the primary source of differences in the data. With a 5% false discovery rate, of the 66 genes upregulated by IFN- gamma by twofold or greater at 8 h and 287 genes upregulated at 24 h, coincubation with Dex inhibited the expression of 2 genes at 8 h and 45 genes at 24 h. Prominent among these were cytokines and secreted proteins. Dex cotreatment increased expression of 65 of the 376 genes that were inhibited by IFN-gamma by 50% at 24 h. The majority of these genes encode cell cycle or nuclear proteins. Dex alone increased the expression of only 22 genes and inhibited the expression of 7 genes compared with controls at 24 h. The effect of Dex on IFN-gamma- induced changes suggests a specific, targeted effect on IFN-gamma responses that is substantially greater than the effect of Dex alone. Dex had little effect on the immediate early response to IFN-gamma but a significant effect on the late responses. C1 NIH, Warren Grant Magnuson Clin Ctr, Crit Care Med Dept, Bethesda, MD 20892 USA. Med Univ Lodz, Dept Allergy & Clin Immunol, PL-90131 Lodz, Poland. NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. RP Shelhamer, JH (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Crit Care Med Dept, 9000 Rockville Pike,Bldg 10,Rm 7D43, Bethesda, MD 20892 USA. EM jshelhamer@nih.gov RI Pawliczak, Rafal/S-9649-2016; OI Pawliczak, Rafal/0000-0001-6784-453X NR 39 TC 23 Z9 24 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD SEP 21 PY 2005 VL 23 IS 1 BP 28 EP 45 DI 10.1152/physiolgenomics.00011.2005 PG 18 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 967AZ UT WOS:000232065200005 PM 15985639 ER PT J AU Maloyan, A Eli-Berchoer, L Semenza, GL Gerstenblith, G Stern, MD Horowitz, M AF Maloyan, A Eli-Berchoer, L Semenza, GL Gerstenblith, G Stern, MD Horowitz, M TI HIF-1 alpha-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart SO PHYSIOLOGICAL GENOMICS LA English DT Article DE hypoxia-inducible factor 1 alpha; vascular endothelial growth factor; erythropoietin; erythropoietin receptor; heme oxygenase-1; heat stress ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; GROWTH-FACTOR EXPRESSION; FACTOR 1-ALPHA; GENE-EXPRESSION; FACTOR-I; NITRIC-OXIDE; CANCER CELLS; ERYTHROPOIETIN; INDUCTION; MECHANISM AB Hypoxiainducible factor-1 (HIF-1) is a key regulator of the cellular hypoxic response. We previously showed that HIF-1 activation is essential for heat acclimation (AC) in Caenorhabditis elegans. Metabolic changes in AC rat hearts indicate HIF-1 alpha activation in mammals as well. Here we characterize the HIF-1 alpha profile and the transcriptional activation of its target genes following AC and following heat stress (HS) in hearts from nonacclimated ( C; 24 degrees C) and AC (34 degrees C, 1 mo) rats. We used Western blot and immunohistochemistry to measure HIF-1 alpha levels and EMSA and RT-PCR/quantitative RT-PCR to detect expression of the HIF-1 alpha-targeted genes, including vascular endothelial growth factor (Vegf), heme oxygenase-1 ( HO1), erythropoietin ( Epo), and Epo receptor ( EpoR). EpoR and Epo mRNA levels were measured to determine systemic effects in the kidneys and cross-tolerance effects in C and AC ischemic hearts ( Langendorff, 75% ischemia, 40 min). The results demonstrated that 1) after AC, HIF-1 alpha protein levels were increased, 2) HS alone induced transient HIF-1 alpha upregulation, and 3) VEGF and HO1 mRNA levels increased after HS, with greater magnitude in the AC hearts. Epo mRNA in AC kidneys and EpoR mRNA in AC hearts were also elevated. In AC hearts, EpoR expression was markedly higher after HS or ischemia. Hearts from AC rats were dramatically protected against infarction after ischemia-perfusion. We conclude that HIF-1 contributes to the acclimation-ischemia cross-tolerance mechanism in the heart by induction of both chronic and inducible adaptive components. C1 Hebrew Univ Jerusalem, Fac Med Dent, Environm Physiol Lab, Jerusalem, Israel. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21218 USA. NIA, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Horowitz, M (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, POB 12272, IL-91120 Jerusalem, Israel. EM horowitz@cc.huji.ac.il NR 58 TC 49 Z9 52 U1 1 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD SEP 21 PY 2005 VL 23 IS 1 BP 79 EP 88 DI 10.1152/physiolgenomics.00279.2004 PG 10 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 967AZ UT WOS:000232065200010 PM 16046617 ER PT J AU Jackson, M Chopra, S Smiley, RD Maynord, PO Rosowsky, A London, RE Levy, L Kalman, TI Howell, EE AF Jackson, M Chopra, S Smiley, RD Maynord, PO Rosowsky, A London, RE Levy, L Kalman, TI Howell, EE TI Calorimetric studies of ligand binding in R67 dihydrofolate reductase SO BIOCHEMISTRY LA English DT Article ID HYDRIDE TRANSFER STEP; FOLYLPOLYGLUTAMATE SYNTHETASE; DISSOCIATION-CONSTANTS; FOLIC-ACID; PYRIDINE-NUCLEOTIDES; MOLECULAR DOCKING; ESCHERICHIA-COLI; TERNARY COMPLEX; ACTIVE-SITE; SIDE-CHAIN AB R67 dihydrofolate reductase (DHFR) is a novel bacterial protein that possesses 222 symmetry and a single active site pore. Although the 222 symmetry implies that four symmetry-related binding sites must exist for each substrate as well as for each cofactor, various studies indicate only two molecules bind. Three possible combinations include two dihydrofolate molecules, two NADPH molecules, or one substrate plus one cofactor. The latter is the productive ternary complex. To explore the role of various ligand substituents during binding, numerous analogues, inhibitors, and fragments of NADPH and/or folate were used in both isothermal titration calorimetry (ITC) and K-i studies. Not surprisingly, as the length of the molecule is shortened, affinity is lost, indicating that ligand connectivity is important in binding. The observed enthalpy change in ITC measurements arises from all components involved in the binding process, including proton uptake. As a buffer dependence for binding of folate was observed, this likely correlates with perturbation of the bound N3 pK(a), such that a neutral pteridine ring is preferred for pairwise interaction with the protein. Of interest, there is no enthalpic signal for binding of folate fragments such as dihydrobiopterin where the p-aminobenzoylglutamate tail has been removed, pointing to the tail as providing most of the enthalpic signal. For binding of NADPH and its analogues, the nicotinamide carboxamide is quite important. Differences between binary (binding of two identical ligands) and ternary complex formation are observed, indicating interligand pairing preferences. For example, while aminopterin and methotrexate both form binary complexes, albeit weakly, neither readily forms ternary complexes with the cofactor. These observations suggest a role for the 04 atom of folate in a pairing preference with NADPH, which ultimately facilitates catalysis. C1 Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA. RP Howell, EE (reprint author), Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA. EM lzh@utk.edu NR 63 TC 15 Z9 15 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 20 PY 2005 VL 44 IS 37 BP 12420 EP 12433 DI 10.1021/bi050881s PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 965HW UT WOS:000231942200018 PM 16156655 ER PT J AU Dimitrov, AS Louis, JM Bewley, CA Clore, GM Blumenthal, R AF Dimitrov, AS Louis, JM Bewley, CA Clore, GM Blumenthal, R TI Conformational changes in HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion and inactivation SO BIOCHEMISTRY LA English DT Article ID TRIMERIC COILED-COIL; VIRUS TYPE-1 ENTRY; CELL-FUSION; TRANSMEMBRANE GLYCOPROTEIN; NEUTRALIZING ANTIBODIES; PEPTIDE INHIBITOR; SYNTHETIC PEPTIDE; MEMBRANE-FUSION; 6-HELIX BUNDLE; HEPTAD REPEAT AB HIV-1 envelope glycoprotein-mediated fusion is driven by the concerted coalescence of the HIV-1 gp41 N- and C-helical regions, which results in the formation of 6-helix bundles. These two regions are considered prime targets for peptides and antibodies that inhibit HIV-1 entry. However, the parameters that govern this inhibition have yet to be elucidated. We address this issue by monitoring the temporal sequence of conformational states of HIV-1 gp41 during the course of HIV-1-mediated cell-cell fusion by quantitative video microscopy using reagents that bind to N- and C-helical regions, respectively. Env-expressing cells were primed by incubation with target cells at different times at 37 degrees C followed by washing. The reactivity of triggered gp41 to the NC-1 monoclonal antibody, which we demonstrate here to bind to N-helical gp41 trimers, increased rapidly to a maximal level in the primed state but decreased once stable fusion junctions had formed. In contrast, reactivity with 5-helix, which binds to the C-helical region of gp41, increased continuously as a function of time following the priming. The peptide N36(Mut(e,g)) reduced NC-1 monoclonal antibody binding and enhanced 5-helix binding, consistent with the notion that this molecule promotes dissociation of gp41 trimers. This inactivation pathway may be important for the design of entry inhibitors and vaccine candidates. C1 NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Blumenthal, R (reprint author), NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. EM blumen@helix.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC008303-33] NR 45 TC 47 Z9 49 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 20 PY 2005 VL 44 IS 37 BP 12471 EP 12479 DI 10.1021/bi051092d PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 965HW UT WOS:000231942200022 PM 16156659 ER PT J AU Fodor, E Mack, JW Maeng, JS Ju, JH Lee, HS Gruschus, JM Ferretti, JA Ginsburg, A AF Fodor, E Mack, JW Maeng, JS Ju, JH Lee, HS Gruschus, JM Ferretti, JA Ginsburg, A TI Cardiac-specific Nkx2.5 homeodomain: Conformational stability and specific DNA binding of Nkx2.5(C56S) SO BIOCHEMISTRY LA English DT Article ID VND/NK-2 HOMEODOMAIN; CIRCULAR-DICHROISM; MUTATIONS; PROTEINS; SEQUENCE; GENE; TRANSCRIPTION; NMR; SPECTROSCOPY; RECOGNITION AB The cardiac-specific Nkx2.5 homeodomain has been expressed as a 79-residue protein with the oxidizable Cys(56) replaced with Ser. The Nkx2.5 or Nkx2.5(C56S) homeodomain is 73% identical in sequence to and has the same NMR structure as the vnd (ventral nervous system defective)/NK-2 homeodomain of Drosophila when bound to the same specific DNA. The thermal unfolding of Nkx2.5(C56S) at pH 6.0 or 7.4 is a reversible, two-state process with unit cooperativity, as measured by differential scanning calorimetry (DSC) and far-UV circular dichroism. Adding 100 mM NaCl to Nkx2.5(C56S) at pH 7.4 increases T-m from 44 to 54 +/- 0.2 degrees C and Delta H from 34 to 45 +/- 2 kcal/mol (giving a Delta C-p of similar to 1.2 kcal K-1 mol(-1) for homeodomain unfolding). DSC profiles of Nkx2.5 indicate fluctuating nativelike structures at <37 degrees C. Titrations of specific 18 bp DNA with Nkx2.5(C56S) in buffer at pH 7.4 with 100 mM NaCl yield binding constants of 2-6x10(8) M-1 from 10 to 37 degrees C and a stoichiometry of 1:1 for homeodomain binding DNA, using isothermal titration calorimetry. The DNA binding reaction of Nkx2.5 is enthalpically controlled, and the temperature dependence of Delta H gives a Delta C-p of -0.18 +/- 0.0 1 kcal K-1 mol(-1). This corresponds to 648 +/- 36 angstrom(2) of buried apolar surface upon Nkx2.5(C56S) binding duplex B-DNA. Thermodynamic parameters differ for Nkx2.5 and vnd/NK-2 homeodomains binding specific DNA. Unbound NK-2 is more flexible than Nkx2.5. C1 NHLBI, Sect Prot Chem, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Howard Univ, Dept Biochem & Mol Biol, Washington, DC 20059 USA. RP Ginsburg, A (reprint author), NHLBI, Sect Prot Chem, Biochem Lab, NIH, Bldg 50,Room 2339, Bethesda, MD 20892 USA. EM ginsbura@nhlbi.nih.gov FU Intramural NIH HHS; NCRR NIH HHS [G12 RR003048]; NIGMS NIH HHS [GM 80615] NR 41 TC 10 Z9 10 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 20 PY 2005 VL 44 IS 37 BP 12480 EP 12490 DI 10.1021/bi050835s PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 965HW UT WOS:000231942200023 PM 16156660 ER PT J AU Arnlov, J Pencina, MJ Nam, BH Meigs, JB Fox, CS Levy, D D'Agostino, RB Vasan, RS AF Arnlov, J Pencina, MJ Nam, BH Meigs, JB Fox, CS Levy, D D'Agostino, RB Vasan, RS TI Relations of insulin sensitivity to longitudinal blood pressure tracking - Variations with baseline age, body mass index, and blood pressure SO CIRCULATION LA English DT Article DE blood pressure; epidemiology; hypertension; insulin; obesity ID SYMPATHETIC-NERVOUS-SYSTEM; GLUCOSE-TOLERANCE TEST; FASTING INSULIN; RESISTANCE ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; INCIDENT HYPERTENSION; NONDIABETIC SUBJECTS; PLASMA-INSULIN; RISK-FACTORS; MEN AB Background - The relations of insulin sensitivity ( IS) to hypertension incidence may vary according to baseline age, body mass index (BMI), and blood pressure ( BP). Methods and Results - We investigated the relations of IS (insulin sensitivity index, ISI0,120) to 4-year incidence of hypertension and BP progression in 1933 nonhypertensive Framingham Study participants ( median age, 51 years; 56% women). Analyses were stratified by age ( less than versus greater than or equal to median), BMI (< 25 [ normal], 25 to < 30 [overweight], >= 30 kg/m(2) [obese]), and BP category (systolic BP >= 130 or diastolic BP >= 85, "high normal" per the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP [JNC-VI] versus BP < 130/85 mm Hg). On follow-up, 41% of participants had BP progression ( >= 1 BP stage increase) and 18% had development of hypertension (systolic BP >= 140 or diastolic BP >= 90 mm Hg or antihypertensive medication use). In younger ( < 51 years) people with normal BMI and baseline BP < 130/ 85 mm Hg, the second-to-fourth ISI0,120 quartiles were associated with lower multivariable-adjusted odds for hypertension incidence (0.27; 95% CI, 0.09 to 0.83; P < 0.05) and BP progression (0.37; 95% CI, 0.18 to 0.77; P < 0.01) relative to the lowest ( most insulin resistant) quartile. IS was not related to BP progression or hypertension incidence in older individuals, in obese participants, or in people with BP >= 130/ 85 mm Hg. Conclusions - In our large community-based sample, reduced IS predicted BP tracking principally in younger people with normal BMI and BP < 130/85 mm Hg. Effect modification by age, BMI, and baseline BP may explain variation in the results of prior clinical investigations relating IS to hypertension incidence. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Cardiol Sect, Dept Med, Boston, MA 02215 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. Uppsala Univ, Dept Publ Hlth & Caring Sci, Sect Geriatr, S-75105 Uppsala, Sweden. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu RI Arnlov, Johan/N-9886-2013; OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [2K24 HL04334, N01-HC-25195] NR 48 TC 24 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 20 PY 2005 VL 112 IS 12 BP 1719 EP 1727 DI 10.1161/CIRCULATIONAHA.105.535039 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 965VP UT WOS:000231978800008 PM 16157770 ER PT J AU Kathiresan, S Gabriel, SB Yang, Q Lochner, AL Larson, MG Levy, D Tofler, GH Hirschhorn, JN O'Donnell, CJ AF Kathiresan, S Gabriel, SB Yang, Q Lochner, AL Larson, MG Levy, D Tofler, GH Hirschhorn, JN O'Donnell, CJ TI Comprehensive survey of common genetic variation at the plasminogen activator inhibitor-1 locus and relations to circulating plasminogen activator inhibitor-1 levels SO CIRCULATION LA English DT Article DE plasminogen; epidemiology; genetics; genomics; fibrinolysis ID INSULIN-RESISTANCE ATHEROSCLEROSIS; ACUTE MYOCARDIAL-INFARCTION; LINKAGE DISEQUILIBRIUM; HUMAN GENOME; ASSOCIATION; DETERMINANTS; DISEASE; TESTS; RISK; IDENTIFICATION AB Background - Using a linkage disequilibrium (LD) - based approach, we sought to comprehensively define common genetic variation at the plasminogen activator inhibitor-1 ( PAI-1) locus and relate common single nucleotide polymorphisms ( SNPs) and haplotypes to plasma PAI-1 levels. Methods and Results - In reference pedigrees, we defined LD structure across a 50-kb genomic segment spanning the PAI-1 locus via a dense SNP map ( 1 SNP every 2 kb). Eighteen sequence variants that capture underlying common genetic variation were genotyped in 1328 unrelated Framingham Heart Study participants who had plasma PAI-1 antigen levels measured. Regression analyses were used to examine associations of individual SNPs and of inferred haplotypes with multivariable-adjusted PAI-1 levels. Two genetic variants, SNP rs2227631 and the 4G/5G polymorphism, were strongly associated ( P < 0.0001) with PAI-1 levels. SNP rs2227631 is in tight LD ( D' = 0.97, r(2) = 0.78) with the 4G/5G polymorphism, which makes it difficult to distinguish which of these 2 polymorphisms is responsible for the association with PAI-1 levels. In stepwise analysis considering all polymorphisms tested, 3 SNPs, rs2227631 ( or the correlated 4G/5G polymorphism), rs6465787,and rs2227674, each explained 2.5%, 1%, and 1%, respectively, of the residual variance in multivariable-adjusted PAI-1 levels ( stepwise P < 0.0001, P = 0.04, and P = 0.03, respectively). A single common haplotype, at 50% frequency among Framingham Heart Study participants, was strongly associated with higher PAI-1 levels ( haplotype-specific P = 0.00001). The susceptibility haplotype harbors the minor alleles of SNP rs2227631 and the 4G/5G polymorphism. Conclusions - Three sequence variants at the PAI-1 locus, in sum, explain approximate to 5% of the residual variance in multivariable-adjusted PAI-1 levels. For quantitative cardiovascular traits such as circulating biomarkers, defining LD structure in a candidate gene followed by association analyses with both SNPs and haplotypes is an effective approach to localize common susceptibility alleles. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Royal N Shore Hosp, Sydney, NSW, Australia. Harvard Univ, Sch Med, Childrens Hosp, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov RI Yang, Qiong/G-5438-2014; OI Larson, Martin/0000-0002-9631-1254 FU NHLBI NIH HHS [HL66582, N01-HC-25195] NR 37 TC 44 Z9 46 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 20 PY 2005 VL 112 IS 12 BP 1728 EP 1735 DI 10.1161/CIRCULATIONAHA.105.547836 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 965VP UT WOS:000231978800009 PM 16172282 ER PT J AU Glushakova, S Yin, D Li, T Zimmerberg, J AF Glushakova, S Yin, D Li, T Zimmerberg, J TI Membrane transformation during malaria parasite release from human red blood cells SO CURRENT BIOLOGY LA English DT Article ID FALCIPARUM-INFECTED ERYTHROCYTES; PLASMODIUM-FALCIPARUM; HOST ERYTHROCYTE; FATTY-ACIDS; FUSION; MEROZOITES; TRANSITION; CURVATURE; PROTEINS; EXIT AB Three opposing pathways are proposed for the release of malaria parasites [1] from infected erythrocytes [2, 3]: coordinated rupture of the two membranes surrounding mature parasites [4, 5]; fusion of erythrocyte and parasitophorus vacuolar membranes (PVM) [6-8]; and liberation of parasites enclosed within the vacuole from the erythrocyte followed by PVM disintegration [9]. Rupture by cell swelling should yield erythrocyte ghosts; membrane fusion is inhibited by inner-leaflet amphiphiles of positive intrinsic curvature [10], which contrariwise promote membrane rupture; and without protease inhibitors [9], parasites would leave erythrocytes packed within the vacuole. Therefore, we visualized erythrocytes releasing P falciparum using fluorescent microscopy of differentially labeled membranes. Release did not yield erythrocyte ghosts, positive-curvature amphiphiles did not inhibit release but promoted it, and release of packed merozoites was shown to be an artifact. Instead, two sequential morphological stages preceded a convulsive rupture of membranes and rapid radial discharge of separated merozoites, leaving segregated internal membrane fragments and plasma membrane vesicles or blebs at the sites of parasite egress. These results, together with the modulation of release by osmotic stress, suggest a pathway of parasite release that features a biochemically altered erythrocyte membrane that folds after pressure-driven rupture of membranes. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. EM joshz@helix.nih.gov FU Intramural NIH HHS NR 33 TC 76 Z9 79 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 20 PY 2005 VL 15 IS 18 BP 1645 EP 1650 DI 10.1016/j.cub.2005.07.067 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 969LK UT WOS:000232235500023 PM 16169486 ER PT J AU Leopold, DA Wilke, M AF Leopold, DA Wilke, M TI Neuroimaging: Seeing the trees for the forest SO CURRENT BIOLOGY LA English DT Editorial Material ID PRIMARY VISUAL-CORTEX; HUMAN BRAIN; FMRI; ORIENTATION; V1 AB New functional imaging studies demonstrate that it is possible to decode a sensory visual pattern, and even an internal perceptual state, by combining seemingly insignificant feature selective signal biases present in a large number of voxels. C1 Unit Cognit Neurophysiol, Bethesda, MD 20892 USA. Imaging Lab Neuropsychol, Bethesda, MD 20892 USA. RP Leopold, DA (reprint author), Unit Cognit Neurophysiol, NIH Bldg 49,Room B2J-45,MSC-4400,49 Convent Dr, Bethesda, MD 20892 USA. OI Leopold, David/0000-0002-1345-6360 NR 15 TC 1 Z9 2 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 20 PY 2005 VL 15 IS 18 BP R766 EP R768 DI 10.1016/j.cub.2005.08.055 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 969LK UT WOS:000232235500015 PM 16169478 ER PT J AU Shen, M Berndt, SI Rothman, N DeMarini, DM Mumford, JL He, XZ Bonner, MR Tian, LW Yeager, M Welch, R Chanock, S Zheng, TZ Caporaso, N Lan, Q AF Shen, M Berndt, SI Rothman, N DeMarini, DM Mumford, JL He, XZ Bonner, MR Tian, LW Yeager, M Welch, R Chanock, S Zheng, TZ Caporaso, N Lan, Q TI Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lung cancer; DNA repair; single nucleotide polymorphism; nucleotide excision repair; polycyclic aromatic hydrocarbon ID COAL COMBUSTION EMISSIONS; ERCC2 POLYMORPHISMS; XPD POLYMORPHISMS; HUMAN-LYMPHOCYTES; INDOOR COAL; POPULATION; XRCC1; SMOKING; MUTATIONS; EXPOSURE AB The lung cancer mortality rate in Xuan Wei County is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Nucleotide excision repair (NER) plays a key role in reversing DNA damage from exposure to environmental carcinogens, such as PAHs, that form bulky DNA adducts. We studied single nucleotide polymorphisms (SNPs) and their corresponding haplotypes in 6 genes (ERCC1, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, RAD23B and XPC) involved in NER in a population-based case-control study of lung cancer in Xuan Wei. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled. Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gin allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18-0.89). Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype. In addition, subjects with one or 2 copies of the Val allele at codon 249 of RAD23B had a 2-fold increased risk of lung cancer (OR = 1.91, 95% CI 1.12-3.24). In summary, our results suggest that genetic variants in genes involved in the NER pathway may play a role in lung cancer susceptibility in Xuan Wei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and in other populations with substantial environmental exposure to PAHs. (c) 2005 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC USA. Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. RP Shen, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM shenmi@mail.nih.gov RI Tian, Linwei/A-9736-2009 OI Tian, Linwei/0000-0002-4739-1534 NR 39 TC 82 Z9 88 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 20 PY 2005 VL 116 IS 5 BP 768 EP 773 DI 10.1002/ijc.21117 PG 6 WC Oncology SC Oncology GA 953BG UT WOS:000231050000016 PM 15849729 ER PT J AU Khan, MJ Schiffman, M Jeronimo, J AF Khan, MJ Schiffman, M Jeronimo, J TI Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: Results from a multicenter study in India SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID CANCER C1 NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. Howard Hughes Med Inst, Chevy Chase, MD USA. RP Khan, MJ (reprint author), 6120 Execut Blvd,EPS Room 7101, Rockville, MD 20852 USA. EM khanmi@mail.nih.gov NR 5 TC 0 Z9 2 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 20 PY 2005 VL 116 IS 5 BP 830 EP 831 DI 10.1002/ijc.21084 PG 2 WC Oncology SC Oncology GA 953BG UT WOS:000231050000026 PM 15849748 ER PT J AU Emanuel, EJ AF Emanuel, EJ TI Depression, euthanasia, and improving end-of-life care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PHYSICIAN-ASSISTED SUICIDE; TERMINALLY-ILL PATIENTS; CANCER-PATIENTS; HASTENED DEATH; ATTITUDES; DESIRE; RISK; ACT C1 NIH, Ctr Clin, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Ctr Clin, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 20 TC 8 Z9 8 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2005 VL 23 IS 27 BP 6456 EP 6458 DI 10.1200/JCO.2005.06.001 PG 3 WC Oncology SC Oncology GA 969KN UT WOS:000232233100005 PM 16116150 ER PT J AU Cloughesy, TF Kuhn, J Robins, HI Abrey, L Wen, P Fink, K Lieberman, FS Mehta, M Chang, S Yung, A DeAngelis, L Schiff, D Junck, L Groves, M Paquette, S Wright, J Lamborn, K Sebti, SM Prados, M AF Cloughesy, TF Kuhn, J Robins, HI Abrey, L Wen, P Fink, K Lieberman, FS Mehta, M Chang, S Yung, A DeAngelis, L Schiff, D Junck, L Groves, M Paquette, S Wright, J Lamborn, K Sebti, SM Prados, M TI Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: A North American brain tumor consortium study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 18-21, 2002 CL ORLANDO, FL SP Amer Soc Clin Oncol ID TRANSFERASE INHIBITOR R115777; FARNESYLTRANSFERASE INHIBITORS; GLIOBLASTOMA-MULTIFORME; GUANOSINE TRIPHOSPHATE; THERAPEUTIC STRATEGY; ADVANCED CANCER; RAS; GROWTH; METABOLISM; PACLITAXEL AB Purpose: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antielpileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs. Patients and Methods: Recurrent malignant glioma patients were treated with tipifarnilb using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed. Results: Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC). Conclusion: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients. C1 Univ Calif Los Angeles, Henry E Singleton Brain Canc Res Program, Los Angeles, CA 90095 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78285 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Wisconsin, Madison, WI USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Univ S Florida, Drug Discovery Program, H Lee Moffit Canc Ctr & Res Inst, Tampa, FL USA. RP Cloughesy, TF (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Neurooncol Program, 710 Westwood Plaza,Reed Bldg,Room 1-230, Los Angeles, CA 90095 USA. EM tcloughe@ucla.edu OI mehta, minesh/0000-0002-4812-5713 FU NCI NIH HHS [U01CA62407-08, 5-U01CA62399-09, CA16672, CA62412, CA62426, CA62455-08, CA76292, U01CA62399, U01CA62405, U01CA62421-08, U01CA62422]; NCRR NIH HHS [M01 RR03186, M01-RR00042, M01-RR00056, M01-RR00079, M01-RR00633, M01-RR0865] NR 50 TC 37 Z9 38 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2005 VL 23 IS 27 BP 6647 EP 6656 DI 10.1200/JCO.2005.10.068 PG 10 WC Oncology SC Oncology GA 969KN UT WOS:000232233100029 PM 16170172 ER PT J AU Buchanan, DR White, JD O'Mara, AM Kelaghan, JW Smith, WB Minasian, LM AF Buchanan, DR White, JD O'Mara, AM Kelaghan, JW Smith, WB Minasian, LM TI Research-design issues in cancer-symptom-management trials using complementary and alternative medicine: Lessons from the National Cancer Institute Community Clinical Oncology Program experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES; STANDARD HISTORY; THERAPIES AB Purpose: To identify major research-design issues in proposals submitted by investigators in the Community Clinical Oncology Program (CCOP) for clinical trials of complementary and alternative medicine (CAM) for cancer-symptom management. Methods: We conducted content analysis of all scientific reviews of concepts and protocols submitted by the CCOP to the National Cancer Institute (NCI) to identify research challenges in conducting clinical trials designed to evaluate CAM interventions for cancer-symptom management. Results: Since the inception of the NCI Office of Cancer Complementary and Alternative Medicine in 1998, a total of 46 symptom-management studies using CAM interventions have been proposed by CCOP investigators, with 20 studies now in progress comprising 22% of the current total CCOP symptom-management portfolio. Proposals fell into four categories: complex natural products; nutritional therapeutics; mind-body interventions; and alternative medical systems. The most significant research-design issues arose as a consequence of the lack of preclinical data for CAM interventions and the lack of quality-control standards comparable with those used in regulating new pharmaceutical agents. Conclusion: Across the different types of CAM interventions, the most common problems found in proposed research designs are related to unwarranted assumptions about the consistency and standardization of CAM interventions, the need for data-based justifications for the study hypotheses, and the need to implement appropriate quality control and monitoring procedures during the course of the trial. To advance the state of the science, future research must address these critical issues if CAM interventions are to be evaluated rigorously and have a consequent impact on clinical practice and general public awareness. C1 NCI, Bethesda, MD 20892 USA. RP Buchanan, DR (reprint author), NCI, 6130 Execut Plaza,Rm 2149, Bethesda, MD 20892 USA. EM buchanad@mail.nih.gov NR 28 TC 31 Z9 33 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2005 VL 23 IS 27 BP 6682 EP 6689 DI 10.1200/JCO.2005.10.728 PG 8 WC Oncology SC Oncology GA 969KN UT WOS:000232233100033 PM 16170176 ER PT J AU Kreitman, RJ Squires, DR Stetler-Stevenson, M Noel, P Fitzgerald, DJP Wilson, WH Pastan, I AF Kreitman, RJ Squires, DR Stetler-Stevenson, M Noel, P Fitzgerald, DJP Wilson, WH Pastan, I TI Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-Cell malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MINIMAL RESIDUAL DISEASE; TERM-FOLLOW-UP; PSEUDOMONAS-EXOTOXIN; MONOCLONAL-ANTIBODY; CYTOTOXIC ACTIVITY; CONTINUOUS-INFUSION; COMPLETE REMISSION; LEUKEMIA PATIENTS; 2-CHLORODEOXYADENOSINE; THERAPY AB Purpose: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. Patients and Methods: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 mu g/Kg every other day x 3 doses. Results: BL22 was active in HCL, with 19 complete remissions (CRs; 61 %) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at >= 40 mu g/Kg every other day x 3, and 41 % at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 mu g/Kg IV. QOD x 3. The most common toxicities at 30 to 50 mu g/Kg every other day x 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. Conclusion: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response. C1 NCI, Mol Biol Lab, Clin Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, Clin Pathol Lab, NIH, Bldg 5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU Intramural NIH HHS NR 51 TC 189 Z9 194 U1 1 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2005 VL 23 IS 27 BP 6719 EP 6729 DI 10.1200/JCO.2005.11.437 PG 11 WC Oncology SC Oncology GA 969KN UT WOS:000232233100037 PM 16061911 ER PT J AU Chen, Q Espey, MG Krishna, MC Mitchell, JB Corpe, CP Buettner, GR Shacter, E Levine, M AF Chen, Q Espey, MG Krishna, MC Mitchell, JB Corpe, CP Buettner, GR Shacter, E Levine, M TI Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell death; ascorbate radical ID RECOMMENDED DIETARY ALLOWANCE; VITAMIN-C PHARMACOKINETICS; ACUTE MYELOID-LEUKEMIA; TERMINAL HUMAN CANCER; SUPPLEMENTAL ASCORBATE; SUPEROXIDE-DISMUTASE; SUPPORTIVE TREATMENT; OXIDATIVE STRESS; SURVIVAL TIMES; LYMPHOMA-CELLS AB Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC50 values of < 4 mM, a concentration easily achievable i.v.Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC50 of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H2O2 formation. Cell death from H2O2 added to cells was identical to that found when H2O2 was generated by ascorbate treatment. H2O2 generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H2O2, ascorbate addition to blood generated no detectable H2O2 and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial. C1 NIDDKD, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Iowa, Free Rad & Radiat Biol Program, Iowa City, IA 52242 USA. US FDA, Ctr Biol Evaluat & Res, Biochem Lab, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDKD, Mol & Clin Nutr Sect, NIH, Bldg 10,Room 4D52,MSC-1372, Bethesda, MD 20892 USA. EM markl@mail.nih.gov RI Chen, Qi/D-8278-2015 OI Chen, Qi/0000-0002-7173-8411 FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK054506] NR 58 TC 353 Z9 368 U1 7 U2 43 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 20 PY 2005 VL 102 IS 38 BP 13604 EP 13609 DI 10.1073/pnas.0506390102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 967TW UT WOS:000232115100046 PM 16157892 ER PT J AU Redmond, TM Poliakov, E Yu, S Tsai, JY Lu, ZJ Gentleman, S AF Redmond, TM Poliakov, E Yu, S Tsai, JY Lu, ZJ Gentleman, S TI Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 11-cis-retinoids; leber congenital amaurosis; retinal pigment epithelium ID LECITHIN-RETINOL ACYLTRANSFERASE; RETINALDEHYDE-BINDING PROTEIN; PIGMENT EPITHELIAL-CELLS; PERFORMANCE LIQUID-CHROMATOGRAPHY; RECESSIVE RETINITIS-PIGMENTOSA; LEBERS CONGENITAL AMAUROSIS; DELAYED DARK-ADAPTATION; BETA-CAROTENE; HEK293S CELLS; CIS-RETINOLS AB RPE65 is essential for isomerization of vitamin A to the visual chromophore. Mutations in RPE65 cause early-onset blindness, and RPE65-deficient mice lack 11-cis-retinal but overaccumulate all-trans-retinyl esters in the retinal pigment epithelium (RPE). RPE65 is proposed to be a substrate chaperone but may have an enzymatic role because it is closely related to carotenoid oxygenases. We hypothesize that, by analogy with other carotenoid oxygenases, the predicted iron-coordinating residues of RPE65 are essential for retinoid isomerization. To clarify RPE65's role in isomerization, we reconstituted a robust minimal visual cycle in 293-F cells. Only cells transfected with RPE65 constructs produced 11-cisretinoids, but coexpression with lecithin:retinol acyltransferase was needed for high-level production. Accumulation was significant, amounting to > 2 nmol of 11-cis-retinol per culture. Transfection with constructs harboring mutations in residues of RPE65 homologous to those required for interlinked enzymatic activity and iron coordination in related enzymes abolish this isomerization. Iron chelation also abolished isomerization activity. Mutating cysteines implicated in palmitoylation of RPE65 had generally little effect on isomerization activity. Mutations associated with Leber congenital amaurosis/early-onset blindness cause partial to total loss of isomerization activity in direct relation to their clinical effects. These findings establish a catalytic role, in conjunction with lecithin:retinol acyltransferase, for RPE65 in synthesis of 11-cis-retinol, and its identity as the isomerohydrolase. C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. RP Redmond, TM (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, 7 Mem Dr,MSC 0706,Bldg 7,Room 303, Bethesda, MD 20892 USA. EM redmond@helix.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU Intramural NIH HHS NR 42 TC 225 Z9 229 U1 1 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 SEP 20 PY 2005 VL 102 IS 38 BP 13658 EP 13663 DI 10.1073/pnas.0504167102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 967TW UT WOS:000232115100055 PM 16150724 ER PT J AU Berg, JM AF Berg, JM TI Untitled SO CHEMICAL & ENGINEERING NEWS LA English DT Letter C1 Natl Inst Gen Med Sci, NIH, Bethesda, MD USA. RP Berg, JM (reprint author), Natl Inst Gen Med Sci, NIH, Bethesda, MD USA. OI Berg, Jeremy/0000-0003-3022-0963 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2347 J9 CHEM ENG NEWS JI Chem. Eng. News PD SEP 19 PY 2005 VL 83 IS 38 BP 3 EP 4 PG 2 WC Chemistry, Multidisciplinary; Engineering, Chemical SC Chemistry; Engineering GA 966DV UT WOS:000232000700002 ER PT J AU Yamane, H Zhu, JF Paul, WE AF Yamane, H Zhu, JF Paul, WE TI Independent roles for IL-2 and GATA-3 in stimulating naive CD4(+) T cells to generate a Th2-inducing cytokine environment SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NF-KAPPA-B; TH2 DIFFERENTIATION; PRODUCE INTERLEUKIN-4; INTERFERON-GAMMA; MESSENGER-RNA; C-MAF; EXPRESSION; RESPONSES; TRANSCRIPTION; ACTIVATION AB T cell receptor (TCR) signaling plays an important role in early interleukin ( IL)-4 production by naive CD4(+) T cells. This "antigen-stimulated" early IL-4 is sufficient for in vitro Th2 differentiation. Here, we provide evidence that early IL-4 production by naive CD4(+) T cells stimulated with cognate peptide requires TCR-induced early GATA-3 expression and IL-2 receptor signaling, both of which are controlled by the degree of activation of extracellular signal-regulated kinase ( ERK). Stimulation of naive CD4(+) T cells from TCR transgenic mice with low concentrations of peptide-induced IL-2-dependent STAT5 phosphorylation, IL-4-independent early GATA-3 expression, and IL-4 production. Neutralization of IL-2 abolished early IL-4 production without affecting early GATA-3 expression. In addition, naive CD4(+) T cells from GATA-3 conditional KO mice failed to produce early IL-4 in response to TCR/CD28 stimulation. Stimulation with high concentrations of peptide abrogated early GATA-3 expression and IL-2-dependent STAT5 phosphorylation, and resulted in the failure to produce early IL-4. This high concentration-mediated suppression of early IL-4 production was reversed by blockade of the ERK pathway. A MEK inhibition rescued early GATA-3 expression and responsiveness to IL-2; these cells were now capable of producing early IL-4 and undergoing subsequent Th2 differentiation. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012 NR 38 TC 140 Z9 145 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 19 PY 2005 VL 202 IS 6 BP 793 EP 804 DI 10.1084/jem.20051304 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 968MI UT WOS:000232166200008 PM 16172258 ER PT J AU Al-Shami, A Spolski, R Kelly, J Keane-Myers, A Leonard, WJ AF Al-Shami, A Spolski, R Kelly, J Keane-Myers, A Leonard, WJ TI A role for TSLP in the development of inflammation in an asthma model SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; IGM(+) B-CELLS; INTERLEUKIN-7 RECEPTOR; ALLERGIC INFLAMMATION; IN-VITRO; T-CELLS; AIRWAY HYPERRESPONSIVENESS; DENDRITIC CELLS; GROWTH-FACTOR; MEMORY CELLS AB Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4(+) T cell homeostasis. We now demonstrate that TSLP is required to mount a normal CD4(+) T cell-mediated inflammatory response. TSLP acts directly on naive, but not, memory CD4(+) T cells, and promotes their proliferation in response to antigen. In addition, TSLP exerts an effect indirectly through DCs to promote Th2 differentiation of CD4(+) T cells. Correspondingly, TSLP receptor (TSLPR) knockout (KO) mice exhibit strong Th1 responses, with high levels of interleukin (IL)-12, interferon-gamma, and immunoglobulin (Ig) G2a, but low production of IL- 4, - 5, - 10, - 13, and IgE; moreover, CD4(+) T cells from these animals proliferate less well in response to antigen. Furthermore, TSLPR KO mice fail to develop an inflammatory lung response to inhaled antigen unless supplemented with wild-type CD4(+) T cells. This underscores an important role for this cytokine in the development of inflammatory and/or allergic responses in vivo. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NIAID, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov RI Al-Shami, Amin/D-3889-2009 FU Intramural NIH HHS NR 29 TC 294 Z9 317 U1 0 U2 15 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 19 PY 2005 VL 202 IS 6 BP 829 EP 839 DI 10.1084/jem.20050199 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 968MI UT WOS:000232166200011 PM 16172260 ER PT J AU Nakamura, N Banno, Y Tamiya-Koizumi, K AF Nakamura, N Banno, Y Tamiya-Koizumi, K TI Arf1-dependent PLD1 is localized to oleic acid-induced lipid droplets in NIH3T3 cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE phospholipase D; ADRP; Arf1; lipid droplets; NIH3T3 cells ID DIFFERENTIATION-RELATED PROTEIN; PHOSPHOLIPASE-D; ADRP; MEMBRANE; FIBROBLASTS; ACTIVATION; 3-KINASE AB Phospholipase D (PLD) is known to play a role in vesicle transport through the hydrolysis of phosphatidyleholine (PC) to produce the bioactive lipid, phosphatidic acid. Lipid droplets (LDs) are surrounded by a monolayer of phospholipids, including PC and its lyso derivative, and exhibit a number of signaling proteins. Our recent report suggests that the association of adipose differentiation-related protein (ADRP) to LDs is regulated by an ADP-ribosylation factor 1 (Arf1)-dependent mechanism. In the present study, we found an increase in PLD activity accompanied with LD formation in oleic acid-treated NIH3T3 cells. Brefeldin A, an inhibitor of ARF-GEFs, suppressed both PLD activation and LD formation in oleic acid-treated cells. PLD1, but not PLD2, was found to exist in LDs by immunocytochemical analysis. Furthermore, co-existence of PLD1, Arf1, and ADRP was observed in the LD-enriched subcellular fractions obtained from oleic acid-treated NIH3T3 cells by Western blot analysis. PLD1 activity in the LD-enriched fractions was stimulated by exogenously added Arf1 Although LDs were induced in either PLD1- or PLD2-overexpressing CHO cells by oleic acid treatment, the stimulation of PLD activity was observed only in PLD1-CHO cells. Taken together, the data suggest that the activation of Arf1-dependent PLD1 occurs in LDs and may be involved in their physiological function. (c) 2005 Elsevier Inc. All rights reserved. C1 Nagoya Univ, Grad Sch Med, Dept Anat & Mol Cell Biol, Showa Ku, Nagoya, Aichi 4668550, Japan. Gifu Univ, Grad Sch Med, Dept Cell Signaling, Gifu 5008705, Japan. Nagoya Univ, CNDC, Div Mol Carcinogenesis, Grad Sch Med,Showa Ku, Nagoya, Aichi 4668550, Japan. RP Nakamura, N (reprint author), NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM nakamur1@niehs.nih.gov NR 25 TC 26 Z9 28 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 16 PY 2005 VL 335 IS 1 BP 117 EP 123 DI 10.1016/j.bbrc.2005.07.050 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 958EP UT WOS:000231427800017 PM 16054594 ER PT J AU Bergen, AW Qi, Y Haque, KA Welch, RA Chanock, SJ AF Bergen, AW Qi, Y Haque, KA Welch, RA Chanock, SJ TI Effects of DNA mass on multiple displacement whole genome amplification and genotyping performance SO BMC BIOTECHNOLOGY LA English DT Article ID SINGLE NUCLEOTIDE POLYMORPHISM; AMPLIFIED DNA; PRIMER; MICROARRAYS; POLYMERASE; DISEASE; SYSTEM; ASSAY; PCR AB Background: Whole genome amplification (WGA) promises to eliminate practical molecular genetic analysis limitations associated with genomic DNA (gDNA) quantity. We evaluated the performance of multiple displacement amplification (MDA) WGA using gDNA extracted from lymphoblastoid cell lines (N = 27) with a range of starting gDNA input of 1 - 200 ng into the WGA reaction. Yield and composition analysis of whole genome amplified DNA (wgaDNA) was performed using three DNA quantification methods ( OD, PicoGreen(R) and RT-PCR). Two panels of N = 15 STR ( using the AmpF/STR(R) Identifiler(R) panel) and N = 49 SNP ( TaqMan(R)) genotyping assays were performed on each gDNA and wgaDNA sample in duplicate. gDNA and wgaDNA masses of 1, 4 and 20 ng were used in the SNP assays to evaluate the effects of DNA mass on SNP genotyping assay performance. A total of N = 6,880 STR and N = 56,448 SNP genotype attempts provided adequate power to detect differences in STR and SNP genotyping performance between gDNA and wgaDNA, and among wgaDNA produced from a range of gDNA templates inputs. Results: The proportion of double-stranded wgaDNA and human-specific PCR amplifiable wgaDNA increased with increased gDNA input into the WGA reaction. Increased amounts of gDNA input into the WGA reaction improved wgaDNA genotyping performance. Genotype completion or genotype concordance rates of wgaDNA produced from all gDNA input levels were observed to be reduced compared to gDNA, although the reduction was not always statistically significant. Reduced wgaDNA genotyping performance was primarily due to the increased variance of allelic amplification, resulting in loss of heterozygosity or increased undetermined genotypes. MDA WGA produces wgaDNA from no template control samples; such samples exhibited substantial false-positive genotyping rates. Conclusion: The amount of gDNA input into the MDA WGA reaction is a critical determinant of genotyping performance of wgaDNA. At least 10 ng of lymphoblastoid gDNA input into MDA WGA is required to obtain wgaDNA TaqMan(R) SNP assay genotyping performance equivalent to that of gDNA. Over 100 ng of lymphoblastoid gDNA input into MDA WGA is required to obtain optimal STR genotyping performance using the AmpF/STR(R) Identifiler(R) panel from wgaDNA equivalent to that of gDNA. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Core Genotyping Facil, NIH, Gaithersburg, MD USA. NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21701 USA. NCI, Sect Genome Variat, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Bergen, AW (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM bergena@mail.nih.gov; qiy@mail.nih.gov; haquek@mail.nih.gov; welchr@mail.nih.gov; chanocks@mail.nih.gov OI Bergen, Andrew/0000-0002-1237-7644 FU Intramural NIH HHS; NIDDK NIH HHS [R01 DK063250] NR 30 TC 56 Z9 57 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD SEP 16 PY 2005 VL 5 AR 24 DI 10.1186/1472-6750-5-24 PG 11 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 973LO UT WOS:000232524400001 PM 16168060 ER PT J AU Leonard, GD Wright, MA Quinn, MG Fioravanti, S Harold, N Schuler, B Thomas, RR Grem, JL AF Leonard, GD Wright, MA Quinn, MG Fioravanti, S Harold, N Schuler, B Thomas, RR Grem, JL TI Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer SO BMC CANCER LA English DT Article ID CAPECITABINE PLUS OXALIPLATIN; PHASE-II TRIAL; 1ST-LINE TREATMENT; PERIPHERAL NEUROPATHY; FLUOROURACIL-LEUCOVORIN; DIFFERENT SCHEDULES; CHEMOTHERAPY; POLYNEUROPATHY; 5-FLUOROURACIL; IRINOTECAN AB Background: New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. Methods: A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. Results: Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia ( lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction ( spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/ 4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. Conclusion: Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, Navy Med Oncol Program,Natl Naval Med Ctr, Bethesda, MD 20889 USA. NCI, Med Oncol Res Unit, Ctr Canc Res, Navy Med Oncol Program,Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, Navy Med Oncol Program,Natl Naval Med Ctr, Bethesda, MD 20889 USA. EM LeonardG@Sehb.ie; Wrightwils@aol.com; mquinn@tech-res.com; fioravas@mail.nih.gov; nharold@mail.nih.gov; schulerb@mail.nih.gov; rebeccathomasmd@yahoo.com; jgrem@unmc.edu NR 44 TC 54 Z9 59 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 16 PY 2005 VL 5 AR 116 DI 10.1186/1471-2407-5-116 PG 10 WC Oncology SC Oncology GA 977KX UT WOS:000232803800001 PM 16168057 ER PT J AU Zhu, WZ Zeng, XK Zheng, M Xiao, RP AF Zhu, WZ Zeng, XK Zheng, M Xiao, RP TI The enigma of beta(2)-adrenergic receptor G(i) signaling in the heart - The good, the bad, and the ugly SO CIRCULATION RESEARCH LA English DT Editorial Material ID CARDIAC MYOCYTES; RECEPTOR SUBTYPES; PERTUSSIS-TOXIN; BETA(1)-ADRENERGIC STIMULATION; CELL-DEATH; KINASE-II; G-PROTEIN; FAILURE; RAT; BETA(2)-ADRENOCEPTOR C1 NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM xiaor@grc.nia.nih.gov FU Intramural NIH HHS NR 30 TC 45 Z9 49 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 16 PY 2005 VL 97 IS 6 BP 507 EP 509 DI 10.1061/01.RES.0000184615.56822.bd PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 964QV UT WOS:000231896500001 PM 16166560 ER PT J AU Yang, Y Kovacs, M Xu, Q Anderson, JB Sellers, JR AF Yang, Y Kovacs, M Xu, Q Anderson, JB Sellers, JR TI Myosin VIIB from Drosophila is a high duty ratio motor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KINETIC MECHANISM; UNCONVENTIONAL MYOSINS; FLUORESCENT-PROBE; HEAVY-MEROMYOSIN; V PROCESSIVITY; RELAY LOOP; ACTIN; COMPLEX; BINDING; IDENTIFICATION AB Myosin VII is an unconventional myosin widely expressed in organisms ranging from amoebae to mammals that has been shown to play vital roles in cell adhesion and phagocytosis. Here we present the first study of the mechanism of action of a myosin VII isoform. We have expressed a truncated single-headed Drosophila myosin VIIB construct in the baculovirus-Sf9 system that bound calmodulin light chains. By using steady-state and transient kinetic methods, we showed that myosin VIIB exhibits a fast release of phosphate and a slower, rate-limiting ADP release from actomyosin. As a result, myosin VIIB will be predominantly strongly bound to actin during steady-state ATP hydrolysis ( its duty ratio will be at least 80%). This kinetic pattern is in many respects similar to that of the single-molecule vesicle transporters myosin V and VI. The enzymatic properties of myosin VIIB provide a kinetic basis for processivity upon possible dimerization via the C-terminal domains of the heavy chain. Our experiments also revealed conformational heterogeneity of the actomyosin VIIB complex in the absence of nucleotide. C1 NHLBI, NIH, Lab Mol Physiol, Bethesda, MD 20892 USA. RP Sellers, JR (reprint author), NHLBI, NIH, Lab Mol Physiol, Bldg 10,Rm 8N202, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov RI Kovacs, Mihaly/A-6841-2011 NR 40 TC 26 Z9 27 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 16 PY 2005 VL 280 IS 37 BP 32061 EP 32068 DI 10.1074/jbc.M506765200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 963HM UT WOS:000231794800005 PM 16055438 ER PT J AU Opresko, PL Mason, PA Podell, ER Lei, M Hickson, ID Cech, TR Bohr, VA AF Opresko, PL Mason, PA Podell, ER Lei, M Hickson, ID Cech, TR Bohr, VA TI POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REPLICATION PROTEIN-A; SINGLE-STRANDED-DNA; WERNER-SYNDROME PROTEIN; BINDING PROTEIN; FISSION YEAST; CELLS; TRF2; END; LENGTH; MAINTENANCE AB Defects in human RecQ helicases WRN and BLM are responsible for the cancer-prone disorders Werner syndrome and Bloom syndrome. Cellular phenotypes of Werner syndrome and Bloom syndrome, including genomic instability and premature senescence, are consistent with telomere dysfunction. RecQ helicases are proposed to function in dissociating alternative DNA structures during recombination and/or replication at telomeric ends. Here we report that the telomeric single-strand DNA-binding protein, POT1, strongly stimulates WRN and BLM to unwind long telomeric forked duplexes and D-loop structures that are otherwise poor substrates for these helicases. This stimulation is dependent on the presence of telomeric sequence in the duplex regions of the substrates. In contrast, POT1 failed to stimulate a bacterial 3'-5'-helicase. We find that purified POT1 binds to WRN and BLM in vitro and that full-length POT1 ( splice variant 1) precipitates a higher amount of endogenous WRN protein, compared with BLM, from the HeLa nuclear extract. We propose roles for the cooperation of POT1 with RecQ helicases WRN and BLM in resolving DNA structures at telomeric ends, in a manner that protects the telomeric 3' tail as it is exposed during unwinding. C1 NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. Univ Colorado, Howard Hughes Med Inst, Dept Chem & Biochem, Boulder, CO 80309 USA. Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Canc Res UK Labs, Oxford OX3 9DS, England. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Opresko, Patricia/0000-0002-6470-2189 NR 49 TC 115 Z9 121 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 SEP 16 PY 2005 VL 280 IS 37 BP 32069 EP 32080 DI 10.1074/jbc.M505211200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 963HM UT WOS:000231794800006 PM 16030011 ER PT J AU Hrabie, JA Citro, ML Chmurny, GN Keefer, LK AF Hrabie, JA Citro, ML Chmurny, GN Keefer, LK TI Carbon-bound diazeniumdiolates from the reaction of nitric oxide with amidines SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID HETEROCYCLIC KETENE AMINALS; FUNCTIONAL-GROUP; DERIVATIVES; CHEMISTRY AB The enediamine tautomer of a variety of substituted amidine free bases reacts with nitric oxide (NO) to produce compounds containing a carbon-bound diazeniumdiolate [(RRRC)-R-1-R-2-C-3-N(O)=NO-] functional group (previously called "nitrosohydroxylamines"). The new reaction has been shown to be quite general, although the nature of the products does vary. Amidines containing more than one replaceable hydrogen produce polydiazeniumdiolates as intermolecular salts, while those in which only one diazeniumdiolation can occur provide zwitterionic salts. These diazeniumdiolated amidines are shown to be useful NO donor compounds which undergo very slow spontaneous dissociation on dissolution in pH 7.4 phosphate buffer to produce mixtures of NO and nitrous oxide containing mostly NO. The most advantageous manifestation of the new discovery is the preparation of the monodiazeniumdiolated amidine zwitterions. Reaction of the medically relevant a-adrenergic agonists tetrahydrozoline and idazoxan produced monodiazeniumdiolated amidine zwitterions from which NO release was observed for up to 28 days and showed little sign of ending. The reaction should be applicable to a variety of pharmaceutical agents, including NO synthase inhibitors, antitumor agents, and antibacterials. C1 SAIC Frederick, Basic Res Program, Natl Canc Inst, Frederick, MD 21702 USA. SAIC Frederick, Lab Proteom & Analyt Chem, Natl Canc Inst, Frederick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. RP Hrabie, JA (reprint author), SAIC Frederick, Basic Res Program, Natl Canc Inst, Frederick, MD 21702 USA. EM hrabie@ncifcrf.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-12400] NR 34 TC 9 Z9 9 U1 0 U2 4 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 SEP 16 PY 2005 VL 70 IS 19 BP 7647 EP 7653 DI 10.1021/jo050921y PG 7 WC Chemistry, Organic SC Chemistry GA 964DN UT WOS:000231859000025 PM 16149795 ER PT J AU Katsanou, V Papadaki, O Milatos, S Blackshear, PJ Anderson, P Kollias, G Kontoyiannis, DL AF Katsanou, V Papadaki, O Milatos, S Blackshear, PJ Anderson, P Kollias, G Kontoyiannis, DL TI HuR as a negative posttranscriptional modulator in inflammation SO MOLECULAR CELL LA English DT Article ID BINDING PROTEIN HUR; MESSENGER-RNA DESTABILIZATION; AU-RICH ELEMENTS; TNF-ALPHA; 3'-UNTRANSLATED REGION; TRANSLATIONAL SILENCER; TRISTETRAPROLIN; EXPRESSION; TARGET; STABILITY AB HuR is an RNA binding protein with an alleged role in the posttranscriptional activation of inflammatory mRNAs bearing AU-rich elements (AREs). Here, we show that the inducible increase of HuR in murine innate compartments suppresses inflammatory responses in vivo. In macrophages, HuR overexpression induced the translational silencing of specific cytokine mRNAs despite positive or nominal effects on their corresponding turnover. By using a model system of ARE dysfunction, we demonstrate that HuR does not alter the accumulation of target mRNAs in the absence of the destabilizing functions of Tristetraprolin but synergizes with the translational silencer TIA-1 to reduce the translation of cytokine mRNAs. Our data suggest that HuR acts in a pleiotropic fashion in inflammation through its functional interactions with specific mRNA subsets and negative posttranscriptional modules. C1 Biomed Sci Res Ctr Alexander Fleming, Inst Immunol, Vari 16672, Greece. Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. RP Kontoyiannis, DL (reprint author), Biomed Sci Res Ctr Alexander Fleming, Inst Immunol, Vari 16672, Greece. EM d.kontoyiannis@fleming.gr RI Kollias, George/A-7079-2012 OI Kollias, George/0000-0003-1867-3150 NR 39 TC 137 Z9 142 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 16 PY 2005 VL 19 IS 6 BP 777 EP 789 DI 10.1016/j.molcel.2005.08.007 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 966BM UT WOS:000231994600009 PM 16168373 ER PT J AU Law, DCG Klebanoff, MA Brock, JW Dunson, DB Longnecker, MP AF Law, DCG Klebanoff, MA Brock, JW Dunson, DB Longnecker, MP TI Maternal serum levels of polychlorinated Biphenyls and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and time to pregnancy SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE dichlorodiphenyl dichloroethylene; fertility; fertilization; hydrocarbons; chlorinated; polychlorinated biphenyls; pregnancy; reproduction ID PERSISTENT ORGANOCHLORINE COMPOUNDS; CONTAMINATED SPORT FISH; HUMAN FOLLICULAR-FLUID; BREAST-FEEDING WOMEN; ENVIRONMENTAL CONTAMINANTS; CHLORINATED HYDROCARBONS; LAKE-ONTARIO; RISK-FACTOR; HUMAN-MILK; CONSUMPTION AB Polychlorinated biphenyls (PCBs), once used widely in transformers and other applications, and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the main metabolite of the pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), are hormonally active agents. Changes in menstrual cycle functioning associated with PCBs and DDE, and increased odds of spontaneous abortion associated with DDE, suggest that these compounds could affect fertility. The authors investigated the association between PCB and DDE exposure and time to pregnancy by using serum levels measured in 390 pregnant women in the Collaborative Perinatal Project enrolled at 12 study centers in the United States from 1959 to 1965. They estimated adjusted fecundability odds ratios by using Cox proportional hazards modeling for discrete time data. Compared with time to pregnancy for women in the lowest exposure category (PCBs < 1.24 mu g/liter, DDE < 14 mu g/liter), time to pregnancy increased for women in the highest exposure category in terms of both PCBs (fecundability odds ratio for PCBs >= 5.00 mu g/liter = 0.65, 95% confidence interval: 0.36, 1.18) and DDE (fecundability odds ratio for DDE >= 60 mu g/liter = 0.65, 95% confidence interval: 0.32, 1.31). Overall, time to pregnancy increased with increasing serum PCB levels but was less suggestive of an association with DDE. Both trends were imprecise and attenuated when expressed on a lipid basis. Overall, evidence of an association between PCB or DDE exposure and time to pregnancy was weak and inconclusive. C1 Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Natl Inst Child Hlth & Human Dev, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Rockville, MD USA. Warren Wilson Coll, Dept Chem, Asheville, NC USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Longnecker, MP (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr,MD A3-05, Res Triangle Pk, NC 27709 USA. EM longnec1@niehs.nih.gov OI Longnecker, Matthew/0000-0001-6073-5322 NR 74 TC 43 Z9 44 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2005 VL 162 IS 6 BP 523 EP 532 DI 10.1093/aje/kwi240 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 961XL UT WOS:000231695000005 PM 16093292 ER PT J AU Sansbury, LB Millikan, RC Schroeder, JC Moorman, PG North, KE Sandler, RS AF Sansbury, LB Millikan, RC Schroeder, JC Moorman, PG North, KE Sandler, RS TI Use of nonsteroidal antiinflammatory drugs and risk of colon cancer in a population-based, case-control study of African Americans and Whites SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE African Americans; anti-inflammatory agents; non-steroidal; case-control studies; colonic neoplasms; European Continental Ancestry Group ID HORMONE REPLACEMENT THERAPY; COLORECTAL-CANCER; ASPIRIN USE; LARGE-BOWEL; BREAST-CANCER; HEALTH; CHEMOPREVENTION; PREVENTION; ADENOMA; MEDICATIONS AB African Americans have the highest colon cancer incidence and mortality rates among all US ethnic groups. Epidemiologic studies suggest that use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a reduced risk of colon cancer, but no study to date with adequate sample size has reported on the association among African Americans. The authors examined the association between NSAID use and risk of colon cancer in a population-based, case-control study in North Carolina that enrolled 731 African-American (294 cases, 437 controls) and 960 White (349 cases, 611 controls) participants between 1996 and 2000. Odds ratios were calculated using unconditional logistic regression for categories of NSAIDs and colon cancer risk. Inverse associations between regular NSAID use and colon cancer were similar for African Americans (odds ratio = 0.41, 95% confidence interval: 0.22, 0.77) and Whites (odds ratio = 0.48, 95% confidence interval: 0.28, 0.83) but stronger for women than men. Inverse associations were slightly weaker for occasional versus regular NSAID use, but they were similar for aspirin and nonaspirin NSAID use. These results add new knowledge suggesting that the protective effect of NSAIDs against colon cancer is similar among African Americans and Whites. C1 NCI, Canc Res Ctr, Canc Prevent Fellowship Program, Div Canc Prevent,NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA. Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA. Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA. RP Sansbury, LB (reprint author), NCI, Canc Res Ctr, Canc Prevent Fellowship Program, Div Canc Prevent,NIH, 6116 Execut Blvd,MSC 8235,Suite 702,Room 7215, Bethesda, MD 20892 USA. EM sansburl@mail.nih.gov FU NCI NIH HHS [T32-CA09330, R01-CA66635] NR 62 TC 28 Z9 30 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2005 VL 162 IS 6 BP 548 EP 558 DI 10.1093/aje/kwi248 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 961XL UT WOS:000231695000008 PM 16093288 ER PT J AU Nakane, T Biesecker, LG AF Nakane, T Biesecker, LG TI No evidence for triallelic inheritance of MKKS/BBS loci in amish Mckusick-Kaufman syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Bardet-Biedl syndrome; McKusick-Kaufman syndrome; modifier; penetrance ID BARDET-BIEDL-SYNDROME; HUMAN OBESITY SYNDROME; GENE; IDENTIFICATION; BBS2 AB It has been hypothesized that two mutations in one gene are not sufficient and that three mutations between two genes are required for penetrance in some cases of Bardet-Biedl syndrome (the so-called "triallelic inheritance" model). McKusick-Kaufman syndrome (MKS) is allelic to one form of Bardet-Biedl syndrome (BBS). We describe an Amish family with MKS, where three children were affected with homozygous MKKS (BBS6) mutations (H84Y and A242S on both alleles), their father was a carrier, and their mother was homozygous for the same MYKS mutations, but she was non-penetrant. Genotyping and/or sequencing of BBS1, BBS2, BBS3, BBS4, BBS5, BBS7, and BBS8 excluded "triallelic inheritance" for each gene either by an incompatible inheritance pattern or an absence of mutations in the coding region and the intronic splice junctions of these genes. We conclude that the "triallelic" model does not explain the incomplete penetrance of MKS. Published 2005 Wiley-Liss, Inc. C1 NHGRI, GDRB, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, GDRB, NIH, Bldg 49,Room 4A80, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov NR 11 TC 10 Z9 10 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD SEP 15 PY 2005 VL 138A IS 1 BP 32 EP 34 DI 10.1002/ajmg.a.30593 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 961AX UT WOS:000231635400007 PM 16104012 ER PT J AU Shinawi, M Szabo, S Popek, E Wassif, CA Porter, FD Potocki, L AF Shinawi, M Szabo, S Popek, E Wassif, CA Porter, FD Potocki, L TI Recognition of Smith-Lemli-Opitz syndrome (RSH) in the fetus: Utility of ultrasonography and biochemical analysis in pregnancies with low maternal serum estriol SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Smith-Lemli-Opitz syndrome; unconjugated estriol; 7-dehydrocholesterol; fetal demise ID UNCONJUGATED ESTRIOL; PRENATAL-DIAGNOSIS; SKIN FIBROBLASTS; AMNIOTIC-FLUID; DHCR7; MUTATIONS; FREQUENCY; SPECTRUM; PLASMA; WOMEN AB Smith-Lemli-Opitz syndrome (SLOS), or RSH, is an autosomal recessive disorder caused by mutations of the gene encoding 7-dehydrocholesterol reductase (DHCR7). The utility of maternal serum screens and ultrasound as prenatal screening methods for SLOS is presently undetermined. We report the clinical, cytogenetic, biochemical, and molecular findings of a stillborn with SLOS. The diagnosis was made postnatally on the basis of physical findings and confirmed by biochemical and DNA analyses of fetal tissue. Although abnormalities were detected by maternal serum triple screen and prenatal ultrasonography, a diagnosis of SLOS was not suspected before delivery. This study demonstrates that patients with SLOS may escape prenatal diagnosis despite the presence of multiple anomalies and abnormal maternal serum screen results, and lends support for consideration of prenatal biochemical testing for SLOS in pregnancies with these findings. As SLOS is a severe autosomal recessive disorder with a recurrence risk of 25%, ultrasonographic, cytogenetic, and biochemical analyses in the second trimester should be considered if abnormal maternal serum screening results, specifically low levels of unconjugated estriol, are detected. (c) 2005 Wiley-Liss, Inc. C1 Texas Childrens Hosp, Baylor Coll Med, Dept Mol & Human Genet, Clin Care Ctr, Houston, TX 77030 USA. Texas Childrens Hosp, Dept Pediat Pathol, Houston, TX 77030 USA. NICHHD, Unit Mol Dysmorphol, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Potocki, L (reprint author), Texas Childrens Hosp, Baylor Coll Med, Dept Mol & Human Genet, Clin Care Ctr, 6621 Fannin,Suite 1560,Mail Code CC-1560, Houston, TX 77030 USA. EM lpotocki@bcm.tmc.edu OI shinawi, Marwan /0000-0003-1329-4100; Wassif, Christopher/0000-0002-2524-1420 NR 28 TC 9 Z9 9 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD SEP 15 PY 2005 VL 138A IS 1 BP 56 EP 60 DI 10.1002/ajmg.a.30898 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 961AX UT WOS:000231635400012 PM 16097001 ER PT J AU Lee, K Boovanahalli, SK Nam, KY Kang, SU Lee, MJ Phan, J Wu, L Waugh, DS Zhang, ZY No, KT Lee, JJ Burke, TR AF Lee, K Boovanahalli, SK Nam, KY Kang, SU Lee, MJ Phan, J Wu, L Waugh, DS Zhang, ZY No, KT Lee, JJ Burke, TR TI Synthesis of tripeptides as potent Yersinia protein tyrosine phosphatase inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE tripeptides; bioterrorism; pTyr mimetics; YopH; PTP1B ID CONTAINING PHOSPHOTYROSYL MIMETICS; SIGNAL-TRANSDUCTION INHIBITORS; ALPHA-KETOCARBOXYLIC ACIDS; 1B PTP1B INHIBITORS; INSULIN SENSITIVITY; DESIGN; IDENTIFICATION; DISCOVERY; PEPTIDES; FORCES AB We report the synthesis of a series of monoanionic phosphotyrosyl (pTyr) mimetic-containing tripeptides based on `Fmoc-Glu(OBn)-Xxx-Leu-amide' (where Xxx = pTyr mimetic) and their N-terminally modified derivatives. The inhibitory potencies of compounds were tested against YopH and human PTP1B enzymes. Several compounds exhibited noteworthy activity against both YopH and PTP1B. Among the N-terminally modified analogues, 5-methylindole derivative 30 was found to be the best moiety to replace base-labile Fmoc group. A mode of binding with YopH is proposed for tripeptides 21, 30, and 31. (c) 2005 Elsevier Ltd. All rights reserved. C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. Albert Einstein Med Sch, Dept Mol Pharmacol, Bronx, NY 10461 USA. KRIBB, Lab Anticanc Res, Taejon 305333, South Korea. Yonsei Univ, Dept Biotechnol, Seoul 120749, South Korea. RP Burke, TR (reprint author), NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NIAID NIH HHS [1U54 AI57158] NR 39 TC 16 Z9 17 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2005 VL 15 IS 18 BP 4037 EP 4042 DI 10.1016/j.bmcl.2005.06.027 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 959CB UT WOS:000231493400011 PM 16039123 ER PT J AU Romagnoli, R Baraldi, PG Jung, MK Iaconinoto, MA Carrion, MD Remusat, V Preti, D Tabrizi, MA Francesca, F De Clercq, E Balzarini, J Hamel, E AF Romagnoli, R Baraldi, PG Jung, MK Iaconinoto, MA Carrion, MD Remusat, V Preti, D Tabrizi, MA Francesca, F De Clercq, E Balzarini, J Hamel, E TI Synthesis and preliminary biological evaluation of new anti-tubulin agents containing different benzoheterocycles SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE anti-tubulin agents; benzoheterocycles; combretastatin-A4 ID ANTIMITOTIC AGENTS; ANTINEOPLASTIC AGENTS; TUBULIN; DERIVATIVES; ANALOGS; COMBRETASTATIN-A-4; POLYMERIZATION; COLCHICINE; GROWTH; DRUGS AB A new series of compounds, in which the 2-amino-4-methoxyphenyl ring of phenstatin analogue 5 was replaced with 2- or 3-amino-benzoheterocycles, was synthesized and evaluated for antiproliferative activity and inhibition of colchicine binding. The lack of activity of 3 ',4 '-dimethoxy- and 4 '-methoxy-benzoyl derivatives (8 and 9, respectively) indicates that the 3 ',4 ',5 '-trimethoxybenzoyl moiety is critical for the activity. Two compounds, 7 and 11, displayed potent antiproliferative activity, with IC50 values ranging from 25 to 100 nM against a variety of cancer cell lines. Derivative 11 was more active than CA-4 as an inhibitor of tubulin polymerization. The results demonstrated that the antiproliferative activity was correlated with inhibition of tubulin polymerization. (c) 2005 Elsevier Ltd. All rights reserved. C1 Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. Sci Applicat Int Corp Frederick Inc, Natl Canc Inst, NIH, Frederick, MD 21702 USA. Rega Inst, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. NCI, Screening Technol Branch, Div Canc Treatment & Diagnosis, NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. EM rmr@unife.it RI Aghazadeh Tabrizi, Mojgan/I-9169-2014; Carrion, M. Dora/G-8638-2015; preti, delia/G-9916-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017 OI Carrion, M. Dora/0000-0002-6794-3949; preti, delia/0000-0002-1075-3781; FU NCI NIH HHS [N01-CO-12400] NR 22 TC 18 Z9 18 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2005 VL 15 IS 18 BP 4048 EP 4052 DI 10.1016/j.bmcl.2005.06.022 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 959CB UT WOS:000231493400013 PM 16005627 ER PT J AU Lee, J Kang, SU Kil, MJ Shin, M Lim, JO Choi, HK Jin, MK Kim, SY Kim, SE Lee, YS Min, KH Kim, YH Ha, HJ Tran, R Welter, JD Wang, Y Szabo, T Pearce, LV Lundberg, DJ Toth, A Pavlyukovets, VA Morgan, MA Blumberg, PM AF Lee, J Kang, SU Kil, MJ Shin, M Lim, JO Choi, HK Jin, MK Kim, SY Kim, SE Lee, YS Min, KH Kim, YH Ha, HJ Tran, R Welter, JD Wang, Y Szabo, T Pearce, LV Lundberg, DJ Toth, A Pavlyukovets, VA Morgan, MA Blumberg, PM TI Analysis of structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N '-[4-(methylsulfonylamino)benzyl]thiourea analogues as TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE TRPV1 antagonist; vanilloid receptor 1 antagonist; capsaicin; resiniferatoxin ID HIGH-AFFINITY ANTAGONISTS; VANILLOID RECEPTOR; CAPSAICIN RECEPTOR; POTENT; SENSITIVITY; CHANNELS; CLONING; FAMILY AB The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N '-[4-(methylsulfonylamino)benzyl]thio-urea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist. (c) 2005 Elsevier Ltd. All rights reserved. C1 Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. Digitalbiotech, Ansan 425839, Kyounggi Do, South Korea. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr RI Toth, Attila/F-4859-2010 OI Toth, Attila/0000-0001-6503-3653 NR 24 TC 17 Z9 18 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2005 VL 15 IS 18 BP 4136 EP 4142 DI 10.1016/j.bmcl.2005.06.009 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 959CB UT WOS:000231493400030 PM 16005215 ER PT J AU Lee, J Jin, MK Kang, SU Kim, SY Lee, J Shin, M Hwang, J Cho, SY Choi, YS Choi, HK Kim, SE Suh, YG Lee, YS Kim, YH Ha, HJ Toth, A Pearce, LV Tran, R Szabo, T Welter, JD Lundberg, DJ Wang, Y Lazar, J Pavlyukovets, VA Morgan, MA Blumberg, PM AF Lee, J Jin, MK Kang, SU Kim, SY Lee, J Shin, M Hwang, J Cho, SY Choi, YS Choi, HK Kim, SE Suh, YG Lee, YS Kim, YH Ha, HJ Toth, A Pearce, LV Tran, R Szabo, T Welter, JD Lundberg, DJ Wang, Y Lazar, J Pavlyukovets, VA Morgan, MA Blumberg, PM TI Analysis of structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N '-[4-(methylsulfonylamino)benzyl]-thiourea analogues as TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE TRPV1 antagonist; vanilloid receptor 1 antagonist; molecular modeling; capsaicin; resiniferatoxin ID VANILLOID RECEPTOR ANTAGONISTS; HIGH-AFFINITY ANTAGONISTS; IODO-RESINIFERATOXIN; CAPSAICIN RECEPTOR; POTENT; DISCOVERY; SENSITIVITY; DERIVATIVES; AGONISTS AB The structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N '-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. A docking model of potent antagonist 2 with the sensor region of TRPV1 is proposed. (c) 2005 Elsevier Ltd. All rights reserved. C1 Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. Digitalbiotech, Ansan 425839, Kyounggi Do, South Korea. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr RI Toth, Attila/F-4859-2010; OI Toth, Attila/0000-0001-6503-3653; Lee, Jiyoun/0000-0003-3819-5889 NR 31 TC 8 Z9 9 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2005 VL 15 IS 18 BP 4143 EP 4150 DI 10.1016/j.bmcl.2005.06.006 PG 8 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 959CB UT WOS:000231493400031 PM 15993063 ER PT J AU Longo, DL AF Longo, DL TI Chimera: from bane to blessing SO BLOOD LA English DT Editorial Material AB New data suggest that a mild preparative regimen of antibodies that block CD40 ligand and deplete host NK cells may make allogeneic hematopoietic stem cell transplants safe, establish long-term immunologic tolerance, and broaden the applicability of cord blood as a source of stem cells by making engraftment more efficient. C1 NIA, Bethesda, MD 20892 USA. RP Longo, DL (reprint author), NIA, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2005 VL 106 IS 6 BP 1890 EP 1891 DI 10.1182/blood-2005-06-2609 PG 2 WC Hematology SC Hematology GA 963PX UT WOS:000231817400002 ER PT J AU Schlom, J AF Schlom, J TI The marriage of cancer vaccines and antiangiogenesis SO BLOOD LA English DT Editorial Material ID TUMOR-GROWTH; DNA VACCINE AB An innovative approach to the use of cancer vaccines targets the vascular endothelial growth factor receptor-2 (FLK-1), suppresses tumor-associated angiogenesis, and results in antitumor activity. C1 NCI, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2005 VL 106 IS 6 BP 1897 EP 1898 DI 10.1182/blood-2005-06-2541 PG 2 WC Hematology SC Hematology GA 963PX UT WOS:000231817400010 ER PT J AU Tamura, T Thotakura, P Tanaka, TS Ko, MSH Ozato, K AF Tamura, T Thotakura, P Tanaka, TS Ko, MSH Ozato, K TI Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages SO BLOOD LA English DT Article ID SEQUENCE-BINDING-PROTEIN; MYELOID PROGENITOR CELLS; TRANSCRIPTION FACTOR; STIMULATED GENE-15; DENDRITIC CELLS; FACTOR PU.1; EXPRESSION; ICSBP; DIFFERENTIATION; LEUKEMIA AB Interferon regulatory factor-8 (IRF-8)/interferon consensus sequence-binding protein (ICSBP) is a transcription factor that controls myeloid-cell development. Microarray gene expression analysis of Irf-8(-/-) myeloid progenitor cells expressing an IRF-8/estrogen receptor chimera (which differentiate into macrophages after addition of estradiol) was used to identify 69 genes altered by IRF-8 during early differentiation (62 up-regulated and 7 down-regulated). Among them, 4 lysosomal/endosomal enzyme-related genes (cystatin C, cathepsin C, lysozyme, and prosaposin) did not require de novo protein synthesis for induction, suggesting that they were direct targets of IRF-8. We developed a reporter assay system employing a self-inactivating retrovirus and analyzed the cystatin C and cathepsin C promoters. We found that a unique cis element mediates IRF-8-induced activation of both promoters. Similar elements were also found in other IRF-8 target genes with a consensus sequence (GAAANN[N]GGAA) comprising a core IRF-binding motif and an Ets-binding motif; this sequence is similar but distinct from the previously reported Ets/IRF composite element. Chromatin immunoprecipitation assays demonstrated that IRF-8 and the PU.1 Ets transcription factor bind to this element in vivo. Collectively, these data indicate that IRF-8 stimulates transcription of target genes through a novel cis element to specify macrophage differentiation. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Tamura, T (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Room 2A05,6 Ctr Dr,MSC 2753, Bethesda, MD 20892 USA. EM tamurat@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 44 TC 82 Z9 82 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2005 VL 106 IS 6 BP 1938 EP 1947 DI 10.1182/blood-2005-01-0080 PG 10 WC Hematology SC Hematology GA 963PX UT WOS:000231817400018 PM 15947094 ER PT J AU Packer, RJ Krailo, M Mehta, M Warren, K Allen, J Jakacki, R Villablanca, JG Chiba, A Reaman, G AF Packer, RJ Krailo, M Mehta, M Warren, K Allen, J Jakacki, R Villablanca, JG Chiba, A Reaman, G TI Phase 1 study of concurrent RMP-7 and carboplatin with radiotherapy for children with newly diagnosed brainstern gliomas SO CANCER LA English DT Article DE brainstem glioma; radiotherapy; radiosensitization; carboplatin ID BLOOD-BRAIN; BRADYKININ ANALOG; INTRACAROTID INFUSION; STEM GLIOMAS; CANCER-GROUP; TUMORS; BARRIER; PERMEABILITY; SURVIVAL; TRIAL AB BACKGROUND. Ninety percent of children with diffuse intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit, and one way to potentially improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing. However, delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The goal of the current Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy. METHODS. RMP-7 was given before the end of carboplatin infusion. Local radiotherapy (5940 centigrays) was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion, in cohorts of 3, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, whose median age was 7 years (range, 3-14 yrs). RESULTS. One child died early in treatment of progressive disease and was not assessable for toxicity. Treatment for 3, 4, or 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. Of 3 children treated at the full duration of therapy (33 doses over 7 wks), I developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival period was 328 days, and I patient remained disease progression free > 400 days from initiation of treatment. CONCLUSIONS. The results of the current study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy. C1 Childrens Natl Med Ctr, Div Neurol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Div Hematol Oncol, Washington, DC 20010 USA. George Washington Univ, Dept Neurol, Washington, DC USA. George Washington Univ, Dept Pediat, Washington, DC USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Childrens Oncol Grp, Arcadia, CA USA. Univ Wisconsin, Med Ctr, Dept Radiat Oncol, Madison, WI 53706 USA. NCI, Div Neurooncol Branch, Bethesda, MD 20892 USA. NYU, Div Oncol, New York, NY USA. Childrens Hosp Pittsburgh, Div Oncol, Pittsburgh, PA 15213 USA. Childrens Hosp Los Angeles, Div Oncol, Los Angeles, CA 90027 USA. RP Packer, RJ (reprint author), Childrens Natl Med Ctr, Div Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM rpacker@cnmc.org NR 30 TC 15 Z9 15 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2005 VL 104 IS 6 BP 1281 EP 1287 DI 10.1002/cnr.21301 PG 7 WC Oncology SC Oncology GA 962PC UT WOS:000231743700019 PM 16078267 ER PT J AU Man, TK Chintagumpala, M Visvanathan, J Shen, JH Perlaky, L Hicks, J Johnson, M Davino, N Murray, J Helman, L Meyer, W Triche, T Wong, KK Lau, CC AF Man, TK Chintagumpala, M Visvanathan, J Shen, JH Perlaky, L Hicks, J Johnson, M Davino, N Murray, J Helman, L Meyer, W Triche, T Wong, KK Lau, CC TI Expression profiles of osteosarcoma that can predict response to chemotherapy SO CANCER RESEARCH LA English DT Article ID SAETHRE-CHOTZEN-SYNDROME; SUPPORT VECTOR MACHINES; HELIX TRANSCRIPTION FACTOR; NEOADJUVANT CHEMOTHERAPY; PROGNOSTIC-SIGNIFICANCE; MICROARRAY DATA; CANCER-CELLS; TWIST; GENE; CLASSIFICATION AB Osteosarcoma is the most common malignant bone tumor in children. After initial diagnosis is made with a biopsy, treatment consists of preoperative chemotherapy followed by definitive surgery and postoperative chemotherapy. The degree of tumor necrosis in response to preoperative chemotherapy is a reliable prognostic factor and is used to guide the choice of postoperative chemotherapy. Patients with tumors, which reveal >= 90% necrosis (good responders), have a much better prognosis than those with <90% necrosis (poor responders). Despite previous attempts to improve the outcome of poor responders by modifying the postoperative chemotherapy, their prognosis remains poor. Therefore, there is a need to predict at the time of diagnosis patients' response to preoperative chemotherapy. This will provide the basis for developing potentially effective therapy that can be given at the outset for those who are likely to have a poor response. Here, we report the analysis of 34 pediatric osteosarcoma samples by expression profiling. Using parametric two-sample t test, we identified 45 genes that discriminate between good and poor responders (P < 0.005) in 20 definitive surgery samples. A support vector machine classifier was built using these predictor genes and was tested for its ability to classify initial biopsy samples. Five of six initial biopsy samples that had corresponding definitive surgery samples in the training set were classified correctly (83%; confidence interval, 36%, 100%). When this classifier was used to predict eight independent initial biopsy samples, there was 100% accuracy (confidence interval, 63%, 100%). Many of the predictor genes are implicated in bone development, drug resistance, and tumorigenesis. C1 Texas Childrens Hosp, Baylor Coll Med, Texas Childrens Canc Ctr, Dept Pediat, Houston, TX 77030 USA. Texas Childrens Hosp, Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Texas Childrens Hosp, Baylor Coll Med, Dept Orthoped Surg, Houston, TX 77030 USA. Cook Childrens Med Ctr, Ft Worth, TX USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP Lau, CC (reprint author), Texas Childrens Hosp, Baylor Coll Med, Texas Childrens Canc Ctr, Dept Pediat, 6621 Fannin St,MC 3-3320, Houston, TX 77030 USA. EM cclau@txcce.org OI Wong, Kwong-Kwok/0000-0002-0375-6669 FU NCI NIH HHS [CA88126] NR 51 TC 84 Z9 88 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2005 VL 65 IS 18 BP 8142 EP 8150 DI 10.1158/0008-5472.CAN-05-0985 PG 9 WC Oncology SC Oncology GA 964AQ UT WOS:000231848800013 PM 16166288 ER PT J AU Morrison, DJ English, MA Licht, JD AF Morrison, DJ English, MA Licht, JD TI WT1 induces apoptosis through transcriptional regulation of the proapoptotic Bcl-2 family member Bak SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; WILMS-TUMOR; CELL-DEATH; KIDNEY DEVELOPMENT; BH3-ONLY PROTEINS; CANCER CELLS; ACTIVATION; GROWTH; EXPRESSION; MUTATIONS AB Wilms' tumor or nephroblastoma is believed to arise from embryonic nephrogenic rests of multipotent cells that fail to terminally differentiate into epithelium and continue to proliferate. The WT1 tumor suppressor gene, a transcription factor controlling the mesenchymal-epithelial transition in renal development, is mutated in 10% to 15% of Wilms' tumors. This potentially explains the disordered differentiation and proliferation program of a subset of Wilms' tumors. To elucidate the role of mutations of WT1 in the etiology of Wilms' tumor, we used an inducible cellular system for expressing wild-type and tumor-derived missense mutant WT1 proteins. Expression of wild-type WT1, but not mutant proteins, blocked cellular proliferation and DNA synthesis and rapidly induced apoptosis. We showed that wild-type WT1 induced transcription of one of the seven studied proapoptotic genes, Bak. Furthermore, WT1 protein bound to specific DNA-binding sites located in the Bak promoter and Bak was critical to WT1-mediated apoptosis, as overexpression of VDAC2, a specific Bak inhibitor, attenuated WT1-mediated cell death. These data support the hypothesis that Wilms' tumors arise, in part, because WT1 mutant proteins fail to promote programmed cell death during kidney development. C1 CUNY Mt Sinai Sch Med, Dept Med, Div Hematol Oncol, New York, NY 10029 USA. NHGRI, Bethesda, MD 20892 USA. RP Licht, JD (reprint author), CUNY Mt Sinai Sch Med, Dept Med, Div Hematol Oncol, Box 1079,1 Gustave L Levy Pl, New York, NY 10029 USA. EM jonathan.licht@mssm.edu FU NCI NIH HHS [CA102270, CA59998] NR 51 TC 49 Z9 50 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2005 VL 65 IS 18 BP 8174 EP 8182 DI 10.1158/0008-5472.CAN-04-3657 PG 9 WC Oncology SC Oncology GA 964AQ UT WOS:000231848800017 PM 16166292 ER PT J AU Simonson, SJS Difilippantonio, MJ Lambert, PF AF Simonson, SJS Difilippantonio, MJ Lambert, PF TI Two distinct activities contribute to human papillomavirus 16 E6's oncogenic potential SO CANCER RESEARCH LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; PROTEASOME-MEDIATED DEGRADATION; LARGE TUMOR-SUPPRESSOR; CELL-CYCLE REGULATION; TRANSGENIC MICE; EPITHELIAL HYPERPLASIA; HUMAN KERATINOCYTES; ADENOVIRUS E4-ORF1; PROTEINS TARGET; HUMAN SCRIBBLE AB High-risk human papillomaviruses, such as HPV16, cause cervical cancers, other anogenital cancers, and a subset of head and neck cancers. E6 and E7, two viral oncogenes expressed in these cancers, encode multifunctional proteins best known for their ability to bind and inactivate the tumor suppressors p53 and pRb, respectively. In skin carcinogenesis experiments using E6 transgenic (K14E6(WT)) mice, HPV16 E6 was found to contribute to two distinct stages in skin carcinogenesis: promotion, a step involved in the formation of benign papillomas, and progression, the step involved in the malignant conversion of benign tumors to frank cancer. In this study, we compared the tumorigenic properties of K14E6(WT) mice with those of K14E6(Delta 146-151) mice, which express a mutant form of E6 that cannot bind a family of cellular proteins known as PDZ domain proteins but retains the ability to inactivate p53. In skin carcinogenesis experiments, the K14E6(Delta 146-151) transgene failed to contribute to the promotion stage of skin carcinogenesis but retained the ability to contribute to the progression stage. Cytogenetic analysis indicated that, although gains of chromosome 6 are consistently seen in tumors arising on K14E6(WT) mice, they are infrequently seen in tumors arising on K14E6(Delta 146-151) mice. This observation supports the premise that the nature of cancer development in these two mouse strains is distinct. Based on these studies, we conclude that E6 contributes to cancer through its disruption of multiple cellular pathways, one of which is mediated through its interaction with PDZ domain partners and the other through E6's inactivation of p53. C1 Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA. NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Lambert, PF (reprint author), Univ Wisconsin, McArdle Lab Canc Res, 1400 Univ Ave, Madison, WI 53706 USA. EM lambert@oncology.wisc.edu FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [CA098428, CA07175, CA22443] NR 37 TC 47 Z9 50 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2005 VL 65 IS 18 BP 8266 EP 8273 DI 10.1158/0008-5472.CAN-05-1651 PG 8 WC Oncology SC Oncology GA 964AQ UT WOS:000231848800028 PM 16166303 ER PT J AU Kioi, M Takahashi, S Kawakami, M Kawakami, K Kreitman, RJ Puri, RK AF Kioi, M Takahashi, S Kawakami, M Kawakami, K Kreitman, RJ Puri, RK TI Expression and targeting of interieukin-4 receptor for primary and advanced ovarian cancer therapy SO CANCER RESEARCH LA English DT Article ID RECOMBINANT HUMAN INTERLEUKIN-4; RENAL-CELL CARCINOMA; PHASE-II TRIAL; GYNECOLOGIC-ONCOLOGY-GROUP; GROWTH-FACTOR; INTRAPERITONEAL CISPLATIN; ANTITUMOR-ACTIVITY; CYTOTOXIN THERAPY; EXOTOXIN; BREAST AB Because the most characteristic property of ovarian cancer is i.p. spread, the majority of patients are diagnosed at an advanced stage, leading to limited availability of options for curative therapies. With an intent to identify targeted therapeutic approaches, we have observed that similar to 60% of 21 ovarian cancer tissue samples express a high density of interleukin-4 receptor (IL-4R), whereas normal ovarian tissues tested (n = 7) expressed no or low levels of IL-4R. To target IL-4R, we have developed IL-4 cytotoxin, in which circular-permuted IL-4 is fused to a mutated form of Pseudomonas exotoxin. This cytotoxin is specifically and highly cytotoxic to PA-1, IGROV-1, and SK-OV3 ovarian carcinoma cell lines in vitro. In addition, it shows remarkable antitumor activities against established s.c. ovarian tumors in immunodeficient animals. i.p. administration of IL-4 cytotoxin in mice with orthotopically implanted ovarian tumors caused regression of established tumors and prevented these animals from tumor metastasis. Continuous i.p. infusion of IL-4 cytotoxin prolonged survival of tumor-bearing mice even with bulky disease. These results indicate that IL-4R-targeted cytotoxin may be a useful agent for the management of patients with ovarian cancer, and further studies need to be done to evaluate its safety, tolerability, and efficacy. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bldg 29B,Room 2NN20,HFM-735,29 Lincoln Dr, Bethesda, MD 20892 USA. EM puri@cber.fda.gov OI Kioi, Mitomu/0000-0002-7981-3340 NR 39 TC 15 Z9 16 U1 1 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 SEP 15 PY 2005 VL 65 IS 18 BP 8388 EP 8396 DI 10.1158/0008-5472.CAN-05-1043 PG 9 WC Oncology SC Oncology GA 964AQ UT WOS:000231848800042 PM 16166317 ER PT J AU Shafran, A Ifergan, I Bram, E Jansen, G Kathmann, I Peters, GJ Robey, RW Bates, SE Assaraf, YG AF Shafran, A Ifergan, I Bram, E Jansen, G Kathmann, I Peters, GJ Robey, RW Bates, SE Assaraf, YG TI ABCG2 harboring the Gly482 mutation confers high-level resistance to various hydrophilic antifolates SO CANCER RESEARCH LA English DT Article ID FOLYLPOLYGLUTAMATE SYNTHETASE-ACTIVITY; REDUCED FOLATE CARRIER; BINDING CASSETTE ABC; BREAST-CANCER CELLS; MULTIDRUG-RESISTANCE; PROTEIN BCRP/ABCG2; METHOTREXATE RESISTANCE; ACQUIRED MUTATIONS; HALF-TRANSPORTER; CROSS-RESISTANCE AB ABCG2 is an ATP-binding cassette transporter that confers resistance to various chemotherapeutic agents. Recent studies have established that an Arg (wild-type) to Gly mutation at amino acid 482 in ABCG2 alters substrate specificity. Here, we explored the role of this G482 mutation in antifolate resistance using a clinically relevant 4-hour drug exposure. Stable transfectants overexpressing the mutant G482 transporter displayed 120-, 1,000-, and >6,250-fold resistance to the antifolates methotrexate, GW1843, and Tomudex, respectively, relative to parental human embryonic kidney cells. Moreover, although overexpressing equal transporter levels at the plasma membrane, G482-ABCG2 cells were 6-, 23-, and >521-fold more resistant to methotrexate, GW1843, and Tomudex, respectively, than R482-ABCG2 cells. In contrast, upon a continuous (72-hour) drug exposure, both the G482- and R482-ABCG2 cells lost almost all their antifolate resistance; this result was consistent with the inability of ABCG2 to extrude long-chain antifolate polyglutamates. Ko143, a specific and potent ABCG2 inhibitor reversed methotrexate resistance in both G482- and R482-ABCG2 cells. Consistently, whereas the pool of free methotrexate in parental human embryonic kidney cells was prominent after 4 hours of transport with 1 mu mol/L [H-3] methotrexate, in R482- and G482-ABCG2 cells, it was minimal. Furthermore, G482-ABCG2 cells contained marked decreases in the di- and triglutamate species of [H-3]methotrexate at 4 hours of incubation with methotrexate and in the tetra- and pentaglutamates at 24 hours. These changes were not associated with any significant decrease in folylypoly-gamma-glutamate synthetase activity. These results provide the first evidence that the G482-ABCG2 mutation confers high-level resistance to various hydrophilic antifolates. C1 Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. VU Univ, Med Ctr, Dept Rheumatol, Amsterdam, Netherlands. VU Univ, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Assaraf, YG (reprint author), Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. EM assaraf@tx.technion.ac.il NR 37 TC 36 Z9 38 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2005 VL 65 IS 18 BP 8414 EP 8422 DI 10.1158/0008-5472.CAN-04-4547 PG 9 WC Oncology SC Oncology GA 964AQ UT WOS:000231848800045 PM 16166320 ER PT J AU Tsurutani, J West, KA Sayyah, J Gills, JJ Dennis, PA AF Tsurutani, J West, KA Sayyah, J Gills, JJ Dennis, PA TI Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy SO CANCER RESEARCH LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; PROTEIN-KINASE-B; C-KIT; DRUG-RESISTANCE; IN-VIVO; GROWTH; CARCINOMA; EXPRESSION; LINES; EFFICACY AB The fact that small cell lung cancer (SCLC) is commonly incurable despite being initially responsive to chemotherapy, combined with disappointing results from a recent SCLC clinical trial with imatinib, has intensified efforts to identify mechanisms of SCLC resistance. Adhesion to extracellular matrix (ECM) is one mechanism that can increase therapeutic resistance in SCLC cells. To address whether adhesion to ECM increases resistance through modulation of signaling pathways, a series of SCLC cell lines were plated on various ECM components, and activation of two signaling pathways that promote cellular survival, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathway, was assessed. Although differential activation was observed, adhesion to laminin increased Akt activation, increased cellular survival after serum starvation, and caused the cells to assume a flattened, epithelial morphology. Inhibitors of the PI3K/ Akt/mTOR pathway (LY294002, rapamycin) but not the MEK/ERK pathway (U0126) abrogated laminin-mediated survival. SCLC cells plated on laminin were not only resistant to serum starvation-induced apoptosis but were also resistant to apoptosis caused by imatinib. Combining imatinib with LY294002 or rapamycin but not U0126 caused greater than additive increases in apoptosis compared with apoptosis caused by the inhibitor or imatinib alone. Similar results were observed when adenoviruses expressing mutant Akt were combined with imatinib, or when LY294002 was combined with cisplatin or etoposide. These studies identify laminin-mediated activation of the PI3K/Akt/mTOR pathway as a mechanism of cellular survival and therapeutic resistance in SCLC cells and suggest that inhibition of the PI3K/ Akt/mTOR pathway is one strategy to overcome SCLC resistance mediated by ECM. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dennis, PA (reprint author), NCI, Navy Med Oncol, Room 5101,Bldg 8,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM pdennis@nih.gov NR 42 TC 83 Z9 91 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 SEP 15 PY 2005 VL 65 IS 18 BP 8423 EP 8432 DI 10.1158/0008-5472.CAN-05-0058 PG 10 WC Oncology SC Oncology GA 964AQ UT WOS:000231848800046 PM 16166321 ER PT J AU Zorn, KK Bonome, T Gangi, L Chandramouli, GVR Awtrey, CS Gardner, GJ Barrett, JC Boyd, J Birrer, MJ AF Zorn, KK Bonome, T Gangi, L Chandramouli, GVR Awtrey, CS Gardner, GJ Barrett, JC Boyd, J Birrer, MJ TI Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID DISTINCT-HISTOLOGIC-TYPE; TUMOR-SUPPRESSOR; POOR-PROGNOSIS; CARCINOMA; RESISTANCE; PLATINUM; ADENOCARCINOMA; IDENTIFICATION; HYBRIDIZATION; CHEMOTHERAPY AB Purpose: The presence of similar histologic subtypes of epithelial ovarian and enclometrial cancers has long been noted, although the relevance of this finding to pathogenesis and clinical management is unclear. Despite similar clinical characteristics, histologic subtypes of cancers cif the ovary and endometrium are treated according to organ of origin. This study compares the gene expression profiles of analogous histologic subtypes of cancers of the ovary and eneometrium using the same genomic platform to determine the similarities and differences between these tumors. Experimental, Design: Gene,expression profiles of 75 cancers (endometrioid, serous, and clear cell) of the ovary and endometrium, five renal clear cell cancers, and seven normal epithelial were determined using a 11,000-element cDNA array. All images were analyzed using BRB ArrayTools. Validation was done using real-time PCR on select genes and immunohisto-chemical staining. Results: Comparison across enclometrial and ovarian cancers and serous and endometrioid tumors showed expression patterns reflecting their organ,of origin. Clear cell tumors, however, showed remarkably similar expression patterns regardless of their origin, even when compared with renal clear cell samples. A set of 43 genes was common to comparisons of each of the three histologic subtypes of ovarian cancer with normal ovarian, surface epithelium. Conclusions: The comparison of the gene expression profiles of endometrioid and serous subtypes of ovarian and enclometrial cancer are largely unique to-the combination of a particular subtype in a specific organ. In contrast, clear cell cancers show a remarkable similarity. in gene expression profiles across organs (icluding kidney) and could not be statistically distinguished. C1 NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Natl Canc Inst, Frederick, MD USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Birrer, MJ (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 37,Room 1130, Bethesda, MD 20892 USA. EM birrerm@bprb.nci.nih.gov NR 33 TC 212 Z9 216 U1 1 U2 10 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 SEP 15 PY 2005 VL 11 IS 18 BP 6422 EP 6430 DI 10.1158/1078-0432.CCR-05.0508 PG 9 WC Oncology SC Oncology GA 966JN UT WOS:000232016100003 PM 16166416 ER PT J AU Bennett, JE AF Bennett, JE TI Salvage therapy for aspergillosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INVASIVE ASPERGILLOSIS AB Participants at the John E. Bennett Forum on Design of Clinical Trials for Fungal Infections suggested guidelines for the regulatory approval of drugs solely on the basis of salvage therapy-that is, the use of an unlicensed drug to treat patients who have experienced failure with or who have been intolerant of an approved drug. The topics covered included requirements for study design (i. e., the design allows the comparison of comparable items), entry criteria (in particular, the duration of therapy before salvage therapy is introduced), and outcome criteria that determine whether or not the treatment was successful. C1 NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bldg 10,Rm 11C304,10 Ctr Dr, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov NR 4 TC 10 Z9 10 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2005 VL 41 SU 6 BP S387 EP S388 DI 10.1086/430921 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 956QC UT WOS:000231313900005 PM 16108004 ER PT J AU Strunnikova, N Hilmer, S Flippin, J Robinson, M Hoffman, E Csaky, KG AF Strunnikova, N Hilmer, S Flippin, J Robinson, M Hoffman, E Csaky, KG TI Differences in gene expression profiles in dermal fibroblasts from control and patients with, age-related macular degeneration elicited by oxidative injury SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE dermal fibroblast; microarray; EASE; oxidative injury; age-related macular degeneration ID EXPERIMENTAL CHOROIDAL NEOVASCULARIZATION; PIGMENT EPITHELIUM-CELLS; APOLIPOPROTEIN-E; MICROARRAY EXPERIMENTS; RHEUMATOID-ARTHRITIS; ALZHEIMERS-DISEASE; DRUSEN FORMATION; GROWTH-FACTORS; MOUSE MODEL; RPE AB The pathogenesis of age-related macular degeneration (AMD) is still unknown but there is growing evidence that a combination of both oxidative injury and genetic factors may play a role. One particle hypothesis proposes that dysregulation of multiple genes in response to an oxidative injury could contribute to the development of AMD. While direct examination of ocular cells from AMD patients is difficult, AMD also appears to have a systemic component. Therefore, as is the case with other central nervous diseases, peripheral sites may also manifest any underlying genetic abnormalities. For the present study, biopsy-derived fibroblasts from 4 patients with the early form and 4 patients with the late form of AMD and 3 age-matched control patients were grown in culture and treated with a nonlethal dose of the oxidative stimulus menadione. Gene expression patterns were quantitatively and qualitatively examined using Human Genome U95A GeneChips (Affymetrix) and verified by real-time PCR analysis. In response to the oxidative injury 755 genes were found to be upregutated at least twofold in one of the patients groups. Cluster analysis of expression profiles detected six patterns of dysregulation initiated by oxidative injury specific for the disease groups (98 genes total). Clusters of genes dysregulated by the sublethal oxidative injury in either early and/or late AMD groups were further categorized by over-representation of GO "biological process" categories using Expression Analysis Systematic Explorer (EASE) software. This approach demonstrated that four major functional gene groups including inflammatory/innate immune response, transcriptional regulation, cell cycle, and proliferation were significantly overrepresented (Fisher test ranging from 0.0393 to 0.00018) in both AMD patients groups in response to the oxidative injury. Despite the small number of patients in the study, specific biological and statistical differences in gene expression profiles between control and AMD patients were identified but only in the presence of an environmental stimulus. (c) 2005 Elsevier Inc. All rights reserved. C1 NEI, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Csaky, KG (reprint author), NEI, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kcsaky@helix.nih.gov NR 81 TC 6 Z9 6 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP 15 PY 2005 VL 39 IS 6 BP 781 EP 796 DI 10.1016/j.freeradbiomed.2005.04.029 PG 16 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 960IJ UT WOS:000231583500009 PM 16109308 ER PT J AU Gorski, S Misteli, T AF Gorski, S Misteli, T TI Systems biology in the cell nucleus SO JOURNAL OF CELL SCIENCE LA English DT Article ID INTERCHROMATIN GRANULE CLUSTERS; NONSENSE-MEDIATED DECAY; CIS-REGULATORY LOGIC; LIVING HUMAN-CELLS; GENE-EXPRESSION; PROTEOMIC ANALYSIS; GENOME-WIDE; HISTONE H1; TRANSCRIPTION FACTOR; MAMMALIAN-CELLS AB The mammalian nucleus is arguably the most complex cellular organelle. It houses the vast majority of an organism's genetic material and is the site of all major genome regulatory processes. Reductionist approaches have been spectacularly successful at dissecting at the molecular level many of the key processes that occur within the nucleus, particularly gene expression. At the same time, the limitations of analyzing single nuclear processes in spatial and temporal isolation and the validity of generalizing observations of single gene loci are becoming evident. The next level of understanding of genome function is to integrate our knowledge of their sequences and the molecular mechanisms involved in nuclear processes with our insights into the spatial and temporal organization of the nucleus and to elucidate the interplay between protein and gene networks in regulatory circuits. To do so, catalogues of genomes and proteomes as well as a precise understanding of the behavior of molecules in living cells are required. Converging technological developments in genomics, proteomics, dynamics and computation are now leading. towards such an integrated biological understanding of genome biology and nuclear function. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Gorski, S (reprint author), NCI, NIH, 41 Lib Dr, Bethesda, MD 20892 USA. EM gorskis@mail.nih.gov; mistelit@mail.nih.gov FU Intramural NIH HHS NR 96 TC 24 Z9 25 U1 1 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2005 VL 118 IS 18 BP 4083 EP 4092 DI 10.1242/jcs.02596 PG 10 WC Cell Biology SC Cell Biology GA 973UV UT WOS:000232549000002 PM 16155251 ER PT J AU Lan, L Nakajima, S Komatsu, K Nussenzweig, A Shimamoto, A Oshima, J Yasui, A AF Lan, L Nakajima, S Komatsu, K Nussenzweig, A Shimamoto, A Oshima, J Yasui, A TI Accumulation of Werner protein at DNA double-strand breaks in human cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE Werner protein; double-strand breaks; laser irradiation; damage accumulation; HRDC domain ID FUNCTIONAL INTERACTION; MRE11 COMPLEX; HELICASE ACTIVITY; DAMAGE RESPONSE; WRN; REPLICATION; ENDS; KU; PATHWAY; DOMAIN AB Werner syndrome is an autosomal recessive accelerated-aging disorder caused by a defect in the WRN gene, which encodes a member of the RecQ family of DNA helicases with an exonuclease activity. In vitro experiments have suggested that WRN functions in several DNA repair processes, but the actual functions of WRN in living cells remain unknown. Here, we analyzed the kinetics of the intranuclear mobilization of WRN protein in response to a variety of types of DNA damage produced locally in the nucleus of human cells. A striking accumulation of WRN was observed at laser-induced double-strand breaks, but not at single-strand breaks or oxidative base damage. The accumulation of WRN at double-strand breaks was rapid, persisted for many hours, and occurred in the absence of several known interacting proteins including polymerase P, poly(ADP-ribose) polymerase 1 (PARP1), Ku80, DNA-dependent protein kinase (DNA-PKcs), NBS1 and histone H2AX. Abolition of helicase activity or deletion of the exonuclease domain had no effect on accumulation, whereas the presence of the HRDC (helicase and RNaseD C-terminal) domain was necessary and sufficient for the accumulation. Our data suggest that WRN functions mainly at DNA double-strand breaks and structures resembling double-strand breaks in living cells, and that an autonomous accumulation through the HRDC domain is the initial response of WRN to the double-strand breaks. C1 Tohoku Univ, Inst Dev Aging & Canc, Dept Mol Genet, Sendai, Miyagi 9808575, Japan. Kyoto Univ, Ctr Radiat Biol, Dept Genome Repair Dynam, Kyoto 6068501, Japan. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. GeneCare Res Inst, Kanagawa 2470063, Japan. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Yasui, A (reprint author), Tohoku Univ, Inst Dev Aging & Canc, Dept Mol Genet, Seiryomachi 4-1, Sendai, Miyagi 9808575, Japan. EM ayasui@idac.tohoku.ac.jp FU NCI NIH HHS [CA78088] NR 52 TC 93 Z9 95 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2005 VL 118 IS 18 BP 4153 EP 4162 DI 10.1242/jcs.02544 PG 10 WC Cell Biology SC Cell Biology GA 973UV UT WOS:000232549000009 PM 16141234 ER PT J AU Lee, DW Zhao, XH Zhang, F Eisenberg, E Greene, LE AF Lee, DW Zhao, XH Zhang, F Eisenberg, E Greene, LE TI Depletion of GAK/auxilin 2 inhibits receptor-mediated endocytosis and recruitment of both clathrin and clathrin adaptors SO JOURNAL OF CELL SCIENCE LA English DT Article DE GAK depletion; clathrin; clathrin adaptors; endocytosis ID G-ASSOCIATED KINASE; COATED VESICLES; IN-VIVO; UNCOATING ATPASE; AUXILIN; PROTEIN; CELLS; EXCHANGE; DOMAIN; PITS AB Cyclin G-associated kinase (GAK/auxilin 2), the ubiquitous form of the neuronal-specific protein auxilin 1, is an essential cofactor for the Hsc70-dependent uncoating of clathrin-coated vesicles. We have now investigated the effect of knocking down GAK in HeLa cells by vector-based small hairpin RNA. Functionally, depletion of GAK caused a marked decrease in internalization of both transferrin and epidermal growth factor and altered mannose 6-phosphate receptor trafficking, but had little effect on the recycling of transferrin receptor back to the plasma membrane. Structurally, depletion of GAK caused a marked reduction in perinuclear clathrin associated with the trans-Golgi network and in the number of clathrin-coated pits on the plasma membrane, and reduced clathrin exchange on the few clathrin-coated pits that remained. Surprisingly, while clathrin depletion does not prevent adaptors from assembling on the membrane, depletion of GAK caused a dramatic reduction in AP2 and epsin on the plasma membrane and AP1 and GGA at the trans-Golgi network. A similar effect was caused by expression of a dominant negative Hsp70 mutant. These results suggest that GAK, in conjunction with Hsc70, not only uncoats clathrin-coated vesicles and induces clathrin exchange on clathrin-coated pits, but also mediates binding of clathrin and adaptors to the plasma membrane and the trans-Golgi network. C1 NHLBI, Cell Biol Lab, Nihon Univ, Bethesda, MD 20892 USA. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, Nihon Univ, 50 South Dr,Rm 2537,MSC 8017, Bethesda, MD 20892 USA. EM greenel@helix.nih.gov NR 34 TC 40 Z9 41 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2005 VL 118 IS 18 BP 4311 EP 4321 DI 10.1242/jcs.02548 PG 11 WC Cell Biology SC Cell Biology GA 973UV UT WOS:000232549000023 PM 16155256 ER PT J AU Vaccari, M Trindade, CJ Venzon, D Zanetti, M Franchini, G AF Vaccari, M Trindade, CJ Venzon, D Zanetti, M Franchini, G TI Vaccine-induced CD8(+) central memory T cells in protection from simian AIDS SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; IMMUNODEFICIENCY VIRUS; RHESUS-MONKEYS; LYMPHOCYTES; INFECTION; CD4(+); MACAQUES; IMMUNITY; VIREMIA; UNRESPONSIVENESS AB Critical to the development of an effective HIV vaccine is the identification of adaptive immune responses that prevent infection or disease. In this study we demonstrate in a relevant nonhuman primate model of AIDS that the magnitude of vaccine-induced virus-specific CD8(+) central memory T cells (T-CM), but not that of CD8(+) effector memory T cells, inversely correlates with the level of SIVmac251 replication, suggesting their pivotal role in the control of viral replication. We propose that effective preventive or therapeutic T cell vaccines for HIV-1 should induce long-term protective central memory T cells. C1 NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, 41-D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov RI Venzon, David/B-3078-2008 NR 32 TC 63 Z9 63 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 SEP 15 PY 2005 VL 175 IS 6 BP 3502 EP 3507 PG 6 WC Immunology SC Immunology GA 966HN UT WOS:000232010800010 PM 16148092 ER PT J AU Yang, SX Hodge, JW Grosenbach, DW Schlom, J AF Yang, SX Hodge, JW Grosenbach, DW Schlom, J TI Vaccines with enhanced costimulation maintain high avidity memory CTL SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-ACTIVATION; CARCINOEMBRYONIC ANTIGEN GENE; IMMUNE-RESPONSES; ADOPTIVE IMMUNOTHERAPY; CD28 COSTIMULATION; ANTITUMOR-ACTIVITY; PROSTATE-CANCER; VIRAL-INFECTION; SELF-ANTIGENS; PHASE-I AB The avidity of Ag-specific CTL is a critical determinant for clearing viral infection and eliminating tumor. Although previous studies have demonstrated that vaccines using enhanced costimulation will enhance the level and avidity of Ag-specific T cells from naive mice, there are conflicting data about the effects of vaccines using enhanced costimulation (vector or dendritic cell based) on the survival of memory T cells. In this study we have first extended previous observations that primary vaccination with a recombinant vaccinia virus (rV-) expressing a model Ag (LacZ) and a triad of T cell costimulatory molecules (B7-1, ICAM-1, and LFA-3 (designated TRICOM)) enhances the level and avidity of T cells from naive vaccinated C57BL/6 (Thy1.2) mice. Adoptive transfer of Thy1.1 memory CD8(+) T cells into naive Thy1.2 C57BL/6 mice was followed by booster vaccinations with a recombinant fowlpox (rF-)-expressing LacZ (rF-LacZ) or booster vaccinations with rF-LacZ/TRICOM. Analysis of levels of beta-galactosidase tetramer-positive T cells and functional assays IFN-gamma expression and lytic activity) determined that booster vaccinations with rF-LacZ/TRICOM were superior to booster vaccinations with rF-LacZ in terms of both maintenance and enhanced avidity of memory CD8(+) T cells. Antitumor experiments using a self-Ag (carcinoembryonic Ag (CEA) vaccines in CEA transgenic mice bearing CEA-expressing tumors) also demonstrated that the use of booster vaccinations with vaccines bearing enhanced costimulatory capacity had superior antitumor effects. These studies thus have implications in the design of more effective vaccine strategies. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC010426-06] NR 52 TC 37 Z9 38 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2005 VL 175 IS 6 BP 3715 EP 3723 PG 9 WC Immunology SC Immunology GA 966HN UT WOS:000232010800035 PM 16148117 ER PT J AU Voyich, JA Braughton, KR Sturdevant, DE Whitney, AR Said-Salim, B Porcella, SF Long, RD Dorward, DW Gardner, DJ Kreiswirth, BN Musser, JM DeLeo, FR AF Voyich, JA Braughton, KR Sturdevant, DE Whitney, AR Said-Salim, B Porcella, SF Long, RD Dorward, DW Gardner, DJ Kreiswirth, BN Musser, JM DeLeo, FR TI Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; PANTON-VALENTINE LEUKOCIDIN; APOPTOSIS-DIFFERENTIATION PROGRAM; GROUP-A STREPTOCOCCUS; VIRULENCE DETERMINANTS; CHRONIC NEUTROPENIA; GENE-EXPRESSION; RURAL WISCONSIN; INFECTION; STRAINS AB Polymorphonuclear leukocytes (PMNs, or neutrophils) are critical for human innate immunity and kill most invading bacteria. However, pathogens such as Staphylococcus aureus avoid destruction by PMNs to survive, thereby causing human infections. The molecular mechanisms used by pathogens to circumvent killing by the immune system remain largely undefined. To that end, we studied S. aureus pathogenesis and bacteria-PMN interactions using strains originally isolated from individuals with community-acquired (CA) and hospital-acquired infections. Compared with strains from hospital infections (COL and MRSA252), strain MW2 and a methicillin-susceptible relative, MnCop, were significantly more virulent in a mouse model of S. aureus infection, and caused the greatest level of pathology in major vital organs. Although phagocytosis of each strain triggered production of reactive oxygen species and granule-phagosome fusion, those from CA infections were significantly more resistant to killing by human PMNs and caused greater host cell lysis. Microarray analysis of the strains during neutrophil phagocytosis identified genes comprising a global S. aureus response to human innate host defense. Genes involved in capsule synthesis, gene regulation, oxidative stress, and virulence, were up-regulated following ingestion of the pathogen. Notably, phagocytosis of strains from CA infections induced changes in gene expression not observed in the other strains, including up-regulation of genes encoding virulence factors and hypothetical proteins. Our studies reveal a gene transcription program in a prominent human pathogen that likely contributes to evasion of innate host defense. C1 NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, Natl Inst Hlth, Hamilton, MT 59840 USA. NIAID, Rocky Mt Lab, Rocky Mt Vet Branch, Natl Inst Hlth, Hamilton, MT 59840 USA. NIAID, Rocky Mt Lab, Rocky Mt Microscopy Branch, Natl Inst Hlth, Hamilton, MT 59840 USA. Int Ctr Publ Hlth, Publ Hlth Res Inst TB Ctr, Newark, NJ 07103 USA. Baylor Univ, Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis Res, Houston, TX USA. RP DeLeo, FR (reprint author), NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, Natl Inst Hlth, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural NIH HHS NR 56 TC 306 Z9 318 U1 4 U2 39 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2005 VL 175 IS 6 BP 3907 EP 3919 PG 13 WC Immunology SC Immunology GA 966HN UT WOS:000232010800055 PM 16148137 ER PT J AU Dabdoub, A Kelley, MW AF Dabdoub, A Kelley, MW TI Planar cell polarity and a potential role for a Wnt morphogen gradient in stereociliary bundle orientation in the mammalian inner ear SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE planar cell polarity; Wnt signaling; cochlea; organ of corti ID HEPARAN-SULFATE PROTEOGLYCANS; NEURAL-TUBE DEFECTS; GUINEA-PIG COCHLEA; HAIR-CELLS; TISSUE POLARITY; GOLDEN-HAMSTERS; CHICK COCHLEA; LOOP-TAIL; DROSOPHILA; PROTEIN AB The planar cell polarity (PCP) pathway, a noncanonical Wnt signaling pathway, is crucial for embryonic development in all animals as it is responsible for the regulation of coordinated orientation of structures within the plane of the various epithelia. In the mammalian cochlea, one of the best examples of planar polarity in vertebrates, stereociliary bundles located on mechanosensory hair cells within the sensory epithelium are all uniformly polarized. Generation of this polarity is important for hair cell mechanotransduction and auditory perception as stereociliary bundles are only sensitive to vibrations in their single plane of polarization. We describe the two step developmental process that results in the generation of planar polarity in the mammalian inner ear. Furthermore, we review evidence for the role of Wnt signaling, and the possible generation of a Wnt gradient, in planar polarity. (c) 2005 Wiley Periodicals, Inc. C1 Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Dabdoub, A (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM dabdouba@nidcd.nih.gov NR 82 TC 58 Z9 61 U1 1 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD SEP 15 PY 2005 VL 64 IS 4 BP 446 EP 457 DI 10.1002/neu.20171 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 953JQ UT WOS:000231072900011 PM 16041762 ER PT J AU Sinha, G Leys, J Glorieux, C Thoen, J AF Sinha, G Leys, J Glorieux, C Thoen, J TI Broadband dielectric study of liquid crystal 4-n-decyl-4 '-cyanobiphenyl (10CB) dispersed with hydrophilic aerosil particles SO JOURNAL OF NON-CRYSTALLINE SOLIDS LA English DT Article; Proceedings Paper CT 3rd International Conference on Broadband Dielectric Spectroscopy and its Applications CY AUG 23-26, 2004 CL Delft, NETHERLANDS SP Delft Univ Technol, KNAW, Fdn Fundamental Res Matter, Novocontrol GmbH, DSM ID PHASE-TRANSITIONS; GLASS-TRANSITION; DYNAMICS; AEROGEL AB Real (epsilon') and imaginary (epsilon") parts of the complex dielectric permittivity (epsilon*) of the liquid crystal 4-n-decyl-4'-cyanobiphenyl (10CB) dispersed with hydrophilic aerosils, were studied by means of broadband dielectric spectroscopy. In bulk 10CB, which has a direct transition from isotropic to a smectic-A phase, there exists one relaxation process for the parallel orientation of the director to the probing field and another fast relaxation process in the perpendicular orientation. All molecular relaxation processes in 10CB have an Arrhenius-like temperature dependence. The aerosil particles in the LC-aerosil system attach to each other via hydrogen bonding and form a three-dimensional interconnecting aerosil network, thus dividing the LC phase into small domains. IOCB dispersed with different concentrations of hydrophilic aerosils lead to the emergence of a slow relaxation process that was stronger for higher concentration of aerosils. The slow process in the LC-hydrophilic aerosil system is attributed to the relaxation of the molecules that are homeotropically aligned close to the surfaces of the aerosil particles. The temperature dependence of the relaxation times of this process is quite weak. (c) 2005 Elsevier B.V. All rights reserved. C1 Katholieke Univ Leuven, Dept Natuurkunde & Sterrenkunde, Lab Akoest & Therm Fys, B-3001 Heverlee, Belgium. RP Sinha, G (reprint author), Natl Inst Deafness & Other Commun Disorders, Biophys Sect, NIH, NIH Bldg 50,Room 4151, Bethesda, MD 20892 USA. EM sinhag@nidcd.nih.gov NR 30 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-3093 J9 J NON-CRYST SOLIDS JI J. Non-Cryst. Solids PD SEP 15 PY 2005 VL 351 IS 33-36 BP 2780 EP 2785 DI 10.1016/j.jnoncrysol.2004.10.008 PG 6 WC Materials Science, Ceramics; Materials Science, Multidisciplinary SC Materials Science GA 966AZ UT WOS:000231993300032 ER PT J AU Arora, G Klauda, JB Sandler, SI AF Arora, G Klauda, JB Sandler, SI TI A comparative study of nitrogen physisorption on different C-70 crystal structures using an ab initio based potential SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SOLID C70; INTERMOLECULAR POTENTIALS; MOLECULAR SIMULATION; QUANTUM-MECHANICS; N-2 ADSORPTION; C-60; FULLERENE; GRAPHITE; SURFACE; CARBON AB Quantum mechanical calculations are performed using the recently developed hybrid method for interaction energies to determine atom site Lennard-Jones potential parameters for the interactions of molecular nitrogen with C-70 molecules. This ab initio based potential is used in grand canonical Monte Carlo simulations to predict surface adsorption properties of N-2 on five known C-70 structures: rhombohedral, fee, ideal hcp, deformed hcp, and monoclinic crystals. Because of the presence of five-membered carbon rings and the surface curvature of C-70 molecule, the Lennard-Jones potential parameters for nitrogen-carbon interactions obtained from ab initio based calculations are found to be different from that with planar graphite. The simulation results obtained from these two sets of force fields are compared and shown to differ, particularly at low coverage, where the nitrogen-carbon interactions are more important than the nitrogen-nitrogen interactions. The surface area, monolayer capacity, and isosteric heat of adsorption are calculated for various C-70 crystals and found to change appreciably as a result of the shear-induced phase transformation from hcp to rhombohedral lattice. C1 Univ Delaware, Dept Chem Engn, Ctr Mol & Engn Thermodynam, Newark, DE 19716 USA. NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Sandler, SI (reprint author), Univ Delaware, Dept Chem Engn, Ctr Mol & Engn Thermodynam, Newark, DE 19716 USA. EM sandler@che.udel.edu RI Klauda, Jeffery/A-4345-2008; Sandler, Stanley/A-8866-2009 NR 41 TC 4 Z9 4 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD SEP 15 PY 2005 VL 109 IS 36 BP 17267 EP 17273 DI 10.1021/jp050590t PG 7 WC Chemistry, Physical SC Chemistry GA 963MV UT WOS:000231809300037 PM 16853204 ER PT J AU Myllykangas, L Wavrant-De Vrieze, F Polvikoski, T Notkola, IL Sulkava, R Niinisto, L Edland, SD Arepalli, S Adighibe, O Compton, D Hardy, J Haltia, M Tienari, PJ AF Myllykangas, L Wavrant-De Vrieze, F Polvikoski, T Notkola, IL Sulkava, R Niinisto, L Edland, SD Arepalli, S Adighibe, O Compton, D Hardy, J Haltia, M Tienari, PJ TI Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: A two-stage study SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Alzheimer; BACE2; secretase; chromosome 21; amyloid; neuropathology ID AMYLOID PRECURSOR PROTEIN; EXPECTATION-MAXIMIZATION ALGORITHM; LINKAGE DISEQUILIBRIUM; BETA-SITE; GENOME SCREEN; LOCUS; APOE; EXPRESSION; DEMENTIA; GENES AB Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n = 515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n = 264) of these subjects. AD patients (n = 100) and controls (n = 48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p = 0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p = 0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p = 0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p = 0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Helsinki, Biomedicum, Program Neurosci, FI-00290 Helsinki, Finland. Univ Helsinki, Dept Pathol, Helsinki, Finland. Univ Helsinki, Cent Hosp, Helsinki, Finland. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Newcastle Upon Tyne, Dept Neuropathol, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Newcastle Upon Tyne, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Univ Kuopio, Dept Publ Hlth & Gen Practice & Med, Div Geriatr, FIN-70211 Kuopio, Finland. Katriina Geriatr Hosp, Vantaa, Finland. Mayo Clin Rochester, Rochester, MN USA. Cent Mil Hosp, Helsinki, Finland. Biomedicum, Dept Neurol, Helsinki, Finland. RP Tienari, PJ (reprint author), Univ Helsinki, Biomedicum, Program Neurosci, POB 700, FI-00290 Helsinki, Finland. EM pentti.tienari@hus.fi RI Tienari, Pentti/A-4893-2012; Hardy, John/C-2451-2009 FU NIA NIH HHS [U24 AG021886] NR 37 TC 14 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD SEP 15 PY 2005 VL 236 IS 1-2 BP 17 EP 24 DI 10.1016/j.jns.2005.04.008 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 965DI UT WOS:000231929900004 PM 16023140 ER PT J AU Jiang, H Tang, BS Xia, K Zhou, YX Xu, B Zhao, GH Li, HY Shen, L Pan, Q Cai, F AF Jiang, H Tang, BS Xia, K Zhou, YX Xu, B Zhao, GH Li, HY Shen, L Pan, Q Cai, F TI Spinocerebellar ataxia type 6 in Mainland China: Molecular and clinical features in four families SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE spinocerebellar ataxia; SCA6; CACNLIA4; allele; trinucleotide repeat; anticipation ID DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; MACHADO-JOSEPH DISEASE; CAG REPEAT LENGTH; TRINUCLEOTIDE REPEAT; CEREBELLAR ATAXIAS; EXPANSION; GENE; SCA6; DRPLA; FREQUENCY AB The hereditary spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The genes causing 11 of these diseases have been identified. To date, there is no report of SCA type 6 (SCA6) in Mainland Chinese. Using a molecular approach, we investigated SCA6 as well as other SCA subtype in 120 Mainland Chinese families with dominantly inherited ataxias and in 60 Mainland Chinese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 13 patients from 4 families. We found that SCA3/MJD was the most common type of autosomal dominant SCA in Mainland Chinese, accounting for 83 patients from 59 families (49.2%), followed by SCA2 (8 [6.7%]), SCA1 (7 [5.8%]), SCA6 (4 [3.3%]), SCA7 (1 [0.8%]), SCA8 (0%), SCA10 (0%), SCA12 (1 [0.8%]), SCA14 (0%), SCA17 (0%) and DRPLA (0%). The genes responsible for 40 (33.3%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) were found to harbor SCA3 mutations, whereas none were found to harbor SCA6 mutations. In the 4 families with SCA6, we found significant anticipation in the absence of genetic instability on transmission. This is the first report of geographic cluster of families with SCA6 subtype in Mainland China. (c) 2005 Elsevier B.V. All rights reserved. C1 Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China. Natl Lab Med Genet China, Changsha 410008, Hunan, Peoples R China. NIH, Clin Neurogenet Unit, Med Neurol Branch, Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Tang, BS (reprint author), Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China. EM bstang7398@yahoo.com.cn NR 34 TC 16 Z9 23 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD SEP 15 PY 2005 VL 236 IS 1-2 BP 25 EP 29 DI 10.1016/j.ins.2005.04.009 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 965DI UT WOS:000231929900005 PM 15979648 ER PT J AU Prybylowski, K Chang, K Sans, N Kan, LL Vicini, S Wenthold, RJ AF Prybylowski, K Chang, K Sans, N Kan, LL Vicini, S Wenthold, RJ TI The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2 SO NEURON LA English DT Article ID D-ASPARTATE RECEPTOR; LONG-TERM POTENTIATION; MEDIATED TYROSINE PHOSPHORYLATION; NR2B SUBUNIT; POSTSYNAPTIC MEMBRANE; HIPPOCAMPAL SYNAPSES; GLUTAMATE RECEPTORS; SURFACE EXPRESSION; CORTICAL-NEURONS; TRAFFICKING AB The NMDA receptor (NMDAR) is a component of excitatory synapses and a key participant in synaptic plasticity. We investigated the role of two domains in the C terminus of the NR2B subunit-the PDZ binding domain and the clathrin adaptor protein (AP-2) binding motif-in the synaptic localization of NMDA receptors. NR2B subunits lacking functional PDZ binding are excluded from the synapse. Mutations in the AP-2 binding motif, YEKL, significantly increase the number of synaptic receptors and allow the synaptic localization of NR2B subunits lacking PDZ binding. Peptides corresponding to YEKL increase the synaptic response within minutes. In contrast, the NR2A subunit localizes to the synapse in the absence of PDZ binding and is not altered by mutations in its motif corresponding to YEKL of NR2B. This study identifies a dynamic regulation of synaptic NR2B-containing NMDARs through PDZ protein-mediated stabilization and AP-2-mediated internalization that is modulated by phosphorylation by Fyn kinase. C1 Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA. RP Prybylowski, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Room 4148 Bldg 50, Bethesda, MD 20892 USA. EM prybylow@nidcd.nih.gov FU NIDCD NIH HHS [Z01 DC000003-17]; NINDS NIH HHS [R01 NS047700, R01 NS047700-06] NR 61 TC 211 Z9 219 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 15 PY 2005 VL 47 IS 6 BP 845 EP 857 DI 10.1016/j.neuron.2005.08.016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 967IN UT WOS:000232085000012 PM 16157279 ER PT J AU Borg, BB Hoofnagle, JH AF Borg, BB Hoofnagle, JH TI Peginterferon alfa-2b and ribavirin for 12 versus 24 weeks in HCV infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CHRONIC HEPATITIS-C C1 NIDDKD, Bethesda, MD 20892 USA. RP Borg, BB (reprint author), NIDDKD, Bethesda, MD 20892 USA. NR 6 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 15 PY 2005 VL 353 IS 11 BP 1182 EP 1183 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 963YG UT WOS:000231841900021 PM 16162894 ER PT J AU Eiden, LE AF Eiden, LE TI PACAP signaling to target genes across central and peripheral synapses SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 NIMH, Mol Neurosci Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 141 EP 141 PG 1 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400011 ER PT J AU Grumolato, L Ghzili, H Montero-Hadjadje, M Lesage, J Galas, L Ait-Ali, D Elkahloun, AG Fournier, A Vieau, D Vaudry, H Anouar, Y AF Grumolato, L Ghzili, H Montero-Hadjadje, M Lesage, J Galas, L Ait-Ali, D Elkahloun, AG Fournier, A Vieau, D Vaudry, H Anouar, Y TI Selenoprotein T is a PACAP- and cAMP-responsive gene that localizes to the endoplasmic reticulum and regulates intracellular calcium during PC12 cell differentiation SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 Univ Rouen, Europ Inst Pept Res IFRMP 23, Lab Cell Mol Neuroendocrinol, INSERM,U413, Mont St Aignan, France. Univ Lille 1, Lab Dev Neuroendocrinol, UPRES EA 2701, F-59655 Villeneuve Dascq, France. NHGRI, NIH, Bethesda, MD 20892 USA. Inst Armand Frappier, INRS, Pointe Claire, PQ, Canada. RI galas, ludovic/A-2500-2014 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 146 EP 146 PG 1 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400021 ER PT J AU Moody, T Mantey, S Pradhan, T Coy, D Jensen, R AF Moody, T Mantey, S Pradhan, T Coy, D Jensen, R TI (Ala(2,8,9,19,24,25,27)Nle(17),Lys(28))VIP-camptothecin, a selective VIP-chemotherapeutic conjugate for cells containing VPAC(1) receptors SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 NCI, DHHS, Off Director, CCR, Bethesda, MD 20892 USA. NIDDK, Digest Dis Branch, Bethesda, MD 20892 USA. Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 149 EP 149 PG 1 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400033 ER PT J AU Gerdin, MJ Ravni, A Vaudry, D Eiden, LE AF Gerdin, MJ Ravni, A Vaudry, D Eiden, LE TI PACAP-mediated signaling through canonical and noncanonical cAMP-dependent pathways SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 NIMH, Mol Neurosci Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 162 EP 162 PG 1 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400073 ER PT J AU Ghzili, H Grumolato, L Elkahloun, AG Fournier, A Vaudry, H Anouar, Y AF Ghzili, H Grumolato, L Elkahloun, AG Fournier, A Vaudry, H Anouar, Y TI Implication of the transcriptional regulator Id3 in PACAP-induced pro-survival signaling during PC12 cell differentiation SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 Univ Rouen, INSERM,U413, Europ Inst Pept Res IFRMP 23, Lab Cell Mol Neuroendocrinol, Mont St Aignan, France. NHGRI, NIH, Bethesda, MD 20892 USA. Inst Armand Frappier, INRS, Pointe Claire, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 162 EP 163 PG 2 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400074 ER PT J AU Mustafa, T Eiden, LE AF Mustafa, T Eiden, LE TI Identification of the PACAP receptor in chromaffin cells mediating calcium influx SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 172 EP 172 PG 1 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400110 ER PT J AU Ravni, A Leuillet, S Chen, Y Fournier, A Vaudry, H Gonzalez, BJ Eiden, LE Vaudry, D AF Ravni, A Leuillet, S Chen, Y Fournier, A Vaudry, H Gonzalez, BJ Eiden, LE Vaudry, D TI EGR1 controls the effect of PACAP on neurite outgrowth in PC12 cells SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 Univ Rouen, INSERM,U413, Lab Neuroendocrinol Cell & Mol, IFRMP23, F-76821 Mont St Aignan, France. NIMH, SMN, Lab Cell & Mol Reg, Bethesda, MD 20892 USA. INRS, Inst Armand Frappier, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 174 EP 175 PG 2 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400120 ER PT J AU Ait-Ali, D Turquier, V Grumolato, L Yon, L Mounien, L Jegou, S Derambure, C Salier, JP Eiden, LE Vaudry, H Anouar, Y AF Ait-Ali, D Turquier, V Grumolato, L Yon, L Mounien, L Jegou, S Derambure, C Salier, JP Eiden, LE Vaudry, H Anouar, Y TI Characterization of the transduction mechanisms involved in the stimulatory effect of the proinflammatory cytokine TNF-alpha on VIP, secretogranin II and galanin gene expression in adrenochromaffin cells: A suppression subtractive hybridization study SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 Univ Rouen, INSERM,U413, Europ Inst Pept Res IFRMP 23, Lab Cell Mol Neuroendocrinol, Mont St Aignan, France. Fac Med Pharm, INSERM, U519, Europ Inst Pept Res IFRMP 23, Rouen, France. NIMH, Lab Cell Mol Regulat, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 183 EP 183 PG 1 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400139 ER PT J AU Eiden, LE Samal, B Mustafa, T Hamelink, C Gerdin, M AF Eiden, LE Samal, B Mustafa, T Hamelink, C Gerdin, M TI Neuropeptide signaling via specific and canonical pathways in diverse neuroendocrine cells SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RI Samal, Babru/C-5563-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 184 EP 184 PG 1 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400142 ER PT J AU Ghzili, H Grumolato, L Elkahloun, AG Fournier, A Vaudry, H Anouar, Y AF Ghzili, H Grumolato, L Elkahloun, AG Fournier, A Vaudry, H Anouar, Y TI Uncovering novel transduction pathways of PACAP through gene expression profiling of neuroendocrine cells SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 Univ Rouen, INSERM,U413, Europ Inst Pept Res IFRMP 23, Lab Cell Mol Neuroendocrinol, Mont St Aignan, France. NHGRI, NIH, Bethesda, MD 20892 USA. INRS, Inst Armand Frappier, Pointe Claire, PQ, Canada. OI grumolato, luca/0000-0001-8231-3032 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 184 EP 185 PG 2 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400144 ER PT J AU Ravni, A Vaudry, D Leuillet, S Chen, Y Fournier, A Vaudry, H Gonzalez, BJ Eiden, LE AF Ravni, A Vaudry, D Leuillet, S Chen, Y Fournier, A Vaudry, H Gonzalez, BJ Eiden, LE TI Cell signalling pathways involved in pacap-induced differentiation of PC12 cells: A transcriptome analysis SO REGULATORY PEPTIDES LA English DT Meeting Abstract CT 7th International Symposium on VIP, PACAP and Related Peptides CY SEP 11-14, 2005 CL Rouen, FRANCE SP Conseil Reg Haute-Normandie, Agglomerat Rouen, Inst Fed Rech Multidisciplinaires Peptides, Inst Natl Sante Rech Med, Municipal Rouen, Sci Act Haute-Normandie, Tech Chime-Biol Sante, Univ Paris 7, Univ Rouen C1 Univ Rouen, INSERM, U413, IFRMP 23, F-76821 Mont St Aignan, France. NIMH, Mol Neurosci Sect, Bethesda, MD 20892 USA. INRS, IAF, Pointe Claire, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 15 PY 2005 VL 130 IS 3 BP 187 EP 188 PG 2 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 959OL UT WOS:000231527400153 ER PT J AU Wong, AHC Lipska, BK Likhodi, O Boffa, E Weinberger, DR Kennedy, JL Van Tol, HHM AF Wong, AHC Lipska, BK Likhodi, O Boffa, E Weinberger, DR Kennedy, JL Van Tol, HHM TI Cortical gene expression in the neonatal ventral-hippocampal lesion rat model SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; genomics; microarray; ventral-hippocampal lesion; animal models; genetics; mRNA ID SCHIZOPHRENIA; DAMAGE; APOMORPHINE; PSYCHOSIS; AMPHETAMINE; STRESS; CORTEX; LOCUS AB Schizophrenia is a chronic, debilitating psychotic illness of unknown etiology that has been the subject of many genetic studies. We studied the neonatal ventral-hippocampal lesioned rat as an animal model of schizophrenia in order to identify novel candidate genes for schizophrenia. Temporal and frontal cortices were assessed using cDNA microarrays for differences in mRNA expression associated with the lesion, haloperidol treatment and in two rat strains with differential sensitivity to the behavioural effects of the lesion. Genes that had altered expression levels as a result of the lesion, that were normalized by haloperidol treatment, and that differed between rat strains were selected. The pattern of differential transcription was confirmed with quantitative PCR for all six candidate genes: large conductance calcium-activated potassium channel, subfamily M, beta member 1 (Kcnmb 1); doublecortex (dcx); adenylyl cyclase-associated protein 1 (CAP 1); adenosine monophosphate deaminase 2-isoform L (AMPD2); malic enzyme 3, NADP(+)-dependent, mitochondrial (Me3); and aspartylglucosaminidasc (AGA). None of these genes has been extensively studied in schizophrenia, and further work with post-mortem tissue and genetic studies are ongoing. (c) 2005 Elsevier B.V. All rights reserved. C1 Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada. Univ Toronto, Fac Med, Dept Psychiat, Toronto, ON M5S 1A1, Canada. Univ Toronto, Fac Med, Inst Med Sci, Toronto, ON M5S 1A1, Canada. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Univ Toronto, Fac Med, Dept Pharmacol, Toronto, ON, Canada. RP Wong, AHC (reprint author), Ctr Addict & Mental Hlth, Room 711,250 Coll St, Toronto, ON M5T 1R8, Canada. EM albert.wong@utoronto.ca OI Wong, Albert/0000-0002-9753-3182 NR 26 TC 21 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 15 PY 2005 VL 77 IS 2-3 BP 261 EP 270 DI 10.1016/j.schres.2005.03.011 PG 10 WC Psychiatry SC Psychiatry GA 962RE UT WOS:000231749100014 PM 15890497 ER PT J AU Gochman, PA Greenstein, D Sporn, A Gogtay, N Keller, B Shaw, P Rapoport, JL AF Gochman, PA Greenstein, D Sporn, A Gogtay, N Keller, B Shaw, P Rapoport, JL TI IQ stabilization in childhood-onset schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE childhood-onset; schizophrenia; intelligence; IQ ID COGNITIVE FUNCTION; CLOZAPINE; DEFICITS; DECLINE; COHORT; RISK AB Objective: To examine the long term IQ trajectory for childhood-onset schizophrenia (COS) in an expanded, prospective longitudinal study. Methods: Seventy children meeting DSM criteria for schizophrenia were tested at 2 year intervals with age appropriate Wechsler intelligence tests and repeated administration of information and comprehension WISC subtests even after age 18. For a subgroup with 31 patients, pre-NIH IQ test administrations were available including 18 pre-psychotic and 13 post-psychotic subjects. The pattern of IQ performance over time was determined using mixed model regression analysis. Results: No progressive cognitive decline was seen up to 13+ years post psychosis onset. For the subgroup of subjects with pre-illness scores, there had been an initial steep decline in IQ, from about 2 years prior to 1.7 years after onset of psychotic symptoms, as reported for adult patients. Conclusions: The level long-term trajectory of IQ measures in COS appears stable, similar to that reported for adult onset patients. For COS, level cognitive functioning extends up to 13+ years post psychosis onset, in spite of chronic illness and concomitant, progressive loss of cortical gray matter. (c) 2005 Elsevier B.V. All rights reserved. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Gochman, PA (reprint author), NIMH, Child Psychiat Branch, Bldg 10,3N202, Bethesda, MD 20892 USA. EM peterg@codon.nih.gov RI Shaw, Philip/A-1129-2008; Gogtay, Nitin/A-3035-2008 NR 39 TC 30 Z9 34 U1 4 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 15 PY 2005 VL 77 IS 2-3 BP 271 EP 277 DI 10.1016/j.schres.2005.04.002 PG 7 WC Psychiatry SC Psychiatry GA 962RE UT WOS:000231749100015 PM 15913958 ER PT J AU Graubard, BI Rao, RS Gastwirth, JL AF Graubard, BI Rao, RS Gastwirth, JL TI Using the Peters-Belson method to measure health care disparities from complex survey data SO STATISTICS IN MEDICINE LA English DT Article DE survey methods; Taylor linearization variance; delete-one-group jackknife variance; logistic regression; multiple linear regression AB The Peters-Belson (PB) method uses regression to assess wage discrimination and can also be used to analyse disparities for a variety of health care issues, e.g. cancer screening. The PB method estimates the proportion of an overall disparity that is not explained by the covariates in the regression, e.g. education, which may be due to discrimination. This method first fits a regression model with individual-level covariates to the majority/advantaged group and then uses the fitted model to estimate the expected values for minority-group members had they been members of the majority group. The data on disparities in health care available to biomedical researchers differ from data used in legal cases as it is often obtained from large-scale studies or surveys with complex sample designs involving stratified multi-stage cluster sampling. Sample surveys with a large representative sample of various racial/ethnic groups and the extensive collection of important social-demographic variables provide excellent sources of data for assessing disparity for a wide range of health behaviours. We extend the PB method for multiple logistic and linear regressions of simple random samples to weighted data from complex designed survey samples. Because of the weighting and complex sample designs, we show how to apply the Taylor linearization method and delete-one-group jackknife methods to obtain estimates of standard errors for the estimated disparity. Data from the 1998 National Health Interview Survey on racial differences in cancer screening among women is used to illustrate the PB method. Published in 2005 by John Wiley & Sons, Ltd. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. ABT Associates Inc, Cambridge, MA 02138 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Graubard, BI (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Execut Plaza S,Room 8024,6120 Execut Blvd,MSC 724, Bethesda, MD 20892 USA. EM graubarb@mail.nih.gov; sowmya-rao@abtassoc.com; jlgast@gwu.edu NR 28 TC 19 Z9 19 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 15 PY 2005 VL 24 IS 17 BP 2659 EP 2668 DI 10.1002/sim.2135 PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 963PS UT WOS:000231816900007 PM 16118808 ER PT J AU Petersen, SL Sidorov, IA Russell, CA Dickmeiss, E Vindelov, LL AF Petersen, SL Sidorov, IA Russell, CA Dickmeiss, E Vindelov, LL TI Limiting dilution analysis of interleukin-2 producing helper T-cell frequencies as a tool in allogeneic hematopoietic cell transplantation SO TRANSPLANTATION LA English DT Article DE graft-versus-host disease; limiting dilution analysis; hematopoietic cell transplantation; nonmyeloablative conditioning regimen; regulatory cells ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; HLA-IDENTICAL SIBLINGS; PRECURSOR FREQUENCY; PREDICTIVE VALUE; IN-VITRO; BLOOD; OPTIMIZATION; MALIGNANCIES; ELIMINATION AB Background. A reliable in vitro test that estimates the level of ongoing alloreactivity would be valuable in allogeneic hematopoietic cell transplantation (HCT) as a help to guide clinical interventions such as donor lymphocyte infusions and changes in the immunosuppression. In the present study, the use of limiting dilution analysis of interleukin-2 (IL-2) producing helper T lymphocyte frequencies (HTL assay) as a way to quantify alloreactivity following HCT was investigated. Methods. Serial HTL assays were performed following allogeneic HCT with myeloablative or nonmyelablative conditioning in 26 patients with hematologic malignancies. Results. Deviations from single-hit kinetics were frequently observed in the HTL assays and a nonlinear model was therefore used for analysis. The results of this analysis suggested the presence of an inhibitory cell population. Inhibition was observed in the majority of patients and was not restricted to a specific transplant regimen. Inhibition occurred more often with high frequencies of IL-2 producing cells, indicating a physiological role of the putative inhibitory cell population in the regulation of an immune response. Higher frequencies of IL-2 producing cells were observed in patients with acute graft-versus-host disease grades II-IV than in patients with grades 0-1 (P = 0.046), indicating that the degree of ongoing alloreactivity is indeed quantified by the HTL assay. Conclusions. We find that the HTL assay may yield interesting insight into regulation of immune responses following allogeneic HCT, but because of the complexity of the results obtained, its use as a routine procedure to guide immunosuppression cannot be recommended. C1 Rigshosp, Lymphocyte Res Lab, Dept Hematol, DK-2100 Copenhagen, Denmark. NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. Rigshosp, Dept Clin Immunol, DK-2100 Copenhagen, Denmark. RP Petersen, SL (reprint author), Rigshosp, Lymphocyte Res Lab, Dept Hematol, L 4041,Blegdamsvej 9, DK-2100 Copenhagen, Denmark. EM slykkep@rh.dk OI Sidorov, Igor/0000-0001-6519-4983 NR 42 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 15 PY 2005 VL 80 IS 5 BP 573 EP 581 DI 10.1097/01.tp.0000173390.31035.10 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 967YM UT WOS:000232127200005 PM 16177628 ER PT J AU Goud, GN Bottazzi, ME Zhan, B Mendez, S Deumic, V Plieskatt, J Liu, S Wang, Y Bueno, L Fujiwara, R Samuel, A Ahn, SY Solanki, M Asojo, OA Wang, J Bethony, JM Loukas, A Roy, M Hotez, PJ AF Goud, GN Bottazzi, ME Zhan, B Mendez, S Deumic, V Plieskatt, J Liu, S Wang, Y Bueno, L Fujiwara, R Samuel, A Ahn, SY Solanki, M Asojo, OA Wang, J Bethony, JM Loukas, A Roy, M Hotez, PJ TI Expression of the Necator americanus hookworm larval antigen Na-ASP-2 in Pichia pastoris and purification of the recombinant protein for use in human clinical trials SO VACCINE LA English DT Article DE hookworm; vaccine; Necator americanus; Na-ASP-2 ID ANCYLOSTOMA-SECRETED PROTEIN; TRANSMITTED HELMINTH INFECTIONS; VACCINE; CLONING; MEBENDAZOLE; CEYLANICUM; CANINUM; DISEASE; FAMILY; ASP-2 AB The ASP-2 protein secreted by infective larvae of the human hookworm, Necator americanus, is under development as a recombinant vaccine. Recombinant Na-ASP-2 was expressed in Pichia pastoris, and the purified protein was characterized. At the 60 L scale, the 21.3 kDa recombinant protein was produced at a yield of 0.4 g/L. When formulated with Alhydrogel (R) and injected into rats to determine immunological potency, three 50 mu g doses of the formulated recombinant protein elicited geometric mean antibody titers up to 1:234,881. Rat anti-Na-ASP-2 antibody recognized larval-derived ASP-2 and also inhibited larval migration through skin in vitro. The processes developed and tested for the high yield production of recombinant Na-ASP-2 provide a foundation for clinical vaccine development. (c) 2005 Elsevier Ltd. All rights reserved. C1 George Washington Univ, Med Ctr, Dept Microbiol & Trop Med, Washington, DC 20037 USA. NIAID, Malaria Vaccine Dev Branch, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Queensland Inst Med Res, Div Infect Dis & Immunol, Brisbane, Qld 4006, Australia. Sci Applicat Int Corp, Frederick, MD USA. RP Goud, GN (reprint author), George Washington Univ, Med Ctr, Dept Microbiol & Trop Med, Ross Hall 736,2300 Eye St NW, Washington, DC 20037 USA. EM mtmgng@gwumc.edu; mtmmeb@gwumc.edu; Photez@gwu.edu RI Loukas, Alex/B-7355-2014; Fujiwara, Ricardo/J-7579-2012; OI Loukas, Alex/0000-0002-0896-8441; Fujiwara, Ricardo/0000-0002-4713-575X; Hotez, Peter/0000-0001-8770-1042; Asojo, Oluwatoyin/0000-0002-4043-2700 FU FIC NIH HHS [1K01 TW00009] NR 30 TC 59 Z9 60 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 15 PY 2005 VL 23 IS 39 BP 4754 EP 4764 DI 10.1016/j.vaccine.2005.04.040 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 963GL UT WOS:000231791900005 PM 16054275 ER PT J AU Nolan, SM Surman, SR Amaro-Carambot, E Collins, PL Murphy, BR Skiadopoulos, MH AF Nolan, SM Surman, SR Amaro-Carambot, E Collins, PL Murphy, BR Skiadopoulos, MH TI Live-attenuated intranasal parainfluenza virus type 2 vaccine candidates developed by reverse genetics containing L polymerase protein mutations imported from heterologous paramyxoviruses SO VACCINE LA English DT Article DE parainfluenza virus; paramyxovirus; L polymerase ID RESPIRATORY SYNCYTIAL VIRUS; AMINO-ACID SUBSTITUTIONS; SENDAI-VIRUS; INFLUENZA-A; TEMPERATURE SENSITIVITY; RHESUS-MONKEYS; GENOME LENGTH; V-PROTEINS; IN-VIVO; RECOMBINANT AB Live-attenuated recombinant human parainfluenza virus type 2 (rHPIV2) vaccine candidates were created using reverse genetics by importing known attenuating mutations in the L polymerase protein from heterologous paramyxoviruses into the homologous sites of the HPIV2 L protein. Four recombinants (rF460L, rY948H, rL1566I, and rS1724I) were recovered and three were attenuated for replication in hamsters. The genetic stability of the imported mutations at three of the four sites was enhanced by use of alternative codons or by deletion of a pair of amino acids. rHPIV2s bearing these modified mutations exhibited enhanced attenuation. The genetically stabilized mutations conferring a high level of attenuation will be useful in generating a live-attenuated virus vaccine for HPIV2. Published by Elsevier Ltd. C1 NIAID, Infect Dis Lab, Resp Viruses Sect, NIH, Bethesda, MD 20892 USA. RP Nolan, SM (reprint author), NIAID, Infect Dis Lab, Resp Viruses Sect, NIH, 50 S Dr,Bldg 50,Room 6509,MSC 8007, Bethesda, MD 20892 USA. EM snotan@niaid.nih.gov NR 39 TC 19 Z9 20 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 15 PY 2005 VL 23 IS 39 BP 4765 EP 4774 DI 10.1016/j.vaccine.2005.04.043 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 963GL UT WOS:000231791900006 PM 15964103 ER PT J AU Park, GS Best, SM Bloom, ME AF Park, GS Best, SM Bloom, ME TI Two mink parvoviruses use different cellular receptors for entry into CRFK cells SO VIROLOGY LA English DT Article DE parvovirus; Aleutian mink disease; mink enteritis virus; transferrin receptor; RNAi ID ACUTE INTERSTITIAL PNEUMONIA; CANINE TRANSFERRIN RECEPTOR; ALEUTIAN DISEASE VIRUS; SHORT-INTERFERING RNAS; IN-VITRO; MEDIATED ENDOCYTOSIS; FELINE PARVOVIRUSES; MAMMALIAN-CELLS; GENE-EXPRESSION; ENTERITIS VIRUS AB Mink enteritis virus (MEV) and Aleutian mink disease parvovirus (ADV) are two mink parvoviruses that replicate permissively ill Crandell feline kidney (CRFK) cells. We have used this cell model to examine if these two mink parvoviruses use the same cellular receptor. Whereas the cellular receptor for MEV is expected to be the transferrin receptor (TfR), the cellular receptor for ADV has not been clearly identified. We used short hairpin RNAs (shRNAs) produced from plasmids to trigger RNA interference (RNAi), specifically and effectively reducing TfR expression in CRFK cells. TfR expression was reduced to levels undetectable by immunofluorescence in the majority of cells. In viral infection assays, we show that TfR expression was necessary for MEV infection but was not required for ADV infection. Thus, our results demonstrate that TfR is the cellular receptor for MEV, but not the cellular receptor for ADV The use of two different receptors by MEV and ADV to infect the same cell line is yet another difference between these two parvoviruses that may contribute to their unique pathogenesis in mink. Published by Elsevier Inc. C1 NIAID, Lab Persistant Viral Dis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Bloom, ME (reprint author), NIAID, Lab Persistant Viral Dis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM mbloom@niaid.nih.gov NR 46 TC 4 Z9 4 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2005 VL 340 IS 1 BP 1 EP 9 DI 10.1016/j.virol.2005.06.038 PG 9 WC Virology SC Virology GA 960ZJ UT WOS:000231631400001 PM 16040076 ER PT J AU Ellenberger, D Wyatt, L Li, B Buge, S Lanier, N Rodriguez, IV Sariol, CA Martinez, M Monsour, M Vogt, J Smith, J Otten, R Montefiori, D Kraiselburd, E Moss, B Robinson, H McNicholl, J Butera, S AF Ellenberger, D Wyatt, L Li, B Buge, S Lanier, N Rodriguez, IV Sariol, CA Martinez, M Monsour, M Vogt, J Smith, J Otten, R Montefiori, D Kraiselburd, E Moss, B Robinson, H McNicholl, J Butera, S TI Comparative immunogenicity in rhesus monkeys of multi-protein HIV-1 (CRF02_AG) DNA/MVA vaccines expressing mature and immxature VLPs SO VIROLOGY LA English DT Article DE immunogenicity; rhesus monkeys; CRF02_AG ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; ANKARA BOOST REGIMEN; DNA VACCINATION; GAG-POL; GENETIC IMMUNIZATION; VIRAL REPLICATION; IMMUNE-RESPONSES; CELL RESPONSES; MVA VACCINES AB We developed an AIDS vaccine for Western and West-Central Africa founded on HIV-1 subtype CRF02_AG. Rhesus macaques were primed with Gag-Pol-Env-expressing plasmid DNA and boosted with a recombinant modified vaccinia virus Ankara (rMVA), expressing matched proteins. Two DNA vaccine constructs (ICI-90 and IC48) that differed by point mutations in gag and pol were compared. ICI-90 produces primarily immature (core comprises unprocessed Pr55Gag) HIV-Iike particles (VLPs) and IC48 produces mature VLP with processed Pr55Gag, immature VLP, and intracellular protein aggregates. Both vaccines raised significant cellular responses for Gag, Pol, and Env. Approximate twofold higher ELISPOT responses to Gag and Env epitopes were observed for IC48 animals than for IC1-90 animals at the peak post-MVA effector (P = 0.028) and late memory (P = 0.051) phases, respectively. Greater breadth for IC48-primed animals was observed than for ICI-90-primed animals at peak response (P = 0.03). Our results indicated that the vaccines elicited high frequency T cell responses and primed anti-Env antibody. They also Suggest that expression of different forms of VLP has a significant effect on elicited cellular and Immoral immunity. Published by Elsevier Inc. C1 Ctr Dis Control & Prevent, Lab Branch, Atlanta, GA 30333 USA. US Dept Hlth & Human Serv, Stat & Data Management Branch, Div HIV AIDS Prevent,Natl Ctr HIV STD & TB Preven, Ctr Dis Control & Prevent,Publ Hlth Serv, Atlanta, GA 30333 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Caribbean Primate Res Ctr, Unit Comparat Med, San Juan, PR 00936 USA. Caribbean Primate Res Ctr, Dept Microbiol & Med Zool, San Juan, PR 00936 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30332 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Ellenberger, D (reprint author), Ctr Dis Control & Prevent, Lab Branch, Mail Stop G-19,1600 Clifton Rd NE, Atlanta, GA 30333 USA. EM dellenberger@cdc.gov FU NCRR NIH HHS [P40 RR03650] NR 47 TC 20 Z9 21 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 SEP 15 PY 2005 VL 340 IS 1 BP 21 EP 32 DI 10.1016/j.virol.2005.06.014 PG 12 WC Virology SC Virology GA 960ZJ UT WOS:000231631400003 PM 16023165 ER PT J AU Zahm, SH Fraumeni, JF AF Zahm, SH Fraumeni, JF TI Hair dye use and non-Hodgkin lymphoma SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID RISK C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Zahm, SH (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM zahms@mail.nih.gov NR 4 TC 2 Z9 2 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 14 PY 2005 VL 294 IS 10 BP 1205 EP 1205 DI 10.1001/jama.294.10.1205-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 963UI UT WOS:000231831200010 PM 16160127 ER PT J AU Lee, DS Tu, JV Juurlink, DN Alter, DA Ko, DT Austin, PC Chong, A Stukel, TA Levy, D Laupacis, A AF Lee, DS Tu, JV Juurlink, DN Alter, DA Ko, DT Austin, PC Chong, A Stukel, TA Levy, D Laupacis, A TI Risk-treatment mismatch in the pharmacotherapy of heart failure SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CONVERTING ENZYME-INHIBITORS; VENTRICULAR EJECTION FRACTIONS; ACUTE CORONARY SYNDROMES; QUALITY-OF-CARE; ELDERLY-PATIENTS; BETA-BLOCKERS; TASK-FORCE; UNSTABLE ANGINA; OLDER PATIENTS AB Context Patients with heart failure have a wide spectrum of mortality risks. To maximize the benefit of available pharmacotherapies, patients with high mortality risk should receive high rates of drug therapy. Objective To examine patterns of drug therapy and underlying mortality risk in patients with heart failure. Design, Setting, and Patients In the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) population-based cohort (1999-2001) of 9942 patients with heart failure hospitalized in Ontario, Canada, we evaluated 1418 patients with documented left ventricular ejection fraction of 40% or less and aged 79 years or younger with low-, average-, and high-predicted risk of death within 1 year; all patients survived to hospital discharge. Administration of angiotensin-converting enzyme (ACE) inhibitors, ACE inhibitors or angiotensin II receptor blockers (ARBs), and beta-adrenoreceptor antagonists was evaluated according to predicted risk of death. Main Outcome Measure Heart failure drug administration rates at time of discharge and 90 days after hospital discharge. Results At hospital discharge, prescription rates for patients in the low-, average-, and high-risk groups were 81%, 73%, 60%, respectively, for ACE inhibitors; 86%, 80%, 65%, respectively, for ACE inhibitors or ARBs; and 40%, 33%, 24%, respectively, for beta-adrenoreceptor antagonists (all P<.001 for trend). Within 90 days following hospital discharge, the rates were 83%, 76%, and 61% for ACE inhibitors; 89%, 83%, and 67% for ACE inhibitors or ARBs; and 43%, 36%, and 28% for beta-adrenoreceptor antagonists for the 3 risk groups, respectively (all P<.001 for trend). The pattern of lower rates of drug administration in those patients at increasing risk was maintained up to 1 year postdischarge (P<.001). After accounting for varying survival time and potential contraindications to therapy, low-risk patients were more likely to receive ACE inhibitors or ARBs (adjusted hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.49-1.74) and beta-adrenoreceptor antagonists (HR, 1.80; 95% CI, 1.60-2.01) compared with high-risk patients (both P<.001). Conclusions Patients with heart failure at greatest risk of death are least likely to receive ACE inhibitors, ACE inhibitors or ARBs, and beta-adrenoreceptor antagonists. Understanding the reasons underlying this mismatch may facilitate improvements in care and outcomes for patients with heart failure. C1 Univ Toronto, Inst Clin Evaluat Sci, Dept Hlth Policy Management & Evaluat, Toronto, ON M4N 3M5, Canada. Univ Toronto, Sunnybrook & Womens Coll, Hlth Sci Ctr, Toronto, ON, Canada. NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. RP Laupacis, A (reprint author), Univ Toronto, Inst Clin Evaluat Sci, Dept Hlth Policy Management & Evaluat, Room G-106,2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM alaupacis@ices.on.ca RI Lee, Douglas/J-4315-2014; OI Ko, Dennis/0000-0001-6840-8051; Tu, Jack/0000-0003-0111-722X; Austin, Peter/0000-0003-3337-233X NR 52 TC 130 Z9 134 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 14 PY 2005 VL 294 IS 10 BP 1240 EP 1247 DI 10.1001/jama.294.10.1240 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 963UI UT WOS:000231831200021 PM 16160132 ER PT J AU Weitlauf, C Honse, Y Auberson, YP Mishina, M Lovinger, DM Winder, DG AF Weitlauf, C Honse, Y Auberson, YP Mishina, M Lovinger, DM Winder, DG TI Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE glutamate; synaptic transmission; synaptic plasticity; NMDA receptor; ion channels; long-term potentiation ID D-ASPARTATE RECEPTORS; HIPPOCAMPAL SYNAPSES; SYNAPTIC PLASTICITY; EPSILON-1 SUBUNIT; MICE; ANTAGONISTS; CURRENTS; NR2A; LTP; AGE AB Activation of NMDA receptors (NMDARs) within the CNS represents a major signal for persistent alterations in glutamatergic signaling, such as long-term potentiation (LTP) and long-term depression. NMDARs are composed of a combination of NR1 and NR2 subunits, with distinct NR2 subunits imparting distinct characteristics on the receptor. One particular NR2 subunit, NR2A (NR epsilon 1), has been proposed to play an integral role in LTP induction in the hippocampus and cortex. Here, we report studies investigating the role of NR2A in LTP induction in the dorsolateral bed nucleus of the stria terminalis (dlBNST). The putative NR2A-specific inhibitor NVP-AAM077(AAM077) has been used previously to demonstrate the dependence of cortical and hippocampal LTP on NMDARs containing NR2A subunits. We report here the same sensitivity of LTP to pretreatment with AAM077 (0.4 mu m) in the dlBNST. However, inconsistent with the conclusion that LTP in the dlBNST is NR2A dependent, we see intact LTP in the dlBNST of NR2A knock-out mice. Because we also see blockade of this dlBNST LTP in NR2A knock-out mice after pretreatment with AAM077, we conclude that the antagonist is targeting non-NR2A subunit-containing receptors. Using a variety of cultured cell types, we find that AAM077 (0.4 mu m) can attenuate transmission of NR2B subunit-containing NMDARs when preapplied rather than coapplied with an agonist. Therefore, we conclude that NR2A is not obligatory for the induction of LTP in the dlBNST. Furthermore, our data demonstrate that care must be exercised in the interpretation of data generated with AAM077 when the compound is applied before an agonist. C1 Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Ctr Mol Neurosci, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, JF Kennedy Ctr Res Humna Dev, Nashville, TN 37232 USA. NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. Novartis Labs, CH-4002 Basel, Switzerland. Univ Tokyo, Tokyo 1130033, Japan. RP Winder, DG (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Room 724B,Roscoe Robinson Bldg,23rd & Pierce Ave, Nashville, TN 37232 USA. EM danny.winder@vanderbilt.edu RI Winder, Danny/H-4857-2013 FU Intramural NIH HHS; NIAAA NIH HHS [AA013641, AA08986, R01 AA019455] NR 16 TC 126 Z9 132 U1 0 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 14 PY 2005 VL 25 IS 37 BP 8386 EP 8390 DI 10.1523/JNEUROSCI.2388-05.2005 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 964OB UT WOS:000231889300006 PM 16162920 ER PT J AU Izquierdo, A Suda, RK Murray, EA AF Izquierdo, A Suda, RK Murray, EA TI Comparison of the effects of bilateral orbital prefrontal cortex lesions and amygdala lesions on emotional responses in rhesus monkeys SO JOURNAL OF NEUROSCIENCE LA English DT Article DE fear; response selection; decision making; aggression; inhibitory control; phobia ID ORBITOFRONTAL CORTEX; NEUROTOXIC LESIONS; NEURONAL-ACTIVITY; DECISION-MAKING; BASOLATERAL AMYGDALA; FRONTAL LESIONS; REWARD VALUE; MULATTA; MACACA; FEAR AB The present study examines the effects of bilateral orbital prefrontal cortex (PFo) lesions on monkeys' emotional responses in two different contexts: in the presence of a rubber snake and in the presence of a human intruder. For comparison, we also assessed the responses of rhesus monkeys with selective amygdala lesions on these same tasks. Monkeys with PFo lesions, like those with amygdala lesions, displayed blunted emotional responses to the fake snake. Unlike monkeys with amygdala lesions, however, monkeys with PFo lesions displayed more mild aggression than controls in the presence of a human intruder. The findings support the idea that the PFo helps integrate sensory signals in the service of choosing among competing responses. In addition, they point to a divergence of the roles of the PFo and amygdala in responding to a social stimulus, the human intruder. C1 NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Izquierdo, A (reprint author), NIAAA, Lab Integrated Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM izquiera@mail.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 FU Intramural NIH HHS NR 43 TC 100 Z9 103 U1 3 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 14 PY 2005 VL 25 IS 37 BP 8534 EP 8542 DI 10.1523/JNEUROSCI.1232-05.2005 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 964OB UT WOS:000231889300021 PM 16162935 ER PT J AU Zhou, Z Feng, HQ Zhou, HY Zhou, YQ Bai, YW AF Zhou, Z Feng, HQ Zhou, HY Zhou, YQ Bai, YW TI Design and folding of a multidomain protein SO BIOCHEMISTRY LA English DT Article ID SINGLE-DOMAIN PROTEINS; NONNATIVE HYDROPHOBIC INTERACTIONS; STATE HYDROGEN-EXCHANGE; 2-STATE PROTEINS; CONTACT ORDER; APOCYTOCHROME B(562); SECONDARY STRUCTURE; TRANSITION-STATE; RATE PREDICTION; B-DOMAIN AB To test whether the folding process of a large protein can be understood on the basis of the folding behavior of the domains that constitute it, we coupled two well-studied small a-helical proteins, the B-domain of protein A (60 amino acids) and Rd-apocytochrome b(562) (Rd-apocyt b(562), 106 amino acids), by fusing the C-terminal helix of the B-domain of protein A with the N-terminal helix of Rd-apocyt b(562) without changing their hydrophobic core residues. The success of the design was confirmed by determining the structure of the engineered protein with multidimensional NMR methods. Kinetic studies showed that the logarithms of the folding/unfolding rate constants of the engineered protein are linearly dependent on concentrations of guanidinium chloride in the measurable range from 1.7 to 4 M. Their slopes (m-values) are close to those of Rd-apocyt b(562). In addition, the H-1-N-15 HSQC spectrum taken at 1.5 M guanidinium chloride reveals that only the Rd-apocyt b(562) domain in the designed protein remained folded. These results suggest that the two domains have weak energetic coupling. Interestingly, the redesigned protein folds faster than Rd-apocyt b(562), suggesting that the fused helix stabilizes the rate-limiting transition state. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. SUNY Buffalo, Howard Hughes Med Inst, Ctr Single Mol Biophys, Dept Physiol & Biophys, Buffalo, NY 14214 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov RI Zhou, Yaoqi/B-3284-2009; Zhou, Hongyi/B-3339-2010 OI Zhou, Yaoqi/0000-0002-9958-5699; NR 48 TC 4 Z9 4 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 13 PY 2005 VL 44 IS 36 BP 12107 EP 12112 DI 10.1021/bi050785r PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 962ZG UT WOS:000231771500018 PM 16142908 ER PT J AU Helip-Wooley, A Westbroek, W Dorward, H Mommaas, M Boissy, RE Gahl, WA Huizing, M AF Helip-Wooley, A Westbroek, W Dorward, H Mommaas, M Boissy, RE Gahl, WA Huizing, M TI Association of the Hermansky-Pudlak syndrome type-3 protein with clathrin SO BMC CELL BIOLOGY LA English DT Article ID STORAGE-POOL DEFICIENCY; HUMAN MELANOCYTES; OCULOCUTANEOUS ALBINISM; HEMORRHAGIC DIATHESIS; AP-3 ADAPTER; COATED PITS; COMPLEX; GENE; BIOGENESIS; FORM AB Background: Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis characterized by oculocutaneous albinism and prolonged bleeding. These clinical findings reflect defects in the formation of melanosomes in melanocytes and dense bodies in platelets. HPS type-3 (HPS-3) results from mutations in the HPS3 gene, which encodes a 1004 amino acid protein of unknown function that contains a predicted clathrin-binding motif (LLDFE) at residues 172 - 176. Results: Clathrin was co-immunoprecipitated by HPS3 antibodies from normal but not HPS3 null melanocytes. Normal melanocytes expressing a GFP-HPS3 fusion protein demonstrated partial colocalization of GFP-HPS3 with clathrin following a 20 degrees C temperature block. GFP-HPS3 in which the predicted clathrin-binding domain of HPS3 was mutated (GFP-HPS3-delCBD) did not co-localize with clathrin under the same conditions. Immunoelectron microscopy of normal melanocytes expressing GFP-HPS3 showed co-localization of GFP-HPS3 with clathrin, predominantly on small vesicles in the perinuclear region. In contrast, GFP-HPS3-delCBD did not co-localize with clathrin and exhibited a largely cytoplasmic distribution. Conclusion: HPS3 associates with clathrin, predominantly on small clathrin- containing vesicles in the perinuclear region. This association most likely occurs directly via a functional clathrin- binding domain in HPS3. These results suggest a role for HPS3 and its protein complex, BLOC-2, in vesicle formation and trafficking. C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Leiden Univ, Med Ctr, Dept Mol Cell Biol, Leiden, Netherlands. Univ Cincinnati, Coll Med, Dept Dermatol, Cincinnati, OH 45221 USA. RP Huizing, M (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM ahwooley@mail.nih.gov; wwestbro@mail.nih.gov; hdorward@mail.nih.gov; a.m.mommaas-kienhuis@lumc.nl; boissyre@email.uc.edu; bgahl@helix.nih.gov; mhuizing@mail.nih.gov FU Intramural NIH HHS; NIAMS NIH HHS [R01 AR045429-04] NR 44 TC 11 Z9 12 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD SEP 13 PY 2005 VL 6 AR 33 DI 10.1186/1471-2121-6-33 PG 10 WC Cell Biology SC Cell Biology GA 973LE UT WOS:000232523300001 PM 16159387 ER PT J AU Paisan-Ruiz, C Lang, AE Kawarai, T Sato, C Salehi-Rad, S Fisman, GK Al-Khairallah, T George-Hyslop, S Singleton, A Rogaeva, E AF Paisan-Ruiz, C Lang, AE Kawarai, T Sato, C Salehi-Rad, S Fisman, GK Al-Khairallah, T George-Hyslop, S Singleton, A Rogaeva, E TI LRRK2 gene in Parkinson disease - Mutation analysis and case control association study SO NEUROLOGY LA English DT Article ID RECESSIVE JUVENILE PARKINSONISM; ONSET; FAMILIES AB Background: In addition to the four well-confirmed genes linked to early-onset Parkinson disease (PD) (SNCA, PARKIN, DJ-1, and PINK1), mutations in the leucine-rich repeat kinase 2 gene(LRRK2) have recently been identified in families with autosomal dominant late-onset PD. Objective: To perform mutation analysis of LRRK2 in probands of families showing dominant inheritance of PD and to conduct a case control association study to test the hypothesis that common coding variations might be associated with increased susceptibility to PD. Methods: All 51 LRRK2 coding exons were sequenced in 23 probands and the mutation frequencies were evaluated in 180 neurologically normal control subjects. For the association study the authors genotyped four coding LRRK2 polymorphisms in 250 normal control subjects and 121 patients with PD ( predominantly white patients of Canadian origin), 84% of whom had age at onset before 50 years and 42% had a positive family history. Results: The authors identified three probands with heterozygous LRRK2 mutations: two of them have the known G2019S substitution and one proband has a novel I1371V substitution. Mutation analysis of a large family demonstrated complete segregation of the G2019S with PD. However, there was no association between PD and any of the four polymorphisms at the allelic or genotypic levels (p > 0.17). Furthermore, the authors did not detect a modifying effect for any genotype or of APOE genotypes upon the age at onset in the PD group (p > 0.20). Conclusions: The results support the prior suggestion that LRRK2 mutations cause PD. The disease in the families reported here presents a phenotype indistinguishable from typical PD. All three families demonstrate a very variable age at onset that is not explained by APOE genotypes. The common coding variations in the LRRK2 gene neither constitute strong PD risk factors nor modify the age at onset; however, the possibility of a modest risk effect remains to be assessed in large datasets. C1 Univ Toronto, Dept Med, Div Neurol, Toronto, ON M5S, Canada. Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M5S, Canada. Toronto Western Hosp, Movement Disorders Ctr, Res Inst, Toronto, ON M5T 2S8, Canada. CSIC, Inst Biomed Valencia, Dept Genom & Proteom, Valencia, Spain. NIA, Mol Genet Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD USA. RP Rogaeva, E (reprint author), Univ Toronto, Dept Med, Div Neurol, 6 Queens Pk Crescent West, Toronto, ON M5S, Canada. EM ekaterina.rogaeva@utoronto.ca RI Paisan-Ruiz, Coro/C-2912-2009; Singleton, Andrew/C-3010-2009 NR 23 TC 115 Z9 121 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 13 PY 2005 VL 65 IS 5 BP 696 EP 700 DI 10.1212/01.WNL.0000167552.79769.b3 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 963RH UT WOS:000231821300008 PM 16157901 ER PT J AU Isenberg, JS Ridnour, LA Perruccio, EM Espey, MG Wink, DA Roberts, DD AF Isenberg, JS Ridnour, LA Perruccio, EM Espey, MG Wink, DA Roberts, DD TI Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE angiogenesis; cell adhesion; chemotaxis; proliferation; CD36 ID VASCULAR SMOOTH-MUSCLE; PROTEIN-KINASE; GROWTH-FACTOR; MODULATES ANGIOGENESIS; BINDING PROTEINS; IN-VITRO; PROLIFERATION; SYNTHASE; ACTIVATION; ADHESION AB Redox signaling plays an important role in the positive regulation of angiogenesis by vascular endothelial growth factor, but its role in signal transduction by angiogenesis inhibitors is less clear. Using muscle explants in 3D culture, we found that explants from mice lacking the angiogenesis inhibitor thrombospondin-1 (TSP1) exhibit exaggerated angiogenic responses to an exogenous NO donor, which could be reversed by providing exogenous TSP1. To define the basis for inhibition by TSP1, we examined the effects of TSP1 on several proangiogenic responses of endothelial cells to NO. NO has a biphasic effect on endothelial cell proliferation. The positive effect at low doses of NO is sensitive to inhibition of cGMP signaling and picomolar concentrations of TSP1. NO stimulates both directed (chemotactic) and random (chemokinetic) motility of endothelial cells in a cGMP-dependent manner. TSP1 potently inhibits chemotaxis stimulated by NO. Low doses of NO also stimulate adhesion of endothelial cells on type I collagen in a cGMP-dependent manner. TSP1 potently inhibits this response both upstream and downstream of cGMP. NO-stimulated endothelial cell responses are inhibited by recombinant type 1 repeats of TSP1 and a CD36 agonist antibody but not by the N-terminal portion of TSP1, suggesting that CD36 or a related receptor mediates these effects. These results demonstrate a potent antagonism between TSP1 and proangiogenic signaling downstream of NO. Further elucidation of this inhibitory signaling pathway may identify new molecular targets to regulate pathological angiogenesis. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 47 TC 136 Z9 143 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 13 PY 2005 VL 102 IS 37 BP 13141 EP 13146 DI 10.1073/pnas.0502977102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 964YG UT WOS:000231916300026 PM 16150726 ER PT J AU Ridnour, LA Isenberg, JS Espey, MG Thomas, DD Roberts, DD Wink, DA AF Ridnour, LA Isenberg, JS Espey, MG Thomas, DD Roberts, DD Wink, DA TI Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE guanyl cyclase; endothelial ID HUMAN-MELANOMA XENOGRAFTS; ENDOTHELIAL-CELL PROLIFERATION; CURATIVE RADIATION-THERAPY; TUMOR-GROWTH; PREVENTS GROWTH; BREAST-CANCER; IN-VITRO; EXPRESSION; SYNTHASE; METASTASIS AB Nitric oxide (NO) donors have been shown to stimulate and inhibit the proliferation, migration, and differentiation of endothelial cells in vitro and angiogenesis in vivo. Recently, we have shown distinct thresholds for NO to regulate p53-Ser-15P, phosphorylated extracellular signal-regulated kinase (pERK), and hypoxia inducible factor la in tumor cells. Because these signaling pathways also promote the growth and survival of endothelial cells, we examined their roles in angiogenic responses of venous endothelial cells and vascular outgrowth of muscle explants elicited by NO. An additional protein involved in the regulation of angiogenesis is thrombospondin-1 (TSP1), a matricellular glycoprotein known to influence adhesion, migration, and proliferation of endothelial cells. Here we demonstrate a triphasic regulation of TSP1 mediated by a slow and prolonged release of NO that depends on ERK phosphorylation. Under conditions of 5% serum, a 24-h exposure of NO donor (0.1-1,000 mu M) mediated a triphasic response in the expression of TSP1 protein: decreasing at 0.1 mu M, rebounding at 100 mu M, and decreasing again at 1,000 mu M. Under the same conditions, we observed a dose-dependent increase in P53 phosphorylation and inverse biphasic responses of pERK and mitogen-activated protein kinase phosphatase-1. Both the growth-stimulating activity of low-dose NO for endothelial cells and suppression of TSP1 expression were ERK-dependent. Conversely, exogenous TSP1 suppressed No-mediated pERK. These results suggest that dose-dependent positive- and negative-feed back loops exist between NO and TSP1. Limiting TSP1 expression by positive feedback through the ERK mitogen-activated protein kinase pathway may facilitate switching to a proangiogenic state at low doses of NO. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Ridnour, LA (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. EM ridnourl@mail.nih.gov; wink@mail.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 47 TC 131 Z9 137 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 SEP 13 PY 2005 VL 102 IS 37 BP 13147 EP 13152 DI 10.1073/pnas.0502979102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 964YG UT WOS:000231916300027 PM 16141331 ER PT J AU Hollander, MC Philburn, RT Patterson, AD Velasco-Miguel, S Friedberg, EC Linnoila, RI Fornace, AJ AF Hollander, MC Philburn, RT Patterson, AD Velasco-Miguel, S Friedberg, EC Linnoila, RI Fornace, AJ TI Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Gadd45a; allelic loss; non-small cell lung cancer; metastasis ID NUCLEOTIDE EXCISION-REPAIR; OXIDATIVE DNA-DAMAGE; XERODERMA-PIGMENTOSUM; HUMAN CANCERS; MOUSE MODELS; MUTANT MICE; UV-RADIATION; GENE XPC; SUSCEPTIBILITY; POLYMORPHISM AB Chromosome 3p and 1p-deletions are among the most frequent genetic changes in human lung cancer and although candidate tumor suppressor genes have been identified in these regions, no causative correlations have been drawn between deletion or mutation of these and lung carcinogenesis. We identify XPC and Gadd45a as genes within each of these regions involved in lung tumor initiation and progression, respectively. One hundred percent of XPC-/- mice develop multiple spontaneous lung tumors with a minority progressing to non-small cell lung adenocarcinoma, occasionally with metastasis to adjacent lymph nodes. Deletion of Gadd45a alone does not lead to increased lung tumors in mice, but coupled with an XPC deletion, it results in lung tumor progression. Analysis of published data indicated allelic loss of XPC in most human lung tumors and allelic loss of Gadd45a in some human lung and other cancer types. Because DNA repair capacity is compromised in XPC+/- cells, it is possible that the loss of a single XPC allele in the human lung might confer a mutator phenotype. Coupled with cigarette carcinogens, decreased DNA repair would lead to additional mutations in genes such as p53 that are frequent targets in lung cancer. C1 NCI, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. RP Hollander, MC (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM ch96b@nih.gov RI Fornace, Albert/A-7407-2008; Patterson, Andrew/G-3852-2012 OI Fornace, Albert/0000-0001-9695-085X; Patterson, Andrew/0000-0003-2073-0070 NR 49 TC 76 Z9 78 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 13 PY 2005 VL 102 IS 37 BP 13200 EP 13205 DI 10.1073/pnas.0503133102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 964YG UT WOS:000231916300036 PM 16141330 ER PT J AU Stewart, CA Laugier-Anfossi, F Vely, F Saulquin, X Riedmuller, J Tisserant, A Gauthier, L Romagne, F Ferracci, G Arosa, FA Moretta, A Sun, PD Ugolini, S Vivier, E AF Stewart, CA Laugier-Anfossi, F Vely, F Saulquin, X Riedmuller, J Tisserant, A Gauthier, L Romagne, F Ferracci, G Arosa, FA Moretta, A Sun, PD Ugolini, S Vivier, E TI Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE natural killer cell ID CELL INHIBITORY RECEPTORS; NK CELL; HLA-C; PSORIASIS-VULGARIS; CRYSTAL-STRUCTURE; VIRAL-INFECTION; DENDRITIC CELLS; DIRECT BINDING; HEAVY-CHAINS; CROSS-TALK AB Inhibitory receptors for MHC class I molecules increase the threshold of lymphocyte activation. Natural Killer (NK) cells express a large number of such inhibitory receptors, including the human killer Ig-like receptors (KIR). However, activating members of the KIR family have poorly defined ligands and functions. Here we describe the use of activating KIR tetramer reagents as probes to detect their ligands. infection of cells with Epstein-Barr virus leads to expression of a detectable ligand for the activating receptor KIR2DS1. In this case, KIR2DS1 interacts with up-regulated peptide-MHC class I complexes on Epstein-Barr virus-infected cells in a transporter associated with antigen processing (TAP)-dependent manner. In tetramer-based cellular assays and direct affinity measurements, this interaction with MHC class I is facilitated by abroad spectrum of peptides. KIR2DS1 and its inhibitory homologue, KIR2DL1, share sensitivity to peptide sequence alterations at positions 7 and 8. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. Importantly, KIR2DS1 is not always sufficient to trigger INK effector responses when faced with cognate ligand, consistent with fine control during INK cell activation. We discuss how our results for KIR2DS1 and parallel studies on KIR2DS2 relate to the association between activating KIR genes and susceptibility to autoimmune disorders. C1 Univ Mediterranee, Ctr Immunol Marseille Luminy, INSERM, CNRS, F-13288 Marseille, France. NIAID, NIH, Rockville, MD 20852 USA. Innate Pharma SA, F-13009 Marseille, France. Inst Jean Roche, Fac Med, Secteur Nord, Unite Methodol Interact Mol, F-13916 Marseille, France. Inst Mol & Cell Biol, P-4150 Oporto, Portugal. Univ Genoa, Dipartimento Med Sperimentale, I-16132 Genoa, Italy. Univ Genoa, Ctr Eccellenza Ric Biomed, I-16132 Genoa, Italy. RP Stewart, CA (reprint author), Univ Mediterranee, Ctr Immunol Marseille Luminy, INSERM, CNRS, Campus Luminy,Case 906, F-13288 Marseille, France. EM stewart@ciml.univ-mrs.fr RI Arosa, Fernando/E-5640-2010; Stewart, Charles/G-2470-2012; SAULQUIN, Xavier/L-2886-2015 OI Arosa, Fernando/0000-0002-7209-4507; NR 53 TC 223 Z9 231 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 13 PY 2005 VL 102 IS 37 BP 13224 EP 13229 DI 10.1073/pnas.0503594102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 964YG UT WOS:000231916300040 PM 16141329 ER PT J AU Kennedy, M Solomon, C Manolio, TA Criqui, MH Newman, AB Polak, JF Burke, GL Enright, P Cushman, M AF Kennedy, M Solomon, C Manolio, TA Criqui, MH Newman, AB Polak, JF Burke, GL Enright, P Cushman, M TI Risk factors for declining ankle-brachial index in men and women 65 years or older - The cardiovascular health study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the Council-on-Epidemiology-and-Prevention of the American-Heart-Association CY MAR 05-08, 2003 CL Miami, FL SP Amer Heart Assoc, Council Epidemiol Prevent ID PERIPHERAL ARTERIAL-DISEASE; EDINBURGH ARTERY; ARM INDEX; OCCLUSIVE DISEASE; HEART-DISEASE; ATHEROSCLEROSIS; MORTALITY; PROGRESSION; PRESSURE; CLAUDICATION AB Background: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population. Methods: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI. Results: The percentage of participants with ABI decline was 9.5% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in noncases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95% CI, 1.02-2.96); hypertension, 1.64 (95% CI, 1.18-2.28); diabetes, 1.77 (95% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95% CI, 1.05-2.89). Conclusion: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors. C1 Univ Vermont, Dept Med, Colchester, VT 05446 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA USA. Tufts Univ, Sch Med, Dept Radiol, Boston, MA 02111 USA. Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Univ Arizona, Resp Sci Ctr, Tucson, AZ USA. RP Cushman, M (reprint author), Univ Vermont, Dept Med, 208 Pk Dr,Suite 2, Colchester, VT 05446 USA. EM mary.cushman@uvm.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NHLBI NIH HHS [T32 HL 07594, 01-HC-35129, HL-03618, N01-HC-15103, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086] NR 25 TC 49 Z9 51 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 12 PY 2005 VL 165 IS 16 BP 1896 EP 1902 DI 10.1001/archinte.165.16.1896 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 963VS UT WOS:000231834900013 PM 16157835 ER PT J AU Le Gouill, C Darden, T Madziva, MT Birnbaumer, M AF Le Gouill, C Darden, T Madziva, MT Birnbaumer, M TI A role for K268 in V2R folding SO FEBS LETTERS LA English DT Article DE vasopressin receptor; ion-pair formation; receptor internalization; receptor phosphorylation ID NEPHROGENIC DIABETES-INSIPIDUS; PROTEIN-COUPLED RECEPTOR; VASOPRESSIN RECEPTOR; ACTIVATION; SUBSTITUTION; EXPRESSION; ALIGNMENT; MUTATION; AGONIST; BETA AB The V2 vasopressin receptor, a member of the rhodopsin subfamily of GPCRs, mediates arginine vasopressin control of water reabsorption in the kidney by activating Gs. Requirement of the third intracellular loop of the V2R for G(s) activation was identified by introducing V2R segments into the Gq coupled V1aR [Liu, J. and Wess, J. (1996) J. Biol. Chem. 271, 8772-8778]; the same approach recognized glutamate 231 and glutamine 225 at the amino terminus of loop 3i as being needed for signal transduction. Site-directed mutagenesis of the V2R confirmed their observations. Recently, we found that a positively charged amino acid at codon 268 is essential for V2R expression, although a double-mutant bearing lysine at position 231 and glutamic acid at position 268 was expressed at higher levels than the wild type V2R and displayed unchanged ligand-binding affinity. Ligand-induced internalization and phosphorylation of the double-mutant receptor was indistinguishable from that observed with the wild type protein but signaling activity was greatly diminished. The data suggested these two amino acids might interact with each other and might play a role in promoting GDP/GTP exchange. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Univ Calif Los Angeles, Dept Anesthesiol, Sch Med, Los Angeles, CA 90095 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Birnbaumer, M (reprint author), Univ Calif Los Angeles, Dept Anesthesiol, Sch Med, Los Angeles, CA 90095 USA. EM birnbau2@niehs.nih.gov NR 27 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 12 PY 2005 VL 579 IS 22 BP 4985 EP 4990 DI 10.1016/j.febslet.2005.08.003 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 963WU UT WOS:000231837800012 ER PT J AU Cai, Q Gerwin, C Sheng, ZH AF Cai, Q Gerwin, C Sheng, ZH TI Syntabulin-mediated anterograde transport of mitochondria along neuronal processes SO JOURNAL OF CELL BIOLOGY LA English DT Article ID KINESIN HEAVY-CHAIN; CULTURED HIPPOCAMPAL-NEURONS; AMYLOID PRECURSOR PROTEIN; FAST AXONAL-TRANSPORT; POLARITY ORIENTATION; MOTOR PROTEIN; LIGHT-CHAIN; RAT-BRAIN; DROSOPHILA; DISEASE AB In neurons, proper distribution of mitochondria in axons and at synapses is critical for neurotransmission, synaptic plasticity, and axonal outgrowth. However, mechanisms underlying mitochondrial trafficking throughout the long neuronal processes have remained elusive. Here, we report that syntabulin plays a critical role in mitochondrial trafficking in neurons. Syntabulin is a peripheral membrane-associated protein that targets to mitochondria through its carboxyl-terminal tail. Using real-time imaging in living cultured neurons, we demonstrate that a significant fraction of syntabulin colocalizes and co-migrates with mitochondria along neuronal processes. Knockdown of syntabulin expression with targeted small interfering RNA or interference with the syntabulin-kinesin-1 heavy chain interaction reduces mitochondrial density within axonal processes by impairing anterograde movement of mitochondria. These findings collectively suggest that syntabulin acts as a linker molecule that is capable of attaching mitochondrial organelles to the microtubule-based motor kinesin-1, and in turn, contributes to anterograde trafficking of mitochondria to neuronal processes. C1 NINDS, Synapt Funct Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU NINDS NIH HHS [Z01 NS002946-09] NR 49 TC 109 Z9 111 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 12 PY 2005 VL 170 IS 6 BP 959 EP 969 DI 10.1083/jcb.200506042 PG 11 WC Cell Biology SC Cell Biology GA 963RI UT WOS:000231821400013 PM 16157705 ER PT J AU Szajner, P Weisberg, AS Lebowitz, J Heuser, J Moss, B AF Szajner, P Weisberg, AS Lebowitz, J Heuser, J Moss, B TI External scaffold of spherical immature poxvirus particles is made of protein trimers, forming a honeycomb lattice SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CONDITIONAL LETHAL MUTANTS; VACCINIA VIRUS; GEL ELECTROPHORESIS; RIFAMPICIN; MEMBRANE; GENE; BIOGENESIS; ENVELOPE; MORPHOGENESIS; POLYPEPTIDE AB During morphogenesis, poxviruses undergo a remarkable transition from spherical immature forms to brick-shaped infectious particles lacking helical or icosahedral symmetry. In this study, we show that the transitory honeycomb lattice coating the lipoprotein membrane of immature vaccinia virus particles is formed from trimers of a 62-kD protein encoded by the viral D13L gene. Deep-etch electron microscopy demonstrated that anti-D13 antibodies bound to the external protein coat and that lattice fragments were in affinity-purified D13 preparations. Soluble D13 appeared mostly trimeric by gel electrophoresis and ultracentrifugation, which is consistent with structural requirements for a honeycomb. In the presence or absence of other virion proteins, a mutated D13 with one amino acid substitution formed stacks of membrane-unassociated flat sheets that closely resembled the curved honeycombs of immature virions except for the absence of pentagonal facets. A homologous domain that is present in D13 and capsid proteins of certain other lipid-containing viruses support the idea that the developmental stages of poxviruses reflect their evolution from an icosahedral ancestor. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Cell Biol, St Louis, MO 63110 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU NIGMS NIH HHS [R01 GM029647, GM 29647] NR 40 TC 64 Z9 67 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 12 PY 2005 VL 170 IS 6 BP 971 EP 981 DI 10.1083/jcb.200504026 PG 11 WC Cell Biology SC Cell Biology GA 963RI UT WOS:000231821400014 PM 16144903 ER PT J AU Huff, J AF Huff, J TI Bisphenol A and carcinogenesis SO SCIENTIST LA English DT Letter C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM huffj@niehs.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD SEP 12 PY 2005 VL 19 IS 17 BP 8 EP 8 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 962EZ UT WOS:000231715100006 ER PT J AU Yang, K Fan, KH Lamprecht, SA Edelmann, W Kopelovich, L Kucherlapati, R Lipkin, M AF Yang, K Fan, KH Lamprecht, SA Edelmann, W Kopelovich, L Kucherlapati, R Lipkin, M TI Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc(1638) (N/+) Mlh1(+/-) double mutant mice SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE small intestine; colon; tumors; PPAR-gamma; Apc; Mlh1; troglitazone; thiazolidinediones ID INTESTINAL POLYP FORMATION; PPAR-GAMMA; COLORECTAL-CANCER; C57BL/6J-APC(MIN)/+ MICE; APC MUTATIONS; ANIMAL-MODELS; MIN MICE; TUMORIGENESIS; MAMMARY; LIGAND AB The role of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in colon tumorigenesis remains controversial. Notwithstanding evidence that PPAR-gamma ligands impede murine colorectal carcinogenesis, PPAR-gamma agonists have been shown to enhance in vivo tumor formation in mouse models of human colon cancer. Our study was designed to determine whether troglitazone (TGZ) induces colonic tumor formation in normal C57BL/6J mice and enhances colorectal carcinogenesis in double mutant Apc(1638N/+) Mlh1(+/-) mice fed a standard AIN-76A diet. We report herein that not only does TGZ enhance carcinogenesis in the large intestine of mutant mice predisposed to intestinal carcinogenesis but TGZ also induces colonic tumors in normal mice without gene targeting or carcinogen administration. This observation indicates that preexisting mutational events are not necessary for induction of colonic tumors by activated PPAR-gamma in vivo. (c) 2005 Wiley-Liss, Inc. C1 Rockefeller Univ, Strang Canc Res Lab, New York, NY 10021 USA. Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10467 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. RP Lipkin, M (reprint author), Rockefeller Univ, Strang Canc Res Lab, 1230 York Ave, New York, NY 10021 USA. EM lipkin@mail.rockefeller.edu FU NCI NIH HHS [N01-CN-15116, U01-CA-84301]; NIEHS NIH HHS [U01-ES-11040] NR 37 TC 52 Z9 55 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 10 PY 2005 VL 116 IS 4 BP 495 EP 499 DI 10.1002/ijc.21018 PG 5 WC Oncology SC Oncology GA 951MV UT WOS:000230935500001 PM 15818612 ER PT J AU Zelmanowicz, ADM Schiffman, M Herrero, R Goldstein, AM Sherman, ME Burk, RD Gravitt, P Viscidi, R Schwartz, P Barnes, W Mortel, R Silverberg, SG Buckland, J Hildesheim, A AF Zelmanowicz, ADM Schiffman, M Herrero, R Goldstein, AM Sherman, ME Burk, RD Gravitt, P Viscidi, R Schwartz, P Barnes, W Mortel, R Silverberg, SG Buckland, J Hildesheim, A TI Family history as a co-factor for adenocarcinoma and squamous cell carcinoma of the uterine cervix: Results from two studies conducted in Costa Rica and the United States SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical carcinoma; family history; human papillomavirus; susceptibility ID HUMAN-PAPILLOMAVIRUS COFACTOR; CANCER; ETIOLOGY; RISK AB Previous work suggests that cervical cancer may aggregate in families. We evaluated the association between a family history of gynecological tumors and risk of squamous cell and adenocarcinomas of the cervix in 2 studies conducted in Costa Rica and the United States. The Costa Rican study consisted of 2,073 women (85 diagnosed with CIN3 or cancer, 55 diagnosed with CIN2 and 1,933 controls) selected from a population-based study of 10,049 women. The U.S. study consisted of 570 women (124 with in situ or invasive adenocarcinomas, 139 with in situ or invasive squamous cell carcinomas of the cervix and 307 community-based controls) recruited as part of a multicentric case-control study in the eastern part of the United States. Information on family history of cervical and other cancers among first-degree relatives was ascertained via questionnaire. Information on other risk factors for cervical cancer was obtained via questionnaire. Human papillomavirus (HPV) exposure was assessed in both studies using broad spectrum HPV L1-based PCR testing of exfoliated cervicovaginal cells and in Costa Rica by additional testing of plasma collected from participants for antibodies against the L1 protein of HPV types 16, 18, 31 and 45 by ELISA. A family history of cervical cancer in a first-degree relative was associated with increased risk of squamous tumors in both studies (odds ration [OR] = 3.2 for CIN3/cancer vs. controls; 95% confidence interval [CI] = 1.1-9.4 in Costa Rica; OR = 2.6 for in situ/invasive squamous cell carcinoma cases vs. controls, 95% CI = 1.1-6.4 in the Eastern United) These associations were evident regardless of States study. T whether the affected relative was a mother, sister or daughter of the study participant. Furthermore, observed effects were not strongly modified by age. In Costa Rica, the effect persisted in analysis restricted to HPV-exposed individuals (OR = 3.0; 95% CI = 1.0-9.0), whereas in the Eastern United States study there was evidence of attenuation of risk in analysis of squamous carcinoma cases restricted to HPV positive women (OR = 1.4; 95% CI = 0.29-6.6). No significant association was observed between a family history of cervical cancer in a first-degree relative and adenocarcinomas (OR = 1.3; 95% CI = 0.43-3.9). History of gynecological tumors other than cervical cancer in a first-degree relative was not significantly associated with risk of disease in either study. These results are consistent with a role of host factors in the pathogenesis of squamous cell cervical cancer, although familial aggregation due to shared environmental exposures cannot be ruled out. (c) 2005 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Univ Fed Rio Grande Sul, Programa Posgrad Epidemiol, Porto Alegre, RS, Brazil. Guanacaste Project, San Jose, Costa Rica. Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth & Obstetr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Gynecol & Womens Hlth, Bronx, NY 10467 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Med Inst, Dept Pediat, Baltimore, MD 21205 USA. Yale Univ, Sch Med, New Haven, CT USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. Milton S Hershey Med Ctr, Hershey, PA USA. Univ Maryland, Dept Anat Pathol, Baltimore, MD 21201 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7062, Rockville, MD 20852 USA. EM Hildesha@exchiange.nih.gov NR 23 TC 14 Z9 16 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 10 PY 2005 VL 116 IS 4 BP 599 EP 605 DI 10.1002/ijc.21048 PG 7 WC Oncology SC Oncology GA 951MV UT WOS:000230935500015 ER PT J AU Bergsagel, PL Kuehl, WM AF Bergsagel, PL Kuehl, WM TI Molecular pathogenesis and a consequent classification of multiple myeloma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR-3; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; 14Q32 TRANSLOCATIONS; TUMOR PROGRESSION; GENETIC EVENTS; BONE-MARROW; ABNORMALITIES; DYSREGULATION; PROGNOSIS AB There appear to be two pathways involved in the pathogenesis of premalignant non-immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Nearly half of tumors are nonhyperdiploid, and mostly have one of five recurrent IgH translocations: 16% 11q13 (CCN DI), 3% 6p21 (CCN D3), 5% 16q23 (MAF), 2% 20q12 (MAFB), and 15% 4p16(FGFR3 and MMSET). The remaining hyperdiploid tumors have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, and infrequently one of these five translocations. Although cyclin D1 is not expressed by healthy lymphoid cells, it is bi-allelically dysregulated in a majority of hyperdiploid tumors. Virtually all MM and MGUS tumors have dysregulated and/or increased expression of cyclin D1, D2, or D3, providing an apparent early, unifying event in pathogenesis. The patterns of translocations and cyclin D expression (TC define a novel classification that includes eight groups: 11q; 6p; MAF; 4p; D1 (34%); D1+D2 (6%); D2 (17%); and none (2%). The hyperdiploid D1 group is virtually absent in extramedullary MM and MM cell lines, suggesting a particularly strong dependence on interaction with the bone marrow microenvironment. Despite shared progression events (RAS mutations, MYC dysregulation, p53 mutations, and additional disruption of the retinoblastoma pathway), the phenotypes of MGUS and MM tumors in the eight TC groups is determined mainly by early oncogenic events. Similar to acute lymphocytic leukemia, MM seems to include several diseases (groups) that have differences in early or initiating events, global gene expression patterns, bone marrow dependence, clinical features, prognosis, and response to therapy. C1 Ctr Comprehens Canc, Scottsdale, AZ USA. Mayo Clin Scottsdale, Div Hematol Oncol, Scottsdale, AZ USA. NCI, Genet Branch, Bethesda, MD 20892 USA. RP Kuehl, WM (reprint author), 8901 Rockville Pike,Bldg 8,Rm 5101, Gaithersburg, MD 20899 USA. EM bergsagel.p@mayo.edu; wmk@helix.nih.gov RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 FU NCI NIH HHS [CA100707] NR 35 TC 322 Z9 327 U1 0 U2 27 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2005 VL 23 IS 26 BP 6333 EP 6338 DI 10.1200/JCO.2005.05.021 PG 6 WC Oncology SC Oncology GA 965GJ UT WOS:000231938300007 PM 16155016 ER PT J AU Bakowska, JC Jenkins, R Pendleton, J Blackstone, C AF Bakowska, JC Jenkins, R Pendleton, J Blackstone, C TI The Troyer syndrome (SPG20) protein spartin interacts with Eps15 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE endocytosis; hereditary spastic paraplegia; MIT domain; signaling; neurodegeneration; axon; Troyer syndrome; Eps15; vesicle; trafficking ID HEREDITARY SPASTIC PARAPLEGIA; TYROSINE KINASE SUBSTRATE; MEMBRANE ASSOCIATION; SH3 DOMAIN; INTERNALIZATION; IDENTIFICATION; TRAFFICKING; ENDOCYTOSIS; LOCALIZES; LINKING AB The hereditary spastic paraplegias comprise a group of inherited neurological disorders in which the primary manifestation is spastic weakness of the lower extremities. Troyer syndrome is an autosomal recessive form of spastic paraplegia caused by a frame-shift mutation in the spartin (SPG20) gene. Currently, neither the localization nor the functions of the spartin protein are known. In this study, we generated anti-spartin antibodies and found that spartin is both cytosolic and membrane-associated. Using a yeast two-hybrid approach, we screened an adult human brain library for binding partners of spartin. We identified Eps15, a protein known to be involved in endocytosis and the control of cell proliferation. This interaction was confirmed by fusion protein "pull-down" experiments as well as a cellular redistribution assay. Our results suggest that spartin might be involved in endocytosis, vesicle trafficking, or mitogenic activity, and that impairment in one of these processes may underlie the long axonopathy in patients with Troyer syndrome. Published by Elsevier Inc. C1 Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, NIH, Bldg 35,Room 2C-913,9000 Rockville Pike, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU Intramural NIH HHS NR 32 TC 25 Z9 27 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 9 PY 2005 VL 334 IS 4 BP 1042 EP 1048 DI 10.1016/j.bbrc.2005.06.201 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 954YH UT WOS:000231190900010 PM 16036216 ER PT J AU Ichiki, H Hoshino, T Kinoshita, T Imaoka, H Kato, S Inoue, H Nakamura, H Yodoi, J Young, HA Aizawa, H AF Ichiki, H Hoshino, T Kinoshita, T Imaoka, H Kato, S Inoue, H Nakamura, H Yodoi, J Young, HA Aizawa, H TI Thioredoxin suppresses airway hyperresponsiveness and airway inflammation in asthma SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE asthma; thioredoxin; redox; airway hyperresponsiveness; airway inflammation; IL-1; IL-18 ID LUNG INJURY; MICE; INTERLEUKIN-18; IL-18; EXPRESSION; INDUCTION; CYTOKINES; RECEPTOR; CELLS; DOGS AB Thioredoxin (TRX) is a 12-kDa redox (reduction/oxidation)-active protein that has a highly conserved site (-Cys-Gly-Pro-Cys-) and scavenges reactive oxygen species. Here we examined whether exogenously administered TRX modulated airway hyperresponsiveness (AHR) and airway inflammation in a mouse asthma model. Increased AHR to inhaled acetylcholine and airway inflammation accompanied by eosinophilia were observed in OVA-sensitized mice. Administration of wild-type but not 32S/35S mutant TRX strongly suppressed AHR and airway inflammation, and upregulated expression of mRNA of several cytokines (e.g., IL-1 alpha, IL-1 beta, IL-1 receptor antagonist, and IL-18) in the lungs of OVA-sensitized mice. In contrast, TRX treatment at the time of OVA sensitization did not improve AHR or airway inflammation in OVA-sensitized mice. Thus, TRX inhibited the asthmatic response after sensitization, but did not prevent sensitization itself. TRX and redox-active protein may have clinical benefits in,patients with asthma. (c) 2005 Elsevier Inc. All rights reserved. C1 Kurume Univ, Sch Med, Dept Internal Med 1, Kurume, Fukuoka 830, Japan. Kurume Univ, Sch Med, Dept Pathol, Kurume, Fukuoka 830, Japan. Kyushu Univ, Grad Sch Med Sci, Res Inst Dis Chest, Fukuoka 812, Japan. Kyoto Univ, Inst Virus Res, Dept Biol Responses, Kyoto, Japan. Natl Canc Inst, Expt Immunol Lab, Canc Res Ctr, Frederick, MD USA. RP Hoshino, T (reprint author), Kurume Univ, Sch Med, Dept Internal Med 1, Kurume, Fukuoka 830, Japan. EM hoshino@med.kurume-u.ac.jp NR 32 TC 44 Z9 45 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 SEP 9 PY 2005 VL 334 IS 4 BP 1141 EP 1148 DI 10.1016/j.bbrc.2005.07.007 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 954YH UT WOS:000231190900023 PM 16039995 ER PT J AU Karim, S Miller, NJ Valenzuela, J Sauer, JR Mather, TN AF Karim, S Miller, NJ Valenzuela, J Sauer, JR Mather, TN TI RNAi-mediated gene silencing to assess the role of synaptobrevin and cystatin in tick blood feeding SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE ticks; cystatin; synaptobrevin; salivary glands; RNAi; SNARE; exocytosis; Amblyomma americanum; APC (antigen-presenting cells); blood feeding ID DOUBLE-STRANDED-RNA; CYSTEINE PROTEINASES; HUMAN DICER; FLESH FLY; INTERFERENCE; RIBONUCLEASE; SUPERFAMILY; INITIATION; SECRETION; EVOLUTION AB In addition to being the conduit for pathogens into hosts, tick saliva contains a broad array of secretory products that facilitate prolonged tick attachment and blood feeding. Proteins found in tick saliva modulate host hemostasis and immune responses. However, it is not clear whether ticks manipulate the immune responses of their hosts by disrupting the antigen-processing pathways of the hosts. Protein secretion into tick saliva from the salivary glands is due to exocytosis of vesicular membrane-bound granular material regulated by SNARE complex proteins. Proteins associated with vesicles (v-SNARES) are essential components of the exocytotic process. In this study, we assessed the functional significance of synaptobrevin, a SNARE protein, and cystatin, a cysteine protease inhibitor to blood feeding success, in the lone star tick, Amblyomma americanum, using in vivo RNA interference. In separate experiments, tick salivary cystatin and synpatobrevin genes were silenced by injecting adult ticks with 500 ng of dsRNA complementing each gene sequence. Silencing was demonstrated by reduced transcript in midguts and salivary glands. Additionally, disrupting expression of cystatin and synaptobrevin by RNAi reduced the ability of ticks to feed successfully, as demonstrated by feeding inhibition and reduced engorgement weights. Moreover, normal ticks exposed to a rabbit previously exposed to cystatin-silenced ticks exhibited significant resistance to tick feeding. Based on these findings, ticks appear to skillfully evade the host immune system by secreting cystatin, which disrupts normal antigen processing in antigen-presenting cells of hosts. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Rockville, MD 20852 USA. Oklahoma State Univ, Stillwater, OK 74078 USA. RP Karim, S (reprint author), Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. EM kshahid@uri.edu FU NIAID NIH HHS [2 R01 AI37230] NR 35 TC 54 Z9 55 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 9 PY 2005 VL 334 IS 4 BP 1336 EP 1342 DI 10.1016/j.bbrc.2005.07.036 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 954YH UT WOS:000231190900051 PM 16040003 ER PT J AU Rouault, TA AF Rouault, TA TI The intestinal heme transporter revealed SO CELL LA English DT Editorial Material ID IRON; ABSORPTION; CLONING AB The iron-containing porphyrin heme provides a rich source of dietary iron for mammals. The fact that animals can derive iron from heme implies the existence of a transporter that would transport heme from the gut lumen into intestinal epithelial cells. In this issue of Cell, Shayeghi, McKie, and coworkers (Shayeghi et al., 2005) now describe a heme transporter that is expressed in the apical region of epithelial cells in the mouse duodenum. Their identification of heme carrier protein 1 (HCP1) provides a major missing piece in our understanding of iron uptake and mammalian nutrition. C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. NR 15 TC 12 Z9 13 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD SEP 9 PY 2005 VL 122 IS 5 BP 649 EP 651 DI 10.1016/j.cell.2005.08.027 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 963ZC UT WOS:000231844300003 PM 16143096 ER PT J AU Chan, SSL Longley, MJ Copeland, WC AF Chan, SSL Longley, MJ Copeland, WC TI The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; ESCHERICHIA-COLI; MULTIPLE DELETIONS; GAMMA MUTATIONS; ALPERS-SYNDROME; SPACER-REGION; IDENTIFICATION; DEPLETION; DEFECTS; BACTERIOPHAGE-T7 AB dAmong the nearly 50 disease mutations in the gene for the catalytic subunit of human DNA polymerase gamma, POLG, the A467T substitution is the most common and has been found in 0.6% of the Belgian population. The A467T mutation is associated with a wide range of mitochondrial disorders, including Alpers syndrome, juvenile spinocerebellar ataxia-epilepsy syndrome, and progressive external ophthalmoplegia, each with vastly different clinical presentations, tissue specificities, and ages of onset. The A467T mutant enzyme possesses only 4% of wild-type DNA polymerase activity, and the catalytic defect is manifest primarily through a 6-fold reduction in k(cat) with minimal effect on exonuclease function. Human DNA polymerase gamma (pol gamma) requires association of a 55-kDa accessory subunit for enhanced DNA binding and highly processive DNA synthesis. However, the A467T mutant enzyme failed to interact with and was not stimulated by the accessory subunit, as judged by processivity, heat inactivation, and N-ethylmaleimide protection assays in vitro. Thermolysin digestion and immunoprecipitation experiments further indicate weak association of the subunits for A467T pol gamma. This is the first example of a mutation in POLG that disrupts physical association of the pol gamma subunits. We propose that reduced polymerase activity and loss of accessory subunit interaction are responsible for the depletion and deletion of mitochondrial DNA observed in patients with this POLG mutation. C1 NIEHS, NIH, Lab Mol Genet, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, NIH, Lab Mol Genet, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov NR 35 TC 87 Z9 87 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2005 VL 280 IS 36 BP 31341 EP 31346 DI 10.1074/jbc.M506762200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 961LZ UT WOS:000231665200002 PM 16024923 ER PT J AU Nony, PA Kennett, SB Glasgow, WC Olden, K Roberts, JD AF Nony, PA Kennett, SB Glasgow, WC Olden, K Roberts, JD TI 15(S)-lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; DIETARY FATTY-ACIDS; COLLAGEN TYPE-IV; PROSTATE ADENOCARCINOMA; CANCER INVASION; RECEPTOR-GAMMA; LIPOXYGENASE; METASTASIS; EXPRESSION; APOPTOSIS AB The dietary cis-polyunsaturated fatty acid, arachidonic acid, stimulates adhesion of metastatic human breast carcinoma cells (MDA-MB-435) to the extracellular matrix, but the molecular mechanisms by which fatty acids modify the behavior of these cells are unclear. Exposure to arachidonic acid activates multiple signaling pathways. Activation of p38 mitogen-activated protein kinase (p38 MAPK) is required for increased cell adhesion to type IV collagen, and this activation is sensitive to inhibitors of lipoxygenases, suggesting a requirement for arachidonic acid metabolism. The goals of the current study were to identify the one or more key metabolites of arachidonic acid that are responsible for activation of p38 MAPK and to elucidate the upstream kinases that lead to p38 MAPK activation. High performance liquid chromatographic analysis revealed that MDA-MB-435 cells metabolize exogenous arachidonic acid predominantly to 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE). Immunoblot analysis with antibodies specific to 15(S)-lipoxygenase-1 (LOX-1) and 15(S)-lipoxygenase-2 (LOX-2) demonstrated the expression of 15-LOX-2, but not 15-LOX-1, in these tumor cells. A LOX inhibitor, nordihydroguaiaretic acid, attenuated production of 15(S)HETE and inhibited the phosphorylation of p38 MAPK following exposure to arachidonic acid. In contrast, overexpression of LOX-2 sensitized the cells to the addition of arachidonic acid, leading to increased activation of p38 MAPK. Addition of exogenous 15(S)-HETE to MDA-MB-435 cells stimulated cell adhesion to type IV collagen and activated the p38 MAPK pathway, including the upstream kinases transforming growth factor-beta(1)-activated protein kinase-1 (TAK1) and MAPK kinase 6. Transfection of these cells with a dominant negative form of TAK1 blocked arachidonic acid-stimulated p38 MAPK phosphorylation. These data demonstrate that 15(S)-LOX-2 generation of 15(S)HETE activates specific growth factor receptor-related signaling pathways, thereby initiating signal transduction events leading to increased cell adhesion to the extracellular matrix. C1 NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. Mercer Univ, Sch Med, Div Bas Med Sci, Macon, GA 31207 USA. RP Roberts, JD (reprint author), NIEHS, Lab Mol Carcinogenesis, NIH, POB 12233,Mail Drop D2-05, Res Triangle Pk, NC 27709 USA. EM roberts1@niehs.nih.gov FU Intramural NIH HHS NR 50 TC 38 Z9 40 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 SEP 9 PY 2005 VL 280 IS 36 BP 31413 EP 31419 DI 10.1074/jbc.M500418200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 961LZ UT WOS:000231665200011 PM 16000313 ER PT J AU Braithwaite, EK Kedar, PS Lan, L Polosina, YY Asagoshi, K Poltoratsky, VP Horton, JK Miller, H Teebor, GW Yasui, A Wilson, SH AF Braithwaite, EK Kedar, PS Lan, L Polosina, YY Asagoshi, K Poltoratsky, VP Horton, JK Miller, H Teebor, GW Yasui, A Wilson, SH TI DNA polymerase lambda protects mouse fibroblasts against oxidative DNA damage and is recruited to sites of DNA damage/repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; MAMMALIAN-CELLS; SACCHAROMYCES-CEREVISIAE; HYDROGEN-PEROXIDE; LYASE ACTIVITY; BETA; GENE; 5-HYDROXYMETHYL-2'-DEOXYURIDINE; IDENTIFICATION; CYTOTOXICITY AB DNA polymerase lambda ( pol lambda) is a member of the X family of DNA polymerases that has been implicated in both base excision repair and non-homologous end joining through in vitro studies. However, to date, no phenotype has been associated with cells deficient in this DNA polymerase. Here we show that pol lambda null mouse fibroblasts are hypersensitive to oxidative DNA damaging agents, suggesting a role of pol lambda in protection of cells against the cytotoxic effects of oxidized DNA. Additionally, pol lambda co-immunoprecipitates with an oxidized base DNA glycosylase, single-strand-selective monofunctional uracil-DNA glycosylase (SMUG1), and localizes to oxidative DNA lesions in situ. From these data, we conclude that pol lambda protects cells against oxidative stress and suggest that it participates in oxidative DNA damage base excision repair. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Tohoku Univ, Inst Dev Aging & Canc, Dept Mol Genet, Sendai, Miyagi 9808575, Japan. SUNY Stony Brook, Dept Pharmacol Sci, Biol Chem Lab, Stony Brook, NY 11794 USA. NYU, Dept Pathol, New York, NY 10016 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov RI Miller, Holly/I-6942-2015 OI Miller, Holly/0000-0002-9076-5335 FU Intramural NIH HHS NR 33 TC 75 Z9 76 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2005 VL 280 IS 36 BP 31641 EP 31647 DI 10.1074/jbc.M500256200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 961LZ UT WOS:000231665200039 PM 16002405 ER PT J AU Vullhorst, D Buonanno, A AF Vullhorst, D Buonanno, A TI Multiple GTF2I-like repeats of general transcription factor 3 exhibit DNA binding properties - Evidence for a common origin as a sequence-specific dna interaction module SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WILLIAMS-BEUREN-SYNDROME; TFII-I FAMILY; PROMOTER ACTIVITY; PROTEIN; RECOGNITION; EXPRESSION; DOMAIN AB A hallmark of general transcription factor 3 (GTF3) is the presence of multiple GTF2I-like repeats that were suggested to mediate protein-protein interactions. However, we have recently demonstrated that repeat 4 is necessary and sufficient for binding of GTF3 to the bicoid-like motif of the Troponin I slow enhancer. Given the sequence similarity between different GTF2I-like repeats we hypothesized that DNA binding might be a common property of this domain type. We subjected five repeats of GTF3 to random oligonucleotide selection (SELEX) to assess their DNA binding potentials. We delineated the consensus sequence G(TC)G(A)GATTA(G)BG(A) for repeat 4 and showed that binding sites for GTF3 in enhancers for Troponin I and homeobox c8 (HOXc8) are in very good agreement with this motif. SELEX selections for repeats 5 and 2 enriched for oligonucleotides that were also bound by R4, suggesting that they share common sequence preferences, whereas repeat 3 exhibited relaxed sequence requirements for DNA binding. No binding was observed for repeat 1. We also show that GTF2I-like repeats 4 and 6 of transcription factor II-I (TFII- I) exhibit modest DNA binding properties. Lastly, we identified several amino acids of GTF3 repeat 4 required for high affinity protein-DNA interaction. Based on the ability of many repeats to bind DNA in vitro, we suggest that GTF2I-like domains evolved by duplication and diversification of a prototypic DNA-binding ancestor. C1 NICHD, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Vullhorst, D (reprint author), NICHD, Mol Neurobiol Sect, NIH, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM vullhord@mail.nih.gov NR 22 TC 23 Z9 24 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2005 VL 280 IS 36 BP 31722 EP 31731 DI 10.1074/jbc.M500593200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 961LZ UT WOS:000231665200049 PM 15987678 ER PT J AU Tretyakova, I Zolotukhin, AS Tan, W Bear, J Propst, F Ruthel, G Felber, BK AF Tretyakova, I Zolotukhin, AS Tan, W Bear, J Propst, F Ruthel, G Felber, BK TI Nuclear export factor family protein participates in cytoplasmic mRNA trafficking SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ROUGH ENDOPLASMIC-RETICULUM; CONTAINING RIBONUCLEOPROTEIN-PARTICLES; HUMAN-IMMUNODEFICIENCY-VIRUS; PERIPHERAL NERVOUS-SYSTEM; GREEN FLUORESCENT PROTEIN; BINDING PROTEIN; MOLECULAR-CLONING; HIPPOCAMPAL-NEURONS; MAMMALIAN STAUFEN; PORE COMPLEX AB In eukaryotes, the nuclear export of mRNA is mediated by nuclear export factor 1 (NXF1) receptors. Metazoans encode additional NXF1-related proteins of unknown function, which share homology and domain organization with NXF1. Some mammalian NXF1-related genes are expressed preferentially in the brain and are thought to participate in neuronal mRNA metabolism. To address the roles of NXF1-related factors, we studied the two mouse NXF1 homologues, mNXF2 and mNXF7. In neuronal cells, mNXF2, but not mNXF7, exhibited mRNA export activity similar to that of Tip-associated protein/NXF1. Surprisingly, mNXF7 incorporated into mobile particles in the neurites that contained poly(A) and ribosomal RNA and colocalized with Staufen1-containing transport granules, indicating a role in neuronal mRNA trafficking. Yeast two-hybrid interaction, coimmunoprecipitation, and in vitro binding studies showed that NXF proteins bound to brain-specific microtubule-associated proteins (MAP) such as MAP1B and the WD repeat protein Unrip. Both in vitro and in vivo, MAP1B also bound to NXF export cofactor U2AF as well as to Staufen1 and Unrip. These findings revealed a network of interactions likely coupling the export and cytoplasmic trafficking of mRNA. We propose a model in which MAP1B tethers the NXF-associated mRNA to microtubules and facilitates their translocation along dendrites while Unrip provides a scaffold for the assembly of these transport intermediates. C1 NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res,NIH, Frederick, MD 21702 USA. Univ Vienna, Vienna Bioctr, Inst Biochem & Mol Cell Biol, A-1030 Vienna, Austria. Goldbelt Raven LLC, Ft Detrick, MD 21702 USA. RP Felber, BK (reprint author), NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res,NIH, Bldg 535,Rm 209, Frederick, MD 21702 USA. EM felber@mail.ncifcrf.gov NR 70 TC 36 Z9 38 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2005 VL 280 IS 36 BP 31981 EP 31990 DI 10.1074/jbc.M502736200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 961LZ UT WOS:000231665200078 PM 16014633 ER PT J AU Ma, ESF Bates, WD Edmunds, A Kelland, LR Fojo, T Farrell, N AF Ma, ESF Bates, WD Edmunds, A Kelland, LR Fojo, T Farrell, N TI Enhancement of aqueous solubility and stability employing a trans acetate axis in trans planar amine platinum compounds while maintaining the biological profile SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID INTERSTRAND CROSS-LINK; HYDROLYSIS PRODUCTS; ANTITUMOR COMPLEXES; CELL-LINES; DNA; CISPLATIN; DRUG; RECOGNITION; KINETICS; PYRIDINE AB A general approach to solubilization and possible in vivo activation of the transplatinum geometry is presented. The synthesis and characterization of new water-soluble cytotoxic transplatinum compounds are described. Use of acetate ligands (and carboxylate ligands in general) in trans[Pt(OAc)(2)(L)(L')J results in significantly enhanced aqueous solubility and chemical stability in comparison to the parent dichlorides. The new compounds are the first cytotoxic transplatinum compounds containing an N2O2 donor set, similar to carboplatin and oxaliplatin. C1 Virginia Commonwealth Univ, Dept Chem, Richmond, VA 23284 USA. Inst Canc Res, CRC Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Farrell, N (reprint author), Virginia Commonwealth Univ, Dept Chem, Med Coll Virginia Campus, Richmond, VA 23284 USA. EM nfarrell@saturn.vcu.edu NR 38 TC 41 Z9 41 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 8 PY 2005 VL 48 IS 18 BP 5651 EP 5654 DI 10.1021/jm050539d PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 962OV UT WOS:000231743000005 PM 16134932 ER PT J AU Kang, JH Peach, ML Pu, YM Lewin, NE Nicklaus, MC Blumberg, PM Marquez, VE AF Kang, JH Peach, ML Pu, YM Lewin, NE Nicklaus, MC Blumberg, PM Marquez, VE TI Conformationally constrained analogues of diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 carbonyl functionality reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GREEN FLUORESCENT PROTEIN; PK-C; PHORBOL ESTERS; LIVING CELLS; C1B DOMAIN; AFFINITY; PHOSPHOLIPIDS; ACTIVATION; MEMBRANES; COMPLEX AB Diacylglycerol (DAG) lactones with altered functionality (C=O -> CH2 or C=O -> C=S) at the sn-1 and sn-2 carbonyl pharmacophores were synthesized and used as probes to dissect the individual role of each carbonyl in the binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen-bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (Cl domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to ensure the correct orientation and disposition of pharmacophores at the binding site. C1 NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick Inc, NIH, Frederick, MD 21702 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS [Z01 BC006176-22]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 32 TC 14 Z9 14 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 8 PY 2005 VL 48 IS 18 BP 5738 EP 5748 DI 10.1021/jm050352m PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 962OV UT WOS:000231743000015 PM 16134942 ER PT J AU Willis, PG Pavlova, OA Chefer, SI Vaupel, DB Mukhin, AG Horti, AG AF Willis, PG Pavlova, OA Chefer, SI Vaupel, DB Mukhin, AG Horti, AG TI Synthesis and structure-activity relationship of a novel series of aminoalkylindoles with potential for imaging the neuronal cannabinoid receptor by positron emission tomography SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID I-123 LABELED AM251; CB1 RECEPTORS; IN-VIVO; BRAIN; LIPOPHILICITY; LOCALIZATION; RADIOLIGANDS; REAGENT; BINDS AB A new series of CB1 ligands with high binding affinity (K-i = 0.7-100 nM) and moderate lipophilicity (cLogD(7.4)) in the range of 2.1-4.5 has been synthesized. A structure-activity relationship study demonstrated that for the studied set of aminoalkylindoles, the molecular dipole of the ground state conformation within the series was inversely related to the affinity. The racemic ligand with highest affinity (0.7 nM), 3-(4-fluoronaphthoyl)-1-(N-methylpiperidin-2-ylmethyl)indole, was radiolabeled with F-18. This radioligand specifically labeled CB, receptors in mouse brain and accumulated in regions of high versus low CB1 receptor density in a ratio of 1.6. The displaceable radioactivity of one enantiomer in the brains of mice determined in a pretreatment study using the CB, antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) was nearly double that of the racemate for the same determination; therefore, the active enantiomer is a candidate for PET studies in animals. A pretreatement study for the other enantiomer found no displaceable radioactivity in the same group of mice; this result suggested the enantiomer was inactive. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHSS, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21287 USA. RP Willis, PG (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHSS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM pwillis@intra.nida.nih.gov NR 34 TC 22 Z9 23 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 8 PY 2005 VL 48 IS 18 BP 5813 EP 5822 DI 10.1021/jm0502743 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 962OV UT WOS:000231743000021 PM 16134948 ER PT J AU Silveira, JR Raymond, GJ Hughson, AG Race, RE Sim, VL Hayes, SF Caughey, B AF Silveira, JR Raymond, GJ Hughson, AG Race, RE Sim, VL Hayes, SF Caughey, B TI The most infectious prion protein particles SO NATURE LA English DT Article ID SCRAPIE INFECTIVITY; AGENT; REPLICATION; RESISTANCE; LIPOSOMES; DISEASES; SIZES; ASSAY AB Neurodegenerative diseases such as Alzheimer's, Parkinson's and the transmissible spongiform encephalopathies (TSEs) are characterized by abnormal protein deposits, often with large amyloid fibrils. However, questions have arisen as to whether such fibrils or smaller subfibrillar oligomers are the prime causes of disease(1,2). Abnormal deposits in TSEs are rich in PrPres, a protease-resistant form of the PrP protein with the ability to convert the normal, protease-sensitive form of the protein (PrPsen) into PrPres (ref. 3). TSEs can be transmitted between organisms by an enigmatic agent (prion) that contains PrPres (refs 4 and 5). To evaluate systematically the relationship between infectivity, converting activity and the size of various PrPres-containing aggregates, PrPres was partially disaggregated, fractionated by size and analysed by light scattering and non-denaturing gel electrophoresis. Our analyses revealed that with respect to PrP content, infectivity and converting activity peaked markedly in 17 - 27- nm (300 - 600 kDa) particles, whereas these activities were substantially lower in large fibrils and virtually absent in oligomers of <= 5 PrP molecules. These results suggest that non-fibrillar particles, with masses equivalent to 14 - 28 PrP molecules, are the most efficient initiators of TSE disease. C1 NIAID, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. NIAID, Electron Microscopy Core Facil, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. EM bcaughey@nih.gov RI Sim, Valerie/C-4137-2013 OI Sim, Valerie/0000-0002-0088-8666 FU Intramural NIH HHS; NIAID NIH HHS [Z01 AI000580-16] NR 27 TC 565 Z9 588 U1 8 U2 77 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 8 PY 2005 VL 437 IS 7056 BP 257 EP 261 DI 10.1038/nature03989 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 961YE UT WOS:000231696900056 PM 16148934 ER PT J AU Eisenberg, DF London, ED Matochik, JA Derbyshire, S Cohen, LJ Steinfeld, M Prosser, J Galynker, II AF Eisenberg, DF London, ED Matochik, JA Derbyshire, S Cohen, LJ Steinfeld, M Prosser, J Galynker, II TI Education-associated cortical glucose metabolism during sustained attention SO NEUROREPORT LA English DT Article DE education; lingual gyrus; posterior cingulate gyrus; positron emission tomography; precuneus ID POSITRON EMISSION TOMOGRAPHY; ALZHEIMERS-DISEASE; CINGULATE CORTEX; BRAIN; PERCEPTION; MUSICIANS; LATENCY; TASK; MRI AB Despite research suggesting that education may mitigate cognitive sequelae of neural injury, little is known about interactions between education and regional brain function. We examined whether educational experience is associated with relative glucose metabolism in brain regions that are important for sustained attention and learning. Fourteen healthy adults, with 12-18 years of schooling, underwent positron emission tomography scanning with 18F-fluorodeoxyglucose during an auditory continuous discrimination task. Years of education correlated positively with relative glucose metabolism in the lingual gyri (bilaterally), left posterior cingulate gyrus, and left precuneus. Previously, these structures have shown early impairment in dementia. Further investigation should explore whether metabolic changes in these regions contribute to the possible protective effect of education on cognition. C1 Albert Einstein Coll Med, Beth Israel Med Ctr, Dept Psychiat & Behav Sci, Bronx, NY 10461 USA. DHHS, Natl Inst Hlth, Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA. Univ Pittsburgh, Ctr Med, Dept Anesthesiol, Pittsburgh, PA USA. RP Eisenberg, DF (reprint author), Albert Einstein Coll Med, Beth Israel Med Ctr, Dept Psychiat & Behav Sci, Bronx, NY 10461 USA. EM deisenbe@chpnet.org RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA012273-02, R01 DA012273-03, R01 DA012273-04, R01 DA12273] NR 24 TC 5 Z9 6 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD SEP 8 PY 2005 VL 16 IS 13 BP 1473 EP 1476 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 972MC UT WOS:000232456900014 PM 16110274 ER PT J AU Vaisman, A Ling, H Woodgate, R Yang, W AF Vaisman, A Ling, H Woodgate, R Yang, W TI Fidelity of Dpo4: effect of metal ions, nucleotide selection and pyrophosphorolysis SO EMBO JOURNAL LA English DT Article DE base stacking; fidelity; metal ion; mismatch; pyrophosphorolysis ID ECORV RESTRICTION-ENDONUCLEASE; FAMILY DNA-POLYMERASE; SYN THYMINE DIMER; CRYSTAL-STRUCTURE; SULFOLOBUS-SOLFATARICUS; REVERSE-TRANSCRIPTASE; STRUCTURAL BASIS; Y-FAMILY; PYROPHOSPHATE EXCHANGE; ERROR-PRONE AB We report the crystal structures of a translesion DNA polymerase, Dpo4, complexed with a matched or mismatched incoming nucleotide and with a pyrophosphate product after misincorporation. These structures suggest two mechanisms by which Dpo4 may reject a wrong incoming nucleotide with its preformed and open active site. First, a mismatched replicating base pair leads to poor base stacking and alignment of the metal ions and as a consequence, inhibits incorporation. By replacing Mg2+ with Mn2+, which has a relaxed coordination requirement and tolerates misalignment, the catalytic efficiency of misincorporation increases dramatically. Mn2+ also enhances translesion synthesis by Dpo4. Subtle conformational changes that lead to the proper metal ion coordination may, therefore, be a key step in catalysis. Second, the slow release of pyrophosphate may increase the fidelity of Dpo4 by stalling mispaired primer extension and promoting pyrophosphorolysis that reverses the polymerization reaction. Indeed, Dpo4 has robust pyrophosphorolysis activity and degrades the primer strand in the presence of pyrophosphate. The correct incoming nucleotide allows DNA synthesis to overcome pyrophosphorolysis, but an incorrect incoming nucleotide does not. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM Wei.Yang@nih.gov RI Yang, Wei/D-4926-2011; Ling, Hong/E-3729-2010; Vaisman, Alexandra/C-3766-2013 OI Yang, Wei/0000-0002-3591-2195; Vaisman, Alexandra/0000-0002-2521-1467 FU Intramural NIH HHS NR 47 TC 118 Z9 121 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 7 PY 2005 VL 24 IS 17 BP 2957 EP 2967 DI 10.1038/sj.emboj.7600786 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 963FR UT WOS:000231789700001 PM 16107880 ER PT J AU Li, YL Huang, YP Lue, J Quandt, JA Martin, R Mariuzza, RA AF Li, YL Huang, YP Lue, J Quandt, JA Martin, R Mariuzza, RA TI Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule SO EMBO JOURNAL LA English DT Article DE autoimmunity; complex; MHC class II; multiple sclerosis; T-cell receptor ID T-CELL-RECEPTOR; CRYSTAL-STRUCTURE; ANTIGEN RECOGNITION; AMINO-ACIDS; COMPLEX; LIGANDS; BINDING; LIBRARIES; ANTIBODY; IDENTIFICATION AB Multiple sclerosis is mediated by T-cell responses to central nervous system antigens such as myelin basic protein (MBP). To investigate self-peptide/major histocompatibility complex (MHC) recognition and T-cell receptor (TCR) degeneracy, we determined the crystal structure, at 2.8 angstrom resolution, of an autoimmune TCR (3A6) bound to an MBP self-peptide and the multiple sclerosis-associated MHC class II molecule, human leukocyte antigen (HLA)-DR2a. The complex reveals that 3A6 primarily recognizes the N-terminal portion of MBP, in contrast with antimicrobial and alloreactive TCRs, which focus on the peptide center. Moreover, this binding mode, which may be frequent among autoimmune TCRs, is compatible with a wide range of orientation angles of TCR to peptide/MHC. The interface is characterized by a scarcity of hydrogen bonds between TCR and peptide, and TCR-induced conformational changes in MBP/HLA-DR2a, which likely explain the low observed affinity. Degeneracy of 3A6, manifested by recognition of superagonist peptides bearing substitutions at nearly all TCR-contacting positions, results from the few specific interactions between 3A6 and MBP, allowing optimization of interface complementarity through variations in the peptide. C1 Univ Maryland, Inst Biotechnol, WM Keck Lab Struct Biol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Inst Biotechnol, WM Keck Lab Struct Biol, Ctr Adv Res Biotechnol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM mariuzza@carb.nist.gov FU NIAID NIH HHS [R01 AI036900, AI36900, R37 AI036900] NR 53 TC 121 Z9 127 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 7 PY 2005 VL 24 IS 17 BP 2968 EP 2979 DI 10.1038/sj.emboj.7600771 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 963FR UT WOS:000231789700002 PM 16079912 ER PT J AU Lim, JH West, KL Rubinstein, Y Bergel, M Postnikov, YV Bustin, M AF Lim, JH West, KL Rubinstein, Y Bergel, M Postnikov, YV Bustin, M TI Chromosomal protein HMGN1 enhances the acetylation of lysine 14 in histone H3 SO EMBO JOURNAL LA English DT Article DE chromatin; epigenetics; histone acetylation; histone H3; HMG protein ID CHROMATIN-STRUCTURE; PHOSPHORYLATION; HMG-14; TRANSCRIPTION; NUCLEOSOME; DOMAIN; PCAF; H1; REPRESSION; MOBILITY AB The acetylation levels of lysine residues in nucleosomes, which are determined by the opposing activities of histone acetyltransferases (HATs) and deacetylases, play an important role in regulating chromatin-related processes, including transcription. We report that HMGN1, a nucleosomal binding protein that reduces the compaction of the chromatin fiber, increases the levels of acetylation of K14 in H3. The levels of H3K14ac in Hmgn1(-/-) cells are lower than in Hmgn1(+/+) cells. Induced expression of wild-type HMGN1, but not of amutant that does not bind to chromatin, in Hmgn1(-/-) cells elevates the levels of H3K14ac. In vivo, HMGN1 elevates the levels of H3K14ac by enhancing the action of HAT. In vitro, HMGN1 enhances the ability of PCAF to acetylate nucleosomal, but not free, H3. Thus, HMGN1 modulates the levels of H3K14ac by binding to chromatin. We suggest that HMGN1, and perhaps similar architectural proteins, modulates the levels of acetylation in chromatin by altering the equilibrium generated by the opposing enzymatic activities that continuously modify and de-modify the histone tails in nucleosomes. C1 NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, NIH, Bldg 37,Room 2D-21,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [Z01 BC004496-30] NR 43 TC 54 Z9 55 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 7 PY 2005 VL 24 IS 17 BP 3038 EP 3048 DI 10.1038/sj.emboj.7600768 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 963FR UT WOS:000231789700008 PM 16096646 ER PT J AU Brachmann, A Baxa, U Wickner, RB AF Brachmann, A Baxa, U Wickner, RB TI Prion generation in vitro: amyloid of Ure2p is infectious SO EMBO JOURNAL LA English DT Article DE amyloid; prion transformation; prion variants; [URE3] ID SACCHAROMYCES-CEREVISIAE; DOMAINS FORM; PROTEIN; YEAST; FIBRILS; FILAMENTS; STRAINS; TRANSMISSION; CONFORMATION; INDUCTION AB [URE3] is a prion ( infectious protein) of the Ure2 protein of yeast. In vitro, Ure2p can form amyloid filaments, but direct evidence that these filaments constitute the infectious form is still missing. Here we demonstrate that recombinant Ure2p converted into amyloid can infect yeast cells lacking the prion. Infection produced a variety of [ URE3] variants. Extracts of [ URE3] strains, as well as amyloid of Ure2p formed in an extract-primed reaction could transmit to uninfected cells the [ URE3] variant present in the cells from which the extracts were made. Infectivity and determinant of [ URE3] variants resided within the N-terminal 65 amino acids of Ure2p. Notably, we could show that amyloid filaments of recombinant Ure2p are nearly as infectious per mass of Ure2p as extracts of [ URE3] strains. Sizing experiments indicated that infectious particles in vitro and in vivo were >20 nm in diameter, suggesting that they were amyloid filaments and not smaller oligomeric structures. Our data indicate that there is no substantial difference between filaments formed in vivo and in vitro. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov RI Brachmann, Andreas/I-2241-2013 OI Brachmann, Andreas/0000-0001-7980-8173 NR 46 TC 156 Z9 156 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 7 PY 2005 VL 24 IS 17 BP 3082 EP 3092 DI 10.1038/sj.emboj.7600772 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 963FR UT WOS:000231789700012 PM 16096644 ER PT J AU Thomsen, M Woldbye, DPD Wortwein, G Fink-Jensen, A Wess, J Caine, SB AF Thomsen, M Woldbye, DPD Wortwein, G Fink-Jensen, A Wess, J Caine, SB TI Reduced cocaine self-administration in muscarinic M-5 acetylcholine receptor-deficient mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE muscarinic; M-5; acetylcholine; knock-out; self-administration; cocaine ID VENTRAL TEGMENTAL AREA; NUCLEUS-LESIONED RATS; DOPAMINE EFFLUX; KNOCKOUT MICE; GLUTAMATE RECEPTORS; LOCOMOTOR-ACTIVITY; SUBSTANTIA-NIGRA; MUTANT MICE; STIMULATION; ACCUMBENS AB The reinforcing effects of cocaine have been related to increased extracellular concentrations of dopamine in the ventral striatum. Several studies suggest that M-5 muscarinic receptors facilitate striatal dopamine release. We tested the hypothesis that the reinforcing effects of cocaine are decreased in M-5 receptor-deficient mice using chronic intravenous cocaine self-administration in extensively backcrossed mice. We also assessed whether operant performance generally, rather than cocaine self-administration specifically, was altered in the mutant mice. To this end, we evaluated both food-maintained operant behavior and cocaine self-administration under a fixed ratio 1 and a progressive ratio (PR) schedule of reinforcement. We also evaluated acquisition of self-administration in experimentally naive mice using several doses of cocaine. M5 receptor deletion decreased self-administration of low to moderate doses of cocaine under a PR schedule of reinforcement and diminished acquisition of self-administration of a low dose in experimentally naive mice. We found no differences between genotypes in food-maintained behavior. The present study extends our previous findings using backcrossed mice and covering various experimental conditions. Our results indicate that M5 receptor deletion diminished the reinforcing effects of low doses of cocaine and identified specific conditions under which this may be observed. C1 Univ Copenhagen, Rigshosp, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark. Univ Copenhagen, Dept Pharmacol, DK-2100 Copenhagen, Denmark. Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. NIDDK, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP Thomsen, M (reprint author), Univ Copenhagen, Rigshosp, Lab Neuropsychiat, 0-6102,9 Blegdamsvej, DK-2100 Copenhagen, Denmark. FU NIDA NIH HHS [DA12142, DA14644] NR 31 TC 52 Z9 57 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 7 PY 2005 VL 25 IS 36 BP 8141 EP 8149 DI 10.1523/JNEUROSCI.2077-05.2005 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 962GI UT WOS:000231718600004 PM 16148222 ER PT J AU Goss, PE Ingle, JN Martino, S Robert, NJ Muss, HB Piccart, MJ Castiglione, M Tu, DS Shepherd, LE Pritchard, KI Livingston, RB Davidson, NE Norton, L Perez, EA Abrams, JS Cameron, DA Palmer, MJ Pater, JL AF Goss, PE Ingle, JN Martino, S Robert, NJ Muss, HB Piccart, MJ Castiglione, M Tu, DS Shepherd, LE Pritchard, KI Livingston, RB Davidson, NE Norton, L Perez, EA Abrams, JS Cameron, DA Palmer, MJ Pater, JL TI Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCICCTG MA.17 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID QUALITY-OF-LIFE; POSTMENOPAUSAL WOMEN; ESTROGEN-RECEPTOR; AROMATASE INHIBITORS; CLINICAL-PHARMACOLOGY; AMERICAN-SOCIETY; RECURRENCE; RESISTANCE; ANASTROZOLE; COMBINATION AB Background. Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. Results: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P<.001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P=.002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P=.3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P=.04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. Conclusion: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patients. C1 Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. John Wayne Canc Inst, Santa Monica, CA USA. Inova Fairfax Hosp, Falls Church, VA USA. Univ Vermont, Burlington, VT USA. Inst Jules Bordet, B-1000 Brussels, Belgium. SAAK IBCSG Operat Off, Bern, Switzerland. Natl Canc Inst canada, Clin Trials Grp, Kingston, ON, Canada. Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. Univ Washington, Seattle, WA 98195 USA. Johns hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Mayo Clin, Jacksonville, FL 32224 USA. NCI, Clin Invest Branch, Rockville, MD USA. Western Gen Hosp, Edinburgh Breast Unit, Edinburgh EH4 2XU, Midlothian, Scotland. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, 55 Fruit St,Cox Bldg,Suite 640, Boston, MA 02114 USA. EM pgoss@partners.org OI Norton, Larry/0000-0003-3701-9250 FU NCI NIH HHS [CA21115, CA25224, CA31946, CA32102, CA38926] NR 45 TC 673 Z9 704 U1 1 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 7 PY 2005 VL 97 IS 17 BP 1262 EP 1271 DI 10.1093/jnci/dji250 PG 10 WC Oncology SC Oncology GA 969YU UT WOS:000232272900012 PM 16145047 ER PT J AU Tasaki, I AF Tasaki, I TI Repetitive abrupt structural changes in polyanionic gels: A comparison with analogous processes in nerve fibers SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE polyanionic gel; repetitive abrupt structural changes; nerve excitation model ID SQUID GIANT-AXONS; EXCITATION; EXCITABILITY AB Repetitive abrupt structural changes can be produced in a small piece of cross-linked polyacrylate hydrogel by exchanging the divalent counter-ions in the superficial gel layer to monovalent cations. The temporal variations of the hydrostatic pressure, electric impedance and potential associated with these structural changes frequently show striking resemblance to those encountered during repetitive excitation of living nerve fibers. Common anions, such as fluoride, phosphate, aspartate, chloride, etc., produce a marked lyotropic (Hofmeister) effect on the repetitive structural changes both in synthetic polyanionic gels and in squid giant nerve fibers. Mechanical stress which brings about constraints in the polymer chains is found to facilitate the production of repetitive structural changes in the gel. In the stretched superficial layer of a synthetic polyanionic gel, a calcium-salt produces highly refractive bundles of polymer chains. In the Appendix, a crude model of ionized polymer chains that facilitates the consideration of cooperative structural changes in the gel is described. (c) 2005 Elsevier Ltd. All rights reserved. C1 NICHD, LIMB, NIH, Bethesda, MD 20892 USA. NIMH, LCMR, NIH, Bethesda, MD 20892 USA. RP Tasaki, I (reprint author), NICHD, LIMB, NIH, Rm 3E-25,Bldg 13, Bethesda, MD 20892 USA. EM itasaki@erols.com NR 21 TC 15 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD SEP 7 PY 2005 VL 236 IS 1 BP 2 EP 11 DI 10.1016/j.jtbi.2005.02.011 PG 10 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 946KC UT WOS:000230569900002 PM 15967179 ER PT J AU Bartlett, EJ Amaro-Carambot, E Surman, SR Newman, JT Collins, PL Murphy, BR Skiadopoulos, MH AF Bartlett, EJ Amaro-Carambot, E Surman, SR Newman, JT Collins, PL Murphy, BR Skiadopoulos, MH TI Human parainfluenza virus type I (HPIV1) vaccine candidates designed by reverse genetics are attenuated and efficacious in African green monkeys SO VACCINE LA English DT Article DE human parainfluenza virus; attenuating mutations; vaccine candidates; non-human primate study ID RESPIRATORY SYNCYTIAL VIRUS; TEMPERATURE-SENSITIVE MUTANT; L-POLYMERASE PROTEIN; VIRAL-RNA SYNTHESIS; ACUTE OTITIS-MEDIA; SENDAI-VIRUS; C-PROTEINS; INFLUENZA-A; SEQUENCE-ANALYSIS; MEASLES-VIRUS AB A set of recombinant, live attenuated human parainfluenza virus type I (rHPIV1) vaccine candidates was evaluated for attenuation, immunogenicity, and protective efficacy in African green monkeys (AGMs). Temperature sensitive (ts) and non-ts attenuating (att) mutations in the P/C and L genes were introduced individually or in various combinations into rHPIV1, including the C-R84G and HNT553A mutations identified in the present work and the C-F170S, L-Y942A, and L-L992C mutations identified previously. The rHPIV1 vaccine candidates exhibited a spectrum of attenuation in AGMs. One genetically and phenotypically stable vaccine candidate, rC(R84G/F170S)L(Y942A/L992C), was attenuated and efficacious in AGMs and is a promising live attenuated intranasal HPIV I vaccine candidate suitable for clinical evaluation. Published by Elsevier Ltd. C1 NIAID, Infect Dis Lab, Resp Viruses Sect, NIH, Bethesda, MD 20892 USA. RP Bartlett, EJ (reprint author), NIAID, Infect Dis Lab, Resp Viruses Sect, NIH, Bldg 50,Room 6511,50 S Dr MSC 8007, Bethesda, MD 20892 USA. EM EBartlett@niaid.nih.gov NR 70 TC 30 Z9 30 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 7 PY 2005 VL 23 IS 38 BP 4631 EP 4646 DI 10.1016/j.vaccine.2005.04.035 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 959DK UT WOS:000231496900001 PM 15951066 ER PT J AU Oh, YS Turner, RJ AF Oh, YS Turner, RJ TI Topology of the C-terminal fragment of human presenilin 1 SO BIOCHEMISTRY LA English DT Article ID IN-VITRO TRANSLATION; MEMBRANE-PROTEIN STRUCTURE; DISEASE-ASSOCIATED PRESENILINS; ALZHEIMERS-DISEASE; ENDOPLASMIC-RETICULUM; TRANSMEMBRANE ORIENTATION; SUBCELLULAR-LOCALIZATION; STRUCTURE PREDICTION; GAMMA-SECRETASE; CULTURED-CELLS AB Mutations of human presenilin I (PSI) have been genetically linked to early-onset familial Alzheimer's disease. PSI contains 10 hydrophobic regions (HRs) sufficiently long to be (x-helical membrane spanning segments. Most previous topology studies agree that the N-terminus of PSI is cytosolic and HRs 1-6 span the membrane but HR 7 does not. However, whether HRs 8 and 9 are membrane spanning segments remains controversial. Here we study the topology and biogenesis of this region of PSI using a reporter gene fusion approach, where portions of the PSI sequence containing possible membrane spanning segments were fused up- or downstream of a reporter sequence whose translocation into the endoplasmic reticulum could be monitored via its glycosylation. We provide strong evidence, supported by cysteine accessibility studies in full-length PSI, that HRs 8 and 9 are indeed membrane spanning and that the integration of HR 8 into the membrane is dependent on the presence of HR 9. We also explain how our results reconcile previous apparently divergent conclusions regarding the topology of HRs 8 and 9. C1 Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Therapy & Therapeut Branch, DHHS,NIH, Bethesda, MD 20892 USA. RP Oh, YS (reprint author), Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Therapy & Therapeut Branch, DHHS,NIH, Bldg 10,Room 1A01,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. EM yoh@mail.nih.gov NR 44 TC 34 Z9 36 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 6 PY 2005 VL 44 IS 35 BP 11821 EP 11828 DI 10.1021/bi0509494 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 962DA UT WOS:000231710000019 PM 16128583 ER PT J AU Jost, N Virag, L Bitay, M Takacs, J Lengyel, C Biliczki, P Nagy, Z Bogats, G Lathrop, DA Papp, JG Varro, A AF Jost, N Virag, L Bitay, M Takacs, J Lengyel, C Biliczki, P Nagy, Z Bogats, G Lathrop, DA Papp, JG Varro, A TI Restricting excessive cardiac action potential and QT prolongation - A vital role for I-Ks in human ventricular muscle SO CIRCULATION LA English DT Article DE arrhythmia; electrophysiology; ion channels; long-QT syndrome; potassium channels ID RECTIFIER K+ CURRENT; ACTIVATING DELAYED RECTIFIER; III ANTIARRHYTHMIC AGENTS; 2 COMPONENTS; SELECTIVE BLOCKER; POTASSIUM CURRENT; CHROMANOL 293B; RATE DEPENDENCE; SLOW COMPONENT; DE-POINTES AB Background - Although pharmacological block of the slow, delayed rectifier potassium current (I-Ks) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of IKs block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of IKs in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline. Methods and Results - Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 mu mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 mu mol/L) produced a < 12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the I-Kr blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L- 735,821 and chromanol 293B each blocked IKs in the presence of E-4031 to block IKr. The E-4031-sensitive current (I-Kr) at the end of a 150-ms-long test pulse to 30 mV was 32.9 +/- 6.7 pA (n = 8); the L-735,821-sensitive current (I-Ks) magnitude was 17.8 +/- 2.94 pA (n = 10). During a longer 500-ms test pulse, IKr was not substantially changed (33.6 +/- 6.1 pA; n = 8), and I-Ks was significantly increased (49.6 +/- 7.24 pA; n = 10). On application of an "action potential-like" test pulse, I-Kr increased as voltage became more negative, whereas I-Ks remained small throughout all phases of the action potential - like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 mu mol/L adrenaline, 1 mu mol/L HMR-1556 significantly increased APD by 14.7 +/- 3.2% (P < 0.05; n = 3). Conclusions - Pharmacological IKs block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, IKs plays an increasingly important role in limiting action potential prolongation. C1 Univ Szeged, Dept Pharmacol & Pharmacotherapy, H-6720 Szeged, Hungary. Univ Szeged, Dept Cardiac Surg, H-6720 Szeged, Hungary. Univ Szeged, Dept Internal Med 1, H-6720 Szeged, Hungary. Hungarian Acad Sci, Div Cardiovasc Pharmacol, Szeged, Hungary. NHLBI, Heart Res Program, Bethesda, MD 20892 USA. RP Varro, A (reprint author), Univ Szeged, Dept Pharmacol & Pharmacotherapy, Dom Ter 12, H-6720 Szeged, Hungary. EM a.varro@phcol.szote.u-szeged.hu RI LATHROP, David/A-2758-2008; Varro, Andras/M-2647-2016 OI Varro, Andras/0000-0003-0745-3603 NR 35 TC 192 Z9 194 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 6 PY 2005 VL 112 IS 10 BP 1392 EP 1399 DI 10.1161/CIRCULATIONHA.105.550111 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 961VC UT WOS:000231688900005 PM 16129791 ER PT J AU Kathiresan, S Larson, MG Vasan, RS Guo, CY Vita, JA Mitchell, GF Keyes, MJ Newton-Cheh, C Musone, SL Lochner, AL Drake, JA Levy, D O'Donnell, CJ Hirschhorn, JN Benjamin, EJ AF Kathiresan, S Larson, MG Vasan, RS Guo, CY Vita, JA Mitchell, GF Keyes, MJ Newton-Cheh, C Musone, SL Lochner, AL Drake, JA Levy, D O'Donnell, CJ Hirschhorn, JN Benjamin, EJ TI Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community SO CIRCULATION LA English DT Article DE endothelium; epidemiology; genetics; nitric oxide synthase ID CORONARY-HEART-DISEASE; LINKAGE DISEQUILIBRIUM; MYOCARDIAL-INFARCTION; SHEAR-STRESS; BLOOD-FLOW; ASSOCIATION; DYSFUNCTION; HAPLOTYPES; RISK; POLYMORPHISMS AB Background - Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited. Methods and Results - In reference pedigrees, we characterized linkage disequilibrium structure at the NOS3 locus using 33 common single nucleotide polymorphisms (SNPs). Eighteen SNPs that capture underlying common variation were genotyped in unrelated Framingham Heart Study participants (49.5% women; mean age, 62 years) with measured brachial artery flow-mediated dilation (n = 1446) or hyperemic flow velocity (n = 1043). Within 3 defined blocks of strong linkage disequilibrium that spanned NOS3, 11 SNPs captured > 80% of common haplotypic variation. Among men, there were nominally significant associations between 8 NOS3 SNPs (minimum P = 0.002) and between haplotypes (minimum P=0.002) and either flow-mediated dilation or hyperemic flow velocity. In women, we did not observe significant associations between NOS3 SNPs or haplotypes and endothelial function measures. To correct for multiple testing, we constructed 1000 bootstrapped null data sets and found that empirical probability values exceeded 0.05 for both phenotypes. Conclusions - A parsimonious set of SNPs captures common genetic variation at the NOS3 locus. A conservative interpretation of our results is that, accounting for multiple testing, we did not observe statistically significant relations between NOS3 sequence variants and endothelial function measures in either sex. The nominal associations of select NOS3 variants with endothelial function in men (unadjusted for multiple testing) should be viewed as hypothesis-generating observations and may merit testing in other cohorts and experimental designs. C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Boston Univ, Evans Dept Med, Boston, MA 02215 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. Cardiovasc Engn Inc, Waltham, MA USA. MIT, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02139 USA. Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Div Cardiol, Div Genet, Childrens Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Div Endocrinol, Childrens Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study, Dept Med, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [HL060040, HL070100, HL071039, HL66582, K24HL004334, N01-HC-25195] NR 50 TC 19 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 6 PY 2005 VL 112 IS 10 BP 1419 EP 1427 DI 10.1161/CIRCULATIONHA.105.544619 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 961VC UT WOS:000231688900009 PM 16129794 ER PT J AU Menzies, FM Yenisetti, SC Min, KT AF Menzies, FM Yenisetti, SC Min, KT TI Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress SO CURRENT BIOLOGY LA English DT Article ID PARKINSONS-DISEASE; MODEL AB The loss of dopaminergic neurons in the substantia nigra is the pathological hallmark of Parkinson's disease (PD). While the etiology of sporadic PD remains elusive, an inherited form of early-onset familial PD is linked to mutations of DJ-1 [1]. To understand the biological function of DJ-1 and its relevance to the pathogenesis of PD, we investigated the function of DJ-1 using Drosophila. Drosophila possesses two homologs of human DJ-1: DJ-1 alpha and DJ-1 beta. We found that DJ-1a is expressed predominantly in the testis, while DJ-1 beta is ubiquitously present in most tissues, resembling the expression pattern of human DJ-1. Loss-of-function DJ-1 beta mutants demonstrated an extended survival of dopaminergic neurons and resistance to paraquat stress, but showed acute sensitivity to hydrogen peroxide treatment. We showed a compensatory upregulation of DJ-1 alpha expression in the brain of the DJ-1 beta mutant and demonstrated that overexpression of DJ-1 alpha in dopaminergic neurons is sufficient to confer protection against paraquat insult. These results suggest that Drosophila homologs of DJ-1 play critical roles in the survival of dopaminergic neurons and response to oxidative stress. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Min, KT (reprint author), NINDS, Neurogenet Branch, NIH, MSC 3705,Bldg 35,Room 2A1002, Bethesda, MD 20892 USA. EM mink@ninds.nih.gov OI min, kyung-tai/0000-0003-0983-4258 FU Intramural NIH HHS NR 13 TC 126 Z9 130 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 SEP 6 PY 2005 VL 15 IS 17 BP 1578 EP 1582 DI 10.1016/j.cub.2005.07.036 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 964FZ UT WOS:000231865700029 PM 16139214 ER PT J AU Yewdell, JW Hickman-Miller, HD AF Yewdell, JW Hickman-Miller, HD TI Back to the fold: T cell recognition of HFE, a MHC class Ib molecule that regulates iron metabolism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HEREDITARY HEMOCHROMATOSIS; GENE; EXPRESSION; RECEPTOR C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS NR 13 TC 1 Z9 1 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 6 PY 2005 VL 102 IS 36 BP 12649 EP 12650 DI 10.1073/pnas.0506002102 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962FP UT WOS:000231716700001 PM 16129824 ER PT J AU Wu, YX Greene, LE Masison, DC Eisenberg, E AF Wu, YX Greene, LE Masison, DC Eisenberg, E TI Curing of yeast [PSI+] prion by guanidine inactivation of Hsp104 does not require cell division SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SACCHAROMYCES-CEREVISIAE; PROPAGATION; CHAPERONE; PROTEIN; HYDROCHLORIDE; PSI(+); URE3; ELIMINATION; MECHANISM; AGGREGATION AB Propagation of the yeast prion [PSI+], a self-replicating aggregated form of Sup35p, requires Hsp104. One model to explain this phenomenon proposes that, in the absence of Hsp104, Sup35p aggregates enlarge but fail to replicate thus becoming diluted out as the yeast divide. To test this model, we used live imaging of Sup35p-GFP to follow the changes that occur in [PSI+] cells after the addition of guanidine to inactivate Hsp104. After guanidine addition there was initially an increase in aggregation of Sup35p-GFP; but then, before the yeast divided, the aggregates began to dissolve, and after approximate to 6 h the Sup35-GFP looked identical to the Sup35-GFP in [psi(-)] cells. Although plating studies showed that the yeast were still [PSI+],this reduction in aggregation suggested that curing of [PSI+] by inactivation of Hsp104 might be independent of cell division. This was tested by measuring the rate of curing of [PSI+] cells in both dividing and nondividing cells. Cell division was inhibited by adding either alpha factor or farnesol. Remarkably, with both of these methods, we found that the rate of curing was not significantly affected by cell division. Thus, cell division is not a determining factor for curing [PSI+] by inactivating Hsp104 with guanidine. Rather, curing apparently occurs because Sup35-GFP polymers slowly depolymerize in the absence of Hsp104 activity. Hsp104 then counteracts this curing possibly by catalyzing formation of new polymers. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Eisenberg, E (reprint author), NHLBI, Cell Biol Lab, NIH, 50 S Dr,Room 2525,MSC 8017, Bethesda, MD 20892 USA. EM eisenbee@nhlbi.nih.gov NR 30 TC 21 Z9 23 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 6 PY 2005 VL 102 IS 36 BP 12789 EP 12794 DI 10.1073/pnas.0506384102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962FP UT WOS:000231716700028 PM 16123122 ER PT J AU Ross, ED Edskes, HK Terry, MJ Wickner, RB AF Ross, ED Edskes, HK Terry, MJ Wickner, RB TI Primary sequence independence for prion formation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE [PSI+]; amyloid; Sup35 ID YEAST SACCHAROMYCES-CEREVISIAE; AMYLOID FIBRIL FORMATION; GUANIDINE-HYDROCHLORIDE; SUP35 GENE; OLIGOPEPTIDE REPEATS; HSP104 INACTIVATION; MOLECULAR-BASIS; IN-VITRO; PROTEIN; URE2P AB Many proteins can adopt self-propagating beta-sheet-rich structures, termed amyloid fibrils. The [URE3] and [PSI+] prions of Saccharomyces cerevisiae are infectious amyloid forms of the proteins Ure2p and Sup35p, respectively. Ure2p forms prions primarily as a result of its sequence composition, as versions of Ure2p with the prion domain amino acids shuffled are still able to form prions. Here we show that prion induction by both Ure2p and Ure2-21p, one of the scrambled versions of Ure2p, is clearly dependent on the length of the inducing fragment. For Ure2-21p, no single sequence is found in all of the inducing fragments, highlighting the sequence independence of prion formation. Furthermore, the sequence of the Sup35p prion domain can also be randomized without blocking prion formation. Indeed, a single shuffled sequence could give rise to several prion variants. These results suggest that [PSI+] formation is driven primarily by the amino acid composition of the Sup35p prion domain, and that the Sup35p oligopeptide repeats are not required for prion maintenance. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov OI Ross, Eric/0000-0002-6473-9977 FU Intramural NIH HHS NR 47 TC 116 Z9 117 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 6 PY 2005 VL 102 IS 36 BP 12825 EP 12830 DI 10.1073/pnas.0506136102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962FP UT WOS:000231716700034 PM 16123127 ER PT J AU Drake, JW Bebenek, A Kissling, GE Peddada, S AF Drake, JW Bebenek, A Kissling, GE Peddada, S TI Clusters of mutations from transient hypermutability SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bacteriophage RB69; multiple mutations; mutation rate; ribovirus ID BLUE(R) TRANSGENIC MICE; DNA-POLYMERASE-BETA; ESCHERICHIA-COLI; ADAPTIVE MUTATION; REVERSE-TRANSCRIPTASE; MULTIPLE MUTATIONS; ACCESSORY PROTEINS; BASE SUBSTITUTION; STATIONARY-PHASE; IN-VIVO AB Collections of mutants usually contain more mutants bearing multiple mutations than expected from the mutant frequency and a random distribution of mutations. This excess is seen in a variety of organisms and also after DNA synthesis in vitro. The excess is unlikely to originate in mutator mutants but rather from transient hypermutability resulting from a perturbation of one of the many transactions that maintain genetic fidelity. The multiple mutations are sometimes clustered and sometimes randomly distributed. We model some spectra as populations comprising a majority with a low mutation frequency and a minority with a high mutation frequency. In the case of mutants produced in vitro by a bacteriophage RB69 mutator DNA polymerase, mutants with two mutations are in approximate to 10-fold excess and mutants with three mutations are in even greater excess. However, phenotypically undetectable mutations seen only as hitchhikers with detectable mutations are approximate to 5-fold more frequent than mutants bearing detectable mutations, indicating that they arose in a subpopulation with a higher mutation frequency. Excess multiple mutations may contribute critically to carcinogenesis and to adaptive mutation, including the adaptations of pathogens as they move from host to host. In the case of the rapidly mutating riboviruses, the viral population appears to be composed of a majority with a mutation frequency substantially lower than the average and a minority with a huge mutational load. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. RP Drake, JW (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM drake@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 FU Intramural NIH HHS NR 65 TC 45 Z9 46 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 6 PY 2005 VL 102 IS 36 BP 12849 EP 12854 DI 10.1073/pnas.0503009102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962FP UT WOS:000231716700038 PM 16118275 ER PT J AU Capell, BC Erdos, MR Madigan, JP Fiordalisi, JJ Varga, R Conneely, KN Gordon, LB Der, CJ Cox, AD Collins, FS AF Capell, BC Erdos, MR Madigan, JP Fiordalisi, JJ Varga, R Conneely, KN Gordon, LB Der, CJ Cox, AD Collins, FS TI Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; lamin; laminopathy ID PROTEIN TRANSFERASE INHIBITORS; LAMIN-A PRECURSOR; FARNESYLTRANSFERASE INHIBITORS; N-RAS; ZMPSTE24; CELLS; MICE; METALLOPROTEINASE; ISOPRENYLATION; LAMINOPATHIES AB Hutchinson-Gilford progeria syndrome (HIGIRS) is a rare genetic disorder that is characterized by dramatic premature aging and accelerated cardiovascular disease. HIGIPS is almost always caused by a de novo point mutation in the lamin A gene (LMNA) that activates a cryptic splice donor site, producing a truncated mutant protein termed "progerin." WT prelamin A is anchored to the nuclear envelope by a farnesyl isoprenoid lipid. Cleavage of the terminal 15 aa and the farnesyl group releases mature lamin A from this tether. In contrast, this cleavage site is deleted in progerin. We hypothesized that retention of the farnesyl group causes progerin to become permanently anchored in the nuclear membrane, disrupting proper nuclear scaffolding and causing the characteristic nuclear blebbing seen in HGPS cells. Also, we hypothesized that blocking farnesylation would decrease progerin toxicity. To test this hypothesis, the terminal CSIM sequence in progerin was mutated to SSIM, a sequence that cannot be farnesylated. SSIM progerin relocalized from the nuclear periphery into nucleoplasmic aggregates and produced no nuclear blebbing. Also, blocking farnesylation of authentic progerin in transiently transfected HeLa, HEK 293, and NIH 3T3 cells with farnesyltransferase inhibitors (FTIs) restored normal nuclear architecture. Last, treatment of both early- and late-passage human HGPS fibroblasts with FTIs resulted in significant reductions in nuclear blebbing. Our results suggest that treatment with FTIs represents a potential therapy for patients with HGPS. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NIH, Hlth Res Scholars Program, Howard Hughes Med Inst, Bethesda, MD 20814 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. RP Collins, FS (reprint author), NHGRI, Genome Technol Branch, NIH, Bldg 31,Room 4B09,31 Ctr Dr,MSC 2152,50 S Dr, Bethesda, MD 20892 USA. EM fc23a@nih.gov OI Capell, Brian/0000-0002-7036-8359 FU NCI NIH HHS [U19 CA067771, U19 CA67771] NR 36 TC 207 Z9 215 U1 2 U2 30 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 6 PY 2005 VL 102 IS 36 BP 12879 EP 12884 DI 10.1073/pnas.0506001102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 962FP UT WOS:000231716700043 PM 16129833 ER PT J AU McMahon, FJ AF McMahon, FJ CA B D Phenome Grp TI The bipolar affective disorder (BPAD) phenome database: A resource for genetic studies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Genet Initiat Bipolar Disorder Consortium, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Univ Heidelberg, Cent Inst Mental Hlth, D-6900 Heidelberg, Germany. Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. EM mcmahonf@intra.nimh.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 3 EP 3 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300004 ER PT J AU Volkow, N AF Volkow, N TI Plenary lecture: Imaging the addicted brain SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIDA, NIH, Bethesda, MD 20892 USA. EM jrutter@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 7 EP 7 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300016 ER PT J AU Callicott, J AF Callicott, J TI DISC-1 genetic variation and human brain development and function SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, NIH, Bethesda, MD 20892 USA. EM jrutter@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 12 EP 12 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300035 ER PT J AU Weinberger, D AF Weinberger, D TI Imaging genomics: Principles and practices SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, NIH, Bethesda, MD 20892 USA. EM jrutter@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 12 EP 12 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300037 ER PT J AU Yao, Y Samuels, JF Willour, V Pinto, A Knowles, J McCracken, J Rauch, S Murphy, D Riddle, M Cullen, B Grados, M Greenberg, B Fyer, A Pauls, D Bienvenu, J Nestadt, G AF Yao, Y Samuels, JF Willour, V Pinto, A Knowles, J McCracken, J Rauch, S Murphy, D Riddle, M Cullen, B Grados, M Greenberg, B Fyer, A Pauls, D Bienvenu, J Nestadt, G TI Genome-wide linkage scan of obsessive-compulsive disorder: Significant evidence for susceptibility loci on chromosomes 3q21-27 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Johns Hopkins Univ, Baltimore, MD USA. Brown Univ, Providence, RI 02912 USA. Columbia Univ, New York, NY 10027 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. MGH, Boston, MA USA. NIMH, Bethesda, MD USA. EM gnestadt@jhmi.edu NR 1 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 12 EP 12 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300034 ER PT J AU Goldberg, TE Egan, MF Straub, R Weinberger, DR AF Goldberg, TE Egan, MF Straub, R Weinberger, DR TI Genotypic effects on episodic memory: Recent experience from BDNF, G72, and GRM3 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. EM goldbert@intra.nimh.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 14 EP 14 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300044 ER PT J AU Burdick, KE Funke, B Hodgkinson, CA Kane, JM Goldman, D Kucherlapati, R Ekholm, J Malhotra, AK AF Burdick, KE Funke, B Hodgkinson, CA Kane, JM Goldman, D Kucherlapati, R Ekholm, J Malhotra, AK TI Differential effects of DISC1 and DTNBP1 risk genotypes on cognition: New evidence for specificity SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Harvard Univ, Sch Med, Boston, MA USA. NIAAA, Rockville, MD 20852 USA. Zucker Hillside Hosp NSLIJHS, LI, New York, NY USA. EM kburdick@lij.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 17 EP 17 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300055 ER PT J AU Malhotra, AK Burdick, KE Funke, B Hodgkinson, CA Kucherlapati, R Goldman, D AF Malhotra, AK Burdick, KE Funke, B Hodgkinson, CA Kucherlapati, R Goldman, D TI Molecular genetic evidence for overlap between bipolar disorder and schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Zucker Hillside Hosp, LI, Glen Oaks, NY USA. Harvard Univ, Sch Med, Boston, MA USA. NIAAA, NIH, Neurogenet Lab, Rockville, MD 20852 USA. EM malhotra@lij.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 24 EP 24 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300080 ER PT J AU Buervenich, S Akula, N Schulze, TG Steele, C Corona, WR Kassem, L Etienne-Austin, L Lopez, V Detera-Wadleigh, SD Schumacher, J Spira, F Cichon, S Cox, NJ McMahon, FJ AF Buervenich, S Akula, N Schulze, TG Steele, C Corona, WR Kassem, L Etienne-Austin, L Lopez, V Detera-Wadleigh, SD Schumacher, J Spira, F Cichon, S Cox, NJ McMahon, FJ CA N Bipolar Dis Consor TI Association of GRIK2 haplotypes with bipolar affective disorder and potential interaction between GRIK2 and alpha-laminins SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Genet Basis Mood & Anxiety Disorders Unit, Mood & Anxiety Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Heidelberg, Cent Inst Mental Hlth, Div Genet Epidemiol Psychiat, D-6900 Heidelberg, Germany. Univ Bonn, Dept Psychiat, D-53115 Bonn, Germany. Univ Bonn, Inst Human Genet, D-53111 Bonn, Germany. Psychiat Zentrum Nordbaden, D-69168 Wiesloch, Germany. Univ Bonn, Dept Genom, Life & Brain Ctr, D-53127 Bonn, Germany. Indiana Univ, Sch Med, Dept Psychiat, Bloomington, IN 47405 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. EM buervens@intra.nimh.nih.gov RI McMahon, Francis/A-7290-2009; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014 OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 27 EP 27 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300090 ER PT J AU Liang, SG Shekhtman, T Gaucher, MA Barrett, TB Schork, NJ Berrettini, WH Byerley, W Coryell, W Gershon, ES McInnis, MG DePaulo, JR Nurnberger, JI Rice, JR Scheftner, W McMahon, FJ Kelsoe, JR AF Liang, SG Shekhtman, T Gaucher, MA Barrett, TB Schork, NJ Berrettini, WH Byerley, W Coryell, W Gershon, ES McInnis, MG DePaulo, JR Nurnberger, JI Rice, JR Scheftner, W McMahon, FJ Kelsoe, JR TI High density SNP association study of 22q13 identifies CACGN2 as a susceptibility locus for bipolar disorder in two independent samples SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Univ Calif San Diego, Biomed Sci Grad Program, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. San Diego VA Healthcare Syst, San Diego, CA USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Washington Univ, Dept Psychiat, St Louis, MO USA. Rush Presbyterian St Lukes Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. NIMH, Genet Basis Mood & Anxiety Disorders Unit, NIH, Bethesda, MD 20892 USA. EM sherri@ucsd.edu RI McMahon, Francis/A-7290-2009; McInnis, Melvin/F-6963-2012 OI McInnis, Melvin/0000-0002-0375-6247 NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 27 EP 28 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300091 ER PT J AU Hu, X Zhou, Z Lipsky, RH Virkkunen, M Goldman, D AF Hu, X Zhou, Z Lipsky, RH Virkkunen, M Goldman, D TI Association of serotonin transporter gene with type I alcohol dependence SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. EM huxz@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 35 EP 35 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300119 ER PT J AU Wang, J Hinrichs, AL Bufe, B Kwon, JM Budde, J Allen, R Bertelsen, S Evans, W Dick, D Rice, J Meyerhof, W Bierut, LJ Goate, AM AF Wang, J Hinrichs, AL Bufe, B Kwon, JM Budde, J Allen, R Bertelsen, S Evans, W Dick, D Rice, J Meyerhof, W Bierut, LJ Goate, AM TI Missense mutation in a bitter taste receptor (HTAS2R16) influences risk for alcohol dependence SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Neurol & Genet, St Louis, MO 63110 USA. German Inst Human Nutr Potsdam Rehbruecke, Dept Mol Genet, Nuthetal, Germany. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM jwang@hg.wustl.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 38 EP 38 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300132 ER PT J AU Fanous, AH Pato, MT Richter, MA Hanna, GL Arnold, PD Burroughs, E Himle, JA Van Etten, M Fischer, DJ Kennedy, JL Murphy, DL Pato, CN AF Fanous, AH Pato, MT Richter, MA Hanna, GL Arnold, PD Burroughs, E Himle, JA Van Etten, M Fischer, DJ Kennedy, JL Murphy, DL Pato, CN TI Sibling resemblance for clinical features of obsessive-compulsive disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Vet Affairs Med Ctr, Washington, DC 20422 USA. Georgetown Univ, Sch Med, Washington, DC 20057 USA. Virginia Commonwealth Univ, Richmond, VA 23284 USA. Upstate Med Univ, Syracuse, NY USA. Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. Univ Toronto, Dept Psychiat, Toronto, ON, Canada. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. EM ahfanous@hsc.vcu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 44 EP 44 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300154 ER PT J AU Bobb, AJ Gornick, MC Addington, AM Shaw, P Greenstein, DK Sharp, WS Clasen, LS Sidransky, E Castellanos, X Rapoport, JL AF Bobb, AJ Gornick, MC Addington, AM Shaw, P Greenstein, DK Sharp, WS Clasen, LS Sidransky, E Castellanos, X Rapoport, JL TI The dopamine D4 gene and ADHD: Association with diagnosis and endophenotypic measures SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD USA. NIMH, Clin Neurosci Branch, NIH, Bethesda, MD USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD USA. NYU, Ctr Child Study, New York, NY USA. EM aaronbobb@gmail.com RI Shaw, Philip/A-1129-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 54 EP 54 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300189 ER PT J AU Detera-Wadleigh, SD Liu, C Badner, JA Corona, W Akula, N Cardona, I Kundu, M Steele, C Maheshwari, M Bonner, TI Gibbs, R Gershon, ES McMahon, FJ AF Detera-Wadleigh, SD Liu, C Badner, JA Corona, W Akula, N Cardona, I Kundu, M Steele, C Maheshwari, M Bonner, TI Gibbs, R Gershon, ES McMahon, FJ TI DOCK9, a candidate gene for bipolar disorder (BPAD) on chromosome 13q32.3 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, MAP Genet Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77098 USA. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. EM sevilladetera@nih.gov RI McMahon, Francis/A-7290-2009; Liu, Chunyu/G-7561-2012 OI Liu, Chunyu/0000-0002-5986-4415 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 75 EP 75 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300269 ER PT J AU Greenwood, TA Schork, NJ Dick, DM Reich, T Foroud, T Nurnberger, JI Berrettini, W Byerley, W Coryell, W DePaulo, R McInnis, M Gershon, ES McMahon, FJ Sheftner, W Kelsoe, JR AF Greenwood, TA Schork, NJ Dick, DM Reich, T Foroud, T Nurnberger, JI Berrettini, W Byerley, W Coryell, W DePaulo, R McInnis, M Gershon, ES McMahon, FJ Sheftner, W Kelsoe, JR TI Differential linkage to bipolar disorder resulting from classification by the existence of comorbid diagnoses SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Univ Calif San Diego, San Diego, CA 92103 USA. San Diego Vet Affairs Healthcare Syst, San Diego, CA USA. Washington Univ, St Louis, MO 63130 USA. Indiana Univ, Indianapolis, IN 46204 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Iowa, Iowa City, IA USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Chicago, Chicago, IL 60637 USA. NIMH, Mood & Anxiety Program, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Rush Presbyterian Med Ctr, Chicago, IL USA. EM tgreenwood@ucsd.edu RI McMahon, Francis/A-7290-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 77 EP 78 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300276 ER PT J AU Kassem, L Lopez, V Steele, J Consortium, ND McMahon, FJ AF Kassem, L Lopez, V Steele, J Consortium, ND McMahon, FJ TI Polarity at onset is a familial feature of bipolar affective disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. EM kasseml@intra.nimh.nih.gov RI McMahon, Francis/A-7290-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 78 EP 78 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300279 ER PT J AU Maheshwari, M Liu, C Badner, JA Smith, CK Christian, SL Zou, H Detera-Wadleigh, SD Bonner, T McMahon, FJ Gershon, ES Gibbs, RA AF Maheshwari, M Liu, C Badner, JA Smith, CK Christian, SL Zou, H Detera-Wadleigh, SD Bonner, T McMahon, FJ Gershon, ES Gibbs, RA TI Resequencing and fine map association study of G72/G30 region in bipolar disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. NIH, MAP Genet, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NIMH, Genet Lab, Bethesda, MD 20892 USA. EM manjulam@bcm.tmc.edu RI McMahon, Francis/A-7290-2009; Liu, Chunyu/G-7561-2012 OI Liu, Chunyu/0000-0002-5986-4415 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 78 EP 79 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300281 ER PT J AU Gornick, MC Addington, AM Bobb, A Sporn, A Gogtay, N Greenstein, D Banville, M Gochman, P Straub, RE Rapoport, JL AF Gornick, MC Addington, AM Bobb, A Sporn, A Gogtay, N Greenstein, D Banville, M Gochman, P Straub, RE Rapoport, JL TI Overview of candidate gene studies in the NIMH childhood-onset schizophrenia sample SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Clin Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. EM GornickM@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 84 EP 85 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300302 ER PT J AU Giegling, I Goldman, D Zhou, Z Dietrich, I Thalmeier, A Schneider, B Hartmann, AM Moller, H Rujescu, D AF Giegling, I Goldman, D Zhou, Z Dietrich, I Thalmeier, A Schneider, B Hartmann, AM Moller, H Rujescu, D TI Searching for new intermediate phenotypes: Aggression-related genes in suicidal behavior SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Univ Munich, Dept Psychiat Mol & Clin Neurobiol, D-80539 Munich, Germany. NIAAA, NIH, Bethesda, MD USA. Univ Frankfurt, Dept Psychiat, D-6000 Frankfurt, Germany. Univ Munich, Dept Psychiat, D-80539 Munich, Germany. EM Dan.Rujescu@med.uni-muenchen.de NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 90 EP 90 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300324 ER PT J AU Zalsman, G Huang, Y Oquendo, MA Hu, X Goldman, D Mann, JJ AF Zalsman, G Huang, Y Oquendo, MA Hu, X Goldman, D Mann, JJ TI A triallelic serotonin transporter gene promoter polymorphism (5-HTTLPR), stressful life events and severity of depression SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Columbia Univ, Dept Psychiat, New York, NY USA. Columbia Univ, New York State Psychiat Inst, Dept Neurosci, New York, NY USA. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. EM zalsman@post.tau.ac.it NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 108 EP 108 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300388 ER PT J AU Addington, AM Gornick, M Shaw, P Gogtay, N Bobb, A Greenstein, D Clasen, L Lenane, M Gochman, P Rapoport, JL AF Addington, AM Gornick, M Shaw, P Gogtay, N Bobb, A Greenstein, D Clasen, L Lenane, M Gochman, P Rapoport, JL TI Neuregulin (NRG1): Susceptibility haplotypes and neurodevelopment in childhood onset schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. EM addingta@intra.nimh.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 115 EP 116 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300415 ER PT J AU Egan, MF Straub, R Nicodemus, K Vakkalanka, K Goldberg, TE Weinberger, DR AF Egan, MF Straub, R Nicodemus, K Vakkalanka, K Goldberg, TE Weinberger, DR TI Evidence for CAPON affecting risk for schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Clin Brain Disorders Branch, NIH, HHS, Bethesda, MD 20892 USA. EM eganm@intra.nimh.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 121 EP 121 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300437 ER PT J AU Fanous, AH Neale, MC Riley, BP Straub, RE O'Neill, AF Walsh, D Kendler, KS AF Fanous, AH Neale, MC Riley, BP Straub, RE O'Neill, AF Walsh, D Kendler, KS TI Genome scan of latent classes of psychotic illness SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Washington VA Med Ctr, Washington, DC USA. Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC 20057 USA. Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23284 USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA 23284 USA. NIMH, Genes Cognit & Psychosis Program, Bethesda, MD USA. Hlth Res Board, Dublin, Ireland. Queens Univ Belfast, Belfast, Antrim, North Ireland. EM ahfanous@hsc.vcu.edu RI Neale, Michael/B-1418-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 121 EP 122 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300438 ER PT J AU Lencz, T Robinson, DG Xu, K Ekholm, JM Sevy, S Gunduz-Bruce, H Woerner, MG Kane, JM Goldman, D Malhotra, AK AF Lencz, T Robinson, DG Xu, K Ekholm, JM Sevy, S Gunduz-Bruce, H Woerner, MG Kane, JM Goldman, D Malhotra, AK TI DRD2 promoter region variation predicts sustained response to antipsychotics in first episode schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. Albert Einstein Coll Med, Dept Psychiat, Bronx, NY 10467 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. EM lencz@lij.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 125 EP 125 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300451 ER PT J AU Nicodemus, KK Straub, RE Egan, MF Weinberger, DR AF Nicodemus, KK Straub, RE Egan, MF Weinberger, DR TI Evidence for statistical epistasis between (COMT) Val158Met polymorphism and multiple putative schizophrenia susceptibility genes SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 Johns Hopkins SPH, Dept Epidemiol, Baltimore, MD USA. NIMH, GCAP, NIH, Bethesda, MD 20892 USA. EM nicodemusk@mail.nih.gov NR 0 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 130 EP 131 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300472 ER PT J AU Prathikanti, S Kolachana, B Nicodemus, K Egan, MF Weinberger, DR AF Prathikanti, S Kolachana, B Nicodemus, K Egan, MF Weinberger, DR TI MYH16 initially shows favorable association to schizophrenia pseudogene or functional link to schizophrenia? SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, GCAP Genes Cognit & Psychosis, Bethesda, MD 20892 USA. EM sridharp@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 130 EP 130 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300470 ER PT J AU Straub, RE Mayhew, MB Vakkalanka, RK Kolachana, B Goldberg, TE Egan, MF Weinberger, DR AF Straub, RE Mayhew, MB Vakkalanka, RK Kolachana, B Goldberg, TE Egan, MF Weinberger, DR TI Detection of dysbindin (DTNBP1) effects on clinical and cognitive phenotypes can be highly dependent on variation in COMT SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. EM STRAUBR@INTRA.NIMH.NIH.GOV NR 2 TC 2 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 135 EP 136 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300490 ER PT J AU Straub, RE Mayhew, MB Vakkalanka, RK Kolachana, B Goldberg, TE Egan, MF Weinberger, DR AF Straub, RE Mayhew, MB Vakkalanka, RK Kolachana, B Goldberg, TE Egan, MF Weinberger, DR TI MUTED, a protein that binds to dysbindin (DTNBP1), is associated with schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. EM Straubr@Intra.Nimh.Nih.Gov NR 0 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 136 EP 136 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300491 ER PT J AU Weinberger, DR Lipska, BK Huffaker, S Kleinman, JE Egan, MF Straub, RE AF Weinberger, DR Lipska, BK Huffaker, S Kleinman, JE Egan, MF Straub, RE TI Variation in PPP1R1B predicts risk for schizophrenia, cognitive function, and gene expression in brain SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 13th World Congress on Psychiatric Genetics CY SEP 04-08, 2005 CL Boston, MA SP Int Soc Psychiat Gen C1 NIMH, GCAP, NIH, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2005 VL 138B IS 1 BP 139 EP 140 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 971BY UT WOS:000232357300506 ER PT J AU Cowley, JA McCulloch, RJ Rajendran, KV Cadogan, LC Spann, KM Walker, PJ AF Cowley, JA McCulloch, RJ Rajendran, KV Cadogan, LC Spann, KM Walker, PJ TI RT-nested PCR detection of Mourilyan virus in Australian Penaeus monodon and its tissue distribution in healthy and moribund prawns SO DISEASES OF AQUATIC ORGANISMS LA English DT Article DE Mourilyan virus; Uukuniemi virus; phlebovirus; bunyavirus; Penaeus monodon; penaeid shrimp; prawn; in situ hybridisation; PCR ID GILL-ASSOCIATED VIRUS; YELLOW-HEAD VIRUS; ISOLATED MORTALITY VIRUS; TAURA-SYNDROME VIRUS; HEMATOPOIETIC NECROSIS VIRUS; IN-SITU HYBRIDIZATION; LYMPHOID ORGAN VIRUS; PERIPHERAL NEUROPATHY; ELECTRON MICROSCOPY; EASTERN AUSTRALIA AB Mourilyan virus (MoV) is a newly identified virus of Penaeus monodon prawns that is genetically related to the Uukuniemi virus and other phleboviruses of the Bunyaviridae. This paper describes an RT-nested PCR test that can reliably detect between 2 and 6 copies of a synthetic MoV RNA. Total RNA isolated from the lymphoid organ, gills and haemocytes of P. monodon with moderate infections gave comparable amplicon yields in the RT-PCR step of the test. However, in prawns with extremely low-level infections, haemocytes and gill tissue proved slightly more reliable in detecting MoV RNA following nested PCR. The distribution of MoV in tissues of healthy and moribund P. monodon was examined by in situ hybridisation (ISH) using a digoxigenin-labelled DNA probe to a similar to 0.8 kb M RNA segment cDNA insert in clone pMoV4.1. The DNA probe targeted a region in the MoV M RNA segment containing a coding sequence with homology to the C-terminus of the G2 glycoprotein of phleboviruses. In healthy prawns harbouring an unapparent MoV infection, ISH signal primarily occurred in the lymphoid organ, where it was more prominent in hypertrophied cells of 'spheroids' than within cells of normal tubules. ISH signal was also sometimes detected in cells of cuticular epithelium, segmental nerve ganglion and the antermal and tegmental glands. MoV was distributed widely throughout these and other cephalothoracic tissues of mesodermal and ectodermal origin in moribund P. monodon following experimental infection or collected from farm pond edges during disease episodes. Transmission electron microscopy of gill of moribund, captive-reared P. monodon identified spherical (similar to 85 nm diameter) to ovoid MoV particles (similar to 85 x 100 nm) in and around highly necrotic cells in which the nucleus and other organelles had disintegrated. MoV virions co-existed with rod-shaped virions of gill-associated virus and were often seen clustered within cytoplasmic vacuoles or associated with the outer rim of concentric ring-shaped structures comprised of endoplasmic membranes likely to represent degenerated Golgi. C1 CSIRO, Livestock Ind, Queensland Biosci Precinct, St Lucia, Qld 4067, Australia. RP Cowley, JA (reprint author), NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. EM jeff.cowley@csiro.au RI Spann, Kirsten/B-4524-2013; Cowley, Jeff/H-7553-2013; Walker, Peter/H-6059-2013 OI Spann, Kirsten/0000-0003-0567-8382; Walker, Peter/0000-0003-1851-642X NR 47 TC 12 Z9 12 U1 0 U2 5 PU INTER-RESEARCH PI OLDENDORF LUHE PA NORDBUNTE 23, D-21385 OLDENDORF LUHE, GERMANY SN 0177-5103 J9 DIS AQUAT ORGAN JI Dis. Aquat. Org. PD SEP 5 PY 2005 VL 66 IS 2 BP 91 EP 104 DI 10.3354/dao066091 PG 14 WC Fisheries; Veterinary Sciences SC Fisheries; Veterinary Sciences GA 983YU UT WOS:000233269100001 PM 16231634 ER PT J AU Le Foll, B Goldberg, SR AF Le Foll, B Goldberg, SR TI Ethanol does not affect discriminative-stimulus effects of nicotine in rats SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE subjective effect; drug discrimination; reward; nicotine; ethanol; (rat) ID FREELY MOVING RATS; CONDITIONED PLACE PREFERENCES; D-3 RECEPTOR LIGANDS; CIGARETTE-SMOKING; DOPAMINE RELEASE; COCAINE-SEEKING; ALCOHOL; MEDICATIONS; ANTAGONISTS; ADDICTION AB The effects of ethanol were evaluated in rats trained to discriminate 0.4 mg/kg of nicotine from saline under a fixed-ratio 10 schedule of food delivery. Ethanol (0.1 - 1 g/kg, i.p.) did not produce any nicotine-like discriminative effects and did not produce any shift in the dose-response curve for nicotine discrimination. Thus, the ability to discriminate nicotine's effects does not appear to be altered by ethanol administration. However, the high dose of I g/kg ethanol, given either alone or in combination with nicotine, markedly depressed food-maintained responding. This later effect was associated in some rats with an attenuation of the discriminative-stimulus effects of the training dose of nicotine. This suggests that previous reports of increased tobacco smoking following ethanol consumption in humans are connected, in some way, with an increase in motivation to consume nicotine that is produced by ethanol, rather than with a decrease in the subjective response to nicotine. (c) 2005 Elsevier B.V. All rights reserved. C1 NIDA, Preclin Pharmacol Branch, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Le Foll, B (reprint author), NIDA, Preclin Pharmacol Branch, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM blefoll@intra.nida.nih.gov RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Intramural NIH HHS NR 48 TC 9 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD SEP 5 PY 2005 VL 519 IS 1-2 BP 96 EP 102 DI 10.1016/j.ejphar.2005.06.051 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 964AD UT WOS:000231847100015 PM 16109399 ER PT J AU Kim, HS Wainer, IW AF Kim, HS Wainer, IW TI The covalent immobilization of microsomal uridine diphospho-glucuronosyltransferase (UDPGT): Initial synthesis and characterization of an UDPGT immobilized enzyme reactor for the on-line study of glucuronidation SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE glucuronides; immobilized enzyme reactors; rat liver microsomes ID IDENTIFICATION; METABOLISM AB The microsomal fraction of rat liver containing uridine diphospho-glucuronosyltransferase (UDPGT; EC 2.4.1.17) has been covalently immobilized on a high performance chromatographic support. In this study Nucleosil Si-500 silica was converted into diol-bonded silica and subsequently converted into an aldehyde form through oxidation with sodium periodate. The microsomal fraction was immobilized via Schiff base formation followed by reduction with sodium cyanoborohydride. The resulting immobilized enzyme reactor (IMER) was placed in a multi-dimensional chromatographic system which utilized a mixed mode (C-18 and anion exchange) column to trap the parent compound and glucuronide and a C18 column to separate the substrate and product. The IMER system was used for the online glucuronidation of 4-methylumbelliferone (4Me70HC) and acetaminophen (APAP). The Michaelis-Menten kinetic parameters (K-m and V-max) associated with the formation of 4Me70HC and APAP glucuronides demonstrated that the immobilization had not significantly affected the enzymatic activity of the UDPGT relative to the non-immobilized enzyme. The IMER retained enzymatic activity for more than 6 weeks. The results of this study demonstrate an easy and convenient way to identify compounds which may be glucuronidated and to synthesize and characterize the resulting products. Published by Elsevier B.V. C1 NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov NR 24 TC 15 Z9 17 U1 1 U2 8 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 SEP 5 PY 2005 VL 823 IS 2 BP 158 EP 166 DI 10.1016/j.jchromb.2005.06.030 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 958DU UT WOS:000231425700012 PM 16023900 ER PT J AU Mannes, AJ Brown, DC Keller, J Cordes, L Eckenhoff, RG Caudle, RM Iadarola, MJ Meng, QC AF Mannes, AJ Brown, DC Keller, J Cordes, L Eckenhoff, RG Caudle, RM Iadarola, MJ Meng, QC TI Measurement of resiniferatoxin in serum samples by high-performance liquid chromatography SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article ID ALPHA-1-ACID GLYCOPROTEIN AB A novel and simple method of extraction, separation, identification and quantification of resiniferatoxin (RTX) in serum samples is reported. Human serum and whole blood were treated with acetonitrile to denature proteins, such as orosomucoid, and the soluble fraction was passed through a reversed-phase C-18 cartridge. RTX eluted from the cartridge was quantified by high-performance liquid chromatography (HPLC) using a reversed-phase C-18 column. Reproducible recovery of RTX and tinyatoxin, an internal standard, from serum was achieved. Isocratic elution with 62% acetonitrile provided a suitable retention time without interfering peaks eluting near the analyte. Therefore, the procedure described provides a useful assay for determination of serum RTX pharmacokinetic parameters. Published by Elsevier B.V. C1 NIH, DASS, Bethesda, MD 20892 USA. Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Anesthesia, Philadelphia, PA 19104 USA. Univ Florida, Coll Dent, Dept Oral & Maxillofacial Surg, Gainesville, FL USA. NIDCR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD USA. RP Mannes, AJ (reprint author), NIH, DASS, Bldg 49,Room 1A08,49 Convent Dr, Bethesda, MD 20892 USA. EM amannes@nih.gov OI Mannes, Andrew/0000-0001-5834-5667 NR 10 TC 0 Z9 0 U1 0 U2 0 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 SEP 5 PY 2005 VL 823 IS 2 BP 184 EP 188 DI 10.1016/j.jchromb.2005.06.042 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 958DU UT WOS:000231425700016 PM 16039169 ER PT J AU Li, SW Takeuchi, F Wang, JA Fuller, C Pacheco-Rodriguez, G Moss, J Darling, TN AF Li, SW Takeuchi, F Wang, JA Fuller, C Pacheco-Rodriguez, G Moss, J Darling, TN TI MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; INSULIN-RESISTANCE; DENDRITIC CELLS; GENE-THERAPY; EXPRESSION; TSC2; COMPLEX; SKIN; RAPAMYCIN; PATHOGENESIS AB Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 (hamartin) or TSC2 (tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor-derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line to a greater extent than conditioned medium from TSC fibroblasts, an effect blocked by neutralizing MCP-1 specific antibody. Overexpression of MCP-1 seems to be caused by loss of tuberin function because Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2(-/-)) produced 28 times as much MCP-1 protein as did EEF Tsc2(+/+) cells; transient expression of WT but not mutant human TSC2 by EEF Tsc2(-/-) cells inhibited MCP-1 production; and pharmacological inhibition of the Rheb-mTOR pathway, which is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2(-/-) cells. Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target. C1 NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. RP Darling, TN (reprint author), NHLBI, Pulm Crit Care Med Branch, Bldg 10, Bethesda, MD 20814 USA. EM tdarling@usuhs.mil OI Darling, Thomas/0000-0002-5161-1974 FU NCI NIH HHS [1 R01 CA100907, R01 CA100907] NR 45 TC 22 Z9 24 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 5 PY 2005 VL 202 IS 5 BP 617 EP 624 DI 10.1084/jem.20042469 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 965PM UT WOS:000231962700006 PM 16129702 ER PT J AU Filippov, S Koenig, GC Chun, TH Hotary, KB Ota, I Bugge, TH Roberts, JD Fay, WP Birkedal-Hansen, H Holmbeck, K Sabeh, F Allen, ED Weiss, SJ AF Filippov, S Koenig, GC Chun, TH Hotary, KB Ota, I Bugge, TH Roberts, JD Fay, WP Birkedal-Hansen, H Holmbeck, K Sabeh, F Allen, ED Weiss, SJ TI MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID 3-DIMENSIONAL EXTRACELLULAR-MATRIX; TISSUE INHIBITOR; CAROTID-ARTERY; GROWTH-FACTOR; MIGRATION; EXPRESSION; DISEASE; MATRIX-METALLOPROTEINASE-9; INJURY; MICE AB During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix. C1 Univ Michigan, Div Med & Mol Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Div Cardiol, Dept Internal Med, Ann Arbor, MI 48109 USA. Natl Inst Dental & Craniofacial Res, Protease & Tissue Remodeling Unit, Bethesda, MD 20892 USA. Natl Inst Dental & Craniofacial Res, Matrix Metalloproteinase Unit, Bethesda, MD 20892 USA. RP Weiss, SJ (reprint author), Univ Michigan, Div Med & Mol Genet, Ann Arbor, MI 48109 USA. EM sjweiss@umich.edu FU NCI NIH HHS [CA71699, R01 CA071699, R01 CA088308, CA088308]; NHLBI NIH HHS [HL57346, HL65224, P01 HL057346, R01 HL065224] NR 46 TC 84 Z9 86 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 5 PY 2005 VL 202 IS 5 BP 663 EP 671 DI 10.1084/jem.20050607 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 965PM UT WOS:000231962700010 PM 16147977 ER PT J AU Yoshida, M Jeang, KT AF Yoshida, M Jeang, KT TI Preface to 25 years of HTLV-1 and ATL research SO ONCOGENE LA English DT Editorial Material ID T-CELL LEUKEMIA; RETROVIRUS C1 Banyu Tsukuba Res Inst, Tsukuba, Ibaraki, Japan. NIAID, Mol Virol Sect, LMM, NIH, Bethesda, MD 20892 USA. RP Yoshida, M (reprint author), Banyu Tsukuba Res Inst, Tsukuba, Ibaraki, Japan. RI Jeang, Kuan-Teh/A-2424-2008 NR 6 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 5 PY 2005 VL 24 IS 39 BP 5925 EP 5925 DI 10.1038/sj.onc.1208967 PG 1 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 960WH UT WOS:000231623400001 ER PT J AU Kashanchi, F Brady, JN AF Kashanchi, F Brady, JN TI Transcriptional and post-transcriptional gene regulation of HTLV-1 SO ONCOGENE LA English DT Review DE HTLV-1; tax; transcription; p53; chromatin; Rex ID T-CELL-LEUKEMIA; VIRUS TYPE-I; LONG TERMINAL REPEAT; NF-KAPPA-B; ELEMENT-BINDING PROTEIN; CAMP-RESPONSIVE ELEMENT; TYPE-1 TAX PROTEIN; TROPICAL SPASTIC PARAPARESIS; NUCLEOLAR TARGETING SIGNAL; DOMINANT-NEGATIVE MUTANTS AB Adult T-cell leukemia (ATL) is an aggressive hematologic malignancy caused by human T-cell leukemia virus type I (HTLV-1). Tax, encoded by the HTLV-1 pX region, has been recognized by its pleiotropic actions to play a critical role in leukemogenesis. Three highly conserved 21-bp repeat elements located within the long terminal repeat, commonly referred to as Tax-responsive element 1 (TRE-1), are critical to Tax-mediated viral transcriptional activation through complex interaction with cyclic AMP-responsive element binding protein (CREB), CBP/ p300 and PCAF. Tax has also been shown to activate transcription from a number of critical cellular genes through the NF-kappa B and serum-responsive factor pathways. Tax transactivation has been attributed to the protein's interaction with transcription factors, chromatin remodeling complexes, cell cycle and repair genes. In this review, we will discuss some of the latest findings on this fascinating viral activator and highlight its regulation of cellular factors including CREB, p300/CBP and their effect on RNA polymerase II and chromatin remodeling, as well as its role in cytoplasmic and nuclear function. W e will highlight the possible contribution of each factor, discuss Tax's critical peptide domains and highlight its post-transcriptional modi. cations. It is quite obvious that, collectively, Tax's effects on a wide variety of cellular targets cooperate in promoting cell proliferation and leukemogenesis. In addition, the post-transcriptional effects of Rex play an important role in virus replication. Understanding these interactions at a molecular level will facilitate the targeted development of drugs to effectively inhibit or treat ATL. C1 George Washington Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20299 USA. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Kashanchi, F (reprint author), George Washington Univ, Sch Med, Dept Biochem & Mol Biol, 2300 Eye St,NW,Ross Hall,Room 551, Washington, DC 20299 USA. EM bcmfxk@gwumc.eduz FU NIAID NIH HHS [AI44357, AI43894]; PHS HHS [13969] NR 157 TC 101 Z9 113 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 5 PY 2005 VL 24 IS 39 BP 5938 EP 5951 DI 10.1038/sj.onc.1208973 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 960WH UT WOS:000231623400004 PM 16155601 ER PT J AU Grassmann, R Aboud, M Jeang, KT AF Grassmann, R Aboud, M Jeang, KT TI Molecular mechanisms of cellular transformation by HTLV-1 Tax SO ONCOGENE LA English DT Review DE HTLV; leukemia; T-lymphocyte; cell cycle; transformation; immortalization; Tax; ATLL apoptosis ID VIRUS TYPE-I; NF-KAPPA-B; HUMAN T-CELLS; INTERLEUKIN-2 GENE-EXPRESSION; PRIMARY HUMAN-LYMPHOCYTES; TUMOR-SUPPRESSOR GENES; ACUTE MYELOID-LEUKEMIA; CREB BINDING-PROTEIN; LONG TERMINAL REPEAT; ONCOGENE PRODUCT TAX AB The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent. broblasts and human T-lymphocytes. Through CREB, NF-kappa B and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL- 2R alpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades ( e. g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells. C1 Univ Erlangen Nurnberg, Inst Klin & Mol Virol, Erlangen, Germany. Ben Gurion Univ Negev, Dept Microbiol, IL-84105 Beer Sheva, Israel. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Grassmann, R (reprint author), Univ Erlangen Nurnberg, Inst Klin & Mol Virol, Schlossgarten 4, Erlangen, Germany. EM Ralph.Grassmann@viro.med.uni-erlangen.de RI Jeang, Kuan-Teh/A-2424-2008 NR 157 TC 243 Z9 252 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 5 PY 2005 VL 24 IS 39 BP 5976 EP 5985 DI 10.1038/sj.onc.1208978 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 960WH UT WOS:000231623400007 PM 16155604 ER PT J AU Nicot, C Harrod, RL Ciminale, V Franchini, G AF Nicot, C Harrod, RL Ciminale, V Franchini, G TI Human T-cell leukemia/lymphoma virus type 1 nonstructural genes and their functions SO ONCOGENE LA English DT Article DE HTLV-1; retrovirus; genes; proteins ID I HTLV-I; BLOOD MONONUCLEAR-CELLS; OPEN READING FRAMES; VACUOLAR H+-ATPASE; P12(I) PROTEIN; P13(II) PROTEIN; 21-BASE-PAIR REPEATS; PRIMARY LYMPHOCYTES; LEUKEMIA-LYMPHOMA; VIRAL INFECTIVITY AB The human T-cell leukemia/lymphoma virus (HTLV) genome, in addition to the structural Gag and Env proteins and retroviral enzymes, carries a region at its 30 end originally designated pX. To date, we know that this region encodes two essential transcriptional and post-transcriptional positive regulators of viral expression, the Tax and Rex proteins, respectively (reviewed elsewhere in this issue). Here, we will review current knowledge of the functions of three additional proteins encoded in the pX region, p12(I), p13(II), and p30(II). C1 NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. Univ Kansas, Med Ctr, Dept Microbiol, Kansas City, KS 66160 USA. So Methodist Univ, Dept Biol Sci, Mol Virol Lab, Dallas, TX 75275 USA. Univ Padua, Dept Oncol & Surg Sci, I-35128 Padua, Italy. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, 41-D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU NCI NIH HHS [R01 CA106258]; NIAID NIH HHS [R01 AI058944] NR 54 TC 66 Z9 71 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 5 PY 2005 VL 24 IS 39 BP 6026 EP 6034 DI 10.1038/sj.onc.1208977 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 960WH UT WOS:000231623400012 PM 16155609 ER PT J AU Van Houten, B Croteau, DL DellaVecchia, MJ Wang, H Kisker, C AF Van Houten, B Croteau, DL DellaVecchia, MJ Wang, H Kisker, C TI 'Close-fitting sleeves': DNA damage recognition by the UvrABC nuclease system SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE protein-DNA interaction; bacterial nucleotide excision repair; DNA damage recognition ID NUCLEOTIDE EXCISION-REPAIR; ESCHERICHIA-COLI-UVRA; C-TERMINAL REGION; SITE-SPECIFIC MUTAGENESIS; INTERSTRAND CROSS-LINKS; ABC EXCINUCLEASE; (A)BC EXCINUCLEASE; CRYSTAL-STRUCTURE; PREINCISION COMPLEX; POLYMERASE-I AB DNA damage recognition represents a long-standing problem in the field of protein-DNA interactions. This article reviews our current knowledge of how damage recognition is achieved in bacterial nucleotide excision repair through the concerted action of the UvrA, UvrB, and UvrC proteins. Published by Elsevier B.V. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. SUNY Stony Brook, Dept Pharmacol, Ctr Struct Biol, Stony Brook, NY 11794 USA. RP Van Houten, B (reprint author), NIEHS, Mol Genet Lab, NIH, 111 Alexander Dr,MD D3-01, Res Triangle Pk, NC 27709 USA. EM vanhout1@niehs.nih.gov RI Wang, Hong/F-3164-2014 OI Wang, Hong/0000-0003-0165-3559 NR 184 TC 79 Z9 81 U1 0 U2 9 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 SEP 4 PY 2005 VL 577 IS 1-2 BP 92 EP 117 DI 10.1016/j.mrfmmm.2005.03.013 PG 26 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 954OR UT WOS:000231164900008 PM 15927210 ER EF