FN Thomson Reuters Web of Science™ VR 1.0 PT B AU Mohapatra, A Wexler, P AF Mohapatra, Asish Wexler, Philip BE Wexler, P VanDerKolk, J Mohapatra, A Agarwal, R TI Information Resources Supporting Global Chemicals Policy and Management SO CHEMICALS, ENVIRONMENT, HEALTH: A GLOBAL MANAGEMENT PERSPECTIVE LA English DT Article; Book Chapter C1 [Mohapatra, Asish] Hlth Canada Alberta Reg Northern Reg, Environm Hlth Program, Calgary, AB, Canada. [Wexler, Philip] Natl Lib Med, Bethesda, MD USA. RP Mohapatra, A (reprint author), Hlth Canada Alberta Reg Northern Reg, Environm Hlth Program, Contaminated Sites, Calgary, AB, Canada. NR 3 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-8470-2 PY 2012 BP 739 EP 758 PG 20 WC Environmental Sciences; Environmental Studies SC Environmental Sciences & Ecology GA BD0YY UT WOS:000357861200052 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Overview of Protein Conjugation SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Editorial Material; Book Chapter ID CROSS-LINKING; DIMETHYL SUBERIMIDATE; SIGNAL-TRANSDUCTION; ESCHERICHIA-COLI; CREATINE-KINASE; ARYL NITRENE; AMINO ACIDS; PROTEOMICS; IDENTIFICATION; DEHYDROGENASE C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 83 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 1 EP 8 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400002 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Review of Protein and Nucleic Acid Chemistry SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Review; Book Chapter ID DISULFIDE BOND FORMATION; METHYL 4-MERCAPTOBUTYRIMIDATE; SULFHYDRYL-GROUPS; ESCHERICHIA-COLI; HETEROBIFUNCTIONAL REAGENT; REDUCTIVE ALKYLATION; CROSSLINKING REAGENT; ENZYMATIC-ACTIVITY; CROSS-LINKING; PEPTIDES C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 94 TC 0 Z9 0 U1 0 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 9 EP 34 PG 26 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400003 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Chemistry of Protein and Nucleic Acid Cross-Linking and Conjugation Second Edition Preface SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Editorial Material; Book Chapter C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP XV EP XV PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400001 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Reagents Targeted to Specific Functional Groups SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID N-ETHYLMALEIMIDE; REDUCTIVE ALKYLATION; METHIONINE RESIDUES; AMINO ACIDS; PROTEINS; CARBODIIMIDES; DEHYDROGENASE; DERIVATIVES; HEMOGLOBIN; STABILITY C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 64 TC 2 Z9 2 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 35 EP 51 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400004 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI How to Design and Choose Cross-Linking Reagents SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID ESCHERICHIA-COLI; BIFUNCTIONAL REAGENTS; MEMBRANE-IMPERMEANT; MASS-SPECTROMETRY; METHYL 4-MERCAPTOBUTYRIMIDATE; HETEROBIFUNCTIONAL REAGENT; ACETYLCHOLINE-RECEPTOR; CROSSLINKING REAGENT; RIBOSOMAL-PROTEINS; LACTOSE PERMEASE C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 126 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 53 EP 80 PG 28 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400005 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Homobifunctional Cross-Linking Reagents SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID DIRECTED ALKYLATING-AGENTS; SEQUENCE-SPECIFIC ALKYLATION; CARBINOLAMINE TUMOR INHIBITORS; QUATERNARY AMMONIUM DERIVATIVES; BOVINE PANCREATIC RIBONUCLEASE; SELECTIVE ANTITUMOR AGENTS; INTACT HUMAN-ERYTHROCYTES; IN-VITRO CYTOTOXICITY; DNA-BINDING AFFINITY; 3-DIMENSIONAL PROTEIN STRUCTURES C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 615 TC 0 Z9 0 U1 1 U2 2 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 81 EP 190 PG 110 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400006 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Heterobifunctional Cross-Linkers SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID BISPECIFIC MONOCLONAL-ANTIBODY; EQUILIBRIUM TRANSFER ALKYLATION; III TRANSCRIPTION COMPLEXES; SITE-SPECIFIC INCORPORATION; LIGHT-ACTIVATED RHODOPSIN; REPLICATION PROTEIN-A; TOBACCO MOSAIC-VIRUS; FACTOR RECEPTOR EGFR; NERVE GROWTH-FACTOR; LINKING REAGENTS C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 286 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 191 EP 237 PG 47 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400007 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Multifunctional Cross-Linking Reagents SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID PROTEIN-PROTEIN INTERACTIONS; WATER-INSOLUBLE DERIVATIVES; ELASTIN-LIKE POLYPEPTIDES; CYTOTOXIC T-CELLS; MASS-SPECTROMETRY; BIOTIN-BINDING; CONCANAVALIN-A; ANTIBODY FRAGMENTS; LINKED HEMOGLOBIN; PLANT-LECTINS C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 93 TC 0 Z9 0 U1 0 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 239 EP 264 PG 26 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400008 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Monofunctional and Zero-Length Cross-Linking Reagents SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID BOVINE PANCREATIC RIBONUCLEASE; TYROSINE-CONTAINING PEPTIDES; RIBOSOMAL-P SITE; PROTEINS IN-VIVO; ESCHERICHIA-COLI; HORSERADISH-PEROXIDASE; SUPEROXIDE-DISMUTASE; MASS-SPECTROMETRY; CYTOCHROME-C; TROPONIN-C C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 230 TC 1 Z9 1 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 265 EP 295 PG 31 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400009 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI General Approaches for Chemical Cross-Linking SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID PROTEIN-PROTEIN INTERACTIONS; ATP SYNTHASE COMPLEX; ESCHERICHIA-COLI; 2-STAGE METHOD; HETEROBIFUNCTIONAL REAGENT; MULTIPROTEIN COMPLEXES; HORSERADISH-PEROXIDASE; BIFUNCTIONAL REAGENTS; SURFACE RECEPTORS; CELL-MEMBRANES C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 104 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 297 EP 320 PG 24 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400010 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Analysis of Cross-Linked Products SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID PROTEIN-PROTEIN INTERACTIONS; MASS-SPECTROMETRY; LINKING REAGENTS; TOP-DOWN; IDENTIFICATION; PROTEOMICS; RESOLUTION; PEPTIDES C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 22 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 321 EP 326 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400011 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Applications of Chemical Cross-Linking to the Study of Biological Macromolecules SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID PROTEIN-PROTEIN INTERACTIONS; APOLIPOPROTEIN-A-I; RESONANCE MASS-SPECTROMETRY; RNA-POLYMERASE-II; ESCHERICHIA-COLI RIBOSOME; MUSCLE HEAVY-MEROMYOSIN; C-TERMINAL DOMAIN; MYOSIN SUBFRAGMENT-1; BIFUNCTIONAL REAGENTS; TROPONIN-I C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 149 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 327 EP 352 PG 26 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400012 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Applications of Chemical Conjugation in the Preparation of Immunoconjugates and Immunogens SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID LINKED-IMMUNOSORBENT-ASSAY; HOMOGENEOUS ENZYME-IMMUNOASSAY; ORGANOPHOSPHORUS INSECTICIDE FENTHION; ALKALINE-PHOSPHATASE-ANTIBODY; STREPTOCOCCAL PROTEIN-G; BETA-D-GALACTOSIDASE; RAT IGG SUBCLASSES; HORSERADISH-PEROXIDASE; MONOCLONAL-ANTIBODIES; DISULFIDE BOND C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 153 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 353 EP 375 PG 23 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400013 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Application of Chemical Conjugation for the Preparation of Immunotoxins and Other Drug Conjugates for Targeting Therapeutics SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID RICIN-A-CHAIN; RIBOSOME-INACTIVATING PROTEINS; DIPHTHERIA-TOXIN FRAGMENT; HORMONE-RELEASING HORMONE; EPIDERMAL-GROWTH-FACTOR; CROSS-LINKING AGENTS; ANTIBODY-CALICHEAMICIN CONJUGATE; CARBOXYMETHYL DEXTRAN CONJUGATE; RECEPTOR-MEDIATED ENDOCYTOSIS; ACUTE LYMPHOBLASTIC-LEUKEMIA C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 194 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 377 EP 408 PG 32 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400014 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Application of Chemical Conjugation to Solid-State Chemistry SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID EFFICIENT HETEROBIFUNCTIONAL REAGENT; PROTEIN-CARBOHYDRATE INTERACTIONS; PHOSPHONATE-MODIFIED SURFACES; SELF-ASSEMBLED MONOLAYER; ATOMIC-FORCE MICROSCOPY; OLIGONUCLEOTIDE MICROARRAYS; COVALENT IMMOBILIZATION; GLASS-SURFACE; ANTIBODY IMMOBILIZATION; CROSS-LINKING C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 224 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 409 EP 445 PG 37 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400015 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Amino Group-Directed Homobifunctional Cross-Linkers SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID DEHYDROGENASE MULTIENZYME COMPLEX; INTACT HUMAN-ERYTHROCYTES; ALPHA-HELICAL STRUCTURES; ANION-EXCHANGE CHANNEL; BIFUNCTIONAL REAGENTS; LINKING REAGENTS; QUATERNARY STRUCTURE; MEMBRANE-IMPERMEANT; MASS-SPECTROMETRY; ESCHERICHIA-COLI C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 79 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 447 EP 481 PG 35 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400016 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Sulfhydryl Group-Directed Homobifunctional Cross-Linkers SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID LINKING REAGENTS; BIFUNCTIONAL REAGENTS; ESCHERICHIA-COLI; CONFORMATIONAL DYNAMICS; ACTIVE-SITES; PROTEINS; DNA; MYOSIN; CONJUGATION; MUSTARD C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 67 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 483 EP 512 PG 30 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400017 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Phenolate- and Imidazolyl-Group-Directed Reagents: Bisdiazonium Precursors SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 513 EP 514 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400018 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Group Selective Heterobifunctional Cross-Linkers SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID EQUILIBRIUM TRANSFER ALKYLATION; LINKING REAGENTS; MONOCLONAL-ANTIBODY; GLASS-SURFACE; BIFUNCTIONAL REAGENTS; CROSSLINKING REAGENTS; COVALENT ATTACHMENT; INCREASED STABILITY; PROTEIN REAGENTS; COUPLING AGENTS C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 88 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 515 EP 548 PG 34 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400019 ER PT J AU Wong, SS Jameson, DM AF Wong, Shan S. Jameson, David M. BA Wong, SS Jameson, DM BF Wong, SS Jameson, DM TI Photoactivatable Heterobifunctional Cross-Linking Reagents SO CHEMISTRY OF PROTEIN AND NUCLEIC ACID CROSS-LINKING AND CONJUGATION, 2ND EDITION LA English DT Article; Book Chapter ID TYPE-1 REVERSE-TRANSCRIPTASE; RIBOSOMAL-PROTEIN L7/L12; NUCLEOTIDE BINDING-SITES; CROSSLINKING REAGENT; TRANSFER-RNA; COVALENT IMMOBILIZATION; MYOSIN SUBFRAGMENT-1; PHOTOAFFINITY LABEL; FINGERS SUBDOMAIN; MEMBRANE-PROTEINS C1 [Wong, Shan S.] Natl Inst Hlth, Bethesda, MD USA. [Wong, Shan S.] Hermann Hosp, Clin Chem, Houston, TX USA. [Wong, Shan S.] Lyndon B Johnson Gen Hosp, Houston, TX USA. [Wong, Shan S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Wong, Shan S.] Univ Massachusetts Lowell, Chem, Lowell, MA USA. [Wong, Shan S.] Denison Univ, Chem Course, Granville, OH 43023 USA. [Wong, Shan S.] Ohio State Univ, Chem Course, Columbus, OH 43210 USA. [Jameson, David M.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jameson, David M.] Univ Texas Southwestern Med Sch, Dept Pharmacol, Dallas, TX USA. [Jameson, David M.] Univ Paris 11, Orsay, France. [Jameson, David M.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wong, Shan S.] Temple Univ, Philadelphia, PA 19122 USA. NR 102 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4200-0764-0 PY 2012 BP 549 EP 586 PG 38 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD5NT UT WOS:000361656400020 ER PT B AU Greten, TF Korangy, F AF Greten, Tim F. Korangy, Firouzeh BE Williams, R TaylorRobinson, SD TI Is immune modulation a possibility? SO CLINICAL DILEMMAS IN PRIMARY LIVER CANCER LA English DT Article; Book Chapter ID HEPATOCELLULAR-CARCINOMA PATIENTS; REGULATORY T-CELLS; RADIOFREQUENCY THERMAL ABLATION; ALPHA-FETOPROTEIN; SUPPRESSOR-CELLS; DENDRITIC CELLS; ACTIVATED MONOCYTES; PERIPHERAL-BLOOD; POOR SURVIVAL; RESPONSES C1 [Greten, Tim F.] NCI, Gastrointestinal Canc Sect, Bethesda, MD 20892 USA. [Korangy, Firouzeh] NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Gastrointestinal Canc Sect, Bethesda, MD 20892 USA. RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 56 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND BN 978-0-470-65797-3; 978-1-119-96217-5 PY 2012 BP 191 EP 198 PG 8 WC Oncology; Gastroenterology & Hepatology SC Oncology; Gastroenterology & Hepatology GA BA4ZI UT WOS:000336446000028 ER PT J AU Kumari, D Usdin, K AF Kumari, Daman Usdin, Karen TI Is Friedreich ataxia an epigenetic disorder? SO CLINICAL EPIGENETICS LA English DT Review DE Friedreich ataxia; heterochromatin; histone modifications; transcription; splicing; triplex AB Friedreich ataxia (FRDA) is a debilitating and frequently fatal neurological disorder that is recessively inherited. It belongs to the group of genetic disorders known as the Repeat Expansion Diseases, in which pathology arises from the deleterious consequences of the inheritance of a tandem repeat array whose repeat number exceeds a critical threshold. In the case of FRDA, the repeat unit is the triplet GAA.TTC and the tandem array is located in the first intron of the frataxin (FXN) gene. Pathology arises because expanded alleles make lower than normal levels of mature FXN mRNA and thus reduced levels of frataxin, the FXN gene product. The repeats form a variety of unusual DNA structures that have the potential to affect gene expression in a number of ways. For example, triplex formation in vitro and in bacteria leads to the formation of persistent RNA: DNA hybrids that block transcription. In addition, these repeats have been shown to affect splicing in model systems. More recently, it has been shown that the region flanking the repeats in the FXN gene is enriched for epigenetic marks characteristic of transcriptionally repressed regions of the genome. However, exactly how repeats in an intron cause the FXN mRNA deficit in FRDA has been the subject of much debate. Identifying the mechanism or mechanisms responsible for the FXN mRNA deficit in FRDA is important for the development of treatments for this currently incurable disorder. This review discusses evidence for and against different models for the repeat-mediated mRNA deficit. C1 [Kumari, Daman; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU Intramural Program of NIDDK [DK057810] FX This work was made possible by a grant to KU from the Intramural Program of NIDDK (DK057810). The Authors declare that there is no conflict of interest. NR 79 TC 16 Z9 16 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PY 2012 VL 4 AR 2 DI 10.1186/1868-7083-4-2 PG 10 WC Oncology SC Oncology GA V30QQ UT WOS:000208830900002 PM 22414340 ER PT S AU Andres, B Kroeger, T Briggman, KL Denk, W Korogod, N Knott, G Koethe, U Hamprecht, FA AF Andres, Bjoern Kroeger, Thorben Briggman, Kevin L. Denk, Winfried Korogod, Natalya Knott, Graham Koethe, Ullrich Hamprecht, Fred A. BE Fitzgibbon, A Lazebnik, S Perona, P Sato, Y Schmidt, C TI Globally Optimal Closed-Surface Segmentation for Connectomics SO COMPUTER VISION - ECCV 2012, PT III SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 12th European Conference on Computer Vision (ECCV) CY OCT 07-13, 2012 CL Florence, ITALY SP Google, Natl Robot Engn Ctr, Adobe, Microsoft Res, Mitsubishi Elect, Mobileye, Nvidia, Point Grey, Technicolor, Toshiba, Toyota, Datalogic, IBM Res, ST, Univ Studi Firenze, Univ Cambridge, Ente Cassa Risparmio Firenze ID CIRCUIT AB We address the problem of partitioning a volume image into a previously unknown number of segments, based on a likelihood of merging adjacent supervoxels. Towards this goal, we adapt a higher-order probabilistic graphical model that makes the duality between supervoxels and their joint faces explicit and ensures that merging decisions are consistent and surfaces of final segments are closed. First, we propose a practical cutting-plane approach to solve the MAP inference problem to global optimality despite its NP-hardness. Second, we apply this approach to challenging large-scale 3D segmentation problems for neural circuit reconstruction (Connectomics), demonstrating the advantage of this higher-order model over independent decisions and finite-order approximations. C1 [Andres, Bjoern; Kroeger, Thorben; Koethe, Ullrich; Hamprecht, Fred A.] Heidelberg Univ, HCI, Bergheimer Str 58, D-69115 Heidelberg, Germany. [Briggman, Kevin L.] NIH, Bethesda, MD USA. [Denk, Winfried] MPI Med Res, Heidelberg, Germany. [Korogod, Natalya; Knott, Graham] Ecole Polytech Fed Lausanne, Lausanne, Switzerland. RP Andres, B (reprint author), Heidelberg Univ, HCI, Bergheimer Str 58, D-69115 Heidelberg, Germany. NR 27 TC 12 Z9 12 U1 1 U2 3 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 978-3-642-33711-6 J9 LECT NOTES COMPUT SC PY 2012 VL 7574 BP 778 EP 791 PG 14 WC Computer Science, Artificial Intelligence; Computer Science, Theory & Methods; Mathematical & Computational Biology SC Computer Science; Mathematical & Computational Biology GA BB3JN UT WOS:000342817300056 ER PT J AU Aljawi, DM Harford, JB AF Aljawi, Deena M. Harford, Joe B. BE Chang, E Johnson, A TI Palliative Care in the Muslim-Majority Countries: The Need for More and Better Care SO CONTEMPORARY AND INNOVATIVE PRACTICE IN PALLIATIVE CARE LA English DT Article; Book Chapter ID EAST CANCER CONSORTIUM; DEATH; PERSPECTIVE; SERVICES; ILL C1 [Aljawi, Deena M.] King Faisal Specialist Hosp & Res Ctr, Riyadh, Saudi Arabia. [Harford, Joe B.] NCI, Bethesda, MD 20892 USA. RP Aljawi, DM (reprint author), King Faisal Specialist Hosp & Res Ctr, Riyadh, Saudi Arabia. NR 35 TC 0 Z9 0 U1 0 U2 0 PU INTECH EUROPE PI RIJEKA PA JANEZA TRDINE9, RIJEKA, 51000, CROATIA BN 978-953-307-986-8 PY 2012 BP 137 EP 150 D2 10.5772/1270 PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA BE9DE UT WOS:000377278700010 ER PT S AU Toman, R Heinzen, RA Samuel, JE Mege, JL AF Toman, Rudolf Heinzen, Robert A. Samuel, James E. Mege, Jean-Louis BE Toman, R Heinzen, RA Samuel, JE Mege, JL TI Coxiella burnetii: Recent Advances and New Perspectives in Research of the Q Fever Bacterium Preface SO COXIELLA BURNETII: RECENT ADVANCES AND NEW PERSPECTIVES IN RESEARCH OF THE Q FEVER BACTERIUM SE Advances in Experimental Medicine and Biology LA English DT Editorial Material; Book Chapter C1 [Toman, Rudolf] Slovak Acad Sci, Inst Virol, Dept Rickettsiol, Bratislava, Slovakia. [Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Rocky Mt Labs, NIH, Hamilton, MT USA. [Samuel, James E.] Texas A&M Hlth Sci Ctr, Coll Med, Dept Microbial & Mol Pathogenesis, Bryan, TX USA. [Mege, Jean-Louis] Univ Aix Marseille 2, CNRS IRD UMR 6236, Unite Rech Malad Infect Transmissibles & Emergent, Inst Federatif Rech 48,Fac Med, Marseille, France. RP Toman, R (reprint author), Slovak Acad Sci, Inst Virol, Dept Rickettsiol, Bratislava, Slovakia. RI MEGE, JEAN-LOUIS/O-6063-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 0065-2598 BN 978-94-007-4314-4; 978-94-007-4315-1 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 984 BP V EP XI D2 10.1007/978-94-007-4315-1 PG 7 WC Cell Biology; Infectious Diseases; Medicine, Research & Experimental SC Cell Biology; Infectious Diseases; Research & Experimental Medicine GA BA2AT UT WOS:000333215000001 ER PT S AU Ghigo, E Colombo, MI Heinzen, RA AF Ghigo, Eric Colombo, Maria I. Heinzen, Robert A. BE Toman, R Heinzen, RA Samuel, JE Mege, JL TI The Coxiella burnetii Parasitophorous Vacuole SO COXIELLA BURNETII: RECENT ADVANCES AND NEW PERSPECTIVES IN RESEARCH OF THE Q FEVER BACTERIUM SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter DE Macrophage; Parasitophorous vacuole; Endosome; Lysosome; Autophagy; Integrin; Lipopolysaccharide; Monocyte; Phase variation; Secretory pathway ID TUMOR-NECROSIS-FACTOR; Q-FEVER ENDOCARDITIS; INTRACELLULAR BACTERIAL PATHOGENS; NITRIC-OXIDE SYNTHASE; TOLL-LIKE RECEPTORS; PHASE-II; CHLAMYDIA-TRACHOMATIS; PHAGOSOME MATURATION; LEGIONELLA-PNEUMOPHILA; HOST-CELLS AB Coxiella burnetii is a bacterial intracellular parasite of eucaryotic cells that replicates within a membrane-bound compartment, or "parasitophorous vacuole" (PV). With the exception of human macrophages/monocytes, the consensus model of PV trafficking in host cells invokes endolysosomal maturation culminating in lysosome fusion. C. burnetii resists the degradative functions of the vacuole while at the same time exploiting the acidic pH for metabolic activation. While at first glance the mature PV resembles a large phagolysosome, an increasing body of evidence indicates the vacuole is in fact a specialized compartment that is actively modified by the pathogen. Adding to the complexity of PV biogenesis is new data showing vacuole engagement with autophagic and early secretory pathways. In this chapter, we review current knowledge of PV nature and development, and discuss disparate data related to the ultimate maturation state of PV harboring virulent or avirulent C. burnetii lipopolysaccharide phase variants in human mononuclear phagocytes. C1 [Ghigo, Eric] Univ Aix Marseille 2, Inst Federatif Rech 48, IRD 3R198, URMITE CNRS UMR 6236, Marseille, France. [Colombo, Maria I.] Univ Nacl Cuyo, Fac Ciencias Med, CONICET, Lab Biol Celular & Mol,Inst Histol & Embriol IHEM, RA-5500 Mendoza, Argentina. [Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov RI Eric, Ghigo/N-9427-2016; MEGE, JEAN-LOUIS/O-6063-2016 FU Intramural NIH HHS NR 150 TC 13 Z9 13 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 0065-2598 BN 978-94-007-4314-4; 978-94-007-4315-1 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 984 BP 141 EP 169 DI 10.1007/978-94-007-4315-1_8 D2 10.1007/978-94-007-4315-1 PG 29 WC Cell Biology; Infectious Diseases; Medicine, Research & Experimental SC Cell Biology; Infectious Diseases; Research & Experimental Medicine GA BA2AT UT WOS:000333215000009 PM 22711631 ER PT S AU Gilk, SD AF Gilk, Stacey D. BE Toman, R Heinzen, RA Samuel, JE Mege, JL TI Role of Lipids in Coxiella burnetii Infection SO COXIELLA BURNETII: RECENT ADVANCES AND NEW PERSPECTIVES IN RESEARCH OF THE Q FEVER BACTERIUM SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter DE Cholesterol biosynthesis; Fatty acid synthesis; Phospholipid synthesis; Sterol reductase; Membrane fluidity; Type IV secretion system; Statin; Membrane composition ID ESCHERICHIA-COLI; INDUCED APOPTOSIS; FATTY-ACIDS; PHASE-I; Q-FEVER; PHOSPHOLIPID-COMPOSITION; REPLACE CHOLESTEROL; OXIDATIVE STRESS; MEMBRANE; PROTEIN AB Lipids are essential components of both eukaryotic and prokaryotic cells, serving diverse functions including energy metabolism and membrane structure. Intracellular vacuolar pathogens such as Coxiella burnetii require lipids for both normal bacterial functions as well as formation of the acidic, phagolysosomal-like parasitophorous vacuole (PV) surrounding the bacteria. As an intracellular pathogen, C. burnetii can acquire lipid through both de novo bacterial synthesis and subversion of host cell pools. The C. burnetii genome encodes enzymes required for de novo synthesis of fatty acids and phospholipids. The high percentage of branched fatty acids suggests C. burnetii modifies these molecules to generate a bacterial cell envelope that can resist the harsh environment of the PV, such as the acidic pH. In addition to fatty acids and their derivatives, C. burnetii requires isoprenoids, particularly sterols as the PV membrane is cholesterol-rich. With the exception of two eukaryote-like sterol reductases, C. burnetii does not have the capability to generate cholesterol, suggesting sterols are actively diverted from the host cell. While C. burnetii utilizes host cell lipids for membrane biogenesis and possibly energy, bacterial manipulation of host cell lipid signaling pathways may support establishment of the intracellular niche. For example, effectors secreted by the C. burnetii Type IV secretion system may either directly or indirectly modify host cell lipids. Further understanding of the lipid biosynthetic capabilities of C. burnetii, along with C. burnetii's manipulation of host cell lipids, will provide insight into the host-pathogen relationship. C1 NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Gilk, SD (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM gilks@niaid.nih.gov RI MEGE, JEAN-LOUIS/O-6063-2016 FU Intramural NIH HHS NR 62 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 0065-2598 BN 978-94-007-4314-4; 978-94-007-4315-1 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 984 BP 199 EP 213 DI 10.1007/978-94-007-4315-1_10 D2 10.1007/978-94-007-4315-1 PG 15 WC Cell Biology; Infectious Diseases; Medicine, Research & Experimental SC Cell Biology; Infectious Diseases; Research & Experimental Medicine GA BA2AT UT WOS:000333215000011 PM 22711633 ER PT S AU Omsland, A AF Omsland, Anders BE Toman, R Heinzen, RA Samuel, JE Mege, JL TI Axenic Growth of Coxiella burnetii SO COXIELLA BURNETII: RECENT ADVANCES AND NEW PERSPECTIVES IN RESEARCH OF THE Q FEVER BACTERIUM SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter DE Axenic cultivation; Culture system; Extracellular; Metabolic activity; Microaerobic ID COMPLETE GENOME SEQUENCE; LEGIONELLA-PNEUMOPHILA; Q-FEVER; PHASE-I; MYCOBACTERIUM-TUBERCULOSIS; CHLAMYDIA-TRACHOMATIS; LYSOSOMAL RESPONSE; HOST-CELLS; DIFFERENTIATION; MACROPHAGES AB Early metabolic studies of C. burnetii showed minimal metabolic activity of axenic (host cell-free) organisms in buffers adjusted to neutral pH. However, our understanding of the organism's physiology was greatly improved upon the discovery that C. burnetii requires an acidic pH for metabolic activation. Indeed, information gained from acid activation studies coupled with contemporary analyses using transcription microarrays, metabolic pathway reconstruction and metabolite typing, led to an axenic culture system that supports robust growth of C. burnetii. While axenic culture of C. burnetii can present some technical challenges, the technique is currently facilitating new lines of investigation and development of genetic tools. Axenic cultivation of C. burnetii should also prove useful in clinical settings. C1 NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Omsland, A (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM omslanda@niaid.nih.gov RI MEGE, JEAN-LOUIS/O-6063-2016 FU Intramural NIH HHS NR 47 TC 11 Z9 11 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 0065-2598 BN 978-94-007-4314-4; 978-94-007-4315-1 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 984 BP 215 EP 229 DI 10.1007/978-94-007-4315-1_11 D2 10.1007/978-94-007-4315-1 PG 15 WC Cell Biology; Infectious Diseases; Medicine, Research & Experimental SC Cell Biology; Infectious Diseases; Research & Experimental Medicine GA BA2AT UT WOS:000333215000012 PM 22711634 ER PT S AU Beare, PA AF Beare, Paul A. BE Toman, R Heinzen, RA Samuel, JE Mege, JL TI Genetic Manipulation of Coxiella burnetii SO COXIELLA BURNETII: RECENT ADVANCES AND NEW PERSPECTIVES IN RESEARCH OF THE Q FEVER BACTERIUM SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter DE Transposon mutagenesis; Electroporation; Antibiotic selection; Allelic exchange; Genetic transformation; Virulence factors; Shuttle vector; Complementation; Targeted gene inactivation ID GREEN FLUORESCENT PROTEIN; GROUP-II INTRONS; RICKETTSIA-PROWAZEKII; TRANSPOSON MUTAGENESIS; Q-FEVER; ANAPLASMA-PHAGOCYTOPHILUM; BACTERIAL GENETICS; GENOME SEQUENCE; PHASE-I; TRANSFORMATION AB Until very recently, Coxiella burnetii was viewed and studied as an obligate intracellular bacterium that relied exclusively on a eucaryotic host cell for growth. Other medically relevant obligate intracellular bacteria reside in the genera lifestyle presents a significant obstacle to genetic transformation. Procedures that are straightforward with free-living bacteria, such as antibiotic selection and cloning, can be very difficult when growth of transformants is restricted to a host cell. Longterm passage in host cells to expand small transformant populations can further complicate the procedure. Despite these and other obstacles, at least rudimentary systems are currently available for genetic transformation of most obligate intracellular bacterial pathogens. Dramatically aiding the development of new genetic methods for C. burnetii is the recent discovery of a medium that supports host cell-free growth of the organism in liquid, and importantly, on solid media as clonal colonies. The expanded C. burnetii genetics toolbox now includes transposon systems for random mutagenesis and single-copy, site-specific chromosomal gene knock-ins, as well as a shuttle vector for heterologous gene expression and in trans complementation. A reliable method of targeted gene inactivation remains a challenge. Advances in C. burnetii genetic manipulation will allow identification of genes essential for intracellular parasitism and disease pathogenesis, and undoubtedly fuel new interest in this minimally studied bacterial pathogen. C1 NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Beare, PA (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM pbeare@niaid.nih.gov RI MEGE, JEAN-LOUIS/O-6063-2016 FU Intramural NIH HHS NR 71 TC 11 Z9 12 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 0065-2598 BN 978-94-007-4314-4; 978-94-007-4315-1 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 984 BP 249 EP 271 DI 10.1007/978-94-007-4315-1_13 D2 10.1007/978-94-007-4315-1 PG 23 WC Cell Biology; Infectious Diseases; Medicine, Research & Experimental SC Cell Biology; Infectious Diseases; Research & Experimental Medicine GA BA2AT UT WOS:000333215000014 PM 22711636 ER PT S AU Grice, EA Segre, JA AF Grice, Elizabeth A. Segre, Julia A. BE Lambris, JD Hajishengallis, G TI Interaction of the Microbiome with the Innate Immune Response in Chronic Wounds SO CURRENT TOPICS IN INNATE IMMUNITY II SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT 7th International Aegean Conference on Innate Immunity CY JUL 04-09, 2010 CL GREECE DE Chronic wounds; Wound healing; Diabetic ulcers; Microbiome; 16S rRNA; Epidermal defense; Antimicrobial peptides; Chronic inflammation ID VENOUS LEG ULCERS; MATRIX METALLOPROTEINASE INDUCER; ENDOTHELIAL GROWTH-FACTOR; ANTIMICROBIAL PEPTIDES; EXTRACELLULAR-MATRIX; DIFFERENTIAL EXPRESSION; BACTERIAL DIVERSITY; OXIDATIVE STRESS; SKIN WOUNDS; MAST-CELLS AB Microbes colonizing and/or infecting chronic wounds undoubtedly play a major and interactive role in impaired healing, especially in amplifying and perpetuating the host innate immune response. The development of molecular techniques to identify and quantify microbial organisms has revolutionized our view of the microbial world. These less-biased, high throughput methods greatly enable investigations regarding host-microbe interactions in the chronic wound environment. This review focuses on the mounting evidence implicating microbes and excessive inflammation in chronic wounds, as well as the challenges associated with understanding how microbes modulate wound healing and the innate immune response. C1 [Grice, Elizabeth A.; Segre, Julia A.] NHGRI, Epithelial Biol Sect, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Epithelial Biol Sect, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM gricee@mail.nih.gov; jsegre@nhgri.nih.gov OI Grice, Elizabeth/0000-0003-3939-2200 FU Intramural NIH HHS [ZIA HG000180-11, ZIA HG000180-12] NR 72 TC 37 Z9 37 U1 3 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 0065-2598 BN 978-1-4614-0106-3; 978-1-4614-0105-6 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 946 BP 55 EP 68 DI 10.1007/978-1-4614-0106-3_4 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA BA4HQ UT WOS:000335736900005 PM 21948362 ER PT B AU Carney, EW Ellis, AL Tyl, RW Foster, PMD Scialli, AR Thompson, K Kim, JH AF Carney, Edward W. Ellis, Amy L. Tyl, Rochelle W. Foster, Paul M. D. Scialli, Anthony R. Thompson, Kary Kim, James H. BE Hood, RD TI Critical evaluation of current developmental toxicity testing strategies-A case of babies and their bathwater SO DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, 3RD EDITION LA English DT Article; Book Chapter ID HUMAN RISK-ASSESSMENT; MATERNAL TOXICITY; FETAL MALFORMATIONS; ETHYLENE-GLYCOL; SCORING SYSTEM; WAVY RIBS; RABBIT; REACH; RAT; ORGANOGENESIS AB This chapter emanated from a workshop entitled "Developmental Toxicology-New Directions," which was sponsored by the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee. This review analyzes the strengths and weaknesses of the current developmental safety testing approaches in an effort to identify those strengths that should be retained in the future versus the weaknesses that should be eliminated. Workshop participants considered the following to be key strengths of current testing approaches: the integrated biology of pregnant animal models including pharmacokinetic and pharmacodynamic processes, the ability to detect low incidence malformations as well as maternally mediated toxicity, and the long history of use coupled with extensive historical data. A number of weaknesses were related to the resource-intensive nature of developmental toxicity testing (e.g., large number of animals, high costs, low throughput, and the inability to keep pace with the demand for more toxicity data). Other weaknesses included the use of very high dose levels that often far exceed human exposure levels, the confounding influence of maternal toxicity, sparse understanding of basic developmental mechanisms and genetics of standard animal models compared with mouse or lower organisms, difficulties interpreting low incidence findings, and issues surrounding the interpretation of minor skeletal variations. An appreciation of these strengths and weaknesses is critical for the design of new approaches to developmental toxicity testing in the 21st century. C1 [Carney, Edward W.] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Ellis, Amy L.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Tyl, Rochelle W.] RTI Int, Discovery & Analyt Sci, Res Triangle Pk, NC USA. [Foster, Paul M. D.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Scialli, Anthony R.] Tetra Tech Sci, Arlington, VA USA. [Thompson, Kary] Bristol Myers Squibb Co, Reprod Toxicol, New Brunswick, NJ USA. [Kim, James H.] ILSI Hlth & Environm Sci Inst HESI, Washington, DC USA. RP Carney, EW (reprint author), Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. NR 55 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL ST, LONDON, EC2A 4LQ, ENGLAND BN 978-1-84184-821-1; 978-1-84184-777-1 PY 2012 BP 592 EP 601 PG 10 WC Toxicology SC Toxicology GA BC8IU UT WOS:000355700500025 ER PT B AU Katyare, SS Modi, HR AF Katyare, Surendra S. Modi, Hiren R. BE Watson, RR TI Dehydroepiandrosterone and Energy Metabolism SO DHEA in Human Health and Aging LA English DT Article; Book Chapter ID OBESE ZUCKER RATS; MITOCHONDRIAL RESPIRATION; IN-VITRO; LIVER-MITOCHONDRIA; SHORT-TERM; 11-BETA-HYDROXYSTEROID DEHYDROGENASES; CEREBRAL MITOCHONDRIA; NONDEMENTED PATIENTS; BRAIN MITOCHONDRIA; THYROID-HORMONE C1 [Katyare, Surendra S.] Maharaja Sayajirao Univ Baroda, Fac Sci, Dept Biochem, Vadodara, India. [Modi, Hiren R.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Katyare, SS (reprint author), Maharaja Sayajirao Univ Baroda, Fac Sci, Dept Biochem, Vadodara, India. NR 75 TC 0 Z9 0 U1 0 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-3884-6; 978-1-4398-3883-9 PY 2012 BP 87 EP 101 PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA BC5SB UT WOS:000353519300008 ER PT B AU Arnold, JT AF Arnold, Julia T. BE Watson, RR TI DHEA Metabolism, Supplementation, and Decline with Age Role on Prostate Health SO DHEA in Human Health and Aging LA English DT Article; Book Chapter ID ESTROGEN-RECEPTOR-BETA; PERIPHERAL TARGET TISSUES; URINARY-TRACT SYMPTOMS; CANCER-CELL-LINES; DEHYDROEPIANDROSTERONE-SULFATE; BREAST-CANCER; EPITHELIAL INTERACTIONS; ADRENAL ANDROGENS; GENE-EXPRESSION; REACTIVE STROMA C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Arnold, JT (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Bldg 10, Bethesda, MD 20892 USA. NR 100 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-3884-6; 978-1-4398-3883-9 PY 2012 BP 363 EP 374 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA BC5SB UT WOS:000353519300031 ER PT B AU Cimino, JJ Rigolosi, RS Cimino, JE AF Cimino, James J. Rigolosi, Robert S. Cimino, James E. BE Ing, TS Rahman, MA Kjellstrand, CM TI James Ernest (Jack) Cimino: Inventor of Arteriovenous Fistula SO DIALYSIS: HISTORY, DEVELOPMENT AND PROMISE LA English DT Article; Book Chapter ID HEMODIALYSIS ACCESS; VENIPUNCTURE C1 [Cimino, James J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. [Cimino, James J.] Columbia Univ Coll Phys & Surg, Bethesda, MD USA. [Rigolosi, Robert S.] Holy Name Hosp, Reg Hemodialysis Ctr, Teaneck, NJ USA. [Cimino, James E.] New York Med Coll, Bronx, NY USA. [Cimino, James E.] Calvary Hosp, Palliat Care Inst, Bronx, NY USA. RP Cimino, JJ (reprint author), NIH, Lab Informat Dev, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM ciminoj@cc.nih.gov; rsrigolosi@aol.com OI Cimino, James/0000-0003-4101-1622 NR 17 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4289-76-4; 978-981-4289-75-7 PY 2012 BP 125 EP 133 D2 10.1142/7522 PG 9 WC Gastroenterology & Hepatology; History & Philosophy Of Science SC Gastroenterology & Hepatology; History & Philosophy of Science GA BA1UB UT WOS:000333100600018 ER PT J AU Shen, HF Blanco, E Godin, B Serda, RE Streiff, AK Ferrari, M AF Shen, Haifa Blanco, Elvin Godin, Biana Serda, Rita E. Streiff, Agathe K. Ferrari, Mauro BE Kratz, F Senter, P Steinhagen, H TI Overview on Nanocarriers as Delivery Systems SO DRUG DELIVERY IN ONCOLOGY: FROM BASIC RESEARCH TO CANCER THERAPY, VOLS 1-3 LA English DT Editorial Material; Book Chapter ID ENCAPSULATED ANTICANCER DRUGS; MESOPOROUS SILICON PARTICLES; KNEDEL-LIKE NANOPARTICLES; WALL CARBON NANOTUBES; I CLINICAL-TRIAL; CANCER-THERAPY; PHASE-I; ENDOTHELIAL-CELLS; PHARMACOKINETIC EVALUATION; PHARMACEUTICAL CARRIERS C1 [Shen, Haifa; Serda, Rita E.] Methodist Hosp Res Inst, Houston, TX 77030 USA. [Shen, Haifa] Univ Texas Houston, Houston, TX 77004 USA. [Godin, Biana] Univ Texas Hlth Sci Ctr Houston, Grp Prof Ferrari, Houston, TX 77030 USA. [Streiff, Agathe K.] Univ Texas Med Sch Houston, Houston, TX 77030 USA. [Ferrari, Mauro] NCI, Bethesda, MD 20892 USA. RP Shen, HF (reprint author), Methodist Hosp Res Inst, Houston, TX 77030 USA. NR 97 TC 0 Z9 0 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PAPPELALLEE 3, W-69469 WEINHEIM, GERMANY BN 978-3-527-32823-9 PY 2012 BP 887 EP 905 PG 19 WC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy GA BA8DL UT WOS:000338009100030 ER PT J AU Walther, W Schlag, PM Stein, U AF Walther, Wolfgang Schlag, Peter M. Stein, Ulrike BE Kratz, F Senter, P Steinhagen, H TI Local Gene Delivery for Therapy of Solid Tumors SO DRUG DELIVERY IN ONCOLOGY: FROM BASIC RESEARCH TO CANCER THERAPY, VOLS 1-3 LA English DT Article; Book Chapter ID PHASE-I TRIAL; EPITHELIAL OVARIAN-CANCER; REPLICATION-SELECTIVE ADENOVIRUS; RECURRENT PROSTATE-CANCER; JET-INJECTION TECHNOLOGY; TYPE-1 THYMIDINE KINASE; CELL LUNG-CANCER; PLASMID DNA; BREAST-CANCER; INTRATUMORAL INJECTION C1 [Walther, Wolfgang] NCI, Frederick, MD 21701 USA. [Walther, Wolfgang] Charite, Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, Expt & Clin Gene Therapy Grp, D-13353 Berlin, Germany. [Schlag, Peter M.] Heidelberg Univ, Dept Surg, Sect Surg Oncol, D-69115 Heidelberg, Germany. [Schlag, Peter M.] Humboldt Univ, Dept Surg & Surg Oncol, Charite, Berlin, Germany. [Schlag, Peter M.] Robert Rossle Canc Ctr, Berlin, Germany. [Schlag, Peter M.] Charite Comprehens Canc Ctr, Berlin, Germany. [Stein, Ulrike] Max Delbruck Ctr, Tumor Metastasis & Therapy Response Grp, Berlin, Germany. [Stein, Ulrike] Charite, Robert Rossle Tumor Clin, D-13353 Berlin, Germany. [Stein, Ulrike] Charite, Expt & Clin Res Ctr, Dept Surg Oncol, D-13353 Berlin, Germany. [Stein, Ulrike] Charite, D-13353 Berlin, Germany. RP Walther, W (reprint author), Univ Strathclyde, Glasgow, Lanark, Scotland. NR 88 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PAPPELALLEE 3, W-69469 WEINHEIM, GERMANY BN 978-3-527-32823-9 PY 2012 BP 1391 EP 1413 PG 23 WC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy GA BA8DL UT WOS:000338009100046 ER PT J AU Fuchs, H Bachran, C AF Fuchs, Hendrik Bachran, Christopher BE Kratz, F Senter, P Steinhagen, H TI Design of Targeted Protein Toxins SO DRUG DELIVERY IN ONCOLOGY: FROM BASIC RESEARCH TO CANCER THERAPY, VOLS 1-3 LA English DT Article; Book Chapter ID PHASE-II TRIAL; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; RIBOSOME-INACTIVATING PROTEINS; CELL-PENETRATING PEPTIDES; ACTIVATED ANTHRAX TOXIN; IN-VIVO; TUMOR-CELLS; ANTITUMOR-ACTIVITY; FUSION PROTEIN; CANCER-CELLS C1 [Fuchs, Hendrik] Benjamin Franklin Univ Hosp, Dept Clin Chem & Pathobiochem, Berlin, Germany. [Fuchs, Hendrik] Charite Univ Med Berlin, Dept Lab Med Clin Chem & Pathobiochem, Berlin, Germany. [Bachran, Christopher] Charite Univ Med Berlin, Lab Hendrik Fuchs, Berlin, Germany. [Bachran, Christopher] NIAID, Lab Stephen Leppla, NIH, Bethesda, MD USA. RP Fuchs, H (reprint author), Benjamin Franklin Univ Hosp, Dept Clin Chem & Pathobiochem, Berlin, Germany. NR 94 TC 0 Z9 0 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PAPPELALLEE 3, W-69469 WEINHEIM, GERMANY BN 978-3-527-32823-9 PY 2012 BP 1443 EP 1487 PG 45 WC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy GA BA8DL UT WOS:000338009100048 ER PT B AU Louis, GMB AF Louis, Germaine M. Buck BE Giudice, LC Evers, JLH Healy, DL TI Early Origins of Endometriosis: Role of Endocrine Disrupting Chemicals SO ENDOMETRIOSIS: SCIENCE AND PRACTICE LA English DT Article; Book Chapter ID FOR-GESTATIONAL-AGE; HIGH PLASMA-CONCENTRATIONS; DIOXIN-LIKE COMPOUNDS; POLYCHLORINATED-BIPHENYLS; IN-UTERO; BIRTH-WEIGHT; DEVELOPMENTAL PLASTICITY; PERITONEAL ENDOMETRIOSIS; ENVIRONMENTAL ESTROGEN; REPRODUCTIVE HEALTH C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. OI Buck Louis, Germaine/0000-0002-1774-4490 NR 105 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND BN 978-1-4443-9848-9; 978-1-4443-3213-1 PY 2012 BP 153 EP 163 PG 11 WC Primary Health Care; Obstetrics & Gynecology SC General & Internal Medicine; Obstetrics & Gynecology GA BA6HA UT WOS:000337140900016 ER PT B AU Stratton, P Berkley, KJ AF Stratton, Pamela Berkley, Karen J. BE Giudice, LC Evers, JLH Healy, DL TI Neuroendocrine Aspects of Endometriosis-Associated Pain SO ENDOMETRIOSIS: SCIENCE AND PRACTICE LA English DT Article; Book Chapter ID CHRONIC PELVIC PAIN; PITUITARY-ADRENAL AXIS; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; ESTROGEN-RECEPTOR-ALPHA; GENITAL SENSORY FIELD; DORSAL-HORN NEURONS; LOW-BACK-PAIN; FEMALE RATS; MENSTRUAL-CYCLE C1 [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Consult Serv, Program Reprod & Adult Endocrinol, Intramural Program,NIH, Bethesda, MD 20892 USA. [Berkley, Karen J.] Florida State Univ, Program Neurosci, Tallahassee, FL 32306 USA. RP Stratton, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Consult Serv, Program Reprod & Adult Endocrinol, Intramural Program,NIH, Bethesda, MD 20892 USA. NR 144 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND BN 978-1-4443-9848-9; 978-1-4443-3213-1 PY 2012 BP 230 EP 239 PG 10 WC Primary Health Care; Obstetrics & Gynecology SC General & Internal Medicine; Obstetrics & Gynecology GA BA6HA UT WOS:000337140900023 ER PT B AU Moon, K Cox, J DeCherney, A AF Moon, Kimberly Cox, Jeris DeCherney, Alan BE Giudice, LC Evers, JLH Healy, DL TI Infertility Therapies: The Role of Assisted Reproductive Technologies SO ENDOMETRIOSIS: SCIENCE AND PRACTICE LA English DT Article; Book Chapter ID IN-VITRO FERTILIZATION; FERTILIZATION/INTRACYTOPLASMIC SPERM INJECTION; ENDOMETRIOSIS-RELATED INFERTILITY; LAPAROSCOPIC OVARIAN CYSTECTOMY; HORMONE AGONIST THERAPY; STAGE-IV ENDOMETRIOSIS; TERM DOWN-REGULATION; EMBRYO-TRANSFER; INVITRO FERTILIZATION; UNEXPLAINED INFERTILITY C1 [Moon, Kimberly; Cox, Jeris; DeCherney, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Moon, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. NR 80 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND BN 978-1-4443-9848-9; 978-1-4443-3213-1 PY 2012 BP 462 EP 472 PG 11 WC Primary Health Care; Obstetrics & Gynecology SC General & Internal Medicine; Obstetrics & Gynecology GA BA6HA UT WOS:000337140900047 ER PT S AU Subrahmanyam, R Sen, R AF Subrahmanyam, Ramesh Sen, Ranjan BE Murre, C TI Epigenetic Features that Regulate IgH Locus Recombination and Expression SO EPIGENETIC REGULATION OF LYMPHOCYTE DEVELOPMENT SE Current Topics in Microbiology and Immunology LA English DT Review; Book Chapter ID HEAVY-CHAIN GENE; B-CELL-DEVELOPMENT; V-H GENE; CLASS-SWITCH RECOMBINATION; V(D)J RECOMBINATION; ALLELIC EXCLUSION; PAX5 BSAP; HISTONE MODIFICATIONS; IMMUNOGLOBULIN GENES; PLANT HOMEODOMAIN AB Precisely regulated rearrangements that yield imprecise recombination junctions are hallmarks of antigen receptor gene assembly. At the immunoglobulin heavy chain (IgH) gene locus this is initiated by rearrangement of a D-H gene segment to a J(H) gene segment to generate DJ(H) junctions, followed by rearrangement of a V-H gene segment to the DJ(H) junction to generate fully recombined VDJ alleles. In this review we discuss the regulatory features of each step of IgH gene assembly and the role of epigenetic mechanisms in achieving regulatory precision. C1 [Subrahmanyam, Ramesh; Sen, Ranjan] NIA, Gene Regulat Sect, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Sen, R (reprint author), NIA, Gene Regulat Sect, Lab Mol Biol & Immunol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rs465z@nih.gov RI Subrahmanyam, Ramesh/K-5503-2012 FU Intramural NIH HHS NR 88 TC 8 Z9 8 U1 1 U2 4 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0070-217X BN 978-3-642-24103-1; 978-3-642-24102-4 J9 CURR TOP MICROBIOL JI Curr.Top.Microbiol.Immunol. PY 2012 VL 356 BP 39 EP 63 DI 10.1007/82_2011_153 D2 10.1007/978-3-642-24103-1 PG 25 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA BJT94 UT WOS:000330361000003 PM 21779986 ER PT J AU Reiter, CEN Alayash, AI AF Reiter, Chad E. N. Alayash, Abdu I. TI Effects of carbon monoxide (CO) delivery by a CO donor or hemoglobin on vascular hypoxia inducible factor 1 alpha and mitochondrial respiration SO FEBS OPEN BIO LA English DT Article DE Hemoglobin; Hypoxia-inducible factor; Mitochondria; Carbon monoxide AB We examined carbon monoxide (CO) delivery by carbon monoxide-releasing molecule 2 (CORM-2) or hemoglobin (Hb) on cellular oxygen sensing and mitochondrial respiration in bovine aortic endothelial cells (BAECs). CORM-2 reduced hypoxia-inducible factor-1 alpha (HIF-1 alpha) and endothelin-1 (ET-1) expression in normoxic and hypoxic cells, but while Hb alone significantly reduced HIF-1a stabilization in hypoxic cells, CO delivered by Hb (Hb-CO) had no effect on HIF-1 alpha stabilization. CO dose-dependently increased basal oxygen consumption and reduced overall mitochondrial respiratory capacity. Hb-CO increased basal oxygen consumption but did not alter respiratory capacity. Together, CO reduced ET-1, and, at low doses, had no effect on endothelial mitochondria oxygen consumption. CO ligation to Hb may be developed further as non-vasoactive oxygen therapeutic without compromising mitochondrial function. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Reiter, Chad E. N.; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Div Hematol, CBER, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, Lab Biochem & Vasc Biol, CBER, 8800 Rockville Pike,NIH Bldg 29,Room 112, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov FU FDA Critical Path Initiative (AIA); FDA Commissioner's Fellowship Program (CENR) FX Financial support was provided by the FDA Critical Path Initiative (AIA) and the FDA Commissioner's Fellowship Program (CENR). The sponsors had no role in study design; collection, analysis, and interpretation of data; in writing this report; or in the decision to submit the article for publication. NR 27 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 2211-5463 J9 FEBS OPEN BIO JI FEBS Open Bio PY 2012 VL 2 BP 113 EP 118 DI 10.1016/j.fob.2012.05.003 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA V33GL UT WOS:000209007200019 PM 23650589 ER PT B AU Nair, S Murthy, MRN Savithri, HS AF Nair, Smita Murthy, M. R. N. Savithri, H. S. BE Uversky, VN Longhi, S TI INTRINSICALLY DISORDERED DOMAINS OF SESBANIA MOSAIC VIRUS ENCODED PROTEINS SO FLEXIBLE VIRUSES: STRUCTURAL DISORDER IN VIRAL PROTEINS SE Wiley Series on Protein and Peptide Science LA English DT Article; Book Chapter ID COMPLETE NUCLEOTIDE-SEQUENCE; TRANSIENT STREAK VIRUS; COCKSFOOT MOTTLE VIRUS; NATIVELY UNFOLDED VPG; ARGININE-RICH MOTIF; VIROID-LIKE RNA-2; SERINE-PROTEASE; SELF-CLEAVAGE; COAT PROTEIN; 3-DIMENSIONAL STRUCTURE C1 [Nair, Smita; Savithri, H. S.] Indian Inst Sci, Dept Biochem, Bangalore 560012, Karnataka, India. [Nair, Smita] NCI, NIH, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Murthy, M. R. N.] Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. RP Nair, S (reprint author), Indian Inst Sci, Dept Biochem, Bangalore 560012, Karnataka, India. NR 52 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER, W SUSSEX PO 19 8SQ, ENGLAND BN 978-1-118-13554-9; 978-0-470-61831-8 J9 WILEY SER PROTEIN P PY 2012 BP 257 EP 276 PG 20 WC Biochemistry & Molecular Biology; Virology SC Biochemistry & Molecular Biology; Virology GA BA6JS UT WOS:000337164000012 ER PT B AU Zhao, XL Wang, XW AF Zhao, Xuelian Wang, Xin Wei BE Cho, CH Yu, J TI Exploration of Cytokine Signaling in Clinical Management of Hepatocellular Carcinoma SO FROM INFLAMMATION TO CANCER: ADVANCES IN DIAGNOSIS AND THERAPY FOR GASTROINTESTINAL AND HEPATOLOGICAL DISEASES LA English DT Article; Book Chapter ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; CHRONIC HEPATITIS-B; FACTOR-ALPHA; PRECLINICAL MODELS; MOLECULAR-CLONING; MULTIPLE-MYELOMA; IMMUNE-RESPONSE; GAMMA-CHAIN; TNF-ALPHA AB Chronic infection and inflammation contribute to about 25% of all cancer cases worldwide. Specifically, hepatocellular carcinoma (HCC), the frequent malignant cancer with the third leading cause of cancer death, is a representative malignancy showing a strong association with chronic inflammatory disease. HCC develops almost exclusively in cirrhotic livers resulting from viral hepatitis, alcoholic or fatty liver disease. Several clinical studies indicate that >85% of HCCs retain markers for HBV and/or HCV. Cytokines, the most common mediators linking inflammation and cancer, show altered expression in cirrhotic disease and HCC, which can be categorized as pro-or anti-carcinogenesis. Thus, understanding the signaling pathway and the exploration of cytokine-based clinical management is representing a promising therapeutic strategy. In this chapter, we provide a general overview of the connection of inflammation and HCC and highlight the process of translating basic science to clinical managements by introducing two cytokines - tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Though promising, current cytokine-based therapies are at an early stage, for example, TNF-alpha have both pro- and anti-tumor effects, which lead to contradictory strategies in clinic applications. As our understanding of the mechanistic connections between inflammation and cancer development accumulate, the cytokine-based clinical management should be more specific and efficient in HCC prognosis, diagnosis and treatment. C1 [Zhao, Xuelian; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM wangx@intra.nci.nih.gov NR 61 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4343-60-2; 978-981-4343-59-6 PY 2012 BP 223 EP 238 D2 10.1142/8117 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA BA5CF UT WOS:000336528100011 ER PT J AU Andrade, BB Teixeira, CR AF Andrade, Bruno Bezerril Teixeira, Clarissa R. TI Biomarkers for exposure to sand flies bites as tools to ale control of leisnmaniasis SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE leishmaniasis; sand fly; biomarkers; salivary proteins; vectors AB Intense research efforts so far have not been sufficient to reduce leishmaniasis burden worldwide. This disease is transmitted by bites of infected sand flies, which inject saliva in the host skin in an attempt to obtain a blood meal. Sand fly saliva has an array of proteins with diverse pharmacological properties that modulates the host homeostatic and immune responses. Some of these proteins are also immunogenic and can induce both cellular and humoral immune responses. Recently, the use of sand fly salivary proteins to estimate exposure to sand fly bites and consequently the risk of infection has emerged. Here, we review evidence that supports the use of the host immune responses against sand fly salivary proteins to estimate risk of infection. We also discuss how the use of recombinant salivary proteins can optimize serological surveys and provide guidance for the implementation of specific measures for disease control in endemic areas. C1 [Andrade, Bruno Bezerril] NIAID, NIH, Immunobiol Sect, Lab Parasit Diseases, Bethesda, MD 20892 USA. [Teixeira, Clarissa R.] NIAID, NIH, Vector Mol Biol Sect, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. RP Teixeira, CR (reprint author), NIH, Vector Mol Biol Sect, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy,Bldg Twinbrook 3, Rockville, MD 20852 USA. EM teixeirac@niaid.nih.gov RI Andrade, Bruno/J-9111-2012 OI Andrade, Bruno/0000-0001-6833-3811 FU National Institutes of Health, NIAID; Intramural Research Program FX The National Institutes of Health, NIAID, and Intramural Research Program support the work developed by the authors. We thank Dr. Jesus Valenzuela, Dr. Shaden Kamhawi, and Dr. Luiz Fabiano Oliveira for critical revision of this manuscript. NR 49 TC 5 Z9 5 U1 1 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 121 DI 10.3389/fimmu.2012.00121 PG 7 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300118 PM 22661974 ER PT J AU Biragyn, A Lee-Chang, C AF Biragyn, Arya Lee-Chang, Catalina TI A new paradigm for an old story: the role of regulatory B cells in cancer SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material C1 [Biragyn, Arya; Lee-Chang, Catalina] NIA, Immunotherapeut Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Biragyn, A (reprint author), NIA, Immunotherapeut Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov RI Lee-Chang, Catalina/A-5580-2015 OI Lee-Chang, Catalina/0000-0002-7675-2124 NR 59 TC 7 Z9 7 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 206 DI 10.3389/fimmu.2012.00206 PG 4 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300201 PM 22837759 ER PT J AU Demberg, T Robert-Guroff, M AF Demberg, Thorsten Robert-Guroff, Marjorie TI Controlling the HIV/AIDS epidemic: current status and global challenges SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE animal model; ART treatment; global strategies; HIV pandemic; prevention; vaccine development AB This review provides an overview of the current status of the global HIV pandemic and strategies to bring it under control. It updates numerous preventive approaches including behavioral interventions, male circumcision (MC), pre- and post-exposure prophylaxis (PREP and PEP), vaccines, and microbicides. The manuscript summarizes current anti-retroviral treatment options, their impact in the western world, and difficulties faced by emerging and resource-limited nations in providing and maintaining appropriate treatment regimens. Current clinical and pre-clinical approaches toward a cure for HIV are described, including new drug compounds that target viral reservoirs and gene therapy approaches aimed at altering susceptibility to HIV infection. Recent progress in vaccine development is summarized, including novel approaches and new discoveries. C1 [Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, NIH, Vaccine Branch, Sect Immune Biol Retroviral Infect, Bethesda, MD 20892 USA. RP Demberg, T (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM dembergt@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX We thank L. Jean Patterson and Janet DiPasquale for critical comments and reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 269 TC 12 Z9 12 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 250 DI 10.3389/fimmu.2012.00250 PG 17 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300245 PM 22912636 ER PT J AU Gasteiger, G Kastenmuller, W AF Gasteiger, Georg Kastenmuller, Wolfgang TI Foxp3+regulatory T-cells and IL-2: the Moirai of T-cell fates? SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material C1 [Gasteiger, Georg] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10021 USA. [Kastenmuller, Wolfgang] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Gasteiger, G (reprint author), Mem Sloan Kettering Canc Ctr, Program Immunol, 1275 York Ave, New York, NY 10021 USA. EM gasteigg@mskcc.org; kastenmullerw@mail.nih.gov OI Gasteiger, Georg/0000-0001-6986-127X NR 49 TC 12 Z9 12 U1 1 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 179 DI 10.3389/fimmu.2012.00179 PG 4 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300176 PM 22807926 ER PT J AU Gomes, R Oliveira, F AF Gomes, Regis Oliveira, Fabiano TI The immune response to sand fly salivary proteins and its influence on Leishmania immunity SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE sand fly; salivary proteins; Leishmania; Lutzomyia longipalpis; Phlebotomus papatasi; Phlebotomus duboscqi AB Leishmaniasis is a vector-borne disease transmitted by bites of phlebotomine sand flies. During Leishmania transmission, sand fly saliva is co-inoculated with parasites into the skin of the mammalian host. Sand fly saliva consists of roughly thirty different salivary proteins, many with known roles linked to blood feeding facilitation. Apart from the anti-hemostatic capacity of saliva, several sand fly salivary proteins have been shown to be immunogenic. Immunization with a single salivary protein or exposure to uninfected bites was shown to result in a protective immune response against leishmaniasis. Antibodies to saliva were not required for this protection. A strong body of evidence points to the role for salivaspecific T cells producing IFN-gamma in the form of a delayed-type hypersensitivity reaction at the bite site as the main protective response. Herein, we review the immunity to sand fly salivary proteins in the context of its vector parasite host combinations and their vaccine potential, as well as some recent advances to shed light on the mechanism of how an immune response to sand fly saliva protects against leishmaniasis. C1 [Gomes, Regis; Oliveira, Fabiano] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Oliveira, F (reprint author), NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,2E-22b, Rockville, MD 20852 USA. EM loliveira@niaid.nih.gov FU National Institutes of Health, NIAID; Intramural Research Program FX We thank Dr. Jesus Valenzuela, Dr. Shaden Kamhawi, and Dana C. Gilmore for critical revision of this manuscript. The National Institutes of Health, NIAID, and Intramural Research Program supported this work. NR 68 TC 32 Z9 32 U1 0 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 110 DI 10.3389/fimmu.2012.00110 PG 8 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300107 PM 22593758 ER PT J AU Krzewski, K Coligan, JE AF Krzewski, Konrad Coligan, John E. TI Human NK cell lytic granules and regulation of their exocytosis SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE NK cells; cytotoxic lymphocytes; lytic granules; lysosomes; cytotoxicity; exocytosis AB Natural killer (NK) cells form a subset of lymphocytes that play a key role in immuno-surveillance and host defense against cancer and viral infections. They recognize stressed cells through a variety of germline-encoded activating cell surface receptors and utilize their cytotoxic ability to eliminate abnormal cells. Killing of target cells is a complex, multi stage process that concludes in the directed secretion of lytic granules, containing perforin and granzymes, at the immunological synapse. Upon delivery to a target cell, perforin mediates generation of pores in membranes of target cells, allowing granzymes to access target cell cytoplasm and induce apoptosis. Therefore, lytic granules of NK cells are indispensable for normal NK cell cytolytic function. Indeed, defects in lytic granule secretion lead or are related to serious and often fatal diseases, such as familial hemophagocytic lymphohistiocytosis (FHL) type 2-5 or Griscelli syndrome type 2. A number of reports highlight the role of several proteins involved in lytic granule release and NK cell-mediated killing of tumor cells. This review focuses on lytic granules of human NK cells and the advancements in understanding the mechanisms controlling their exocytosis. C1 [Krzewski, Konrad; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Lab Immunogenet, NIH, Rockville, MD 20852 USA. RP Krzewski, K (reprint author), NIAID, Receptor Cell Biol Sect, Lab Immunogenet, NIH, 12441 Parklawn Dr,Twinbrook 2,Room 205, Rockville, MD 20852 USA. EM krzewskikj@niaid.nih.gov NR 220 TC 29 Z9 30 U1 2 U2 7 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 335 DI 10.3389/fimmu.2012.00335 PG 16 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300330 PM 23162553 ER PT J AU Lu, T Kobayashi, SD Quinn, MT Deleo, FR AF Lu, Thea Kobayashi, Scott D. Quinn, Mark T. DeLeo, Frank R. TI A NET outcome SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE neutrophil; apoptosis; necrosis; phagocytosis; inflammation AB Neutrophils constitute a critical part of innate immunity and are well known for their ability to phagocytose and kill invading microorganisms. The microbicidal processes employed by neutrophils are highly effective at killing most ingested bacteria and fungi. However, an alternative non-phagocytic antimicrobial mechanism of neutrophils has been proposed whereby microorganisms are eliminated by neutrophil extracellular traps (NETs). NETs are comprised of DNA, histones, and antimicrobial proteins extruded by neutrophils during NETosis, a cell death pathway reported to be distinct from apoptosis, phagocytosis-induced cell death, and necrosis. Although multiple laboratories have reported NETs using various stimuli in vitro, the molecular mechanisms involved in this process have yet to be definitively elucidated, and many questions regarding the formation and putative role or function of NETs in innate host defense remain unanswered. It is with these questions in mind that we provide some reflection and perspective on NETs and NETosis. C1 [Lu, Thea; Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Quinn, Mark T.] Montana State Univ, Dept Immunol & Infect Dis, Bozeman, MT 59717 USA. RP Deleo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institute of General Medical Sciences, National Institutes of Health [GM103500] FX Thea Lu, Scott D. Kobayashi, and Frank R. DeLeo are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Mark T. Quinn is supported by a grant (GM103500) from the National Institute of General Medical Sciences, National Institutes of Health. NR 145 TC 20 Z9 20 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 365 DI 10.3389/fimmu.2012.00365 PG 9 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300360 PM 23227026 ER PT J AU Rajagopalan, S Long, EO AF Rajagopalan, Sumati Long, Eric O. TI KIR2DL4 (CD158d). an activation receptor for HLA-G SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE NK; KIR; HLA-G; pregnancy AB KIR2DL4 is an unusual killer cell immunoglobulin-like receptor (KIR) family member in terms of its structure, expression, cellular localization, and signaling properties. The most conserved KIR in evolution, it is referred to as a framework KIR gene and is expressed by all natural killer (NK) cells and a subset of T cells. Although it has a long cytoplasmic tail that is typical of inhibitory KIR, engagement of this receptor results in the activation of NK cells, not for cytotoxicity, but for cytokine and chemokine secretion. Unlike all other KIRs, which are expressed on the surface of NK cells, KIR2DL4 resides in endosomes. It signals from this intracellular site fora proinflammatory and proangiogenic response, using a novel endosomal signaling pathway that involves the serine/threonine kinases DNA-PKcs and Akt. The only known ligand of KIR2DL4 is HLA-G. Soluble HLA-G accumulates in KIR2DL4(+) endosomes. Unlike classical HLA molecules that serve as ligands for other KIR family members, in healthy individuals, HLA-G expression is restricted to the fetal trophoblast cells that invade the maternal decidua during early pregnancy. Since NK cells constitute the predominant lymphocyte subset at this site, the proinflammatory/proangiogenic outcome of the interaction between KIR2DL4 and soluble HLA-G supports a role for KIR2DL4 in the extensive remodeling of the maternal vasculature during the early weeks of pregnancy. C1 [Rajagopalan, Sumati; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Rajagopalan, S (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM sumi@nih.gov NR 37 TC 39 Z9 42 U1 1 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 258 DI 10.3389/fimmu.2012.00258 PG 6 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300253 PM 22934097 ER PT J AU Ratts, RB Weng, NP AF Ratts, Robert B. Weng, Nan-Ping TI Homeostasis of lymphocytes and monocytes in frequent blood donors SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE T cell; telomere; telomerase aging; leukapheresis; TREC; CD31 AB Age-associated decline of immune function is believed to be mainly due to alterations of immune cells. However, longitudinal changes of human immune cells with age have not yet been adequately addressed. To test the hypothesis that regeneration of lymphocytes and monocytes is robust throughout most of adult life until advanced age, we examined six leukapheresis donors (3 young and 3 middle-aged/old) who donated approximately 10% of their peripheral blood mononuclear cells (PBMC) every other month over 3-5 years. We found the number of both lymphocytes and monocytes were quite stable in the blood of all six donors. As expected, young donors had more T cell receptor excision circles (TRECs), CD31(+) cells (CD4 only) and longer telomeres in T cells than did the middle-aged donors. Interestingly, more variation in TREC number, V beta usages, and telomere lengths were observed in young donors during the 3-5 years course of donation whereas the middle-aged/old donors showed a rather striking stability in these measurements. This may reflect a more prominent role of thymic output in T cell regeneration in young than in middle-aged/old donors. Together, these findings provide an in vivo glimpse into the homeostasis of lymphocytes and monocytes in the blood at different ages, and support the notion that regeneration of lymphocytes and monocytes is robust throughout adult life up to the early 70s. C1 [Ratts, Robert B.; Weng, Nan-Ping] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Weng, NP (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Room 8C232,251 Bayview Blvd, Baltimore, MD 21224 USA. EM wengn@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH) FX The authors wish to thank Dr. Josephine Egan for critical reading of the manuscript, Crista Morris for flow cytometry assistance, and Karen Madara of the Apheresis Unit for collecting apheresis packs. This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). NR 30 TC 6 Z9 6 U1 0 U2 0 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 271 DI 10.3389/fimmu.2012.00271 PG 10 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300266 PM 22936935 ER PT J AU Yung, SC Murphy, PM AF Yung, Sunny C. Murphy, Philip M. TI Antimicrobial chemokines SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE chemoattractant; immunology; G protein-coupled receptor; mucosa; microbiome AB Chemokines are best known for their classic leukocyte chemotactic activity, which is critical for directing the immune response to sites of infection and injury. However, recent studies have suggested that at least some chemokines may also interfere with infectious agents directly. Antimicrobial chemokines tend to contain amphipathic alpha helical secondary structure, and broad-spectrum activity against both Gram-positive and Gram negative bacteria, as well as fungi. Conversely, several bacteria have been identified that possess mechanisms for specifically blocking the antimicrobial activities of chemokines. Although the precise mechanisms by which chemokines and microbes disarm one another in vitro remain unknown, there is now emerging evidence in vivo that such interactions may be biologically significant. More research will be needed to determine whether chemokines with direct antimicrobial activity may be translated into a novel class of antibiotics. C1 [Yung, Sunny C.; Murphy, Philip M.] NIAID, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, NIH, Lab Mol Immunol, Bldg 10,Room 11N113,9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov FU Division of Intramural Research of the NIAID, National Institutes of Health FX This work was supported by the Division of Intramural Research of the NIAID, National Institutes of Health. NR 68 TC 13 Z9 13 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 276 DI 10.3389/fimmu.2012.00276 PG 11 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300271 PM 22973274 ER PT J AU Zinocker, S Dressel, R Wang, XN Dickinson, AM Rolstad, B AF Zinocker, Severin Dressel, Ralf Wang, Xiao-Nong Dickinson, Anne M. Rolstad, Bent TI Immune reconstitution and graft-versus-host reactions in rat models of allogeneic hematopoietic cell transplantation SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE hematopoietic stem cell transplantation; graft-versus-host disease; rodentia; animal models; skin explant assay AB Allogeneic hematopoietic cell transplantation (alloHCT) extends the lives of thousands of patients who would otherwise succumb to hematopoietic malignancies such as leukemias and lymphomas, aplastic anemia, and disorders of the immune system. In alloHCT, different immune cell types mediate beneficial graft-versus-tumor (GvT) effects, regulate detrimental graft-versus-host disease (GvHD), and are required for protection against infections. Today, the "good" (GvT effector cells and memory cells conferring protection) cannot be easily separated from the "bad" (GvHD-causing cells), and alloHCT remains a hazardous medical modality. The transplantation of hematopoietic stem cells into an immunosuppressed patient creates a delicate environment for the reconstitution of donor blood and immune cells in co-existence with host cells. Immunological reconstitution determines to a large extent the immune status of the allo-transplanted host against infections and the recurrence of cancer, and is critical for long-term protection and survival after clinical alloHCT. Animal models continue to be extremely valuable experimental tools that widen our understanding of, for example, the dynamics of post-transplant hematopoiesis and the complexity of immune reconstitution with multiple ways of interaction between host and donor cells. In this review, we discuss the rat as an experimental model of HCT between allogeneic individuals. We summarize our findings on lymphocyte reconstitution in transplanted rats and illustrate the disease pathology of this particular model. We also introduce the rat skin explant assay, a feasible alternative to in vivo transplantation studies. The skin explant assay can be used to elucidate the biology of graft-versus-host reactions, which are known to have a major impact on immune reconstitution, and to perform genome-wide gene expression studies using controlled combinations of minor and major histocompatibility between the donor and the recipient. C1 [Zinocker, Severin; Rolstad, Bent] Univ Oslo, Inst Basic Med Sci, Dept Anat, Oslo, Norway. [Zinocker, Severin] Oslo Univ Hosp, Rikshosp, Dept Immunol, Oslo, Norway. [Dressel, Ralf] Univ Med Ctr Gottingen, Dept Cell & Mol Immunol, Gottingen, Germany. [Wang, Xiao-Nong; Dickinson, Anne M.] Newcastle Univ, Sch Med, Inst Cell Med, Dept Haematol Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Zinocker, S (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr,MSC 8180, Rockville, MD 20852 USA. EM zinockers@mail.nih.gov RI Dressel, Ralf/R-7065-2016; OI Dressel, Ralf/0000-0002-1651-1214; Zinocker, Severin/0000-0003-1730-0125 FU European Union [MRTN-CT-2004-512253, FP7-PEOPLE-2012-ITN-315963] FX We thank Dr. A. Neil Barclay for help with the definition of rat leukocyte phenotypes. This work was supported by the grants MRTN-CT-2004-512253 (TRANS-NET) and FP7-PEOPLE-2012-ITN-315963 (CELLEUROPE) from the European Union. NR 150 TC 4 Z9 4 U1 1 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PY 2012 VL 3 AR 355 DI 10.3389/fimmu.2012.00355 PG 12 WC Immunology SC Immunology GA V40TQ UT WOS:000209501300350 PM 23226148 ER PT J AU Pique, C Jones, KS AF Pique, Claudine Jones, Kathryn S. TI Pathways of cell cell transmission of HTLV-1 SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE retrovirus; HTLV-1; cell cell transmission; HTLV-1 infectivity; T cell; antigen-presenting cells; HTLV-2; virological synapse AB The deltaretroviruses human T cell lymphotropic virus type 1 (HTLV-1) and human T cell lymphotropic virus type 2 (HTLV-2) have long been believed to differ from retroviruses in other genera by their mode of transmission. While other retroviruses were thought to primarily spread by producing cell-free particles that diffuse through extracellular fluids prior to binding to and infecting target cells, HTLV-1 and HTLV-2 were believed to transmit the virus solely by cell cell interactions. This difference in transmission was believed to reflect the fact that, relative to other retroviruses, the cell-free virions produced by HTLV-infected cells are very poorly infectious. Since HTLV-1 and HTLV-2 are primarily found in T cells in the peripheral blood, spread of these viruses was believed to occur between infected and uninfected T cells, although little was known about the cellular and viral proteins involved in this interaction. Recent studies have revealed that the method of transmission of HTLV is not unique: other retroviruses including human immunodeficiency virus (HIV) are also transmitted from cell-to-cell, and this method is dramatically more efficient than cell-free transmission. Moreover, cell cell transmission of HTLV-1, as well as HIV, can occur following interactions between dendritic cells and T cells, as well as between T cells. Conversely, other studies have shown that cell-free HTLV-1 is not as poorly infectious as previously thought, since it is capable of infecting certain cell types. Here we summarize the recent insights about the mechanisms of cell cell transmission of HTLV-1 and other retroviruses. We also review in vitro and in vivo studies of infection and discuss how these finding may relate to the spread of HTLV-1 between individuals. C1 [Pique, Claudine] Univ Paris 05, Inst Cochin, CNRS UMR 8104, INSERM U567, Paris, France. [Jones, Kathryn S.] SAIC Frederick Inc, Ctr Canc Res, Natl Canc Inst, Frederick Natl Lab Canc Res,Basic Res Program,Can, Ft Detrick, MD 21702 USA. RP Jones, KS (reprint author), SAIC Frederick Inc, Ctr Canc Res, Natl Canc Inst, Frederick Natl Lab Canc Res,Basic Res Program,Can, Bldg 567,Room 253, Ft Detrick, MD 21702 USA. EM joneska@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX The authors wish to thank Drs Vineet KewalRamani and Nick Llewellyn for their helpful comments regarding the manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government, The authors would also like to thank the Cent pour sang la vie foundation and the Institut National du Cancer (InCA) for their support. NR 156 TC 25 Z9 25 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PY 2012 VL 3 AR 378 DI 10.3389/fmicb.2012.00378 PG 14 WC Microbiology SC Microbiology GA V31DF UT WOS:000208863600379 PM 23109932 ER PT J AU Polizzotto, MN Uldrick, TS Hu, DS Yarchoan, R AF Polizzotto, Mark N. Uldrick, Thomas S. Hu, Duosha Yarchoan, Robert TI Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: rnulticentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE Kaposi sarcoma-associated hetpesvirus; human herpesvirus 8; multicentric Castleman disease; KSHV inflammatory cytokine syndrome; interleukin-6; human immunodeficiency virus AB Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV-MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV-MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV-MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV-MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of MO and other cytokines. Until recently, the prognosis of patients with KSHV-MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV-MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV-MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV-MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV-MCD, as well as the optimal therapy for both of these disorders. C1 [Polizzotto, Mark N.; Uldrick, Thomas S.; Hu, Duosha; Yarchoan, Robert] NCI, HIV AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, HIV AIDS Malignancy Branch, Ctr Canc Res, NIH, Room 6N106, Bldg 10, Bethesda, MD 20892 USA. EM robert.yarchoan@mail.nih.gov FU Intramural Research Program on the NIH, National Cancer Institute FX This work was supported by the Intramural Research Program on the NIH, National Cancer Institute. The authors thank the patients who volunteered for the protocols and their families. The authors also acknowledge the help of Dr, Stefania Pittaluga, Dr. Denise Whitby, Dr, Richard Little, Dr. Victoria Wang, all of the NCI, the research nurses of HAMR, NCI, and the nurses, physicians, and medical staff of the Medical Oncology Branch of the NCI, and the medical staff of the NIH Clinical Center. NR 71 TC 38 Z9 39 U1 1 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PY 2012 VL 3 AR 73 DI 10.3389/fmicb.2012.00073 PG 9 WC Microbiology SC Microbiology GA V31DF UT WOS:000208863600127 PM 22403576 ER PT J AU Rusu, M Bonneau, R Holbrook, MR Watowich, SJ Birmanns, S Wriggers, W Freiberg, AN AF Rusu, Mirabela Bonneau, Richard Holbrook, Michael R. Watowich, Stanley J. Birmanns, Stefan Wriggers, Willy Freiberg, Alexander N. TI An assembly model of Rift Valley fever virus SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE bunyavirus assembly; protein structure prediction; hybrid modeling; multi-body refinement; multi-resolution registration AB Rift Valley fever virus (RVFV) is a bunyavirus endemic to Africa and the Arabian Peninsula that infects humans and livestock. The virus encodes two glycoproteins, Gn and Gc, which represent the major structural antigens and are responsible for host cell receptor binding and fusion. Both glycoproteins are organized on the virus surface as cylindrical hollow spikes that cluster into distinct capsomers with the overall assembly exhibiting an icosahedral symmetry. Currently, no experimental three-dimensional structure for any entire bunyavirus glycoprotein is available. Using fold recognition, we generated molecular models for both RVFV glycoproteins and found significant structural matches between the RVFV Gn protein and the influenza virus hemagglutinin protein and a separate match between RVFV Gc protein and Sindbis virus envelope protein El. Using these models, the potential interaction and arrangement of both glycoproteins in the RVFV particle was analyzed, by modeling their placement within the cryo-electron microscopy density map of RVFV. We identified four possible arrangements of the glycoproteins in the virion envelope. Each assembly model proposes that the ectodomain of Gn forms the majority of the protruding capsomer and that Gc is involved in formation of the capsomer base. Furthermore, Gc is suggested to facilitate intercapsomer connections. The proposed arrangement of the two glycoproteins on the RVFV surface is similar to that described for the alphavirus El-E2 proteins. Our models will provide guidance to better understand the assembly process of phleboviruses and such structural studies can also contribute to the design of targeted antivirals. C1 [Rusu, Mirabela; Birmanns, Stefan] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA. [Bonneau, Richard] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Bonneau, Richard] NYU, Inst Math Sci, Dept Comp Sci, New York, NY USA. [Holbrook, Michael R.; Freiberg, Alexander N.] Univ Texas Med Branch, Dept Pathol, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Holbrook, Michael R.] NIAID, Integrated Res Facil, Frederick, MD USA. [Watowich, Stanley J.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Wriggers, Willy] Cornell Univ, Weill Med Coll, Inst Computat Biomed, Dept Phys & Biophys, New York, NY 10021 USA. RP Freiberg, AN (reprint author), Univ Texas Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. EM anfreibe@utmb.edu FU M. Keck Foundation through the Keck Center for Virus Imaging; National Institutes of Health [R01GM62968] FX We thank Drs. Alan Barrett and Fred Murphy for helpful comments and discussions. This work was supported by a training fellowship from the W. M. Keck Foundation to the Gulf Coast Consortia through the Keck Center for Virus Imaging (Alexander N. Freiberg), and in part by a grant from the National Institutes of Health (R01GM62968, Willy Wriggers). NR 59 TC 17 Z9 17 U1 2 U2 9 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PY 2012 VL 3 AR 254 DI 10.3389/fmicb.2012.00254 PG 15 WC Microbiology SC Microbiology GA V31DF UT WOS:000208863600302 PM 22837754 ER PT J AU Terahara, K Yamamoto, T Mitsuki, Y Shibusawa, K Ishige, M Mizukoshi, F Kobayashi, K Tsunetsugu-Yokota, Y AF Terahara, Kazutaka Yamamoto, Takuya Mitsuki, Yu-ya Shibusawa, Kentaro Ishige, Masayuki Mizukoshi, Fuminori Kobayashi, Kazuo Tsunetsugu-Yokota, Yasuko TI Fluorescent reporter signals, EGFP, and DsRed, encoded in HIV-1 facilitate the detection of productively infected cells and cell-associated viral replication levels SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE HIV-1; flow cytometry; EGFP; DsRed; Gag; productive infection AB Flow cytometric analysis is a reliable and convenient method for investigating molecules at the single cell level. Previously, recombinant human immunodeficiency virus type 1 (HIV-1) strains were constructed that express a fluorescent reporter, either enhanced green fluorescent protein, or DsRed, which allow the monitoring of HIV-1-infected cells by flow cytometry. The present study further investigated the potential of these recombinant viruses in terms of whether the HIV-1 fluorescent reporters would be helpful in evaluating viral replication based on fluorescence intensity. When primary CD4(+) T cells were infected with recombinant viruses, the fluorescent reporter intensity measured by flow cytometry was associated with the level of CD4 downmodulation and Gag p24 expression in infected cells. Interestingly, some HIV-1-infected cells, in which CD4 was only moderately down-modulated, were reporter-positive but Gag p24-negative. Furthermore, when the activation status of primary CD4(+) T cells was modulated by T cell receptor-mediated stimulation, we confirmed the preferential viral production upon strong stimulation and showed that the intensity of the fluorescent reporter within a proportion of HIV-1-infected cells was correlated with the viral replication level. These findings indicate that a fluorescent reporter encoded within HIV-1 is useful for the sensitive detection of productively infected cells at different stages of infection and for evaluating cell-associated viral replication at the single cell level. C1 [Terahara, Kazutaka; Mitsuki, Yu-ya; Shibusawa, Kentaro; Ishige, Masayuki; Kobayashi, Kazuo; Tsunetsugu-Yokota, Yasuko] Natl Inst Infect Dis, Dept Immunol, Tokyo 1628640, Japan. [Yamamoto, Takuya] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Mitsuki, Yu-ya; Shibusawa, Kentaro] Japan Fdn AIDS Prevent, Tokyo, Japan. [Ishige, Masayuki] Kumamoto Univ, Ctr AIDS Res, Div Hematopoiesis, Kumamoto, Japan. [Mizukoshi, Fuminori] Tochigi Prefectural Inst Publ Hlth & Environm Sci, Dept Microbiol, Utsunomiya, Tochigi, Japan. RP Tsunetsugu-Yokota, Y (reprint author), Natl Inst Infect Dis, Dept Immunol, Shinjuku Ku, 1-23-1 Toyama, Tokyo 1628640, Japan. EM yyokota@nih.go.jp OI Yamamoto, Takuya/0000-0003-3753-1211 FU Ministry of Education, Science, Sports, and Culture of Japan; Ministry of Health, Labour, and Welfare of Japan FX We thank Kaori Okano for technical support. This work was supported in part by Grants from the Ministry of Education, Science, Sports, and Culture of Japan (Kazutaka Terabara), and the Ministry of Health, Labour, and Welfare of Japan (Kazutaka Terabara and Yasuko Tsunetsugu-Yokota). NR 32 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PY 2012 VL 3 AR 280 DI 10.3389/fmicb.2011.00280 PG 11 WC Microbiology SC Microbiology GA V31DF UT WOS:000208863600049 ER PT J AU Zhu, J O'Dell, S Ofek, G Pancera, M Wu, X Zhang, B Zhang, Z Mullikin, JC Simek, M Burton, DR Koff, WC Shapiro, L Mascola, JR Kwong, PD AF Zhu, Jiang O'Dell, Sijy Ofek, Gilad Pancera, Marie Wu, Xueling Zhang, Baoshan Zhang, Zhenhai Mullikin, James C. Simek, Melissa Burton, Dennis R. Koff, Wayne C. Shapiro, Lawrence Mascola, John R. Kwong, Peter D. CA NISC Comparative Sequencing Prog TI Somatic populations of PGT135-137 HIV-1-neutralizing antibodies identified by 454 pyrosequencing and bioinfornnatics SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE antibody bioinformatics; high-throughput sequencing; HIV-1; immunity; N-linked glycan AB Select HIV-1-infected individuals develop sera capable of neutralizing diverse viral strains. The molecular basis of this neutralization is currently being deciphered by the isolation of HIV-1-neutralizing antibodies. In one infected donor, three neutralizing antibodies, PGT135-137, were identified by assessment of neutralization from individually sorted B cells and found to recognize an epitope containing an N-linked glycan at residue 332 on HIV-1 gp120. Here we use next-generation sequencing and bioinformatics methods to interrogate the B cell record of this donor to gain a more complete understanding of the humoral immune response. PGT135-137-gene family specific primers were used to amplify heavy-chain and light-chain variable-domain sequences. Pyrosequencing produced 141,298 heavy-chain sequences of IGHV4-39 origin and 87,229 light-chain sequences of IGKV3-15 origin. A number of heavy and light-chain sequences of similar to 90% identity to PGT137, several to PGT136, and none of high identity to PGT135 were identified. After expansion of these sequences to include close phylogenetic relatives, a total of 202 heavy-chain sequences and 72 light-chain sequences were identified. These sequences were clustered into populations of 95% identity comprising 15 for heavy chain and 10 for light chain, and a select sequence from each population was synthesized and reconstituted with a PGT137-partner chain. Reconstituted antibodies showed varied neutralization phenotypes for HIV-1 clade A and D isolates. Sequence diversity of the antibody population represented by these tested sequences was notably higher than observed with a 454 pyrosequencing-control analysis on 10 antibodies of defined sequence, suggesting that this diversity results primarily from somatic maturation. Our results thus provide an example of how pathogens like HIV-1 are opposed by a varied humoral immune response, derived from intrinsic mechanisms of antibody development, and embodied by somatic populations of diverse antibodies. C1 [Zhu, Jiang; O'Dell, Sijy; Ofek, Gilad; Pancera, Marie; Wu, Xueling; Zhang, Baoshan; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Zhang, Zhenhai; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Mullikin, James C.; NISC Comparative Sequencing Prog] Natl Human Genome Res Inst, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD USA. [Simek, Melissa; Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA USA. [Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat, Neutralizing Antibody Ctr, La Jolla, CA USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 4508, Bethesda, MD 20892 USA. EM pdkwong@nih.gov FU Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; National Institutes of Health; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium FX We thank H. Coleman, M. Park, B. Schmidt, and A. Young for 454 pyrosequencing at the NIH Intramural Sequencing Center (NISC), J. Stuckey for assistance with figures. We also thank members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions or comments on the manuscript. We would like to thank all the study participants and research staff at each of the Protocol G clinical centers, and all of the Protocol G team members, the IAVI Human Immunology Laboratory, and all of the Protocol G clinical investigators, specifically, George Miiro, Anton Pozniak, Dale McPhee, Olivier Manigart, Etienne Karita, Andre Inwoley, Walter Jaoko, Jack DeHovitz, Linda-Gail Bekker, Punnee Pitisuttithum, Robert Paris, Jennifer Serwanga, and Susan Allen. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute, National Institutes of Health, and by grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium. NR 62 TC 33 Z9 35 U1 0 U2 14 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PY 2012 VL 3 AR 315 DI 10.3389/fmicb.2012.00315 PG 18 WC Microbiology SC Microbiology GA V31DF UT WOS:000208863600323 PM 23024643 ER PT J AU Hansen, KA Hillenbrand, SF Ungerleider, LG AF Hansen, Kathleen A. Hillenbrand, Sarah F. Ungerleider, Leslie G. TI Effects of prior knowledge on decisions made under perceptual vs. categorical uncertainty SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE prior probability; expectation; frontoparietal; dorsolateral prefrontal cortex AB Humans use prior knowledge to bias decisions made under uncertainty. In this fMRI study we predicted that different brain dynamics play a role when prior knowledge is added to decisions made under perceptual vs. categorical uncertainty. Subjects decided whether shapes belonged to Category S - smoother or Category B - bumpier - under both uncertainty conditions, with or without prior knowledge cues. When present, the prior knowledge cue, 80/20 or 50/50, indicated that 80 and 20% (or 50 and 50%) were the chances that responding "S" and "B" (or vice versa) would be correct. During perceptual uncertainty, shapes were degraded with noise. During categorical uncertainty, shapes were ambiguous. Adding the 80/20 cue increased activation during perceptual uncertainty in bilateral lateral occipital (LO) cortex and left middle frontal gyrus (MidFG), and decreased activity in bilateral LO cortex during categorical uncertainty. Right MidFG and other frontoparietal regions were active in all conditions. The results demonstrate that left MidFG shows activation changes, suggestive of an influence on visual cortex, that depend on the factor that makes the decisions difficult. When sensory evidence is difficult to perceive, prior knowledge increases visual cortical activity. When the sensory evidence is easy to perceive but difficult to interpret, prior knowledge decreases visual cortical activity. C1 [Hansen, Kathleen A.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Hillenbrand, Sarah F.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. RP Hansen, KA (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM hansenka@mail.nih.gov FU NIMH Intramural Research Program FX This work was supported by the NIMH Intramural Research Program. NR 29 TC 3 Z9 3 U1 1 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PY 2012 VL 6 AR UNSP 163 DI 10.3389/fnins.2012.00163 PG 10 WC Neurosciences SC Neurosciences & Neurology GA V35RF UT WOS:000209165300168 PM 23162424 ER PT J AU IIango, A Shumake, J Wetzel, W Scheich, H Ohl, FW AF IIango, Anton Shumake, Jason Wetzel, Wolfram Scheich, Henning Ohl, Frank W. TI The role of dopamine in the context of aversive stimuli with particular reference to acoustically signaled avoidance learning SO FRONTIERS IN NEUROSCIENCE LA English DT Review DE dopamine; aversive stimuli; avoidance learning; intracranial self-stimulation; reward and punishment; dorsal vs. ventral striatum; lateral habenula; ventral tegmental area AB Learning from punishment is a powerful means for behavioral adaptation with high relevance for various mechanisms of self-protection. Several studies have explored the contribution of released dopamine (DA) or responses of DA neurons on reward seeking using rewards such as food, water, and sex. Phasic DA signals evoked by rewards or conditioned reward predictors are well documented, as are modulations of these signals by such parameters as reward magnitude, probability, and deviation of actually occurring from expected rewards. Less attention has been paid to DA neuron firing and DA release in response to aversive stimuli, and the prediction and avoidance of punishment. In this review, we first focus on DA changes in response to aversive stimuli as measured by microdialysis and voltammetry followed by the change in electrophysiological signatures by aversive stimuli and fearful events. We subsequently focus on the role of DA and effect of DA manipulations on signaled avoidance learning, which consists of learning the significance of a warning cue through Pavlovian associations and the execution of an instrumental avoidance response. We present a coherent framework utilizing the data on microdialysis, voltammetry, electrophysiological recording, electrical brain stimulation, and behavioral analysis. We end by outlining current gaps in the literature and proposing future directions aimed at incorporating technical and conceptual progress to understand the involvement of reward circuit on punishment based decisions. C1 [IIango, Anton; Shumake, Jason; Wetzel, Wolfram; Scheich, Henning; Ohl, Frank W.] Leibniz Inst Neurobiol, Magdeburg, Germany. [Ohl, Frank W.] Univ Magdeburg, Inst Biol, D-39106 Magdeburg, Germany. [Shumake, Jason] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. RP IIango, A (reprint author), NIDA, Intramural Res Programme, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM antonilango@hotmail.com; frank.ohl@ifn-magdeburg.de FU Deutsche Forschungsgemeinschaft (DFG) [SFB 779, SFB TRR 62] FX This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG), SFB 779 and SFB TRR 62. We thank all the technicians involved in the work over the years especially Kathrin Ohl, and Lydia Low for help in animal training, care, and histology. NR 103 TC 0 Z9 0 U1 2 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PY 2012 VL 6 AR UNSP 132 DI 10.3389/fnins.2012.00132 PG 9 WC Neurosciences SC Neurosciences & Neurology GA V35RF UT WOS:000209165300138 ER PT J AU Kawamoto, EM Vivar, C Camandola, S AF Kawamoto, Elisa Mitiko Vivar, Carmen Camandola, Simonetta TI Physiology and pathology of calcium signaling in the brain SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE calcium channels; synaptic plasticity AB Calcium (Ca2+) plays fundamental and diversified roles in neuronal plasticity. As second messenger of many signaling pathways, Ca2+ as been shown to regulate neuronal gene expression, energy production, membrane excitability, synaptogenesis, synaptic transmission, and other processes underlying learning and memory and cell survival. The flexibility of Ca2+ signaling is achieved by modifying cytosolic Ca2+ concentrations via regulated opening of plasma membrane and subcellular Ca2+ sensitive channels. The spatiotemporal patterns of intracellular Ca2+ signals, and the ultimate cellular biological outcome, are also dependent upon termination mechanism, such as Ca2+ buffering, extracellular extrusion, and intra-organelle sequestration. Because of the central role played by Ca2+ in neuronal physiology, it is not surprising that even modest impairments of Ca2+ homeostasis result in profound functional alterations. Despite their heterogeneous etiology neurodegenerative disorders, as well as the healthy aging process, are all characterized by disruption of Ca2+ homeostasis and signaling. In this review we provide an overview of the main types of neuronal Ca2+ channels and their role in neuronal plasticity. We will also discuss the participation of Ca2+ signaling in neuronal aging and degeneration. C1 [Kawamoto, Elisa Mitiko; Vivar, Carmen; Camandola, Simonetta] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Camandola, S (reprint author), NIA, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM camandolasi@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This research was entirely supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 366 TC 31 Z9 31 U1 1 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PY 2012 VL 3 AR UNSP 61 DI 10.3389/fphar.2012.00061 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V35XE UT WOS:000209177700060 PM 22518105 ER PT J AU Lund, IK Rasch, MG Ingvarsen, S Pass, J Madsen, DH Engelholm, LH Behrendt, N Hoyer-Hansen, G AF Lund, Ida K. Rasch, Morten G. Ingvarsen, Signe Pass, Jesper Madsen, Daniel H. Engelholm, Lars H. Behrendt, Niels Hoyer-Hansen, Gunilla TI Inhibitory monoclonal antibodies against mouse proteases raised in gene-deficient mice block proteolytic functions in vivo SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE mouse monoclonal antibodies; extracellular proteolysis; collagen internalization; in vivo models; plasminogen activation AB Identification of targets for cancer therapy requires the understanding of the in vivo roles of proteins, which can be derived from studies using gene-targeted mice. An alternative strategy is the administration of inhibitory monoclonal antibodies (mAbs), causing acute disruption of the target protein function(s). This approach has the advantage of being a model for therapeutic targeting. mAbs for use in mouse models can be obtained through immunization of gene-deficient mice with the autologous protein. Such mAbs react with both species-specific epitopes and epitopes conserved between species. mAbs against proteins involved in extracellular proteolysis, including plasminogen activators urokinase plasminogen activator (uPA), tissue-type plasminogen activator (tPA), their inhibitor PAI-1, the uPA receptor (uPAR), two matrix metalloproteinases (MMP9 and MMP14), as well as the collagen internalization receptor uPARAP have been developed. The inhibitory mAbs against uPA and uPAR block plasminogen activation and thereby hepatic fibrinolysis in vivo. Wound healing, another plasmin-dependent process, is delayed by an inhibitory mAb against uPA in the adult mouse. Thromboembolism can be inhibited by anti-PAI-1 mAbs in vivo. In conclusion, function-blocking mAbs are well-suited for targeted therapy in mouse models of different diseases, including cancer. C1 [Lund, Ida K.; Rasch, Morten G.; Ingvarsen, Signe; Pass, Jesper; Madsen, Daniel H.; Engelholm, Lars H.; Behrendt, Niels; Hoyer-Hansen, Gunilla] Copenhagen Univ Hosp, Finsen Lab, DK-2200 Copenhagen N, Denmark. [Lund, Ida K.; Rasch, Morten G.; Ingvarsen, Signe; Pass, Jesper; Madsen, Daniel H.; Engelholm, Lars H.; Behrendt, Niels; Hoyer-Hansen, Gunilla] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. [Rasch, Morten G.; Pass, Jesper] Novo Nordisk AS, Biopharmaceut Res Unit, Antibody Technol, Malov, Denmark. [Madsen, Daniel H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Hoyer-Hansen, G (reprint author), Copenhagen Univ Hosp, Copenhagen Bioctr, Finsen Lab, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark. EM gunilla@finsenlab.dk OI Madsen, Daniel Hargboel/0000-0002-3183-6201; Engelholm, Lars/0000-0002-6616-1232 FU European Community [201279] FX We thank all the partners in Microenvimet for fruitful and inspiring discussions and collaborations. We thank John Post for graphic assistance. Much of the research leading to these results has received funding from the European Community's Seventh Framework Program FP7/2007-2011 under grant agreement no201279. NR 41 TC 6 Z9 6 U1 0 U2 0 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PY 2012 VL 3 AR UNSP 122 DI 10.3389/fphar.2012.00122 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V35XE UT WOS:000209177700117 PM 22754528 ER PT J AU Mathur, BN Lovinger, DM AF Mathur, Brian N. Lovinger, David M. TI Endocannabinoid-dopamine interactions in striatal synaptic plasticity SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE long-term depression; CBI; serotonin; 5-HT1b; adenosine; Parkinson's disease; medium spiny neuron AB The nigrostriatal dopaminergic system is implicated in action control and learning. A large body of work has focused on the contribution of this system to modulation of the corticostriatal synapse, the predominant synapse type in the striatum. Signaling through the D2 dopamine receptor is necessary for endocannabinoid-mediated depression of corticostriatal glutamate release. Here we review the known details of this mechanism and discuss newly discovered signaling pathways interacting with this system that ultimately exert dynamic control of cortical input to the striatum and striatal output. This topic is timely with respect to Parkinson's disease given recent data indicating changes in the striatal endocannabinoid system in patients with this disorder. C1 [Mathur, Brian N.; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, US Natl Inst Hlth, Rockville, MD USA. RP Lovinger, DM (reprint author), NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, US Natl Inst Hlth, TS-13,5625 Fishers Lane, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov NR 114 TC 14 Z9 15 U1 1 U2 11 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PY 2012 VL 3 AR UNSP 66 DI 10.3389/fphar.2012.00066 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V35XE UT WOS:000209177700064 PM 22529814 ER PT J AU Yao, XL Vitek, MP Remaley, AT Levine, SJ AF Yao, Xianglan Vitek, Michael P. Remaley, Alan T. Levine, Stewart J. TI Apolipoprotein mimetic peptides: a new approach for the treatment of asthma SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE asthma; apolipoprotein E; apolipoprotein A-I; apolipoprotein E mimetic peptide; apolipoprotein A-I mimetic peptide AB New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM)-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR, and goblet cell hyperplasia is mediated by low density lipoprotein (LDL) receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130-149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE(-/-) mice.These findings identified the apolipoprotein E - LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE-mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling, and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease. C1 [Yao, Xianglan; Remaley, Alan T.; Levine, Stewart J.] NHLBI, Cardiovasc & Pulmonary Branch, Bethesda, MD 20892 USA. [Vitek, Michael P.] Cognosci Inc, Res Triangle Pk, NC USA. RP Levine, SJ (reprint author), NHLBI, Cardiovasc & Pulmonary Branch, Natl Inst Hlth, Bldg10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA FX This work was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA. NR 66 TC 9 Z9 9 U1 0 U2 0 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PY 2012 VL 3 AR UNSP 37 DI 10.3389/fphar.2012.00037 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V35XE UT WOS:000209177700037 PM 22408624 ER PT J AU Chantler, PD Lakatta, EG AF Chantler, Paul D. Lakatta, Edward G. TI Arterial-ventricular coupling with aging and disease SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE left ventricular function; arterial system; exercise; aging; disease AB Age is the dominant risk factor for cardiovascular diseases. Understanding the coupling between the left ventricle (LV) and arterial system, termed arterial ventricular coupling (E-A/E-LV), provides important mechanistic insights into the complex cardiovascular system and its changes with aging in the absence and presence of disease. E-A/E-LV can be indexed by the ratio of effective arterial elastance (E-A; a measure of the net arterial load exerted on the LV) to left ventricular end-systolic elastance (E-LV; a load-independent measure of left ventricular chamber performance). Age-associated alterations in arterial structure and function, including diameter, wall thickness, wall stiffness, and endothelial dysfunction, contribute to a gradual increase in resting E-A with age. Remarkably there is a corresponding increase in resting E-LV with age, due to alterations to LV remodeling (loss in myocyte number, increased collagen) and function. These age-adaptations at rest likely occur, at least, in response to the age-associated increase in E-A and ensure that E-A/E-LV is closely maintained within a narrow range, allowing for optimal energetic efficiency at the expense of mechanical efficacy. This optimal coupling at rest is also maintained when aging is accompanied by the presence of hypertension, and obesity, despite further increases in E-A and E-LV in these conditions. In contrast, in heart failure patients with either reduced or preserved ejection fraction, E-A/E-LV at rest is impaired. During dynamic exercise, E-A/E-LV decreases, due to an acute mismatch between the arterial and ventricular systems as E-LV increases disproportionate compared to E-A (approximate to 200 vs. 40%), to ensure that sufficient cardiac performance is achieved to meet the increased energetic requirements of the body. However, with advancing age the reduction in E-A/E-LV during acute maximal exercise is blunted, due to a blunted increase E-LV. This impaired E-A/E-LV is further amplified in the presence of disease, and may explain, in part, the reduced cardiovascular functional capacity with age and disease. Thus, although increased stiffness of the arteries itself has important physiological and clinical relevance, such changes also have major implications on the heart, and vice versa, and the manner in the way they interact has important ramifications on cardiovascular function both at rest and during exercise. Examination of the alterations in arterial ventricular coupling with aging and disease can yield mechanistic insights into the pathophysiology of these conditions and increase the effectiveness of current therapeutic interventions. C1 [Chantler, Paul D.] W Virginia Univ, Sch Med, Div Exercise Physiol, Morgantown, WV 26506 USA. [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Chantler, PD (reprint author), W Virginia Univ, Sch Med, Div Exercise Physiol, Morgantown, WV 26506 USA. EM pchantler@hsc.wvu.edu FU Intramural Research Program of the NIH; National Institute on Aging FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 73 TC 30 Z9 32 U1 1 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PY 2012 VL 3 AR UNSP 90 DI 10.3389/fphys.2012.00090 PG 12 WC Physiology SC Physiology GA V35UH UT WOS:000209173000088 PM 22586401 ER PT J AU DePamphilis, ML de Renty, CM Ullah, Z Lee, CY AF DePamphilis, Melvin L. de Renty, Christelle M. Ullah, Zakir Lee, Chrissie Y. TI "The octet": eight protein kinases that control mammalian DNA replication SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE cyclin-dependent kinases; cyclins; checkpoint kinases; mitotic cell cycle; endoreplication; DNA re-replication; Cdc7; Dbf4 ID ORIGIN RECOGNITION COMPLEX; TROPHOBLAST GIANT-CELLS; BUDDING YEAST; S-PHASE; DROSOPHILA ENDOCYCLE; G(2)/M CHECKPOINT; RE-REPLICATION; TARGETED DISRUPTION; INHIBITOR P57(KIP2); EMBRYONIC LETHALITY AB Development of a fertilized human egg into an average sized adult requires about 29 trillion cell divisions, thereby producing enough DNA to stretch to the Sun and back 200 times (DePamphilis and Bell, 2011)! Even more amazing is the fact that throughout these mitotic cell cycles, the human genome is duplicated once and only once each time a cell divides. If a cell accidentally begins to re-replicate its nuclear DNA prior to cell division, checkpoint pathways trigger apoptosis. And yet, some cells are developmentally programmed to respond to environmental cues by switching from mitotic cell cycles to endocycles, a process in which multiple S phases occur in the absence of either mitosis or cytokinesis. Endocycles allow production of viable, differentiated, polyploid cells that no longer proliferate. What is surprising is that among the 516 (Manning et al., 2002) to 557 (BioMart web site) protein kinases encoded by the human genome, only eight regulate nuclear DNA replication directly. These are Cdk1, Cdk2, Cdk4, Cdk6, Cdk7, Cdc7, Checkpoint kinase-1 (Chk1), and Checkpoint kinase-2. Even more remarkable is the fact that only four of these enzymes (Cdk1, Cdk7, Cdc7, and Chk1) are essential for mammalian development. Here we describe how these protein kinases determine when DNA replication occurs during mitotic cell cycles, how mammalian cells switch from mitotic cell cycles to endocycles, and how cancer cells can be selectively targeted for destruction by inducing them to begin a second S phase before mitosis is complete. C1 [DePamphilis, Melvin L.; de Renty, Christelle M.; Lee, Chrissie Y.] NICHHD, NIH, Program Genom Differentiat, Bethesda, MD 20892 USA. [Ullah, Zakir] Lahore Univ Management Sci, Dept Biol, Syed Babar Ali Sch Sci & Engn, Lahore, Pakistan. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6A,Room 3A-15,9000 Rockville Pike, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU NIH/NICHD intramural program FX This work was supported by the NIH/NICHD intramural program. NR 138 TC 15 Z9 15 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PY 2012 VL 3 AR 368 DI 10.3389/fphys.2012.00368 PG 20 WC Physiology SC Physiology GA V35UH UT WOS:000209173000361 PM 23055977 ER PT J AU Kobilo, T van Praag, H AF Kobilo, Tali van Praag, Henriette TI Muscle fatigue and cognition: what is the link? SO FRONTIERS IN PHYSIOLOGY LA English DT Editorial Material C1 [Kobilo, Tali; van Praag, Henriette] NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X NR 22 TC 2 Z9 2 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PY 2012 VL 3 AR UNSP 14 DI 10.3389/fphys.2012.00014 PG 3 WC Physiology SC Physiology GA V35UH UT WOS:000209173000014 PM 22347193 ER PT J AU Kong, XN Horiguchi, N Mori, M Gao, B AF Kong, Xiaoni Horiguchi, Norio Mori, Masatomo Gao, Bin TI Cytokines and STATs in liver fibrosis SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE stellate cells; interferon; interleukin; STATs AB Liver fibrosis, or cirrhosis, is a common end-stage condition of many chronic liver diseases after incomplete recovery from hepatocyte damage. During fibrosis progression, hepatocellular damage and inflammation trigger complex cellular events that result in collagen deposition and the disruption of the normal liver architecture. Hepatic stellate cell activation and transdifferentiation into myofibroblasts are key events in liver fibrogenesis. Research findings from cell culture and animal models have revealed that the Janus kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway, which can be activated by many cytokines, growth factors, and hormones, plays a critical role in hepatic fibrogenesis. This review summarizes the biological significance of diverse cytokines and their downstream signaling protein STATs in hepatic fibrogenesis. C1 [Kong, Xiaoni; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Horiguchi, Norio; Mori, Masatomo] Gunma Univ, Grad Sch Med, Dept Med & Mol Sci, Gunma, Japan. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane,Room 2S-33, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 86 TC 32 Z9 34 U1 2 U2 11 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PY 2012 VL 3 AR UNSP 69 DI 10.3389/fphys.2012.00069 PG 7 WC Physiology SC Physiology GA V35UH UT WOS:000209173000068 PM 22493582 ER PT J AU Jasinska, AJ Yasuda, M Rhodes, RE Wang, C Polk, TA AF Jasinska, Agnes J. Yasuda, Marie Rhodes, Rebecca E. Wang, Cheng Polk, Thad A. TI Task difficulty modulates the impact of emotional stimuli on neural response in cognitive-control regions SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE emotion; cognitive control; executive function; emotion-cognition interactions; fMRI; ACC; DLPFC; IFG AB Both heightened reactivity to emotional stimuli and impaired cognitive control are key aspects of depression, anxiety, and addiction. But the impact of emotion on cognitive-control processes, and the factors that modulate this impact, are still not well understood. We examined the effects of threat and reward distracters on the neural correlates of cognitive control using functional MRI (fMRI) and the Multi-Source Interference Task (MSIT). Behaviorally, subjects were slower and less accurate on the more demanding incongruent trials compared to the easier congruent trials. In addition, both threat and reward distracters significantly impaired the speed of responding on incongruent trials relative to the no-distracter condition. At the neural level, we used the incongruent congruent contrast to functionally define four cognitive-control regions of interest (ROIs): anterior cingulate cortex (ACC), left and right inferior frontal gyrus (IFG)/insula, and right dorsolateral prefrontal cortex (DLPFC). A repeated-measures analysis of variance on the extracted contrast values in these ROIs indicated a significant interaction of stimulus salience and task difficulty on the neural response in cognitive-control regions. Specifically, threat distracters significantly decreased the response in cognitive-control regions on incongruent trials, whereas they significantly increased that response on congruent trials, relative to the no-distracter condition. Exploratory analyses of the amygdala response showed a similar interaction of stimulus salience and task difficulty: threat distracters significantly decreased the amygdala response only on incongruent trials. Overall, our results suggest that the impact of emotional distracters on the neural response in cognitive-control regions as well as in the amygdala is modulated by task difficulty, and add to our understanding of the factors that determine whether emotion enhances or impairs cognition. C1 [Jasinska, Agnes J.] Univ Michigan, Michigan Inst Clin & Hlth Res, Ann Arbor, MI 48109 USA. [Jasinska, Agnes J.; Yasuda, Marie; Rhodes, Rebecca E.; Wang, Cheng; Polk, Thad A.] Univ Michigan, Dept Psychol, Ann Arbor, MI USA. RP Jasinska, AJ (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jasinskaaj@mail.nih.gov FU NCI NIH HHS [P50 CA101451]; NCRR NIH HHS [UL1 RR024986] NR 54 TC 11 Z9 13 U1 1 U2 10 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PY 2012 VL 3 AR 345 DI 10.3389/fpsyg.2012.00345 PG 12 WC Psychology, Multidisciplinary SC Psychology GA V31DJ UT WOS:000208864000061 PM 23060828 ER PT J AU Lange-Kuttner, C Averbeck, BB Hirsch, SV Wiessner, I Lamba, N AF Lange-Kuettner, Christiane Averbeck, Bruno B. Hirsch, Silvia V. Wiessner, Isabel Lamba, Nishtha TI Sequence learning under uncertainty in children: self-reflection vs. self-assertion SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE sequence learning; learning under uncertainty; stochastic feedback; positive and negative feedback AB We know that stochastic feedback impairs children's associative stimulus response (S R) learning (Crone et al., 2004a; Eppinger et al., 2009), but the impact of stochastic feedback on sequence learning that involves deductive reasoning has not been not tested so far. In the current study, 8- to 11-year-old children (N = 171) learned a sequence of four left and right button presses, LLRR, RRLL, LRLR, RLRL, LRRL, and RLLR, which needed to be deduced from feedback because no directional cues were given. One group of children experienced consistent feedback only (deterministic feedback, 100% correct). In this condition, green feedback on the screen indicated that the children had been right when they were right, and red feedback indicated that the children had been wrong when they were wrong. Another group of children experienced inconsistent feedback (stochastic feedback, 85% correct, 15% false), where in some trials, green feedback on the screen could signal that children were right when in fact they were wrong, and red feedback could indicate that they were wrong when in fact they had been right. Independently of age, children's sequence learning in the stochastic condition was initially much lower than in the deterministic condition, but increased gradually and improved with practice. Responses toward positive vs. negative feedback varied with age. Children were increasingly able to understand that they could have been wrong when feedback indicated they were right (self-reflection), but they remained unable to understand that they could have been right when feedback indicated they were wrong (self-assertion). C1 [Lange-Kuettner, Christiane] London Metropolitan Univ, Sch Psychol, Fac Life Sci, London E1 7NT, England. [Lange-Kuettner, Christiane; Wiessner, Isabel] Univ Konstanz, Fac Psychol, Constance, Germany. [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Averbeck, Bruno B.] UCL, Inst Neurol, London, England. [Hirsch, Silvia V.] Univ Klagenfurt, Klagenfurt, Austria. [Lamba, Nishtha] NYU, Hunter Coll, New York, NY USA. RP Lange-Kuttner, C (reprint author), London Metropolitan Univ, Sch Psychol, Fac Life Sci, Room CS2-13,1 Old Castle St, London E1 7NT, England. EM c.langekuettner@londonmet.ac.uk OI Lange-Kuttner, Prof. Dr. Chris/0000-0001-6021-8931 NR 73 TC 4 Z9 4 U1 7 U2 9 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PY 2012 VL 3 AR 127 DI 10.3389/fpsyg.2012.00127 PG 11 WC Psychology, Multidisciplinary SC Psychology GA V31DI UT WOS:000208863900139 PM 22563324 ER PT J AU Smith, DW Aouad, RK Keil, A AF Smith, David W. Aouad, Rony K. Keil, Andreas TI Cognitive task demands modulate the sensitivity of the human cochlea SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE corticofugal pathways; medial olivocochlear efferents; MOC; selective auditory attention; distortion product otoacoustic emission; DPOAE; human AB Recent studies lead to the conclusion that focused attention, through the activity of corti-cofugal and medial olivocochlear (MOC) efferent pathways, modulates activity at the most peripheral aspects of the auditory system within the cochlea. In two experiments, we investigated the effects of different intermodal attention manipulations on the response of outer hair cells (OHCs), and the control exerted by the MOC efferent system. The effect of the MOCs on OHC activity was characterized by measuring the amplitude and rapid adaptation time course of distortion product otoacoustic emissions (DPOAEs). In the first, DPOAE recordings were compared while participants were reading a book and counting the occurrence of the letter "a" (auditory-ignoring) and while counting either short- or long-duration eliciting tones (auditory-attending). In the second, DPOAEs were recorded while subjects watched muted movies with subtitles (auditory-ignoring/visual distraction) and were compared with DPOAEs recorded while subjects counted the same tones (auditory-attending) as in Experiment 1. In both Experiments 1 and 2, the absolute level of the averaged DPOAEs recorded during the auditory-ignoring condition was statistically higher than that recorded in the auditory-attending condition. Efferent-induced rapid adaptation was evident in all DPOAE contours, under all attention conditions, suggesting that two medial efferent processes act independently to determine rapid adaptation, which is unaffected by attention, and the overall DPOAE level, which is significantly affected by changes in the focus of attention. C1 [Smith, David W.; Keil, Andreas] Univ Florida, Dept Psychol, Program Behav & Cognit Neurosci, Gainesville, FL 32611 USA. [Smith, David W.] Univ Florida, Ctr Smell & Taste, Gainesville, FL 32611 USA. [Smith, David W.] Univ Florida, Dept Otolaryngol Head & Neck Surg, Gainesville, FL 32611 USA. [Aouad, Rony K.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Keil, Andreas] Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL 32611 USA. RP Smith, DW (reprint author), Univ Florida, Dept Psychol, Program Behav & Cognit Neurosci, Box 112250, Gainesville, FL 32611 USA. EM dwsmith@ufl.edu RI Keil, Andreas/F-9427-2011 OI Keil, Andreas/0000-0002-4064-1924 FU NIMH NIH HHS [R01 MH084932] NR 47 TC 10 Z9 11 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PY 2012 VL 3 AR 30 DI 10.3389/fpsyg.2012.00030 PG 8 WC Psychology, Multidisciplinary SC Psychology GA V31DI UT WOS:000208863900044 PM 22347870 ER PT J AU Thomas, AG Dennis, A Bandettini, PA Johansen-Berg, H AF Thomas, Adam G. Dennis, Andrea Bandettini, Peter A. Johansen-Berg, Heidi TI The effects of aerobic activity on brain structure SO FRONTIERS IN PSYCHOLOGY LA English DT Review DE exercise; plasticity; hippocampus; neurogenesis; angiogenesis; learning; environmental enrichment; aging AB Aerobic activity is a powerful stimulus for improving mental health and for generating structural changes in the brain. We review the literature documenting these structural changes and explore exactly where in the brain these changes occur as well as the underlying substrates of the changes including neural, glial, and vasculature components. Aerobic activity has been shown to produce different types of changes in the brain. The presence of novel experiences or learning is an especially important component in how these changes are manifest. We also discuss the distinct time courses of structural brain changes with both aerobic activity and learning as well as how these effects might differ in diseased and elderly groups. C1 [Thomas, Adam G.; Bandettini, Peter A.] NIMH, Funct MRI Facil, NIH, DHHS, Bethesda, MD 20892 USA. [Thomas, Adam G.; Dennis, Andrea; Johansen-Berg, Heidi] Univ Oxford, FMRIB, Oxford, England. [Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, NIH, DHHS, Bethesda, MD 20892 USA. RP Thomas, AG (reprint author), NIH, 10 Ctr Dr,Room 1D80, Bethesda, MD 20892 USA. EM adamt@nih.gov OI Johansen-Berg, Heidi/0000-0002-4134-9730; Thomas, Adam/0000-0002-2850-1419 FU Medical Research Council [G0700399]; Wellcome Trust [090955] NR 94 TC 57 Z9 59 U1 6 U2 26 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PY 2012 VL 3 AR 86 DI 10.3389/fpsyg.2012.00086 PG 9 WC Psychology, Multidisciplinary SC Psychology GA V31DI UT WOS:000208863900098 PM 22470361 ER PT J AU Young, KD Erickson, K Drevets, WC AF Young, Kymberly D. Erickson, Kristine Drevets, Wayne C. TI Differential effects of emotionally versus neutrally cued autobiographical memories on performance of a subsequent cognitive task: effects of task difficulty SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE autobiographical memory; cognition; task difficulty; episodic memory; emotion; rumination AB Attention is a limited resource, and in order to improve processing of the attended information, competing processes must be suppressed. Although it is well established that an experimentally induced change in mood state comprises one type of competing process that can impair performance on a subsequent task, no study has investigated whether an emotionally valenced autobiographical memory (AM) also can alter performance on a subsequent task. We therefore examined the effects of AM recall on cognitive performance. Healthy participants (n = 20 per experiment) recalled AMs in response to positive, negative, and neutral cue words. Following each AM participants completed a simple perceptual task (Experiment 1) or solved moderately difficult subtraction problems (Experiment 2). In Experiment 1 participants performed less accurately following exposure to positive or negative versus neutral cue words (ps < 0.001), and also were less accurate following negative versus positive cue words (p < 0.001). In Experiment 2, in contrast, no difference in accuracy or response times reached statistical significance. Performance accuracy even trended toward being higher following exposure to negative versus neutral cue words (p = 0.08). The results of Experiment 1 suggested that recalling emotionally salient AMs reduces the attention directed toward a simple continuous performance task administered immediately following the AM task, conceivably due to persistent contemplation of the AM. The negative results of Experiment 2 suggested that the effect of AMs on attention was attenuated, however, by increasing the difficulty of the subsequent task. Our results have implications for patients with major depressive disorder (MDD), as performing cognitively demanding tasks may allow them to attenuate the impairing effects of negative rumination on cognition. C1 [Young, Kymberly D.; Erickson, Kristine; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Young, Kymberly D.; Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK 74136 USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. RP Young, KD (reprint author), Laureate Inst Brain Res, 6655 South Yale Ave, Tulsa, OK 74136 USA. EM kyoung@laureateinstitute.org FU NIMH NIH HHS [Z01 MH002792] NR 35 TC 2 Z9 2 U1 1 U2 5 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PY 2012 VL 3 AR 299 DI 10.3389/fpsyg.2012.00299 PG 8 WC Psychology, Multidisciplinary SC Psychology GA V31DJ UT WOS:000208864000017 PM 23060823 ER PT S AU Sharov, A AF Sharov, Alexei BE Rattasepp, S Bennett, T TI The origin of mind: Transition from protosemiosis to eusemiosis SO GATHERINGS IN BIOSEMIOTICS SE Tartu Semiotics Library LA English DT Meeting Abstract CT Conference on Gatherings in Biosemiotics CY JUL 16-21, 2012 CL Tartu, ESTONIA C1 [Sharov, Alexei] NIA, Baltimore, MD 21224 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU UNIV TARTU PRESS PI TARTU PA 1 W STRUVE ST, TARTU, 50091, ESTONIA SN 1406-4278 BN 978-9949-32-048-6 J9 TARTU SEMIO LIBR PY 2012 VL 11 BP 215 EP 216 PG 2 WC Communication; Linguistics SC Communication; Linguistics GA BB5EE UT WOS:000343722800092 ER PT J AU Li, YR Xu, X Song, LT Hou, Y Li, ZS Tsang, S Li, FQ Im, KM Wu, K Wu, HJ Ye, XF Li, GB Wang, LL Zhang, B Liang, J Xie, W Wu, RH Jiang, H Liu, X Yu, C Zheng, HC Jian, M Nie, LP Wan, L Shi, M Sun, XJ Tang, AF Guo, GW Gui, YT Cai, ZM Li, JX Wang, W Lu, ZH Zhang, XQ Bolund, L Kristiansen, K Wang, J Yang, HM Dean, M Wang, J AF Li, Yingrui Xu, Xun Song, Luting Hou, Yong Li, Zesong Tsang, Shirley Li, Fuqiang Im, Kate McGee Wu, Kui Wu, Hanjie Ye, Xiaofei Li, Guibo Wang, Linlin Zhang, Bo Liang, Jie Xie, Wei Wu, Renhua Jiang, Hui Liu, Xiao Yu, Chang Zheng, Hancheng Jian, Min Nie, Liping Wan, Lei Shi, Min Sun, Xiaojuan Tang, Aifa Guo, Guangwu Gui, Yaoting Cai, Zhiming Li, Jingxiang Wang, Wen Lu, Zuhong Zhang, Xiuqing Bolund, Lars Kristiansen, Karsten Wang, Jian Yang, Huanming Dean, Michael Wang, Jun TI Single-cell sequencing analysis characterizes common and cell-lineage-specific mutations in a muscle-invasive bladder cancer SO GIGASCIENCE LA English DT Article DE Single-cell exome sequencing; Bladder cancer; Tumor evolution; Population genetics AB Background: Cancers arise through an evolutionary process in which cell populations are subjected to selection; however, to date, the process of bladder cancer, which is one of the most common cancers in the world, remains unknown at a single-cell level. Results: We carried out single-cell exome sequencing of 66 individual tumor cells from a muscle-invasive bladder transitional cell carcinoma (TCC). Analyses of the somatic mutant allele frequency spectrum and clonal structure revealed that the tumor cells were derived from a single ancestral cell, but that subsequent evolution occurred, leading to two distinct tumor cell subpopulations. By analyzing recurrently mutant genes in an additional cohort of 99 TCC tumors, we identified genes that might play roles in the maintenance of the ancestral clone and in the muscle-invasive capability of subclones of this bladder cancer, respectively. Conclusions: This work provides a new approach of investigating the genetic details of bladder tumoral changes at the single-cell level and a new method for assessing bladder cancer evolution at a cell-population level. C1 [Li, Yingrui; Xu, Xun; Song, Luting; Hou, Yong; Li, Fuqiang; Wu, Kui; Wu, Hanjie; Ye, Xiaofei; Li, Guibo; Wang, Linlin; Zhang, Bo; Liang, Jie; Xie, Wei; Wu, Renhua; Jiang, Hui; Liu, Xiao; Yu, Chang; Zheng, Hancheng; Jian, Min; Guo, Guangwu; Li, Jingxiang; Zhang, Xiuqing; Bolund, Lars; Kristiansen, Karsten; Wang, Jian; Yang, Huanming; Wang, Jun] BGI Shenzhen, Beishan Ind Zone, Shenzhen 518083, Peoples R China. [Song, Luting; Wang, Wen] Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, CAS Max Planck Jr Res Grp, Kunming 650223, Yunnan, Peoples R China. [Song, Luting] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. [Song, Luting] Wuhan Univ, Coll Life Sci, Wuhan 430072, Peoples R China. [Hou, Yong; Xie, Wei; Lu, Zuhong] Southeast Univ, Sch Biol Sci & Med Engn, Nanjing 210096, Jiangsu, Peoples R China. [Hou, Yong; Xie, Wei; Lu, Zuhong] Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China. [Li, Zesong; Sun, Xiaojuan; Tang, Aifa] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Shenzhen Key Lab Genitourinary Tumor, Shenzhen 518035, Peoples R China. [Li, Zesong; Sun, Xiaojuan; Tang, Aifa; Cai, Zhiming] Shenzhen Second Peoples Hosp, Dept Urol, Shenzhen 518035, Peoples R China. [Li, Zesong; Sun, Xiaojuan; Tang, Aifa; Cai, Zhiming] Shenzhen Univ, Inst Urogenital Dis, Shenzhen 518060, Peoples R China. [Tsang, Shirley] BioMatrix LLC, Rockville, MD 20850 USA. [Im, Kate McGee; Dean, Michael] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Wu, Hanjie] S China Univ Technol, Guangzhou Higher Educ Mega Ctr, Sch Biosci & Biotechnol, Guangzhou 510006, Guangdong, Peoples R China. [Nie, Liping; Shi, Min; Gui, Yaoting; Cai, Zhiming] Peking Univ, Guangdong & Shenzhen Key Lab Male Reprod Med & Ge, Shenzhen PKU HKUST Med Ctr, Inst Urol,Shenzhen Hosp, Shenzhen 518036, Peoples R China. [Wan, Lei] Longgang Cent Hosp, Dept Urol, Shenzhen 518116, Peoples R China. [Bolund, Lars] Univ Aarhus, Inst Human Genet, DK-8100 Aarhus, Denmark. [Kristiansen, Karsten; Wang, Jun] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark. [Wang, Jun] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark. RP Yang, HM (reprint author), BGI Shenzhen, Beishan Ind Zone, Beishan Rd, Shenzhen 518083, Peoples R China. EM yanghm@genomics.cn; deanm@mail.nih.gov; wangj@genomics.cn RI Li, Yingrui/K-1064-2015; Kristiansen, Karsten/J-5148-2014; Wang, Jun/C-8434-2016; Li, Guobao/F-3690-2016; Wang, Jun/B-9503-2016; OI Kristiansen, Karsten/0000-0002-6024-0917; Wang, Jun/0000-0002-8540-8931; Li, Guobao/0000-0003-3061-193X; Wang, Jun/0000-0002-2113-5874; hou, yong/0000-0002-0420-0726; Zhang, Bo/0000-0001-8890-8416 FU National Basic Research Program of China (973 program) [2011CB809202, 2011CB809203]; Chinese 863 program [2009AA022707]; Shenzhen Municipal Government of China [ZYC201005250020A]; Key Laboratory Project - Shenzhen City [CX B200903 110066A, CXB201108250096A]; Shenzhen Key Laboratory of Gene Bank for National Life Science; Innovative Research Team Project of GuangDong; Guangdong Enterprise Key Laboratory of Human Disease Genomics; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Danish Natural Science Research Council; Shenzhen Municipal Government; Local Government of Yantian District of Shenzhen FX This work was supported by a National Basic Research Program of China (973 program no.2011CB809202;2011CB809203), the Chinese 863 program (no. 2009AA022707), the Shenzhen Municipal Government of China (grants ZYC201005250020A), the Key Laboratory Project Supported by Shenzhen City (grants CX B200903 110066A; CXB201108250096A), and Shenzhen Key Laboratory of Gene Bank for National Life Science. This project was also supported by a grant from the Innovative Research Team Project of GuangDong and the Guangdong Enterprise Key Laboratory of Human Disease Genomics, and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We also thank the Danish Natural Science Research Council for the Ole Romer grant and the Shenzhen Municipal Government and the Local Government of Yantian District of Shenzhen for providing funding and an in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, USA. NR 37 TC 31 Z9 31 U1 2 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 2047-217X J9 GIGASCIENCE JI GigaScience PY 2012 VL 1 AR 12 DI 10.1186/2047-217X-1-12 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V41IB UT WOS:000209538800012 PM 23587365 ER PT J AU Wong, PBY Wiley, EO Johnson, WE Ryder, OA O'Brien, SJ Haussler, D Koepfli, KP Houck, ML Perelman, P Mastromonaco, G Bentley, AC Venkatesh, B Zhang, YP Murphy, RW AF Wong, Pamela B. Y. Wiley, Edward O. Johnson, Warren E. Ryder, Oliver A. O'Brien, Stephen J. Haussler, David Koepfli, Klaus-Peter Houck, Marlys L. Perelman, Polina Mastromonaco, Gabriela Bentley, Andrew C. Venkatesh, Byrappa Zhang, Ya-ping Murphy, Robert W. CA G10KCOS TI Tissue sampling methods and standards for vertebrate genomics SO GIGASCIENCE LA English DT Review DE Genome 10K; Sequencing; Vertebrates; Genomics; Tissue sampling; Tissue storage; Cell line; Tissue culture; RNA; DNA AB The recent rise in speed and efficiency of new sequencing technologies have facilitated high-throughput sequencing, assembly and analyses of genomes, advancing ongoing efforts to analyze genetic sequences across major vertebrate groups. Standardized procedures in acquiring high quality DNA and RNA and establishing cell lines from target species will facilitate these initiatives. We provide a legal and methodological guide according to four standards of acquiring and storing tissue for the Genome 10K Project and similar initiatives as follows: four-star (banked tissue/cell cultures, RNA from multiple types of tissue for transcriptomes, and sufficient flash-frozen tissue for 1 mg of DNA, all from a single individual); three-star (RNA as above and frozen tissue for 1 mg of DNA); two-star (frozen tissue for at least 700 mu g of DNA); and one-star (ethanol-preserved tissue for 700 mu g of DNA or less of mixed quality). At a minimum, all tissues collected for the Genome 10K and other genomic projects should consider each species' natural history and follow institutional and legal requirements. Associated documentation should detail as much information as possible about provenance to ensure representative sampling and subsequent sequencing. Hopefully, the procedures outlined here will not only encourage success in the Genome 10K Project but also inspire the adaptation of standards by other genomic projects, including those involving other biota. C1 [Wong, Pamela B. Y.; Murphy, Robert W.] Univ Toronto, Dept Ecol & Evolutionary Biol, Toronto, ON M5S 3B2, Canada. [Wong, Pamela B. Y.; Murphy, Robert W.] Royal Ontario Museum, Ctr Biodivers & Conservat Biol, Toronto, ON M5S 2C6, Canada. [Wiley, Edward O.; Bentley, Andrew C.] Univ Kansas, Biodivers Inst, Div Ichthyol, Lawrence, KS 66045 USA. [Johnson, Warren E.; Koepfli, Klaus-Peter] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Ryder, Oliver A.; Houck, Marlys L.] San Diego Zoo Inst Conservat Res, Escondido, CA 92027 USA. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 194044, Russia. [Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Perelman, Polina] Inst Mol & Cellular Biol, Lab Anim Cytogenet, Novosibirsk 630090, Russia. [Mastromonaco, Gabriela] Toronto Zoo, Reprod Physiol, Scarborough, ON M1B 5K7, Canada. [Venkatesh, Byrappa] ASTAR, Inst Mol & Cell Biol, Comparat Genom Lab, Biopolis, Singapore 138673, Singapore. [G10KCOS] Genome 10K Community Scientists, Santa Cruz, CA USA. [Zhang, Ya-ping; Murphy, Robert W.] Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resource & Evolut, Kunming 650223, Yunnan, Peoples R China. [Zhang, Ya-ping] Yunnan Univ, Lab Conservat & Utilizat Bioresources, Kunming 650091, Yunnan, Peoples R China. RP Murphy, RW (reprint author), Univ Toronto, Dept Ecol & Evolutionary Biol, 25 Willcocks St, Toronto, ON M5S 3B2, Canada. EM bob.murphy@utoronto.ca RI Perelman, Polina/N-8088-2015; OI Perelman, Polina/0000-0002-0982-5100; Venkatesh, Byrappa/0000-0003-3620-0277 FU Natural Sciences and Research Council of Canada Discovery Grant [3148]; Visiting Professorship for Senior International Scientists from the Chinese Academy of Sciences; National Science Foundation Assembling the Tree of Life Grant [DEB0732819] FX This research was supported by a Natural Sciences and Research Council of Canada Discovery Grant 3148 and by a Visiting Professorship for Senior International Scientists from the Chinese Academy of Sciences to RWM. This effort was also supported by the National Science Foundation Assembling the Tree of Life Grant DEB0732819 to EOW. The authors would like to thank R.E. Green and B. Shapiro for providing insight into G10K's sequencing initiative for extinct species. This project grew out of discussions by G10KCOS at the second G10K meeting held in Santa Cruz, California on 14-18 March, 2011. NR 63 TC 18 Z9 18 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 2047-217X J9 GIGASCIENCE JI GigaScience PY 2012 VL 1 AR 8 DI 10.1186/2047-217X-1-8 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V41IB UT WOS:000209538800008 PM 23587255 ER PT J AU Valencia, JC Hearing, VJ AF Valencia, Julio C. Hearing, Vincent J. BE Petrescu, S TI The Role of Glycosylation in the Control of Processing and Cellular Transport of the Functional Amyloid PMEL17 SO GLYCOSYLATION LA English DT Article; Book Chapter ID O-LINKED GLYCOSYLATION; SIALIC-ACID; GOLGI-APPARATUS; REPEAT DOMAIN; TYROSINASE ACTIVITY; INVASIVE PHENOTYPE; PLASMA-MEMBRANE; MELANOMA-CELLS; UDP-GALACTOSE; CANCER-CELLS C1 [Valencia, Julio C.; Hearing, Vincent J.] NCI, Pigment Cell Biol Sect, Cell Biol Lab, Bethesda, MD 20892 USA. RP Valencia, JC (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, Bethesda, MD 20892 USA. NR 66 TC 0 Z9 0 U1 0 U2 0 PU INTECH EUROPE PI RIJEKA PA JANEZA TRDINE9, RIJEKA, 51000, CROATIA BN 978-953-51-0771-2 PY 2012 BP 327 EP 350 DI 10.5772/48265 D2 10.5772/2917 PG 24 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BE9CZ UT WOS:000377277200016 ER PT S AU Geisbert, TW Feldmann, H Broder, CC AF Geisbert, Thomas W. Feldmann, Heinz Broder, Christopher C. BE Lee, B Rota, PA TI Animal Challenge Models of Henipavirus Infection and Pathogenesis SO HENIPAVIRUS: ECOLOGY, MOLECULAR VIROLOGY, AND PATHOGENESIS SE Current Topics in Microbiology and Immunology LA English DT Review; Book Chapter ID NIPAH-VIRUS-INFECTION; EQUINE MORBILLIVIRUS INFECTION; BATS PTEROPUS-POLIOCEPHALUS; TO-PERSON TRANSMISSION; HENDRA VIRUS; HAMSTER MODEL; SUBUNIT VACCINE; FRUIT BATS; ENCEPHALITIS OUTBREAK; RIBAVIRIN TREATMENT AB The henipaviruses, Hendra virus (HeV), and Nipah virus (NiV), are enigmatic emerging pathogens that causes severe and often fatal neurologic and/or respiratory disease in both animals and humans. Amongst people, case fatality rates range between 40 and 75% and there are no vaccines or treatments approved for human use. A number of species of animals including guinea pigs, hamsters, cats, ferrets, pigs, and African green monkeys have been employed as animal models of human henipavirus infection. Here, we review the development of animal models for henipavirus infection, discuss the pathology and pathogenesis of these models, and assess the utility of each model to recapitulate important aspects of henipavirus-mediated disease seen in humans. C1 [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Dept Microbiol & Immunol, Galveston, TX 77550 USA. [Feldmann, Heinz] NIAID, Virol Lab, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Emerging Infect Dis Grad Program, Bethesda, MD 20814 USA. RP Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab, Dept Microbiol & Immunol, 301 Univ Blvd,L29059, Galveston, TX 77550 USA. EM tom.geisbert@utmb.edu; feldmannh@niaid.nih.gov; chris.basler@mssm.edu NR 85 TC 26 Z9 26 U1 2 U2 11 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0070-217X BN 978-3-642-29819-6; 978-3-642-29818-9 J9 CURR TOP MICROBIOL JI Curr.Top.Microbiol.Immunol. PY 2012 VL 359 BP 153 EP 177 DI 10.1007/82_2012_208 D2 10.1007/978-3-642-29819-6 PG 25 WC Marine & Freshwater Biology; Virology SC Marine & Freshwater Biology; Virology GA BJT97 UT WOS:000330362500011 PM 22476556 ER PT S AU Patel, V Iglesias-Bartolome, R Siegele, B Marsh, CA Leelahavanichkul, K Molinolo, AA Gutkind, JS AF Patel, Vyomesh Iglesias-Bartolome, Ramiro Siegele, Bradford Marsh, Christina A. Leelahavanichkul, Kantima Molinolo, Alfredo A. Gutkind, J. Silvio BE Rhim, JS Kremer, R TI Cellular Systems for Studying Human Oral Squamous Cell Carcinomas SO HUMAN CELL TRANSFORMATION: ROLE OF STEM CELLS AND THE MICROENVIRONMENT SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT Conference on Human Cell Transformation - Role of Stem Cells and the Microenvironment CY OCT 20-21, 2010 CL McGill Univ Hlth Ctr, Montreal, CANADA SP Inst Recherche Sante Canada, Canadian Inst Hlth Res, Amgen, Reseau Rech sante Buccodentaire & Osseuse, Ctr Bone & Periodontal Res HO McGill Univ Hlth Ctr ID HUMAN EPIDERMAL-KERATINOCYTES; STEM-CELLS; HAIR FOLLICLE; HUMAN GINGIVA; NECK-CANCER; CULTURE; EXPRESSION; EPITHELIUM; GROWTH; HEAD AB The human oral squamous epithelium plays an important role in maintaining a barrier function against mechanical, physical, and pathological injury. However, the self-renewing cells residing on the basement membrane of the epithelium can give rise to oral squamous cell carcinomas (OSCC), now the sixth most common cancer in the developed world, which is still associated with poor prognosis. This is due, in part, to the limited availability of well-defined culture systems for studying oral epithelial cell biology, which could advance our understanding of the molecular basis of OSCC. Here, we describe methods to successfully isolate large cultures of human oral epithelial cells and fibroblasts from small pieces of donor tissues for use in techniques such as three-dimensional cultures and animal grafts to validate genes suspected of playing a role in OSCC development and progression. Finally, the use of isolated oral epithelial cells in generating iPS cells is discussed which holds promise in the field of oral regenerative medicine. C1 [Patel, Vyomesh; Iglesias-Bartolome, Ramiro; Siegele, Bradford; Marsh, Christina A.; Leelahavanichkul, Kantima; Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Patel, V (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. EM vpatel@mail.nih.gov RI Iglesias-Bartolome, Ramiro/H-4460-2014 OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 FU National Institutes of Health, National Institute of Dental and Craniofacial Research [Z01DE00558] FX This article was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research, project Z01DE00558. NR 59 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-1-4614-0253-4; 978-1-4614-0254-1 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 720 BP 27 EP 38 DI 10.1007/978-1-4614-0254-1_3 PG 12 WC Oncology; Cell Biology; Medicine, Research & Experimental SC Oncology; Cell Biology; Research & Experimental Medicine GA BA9CP UT WOS:000339175100004 ER PT S AU Ji, YM Christopherson, GT Kluk, MW Amrani, O Jackson, WM Nesti, LJ AF Ji, Youngmi Christopherson, Gregory T. Kluk, Matthew W. Amrani, Orna Jackson, Wesley M. Nesti, Leon J. BE Rhim, JS Kremer, R TI Heterotopic Ossification Following Musculoskeletal Trauma: Modeling Stem and Progenitor Cells in Their Microenvironment SO HUMAN CELL TRANSFORMATION: ROLE OF STEM CELLS AND THE MICROENVIRONMENT SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT Conference on Human Cell Transformation - Role of Stem Cells and the Microenvironment CY OCT 20-21, 2010 CL McGill Univ Hlth Ctr, Montreal, CANADA SP Inst Recherche Sante Canada, Canadian Inst Hlth Res, Amgen, Reseau Rech sante Buccodentaire & Osseuse, Ctr Bone & Periodontal Res HO McGill Univ Hlth Ctr ID SKELETAL-MUSCLE; BONE-FORMATION; OSTEOGENIC DIFFERENTIATION; GENETIC DISORDER; TISSUE; PROGRESSIVA; BIOMATERIALS; REGENERATION; MANIPULATION; MECHANISMS AB Heterotopic ossification (HO), characterized by the formation of mature bone in the soft tissues, is a complication that can accompany musculoskeletal injury, and it is a frequent occurrence within the military population that has experienced orthopaedic combat trauma. The etiology of this disease is largely unknown. Our laboratory has developed strategies to investigate the cellular and molecular events leading to HO using clinical specimens that were obtained during irrigation and debridement of musculoskeletal injuries. Our approach enables to study (1) the cell types that are responsible for pathological transformation and ossification, (2) the cell-and tissue-level signaling that induces the pathologic transformation, and (3) the effect of extracellular matrix topography and force transduction on HO progression. In this review, we will report on our findings in each of these aspects of HO etiology and describe our efforts to recapitulate our findings in an animal model for traumatic HO. C1 [Ji, Youngmi; Christopherson, Gregory T.; Kluk, Matthew W.; Amrani, Orna; Nesti, Leon J.] NIAMSD, Clin & Expt Orthopaed Grp, NIH, Bethesda, MD 20892 USA. [Kluk, Matthew W.; Nesti, Leon J.] Walter Reed Army Med, Integrated Dept Orthopaed & Rehabil, Bethesda, MD USA. [Jackson, Wesley M.] Uniformed Serv Univ Hlth Sci, Clin & Expt Orthopaed Lab, Dept Surg, Bethesda, MD 20814 USA. RP Nesti, LJ (reprint author), NIAMSD, Clin & Expt Orthopaed Grp, NIH, Bldg 50,Room 1525,50 South Dr,MSC 8022, Bethesda, MD 20892 USA. EM nestil@mail.nih.gov RI Amrani, OFer/K-3813-2015 FU NIH [Z01 AR41131, 1ZIAAR041191]; Department of Defense Military Amputee Research Program at WRAMC [PO5-A011]; Comprehensive Neurosciences Program [CNP-2008-CR01]; Peer-Reviewed Orthopaedic Research Program [W81XWH-10-2-0084] FX This work was supported acknowledged as part of the NIH Intramural Research Program. (Z01 AR41131 and 1ZIAAR041191), grants from the Department of Defense Military Amputee Research Program at WRAMC (PO5-A011), Comprehensive Neurosciences Program (CNP-2008-CR01) and Peer-Reviewed Orthopaedic Research Program (W81XWH-10-2-0084). NR 46 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-1-4614-0253-4; 978-1-4614-0254-1 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 720 BP 39 EP 50 DI 10.1007/978-1-4614-0254-1_4 PG 12 WC Oncology; Cell Biology; Medicine, Research & Experimental SC Oncology; Cell Biology; Research & Experimental Medicine GA BA9CP UT WOS:000339175100005 ER PT J AU Wade, AR Norcia, AM AF Wade, Alex R. Norcia, Anthony M. TI Dynamic Glass patterns have little effect on coherent motion detection thresholds SO I-PERCEPTION LA English DT Meeting Abstract C1 [Wade, Alex R.; Norcia, Anthony M.] NIH, Bethesda, MD USA. EM wade@wadelab.net NR 0 TC 0 Z9 0 U1 0 U2 0 PU PION LTD PI LONDON PA 207 BRONDESBURY PARK, LONDON NW2 5JN, ENGLAND SN 2041-6695 J9 I-PERCEPTION JI I-Perception PY 2012 VL 3 IS 4 BP 224 EP 224 PG 1 WC Psychology, Experimental SC Psychology GA V32HN UT WOS:000208942400010 ER PT S AU Okun, E Chen, XZ Basta, M Mattson, MP AF Okun, Eitan Chen, XinZhi Basta, Milan Mattson, Mark P. BE Aggarwal, BB Krishnan, S Guha, S TI Roles of Innate Immunity and Inflammation in the Aging Brain SO INFLAMMATION, LIFESTYLE AND CHRONIC DISEASES: THE SILENT LINK SE Oxidative Stress and Disease LA English DT Article; Book Chapter ID TOLL-LIKE-RECEPTORS; CENTRAL-NERVOUS-SYSTEM; AMYLOID-BETA-PEPTIDE; ADULT HIPPOCAMPAL NEUROGENESIS; AMYOTROPHIC-LATERAL-SCLEROSIS; NEURAL PRECURSOR CELLS; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; HUMAN NEURODEGENERATIVE DISORDERS; CLASSICAL COMPLEMENT PATHWAY C1 [Okun, Eitan; Chen, XinZhi; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Basta, Milan] Biovisions Inc, Potomac, MD USA. RP Okun, E (reprint author), NIA, Lab Neurosci, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. NR 281 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA SN 2155-0255 BN 978-1-4398-3990-4; 978-1-4398-3989-8 J9 OXIDAT STRESS DIS PY 2012 BP 1 EP 39 PG 39 WC Primary Health Care; Immunology SC General & Internal Medicine; Immunology GA BC8CS UT WOS:000355550900002 ER PT B AU Luger, D Wakefield, LM AF Luger, Dror Wakefield, Lalage M. BE BenBaruch, A TI Inflammation and Beyond: Complex Roles for TGF-beta in the Tumor Microenvironment SO INFLAMMATORY MILIEU OF TUMORS: CYTOKINES AND CHEMOKINES THAT AFFECT TUMOR GROWTH AND METASTASIS LA English DT Article; Book Chapter DE TGF-beta; immunosuppression; inflammation; smad; tumor suppression; metastasis; cancer therapy ID TRANSFORMING-GROWTH-FACTOR; INTERSTITIAL FLUID PRESSURE; REGULATORY T-CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; BREAST-CANCER CELLS; MAMMARY-CARCINOMA CELLS; IN-VIVO; SUPPRESSOR-CELLS; XENOGRAFT MODEL; STEM-CELLS AB TGF-beta s are pleiotropic regulatory proteins that are often highly overexpressed in the microenvironment of advanced tumors. Since nearly all cell types respond to TGF-beta, TGF-beta s are well-positioned to integrate cellular responses in the parenchymal and stromal compartments of normal tissues and of tumors, and to mediate cross-talk between the two. Pre-clinical studies have uncovered complex roles for TGF-beta s in tumorigenesis, with tumor suppressive and tumor promoting effects on both compartments. In this review, we discuss the biological activities of TGF-beta that underlie these effects and address some of the mechanisms that determine which type of effect dominates at different stages of the tumorigenic process. Finally, we consider the prospects for therapeutic targeting of TGF-beta in cancer, as a way to simultaneously normalize both the microenvironmental and parenchymal compartments of the tumor, and thus prevent or reverse tumor progression. C1 [Luger, Dror; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bldg 37,Rm 4032A,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RP Wakefield, LM (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Rm 4032A,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM lw34g@nih.gov NR 195 TC 0 Z9 0 U1 1 U2 1 PU BENTHAM SCIENCE PUBL PI BUSUM PA PO BOX 294, BUSUM, 1400 AG, NETHERLANDS BN 978-1-60805-256-1; 978-1-60805-520-3 PY 2012 BP 123 EP 154 D2 10.2174/97816080525611120101 PG 32 WC Biochemistry & Molecular Biology; Oncology; Cell Biology SC Biochemistry & Molecular Biology; Oncology; Cell Biology GA BE1YQ UT WOS:000368730700011 ER PT S AU Sastry, M Bewley, CA Kwong, PD AF Sastry, Mallika Bewley, Carole A. Kwong, Peter D. BE Atreya, HS TI Mammalian Expression of Isotopically Labeled Proteins for NMR Spectroscopy SO ISOTOPE LABELING IN BIOMOLECULAR NMR SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter ID HUMAN CD2; RESONANCE ASSIGNMENTS; ADHESION DOMAIN; VIRAL VECTORS; BINDING-SITE; GENE-THERAPY; HIV-1 GP120; IN-VITRO; CELLS; ADENOVIRUS AB NMR spectroscopic characterization of biologically interesting proteins generally requires the incorporation of N-15/C-13 and/ or H-2 stable isotopes. While prokaryotic incorporation systems are regularly used, mammalian ones are not: of the nearly 9,000 NMR macromolecular structures currently deposited in the Protein Data Bank, only a handful (<0.5%) were solved with proteins expressed in mammalian systems. This low number of structures is largely a re flection of the difficulty in producing uniformly labeled, mammalian-expressed proteins. This is unfortunate, as many interesting proteins require mammalian cofactors, chaperons, or post-translational modifications such as N-linked glycosylation, and mammalian cells have the necessary machinery to produce them correctly. Here we describe recent advances in mammalian expression, including an efficient adenoviral vector-based system, for the production of isotopically enriched proteins. This system allows for the expression of mammalian proteins and their complexes, including proteins that require post-translational modifications. We describe how this system can produce isotopically labeled N-15 and C-13 post-translationally modified proteins, such as the outer domain of HIV-1 gp120, which has 15 sites of N-linked glycosylation. Selective amino-acid labeling is also described. These developments should reduce barriers to the determination of NMR structures with isotopically labeled proteins from mammalian expression systems. C1 [Sastry, Mallika; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Sastry, M (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 2613B, Bethesda, MD 20892 USA. EM sastrym@mail.nih.gov FU Intramural NIH HHS NR 62 TC 5 Z9 5 U1 1 U2 7 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-94-007-4953-5; 978-94-007-4954-2 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 992 BP 197 EP 211 DI 10.1007/978-94-007-4954-2_11 D2 10.1007/978-94-007-4954-2 PG 15 WC Medicine, Research & Experimental; Spectroscopy SC Research & Experimental Medicine; Spectroscopy GA BA2XS UT WOS:000333982300012 PM 23076586 ER PT B AU Villarino, A Yang, XP Hirahara, K Kanno, Y O'Shea, JJ Laurence, A AF Villarino, Alejandro Yang, Xiang-Ping Hirahara, Kiyoshi Kanno, Yuka O'Shea, John J. Laurence, Arian BE Decker, T Muller, M TI Function of JAKs and STATs in Lymphocytes: Bench to Bedside SO JAK-STAT SIGNALING: FROM BASICS TO DISEASE LA English DT Article; Book Chapter ID REGULATORY T-CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENOME-WIDE ASSOCIATION; HYPER-IGE SYNDROME; ACUTE LYMPHOBLASTIC-LEUKEMIA; FOLLICULAR-HELPER-CELLS; CHRONIC MUCOCUTANEOUS CANDIDIASIS; SEVERE COMBINED IMMUNODEFICIENCY; ACUTE MEGAKARYOBLASTIC LEUKEMIA; TYROSINE KINASE JAK2 AB There are four members of Janus Kinase family (JAK-1, -2, -3 and TYK2) and seven members of STAT family (STAT-1, -2, -3, -4, -5a, -5b and -6) in the mammalian genome, each with unique functions in immune cells. Consistent with studies in mice, genetic evidence in humans has strongly linked the JAK/STAT pathway to primary immunodeficiencies, infection, autoimmunity and cancers. The following chapter will discuss the key role played by JAKs and STATs in the lymphocytes, with special emphasis on helper T cells, which are not only critical mediators of pathogenic inflammation, but also an outstanding model system for investigating JAK/STAT biology. Recent conceptual and technological advances will be highlighted, particularly those relating to human disease and the generation of JAK/STAT based therapeutics. C1 [Villarino, Alejandro; Yang, Xiang-Ping; Hirahara, Kiyoshi; Kanno, Yuka; O'Shea, John J.; Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Villarino, A (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM villarinoav@mail.nih.gov; yangx2@mail.nih.gov OI Kanno, Yuka/0000-0001-5668-9319; Villarino, Alejandro/0000-0001-8068-2176 NR 187 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, A-1201 VIENNA, AUSTRIA BN 978-3-7091-0891-8; 978-3-7091-0890-1 PY 2012 BP 205 EP 237 DI 10.1007/978-3-7091-0891-8_13 D2 10.1007/978-3-7091-0891-8 PG 33 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA BE6BG UT WOS:000373804500014 ER PT J AU Onaivi, ES Ishiguro, H Gu, SZ Liu, QR AF Onaivi, Emmanuel S. Ishiguro, Hiroki Gu, Shanzhi Liu, Qing-Rong TI CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Review DE Brain; CB2 cannabinoid receptors; CNR2; neuronal and glial distribution; neuropsychiatry ID GENOME-WIDE ASSOCIATION; VIRUS INTEGRATION SITE; ENDOCANNABINOID SYSTEM; ALCOHOL DEPENDENCE; PREPULSE INHIBITION; NERVOUS-SYSTEM; HUMAN BRAIN; MOLECULAR CHARACTERIZATION; SWEDISH CONSCRIPTS; EATING-DISORDERS AB There are two well characterized cannabinoid receptors (CBRs), CB1-Rs and CB2-Rs, with other candidates, such as GPR55, PPARs and vanilloid TRPV1 (VR1) receptors, which are either activated by cannabinoids and/or endocannabinoids (eCBs). The neuronal and functional expression of CB2-Rs in the brain has been much less well characterized in comparison with the expression of the ubiquitous CB1-Rs. CB2-Rs were previously thought to be predominantly expressed in immune cells in the periphery and were traditionally referred to as peripheral CB2-Rs. We and others have now demonstrated the expression of CB2-Rs in neuronal, glial and endothelial cells in the brain, and this warrants a re-evaluation of the CNS effects of CB2-Rs. In the present review we summarize our current understanding of CNR2 genomic structure, its polymorphic nature, subtype specificity, from mice to human subjects, and its variants that confer vulnerabilities to neuropsychiatric disorders beyond neuro-immuno-cannabinoid activity. C1 [Onaivi, Emmanuel S.] William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. [Ishiguro, Hiroki] Univ Yamanashi, Dept Psychiat, Yamanashi, Japan. [Gu, Shanzhi] Xi An Jiao Tong Univ, Dept Forens Med, Xian 710049, Peoples R China. [Liu, Qing-Rong] NIDA, Behav Neurosci Branch, NIH, Baltimore, MD USA. [Onaivi, Emmanuel S.; Ishiguro, Hiroki] NIDA, Mol Neurobiol Branch, NIH, Baltimore, MD USA. RP Onaivi, ES (reprint author), William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. EM onaivie@wpunj.edu RI Liu, Qing-Rong/A-3059-2012 OI Liu, Qing-Rong/0000-0001-8477-6452 FU William Paterson University [20390098, 20023006]; Imai-Kimi Memorial Stress-Related Disorders; NIDA/NIH FX This work was supported by William Paterson University (ESO); KAKENHI (grant numbers 20390098 and 20023006) and Imai-Kimi Memorial Stress-Related Disorders (HI); and the Intramural Research Program of the NIDA/NIH (QL). NR 128 TC 47 Z9 47 U1 1 U2 23 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD JAN PY 2012 VL 26 IS 1 SI SI BP 92 EP 103 DI 10.1177/0269881111400652 PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 882JN UT WOS:000299560000008 PM 21447538 ER PT J AU Organ, C Janes, D AF Organ, Chris Janes, Dan TI EVOLUTION OF SEX CHROMOSOMES IN DINOSAURS SO JOURNAL OF VERTEBRATE PALEONTOLOGY LA English DT Meeting Abstract CT 72nd Annual Meeting of the Society-of-Vertebrate-Paleontology CY OCT 17-20, 2012 CL N Carolina Museum Nat Sci, Raleigh, NC SP Soc Vertebrate Paleontol, N Carolina State Univ HO N Carolina Museum Nat Sci C1 [Organ, Chris] Univ Utah, Park City, UT USA. [Janes, Dan] NIH, Washington Dc, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0272-4634 EI 1937-2809 J9 J VERTEBR PALEONTOL JI J. Vertebr. Paleontol. PY 2012 VL 32 SU 2 SI SI BP 152 EP 152 PG 1 WC Paleontology SC Paleontology GA 070HE UT WOS:000313496400441 ER PT B AU Lester, PA Moore, RM Shuster, KA Myers, DD AF Lester, Patrick A. Moore, Rashida M. Shuster, Katherine A. Myers, Daniel D. BE Suckow, MA Stevens, KA Wilson, RP TI Anesthesia and Analgesia SO LABORATORY RABBIT, GUINEA PIG, HAMSTER, AND OTHER RODENTS SE American College of Laboratory Animal Medicine Series LA English DT Article; Book Chapter ID ZEALAND WHITE-RABBITS; MINIMUM ALVEOLAR CONCENTRATION; ARTERIAL-BLOOD-PRESSURE; KETAMINE-XYLAZINE; GUINEA-PIG; ENDOTRACHEAL INTUBATION; ORYCTOLAGUS-CUNICULUS; LABORATORY-ANIMALS; MEDETOMIDINE-PROPOFOL; INHALATION ANESTHESIA C1 [Lester, Patrick A.; Shuster, Katherine A.; Myers, Daniel D.] Univ Michigan, Unit Lab Anim Med, Ann Arbor, MI 48109 USA. [Lester, Patrick A.; Myers, Daniel D.] Univ Michigan, Conrad Jobst Vasc Res Labs, Ann Arbor, MI 48109 USA. [Moore, Rashida M.] NIAID, NIH, Comparat Med Branch, Bethesda, MD 20892 USA. RP Lester, PA (reprint author), Univ Michigan, Unit Lab Anim Med, Ann Arbor, MI 48109 USA. NR 142 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-380921-6; 978-0-12-380920-9 J9 AM COLL LAB PY 2012 BP 33 EP 56 DI 10.1016/B978-0-12-380920-9.00002-X PG 24 WC Veterinary Sciences SC Veterinary Sciences GA BA2YY UT WOS:000333993900003 ER PT B AU Burkholder, TH Linton, G Hoyt, RF Young, R AF Burkholder, Tanya H. Linton, Garry Hoyt, Robert F., Jr. Young, Richard BE Suckow, MA Stevens, KA Wilson, RP TI The Rabbit as an Experimental Model SO LABORATORY RABBIT, GUINEA PIG, HAMSTER, AND OTHER RODENTS SE American College of Laboratory Animal Medicine Series LA English DT Article; Book Chapter ID ENTEROPATHOGENIC ESCHERICHIA-COLI; ENDOTOXIN-INDUCED UVEITIS; SIMPLEX-VIRUS TYPE-1; HEMATOGENOUS CANDIDA MENINGOENCEPHALITIS; PNEUMONIAE-INDUCED ATHEROSCLEROSIS; ASSOCIATION STATISTICS-COMMITTEE; RESISTANT STAPHYLOCOCCUS-AUREUS; ACQUIRED BACTERIAL-MENINGITIS; MACULAR DEGENERATION MODEL; HYPERLIPIDEMIC SMHL RABBIT C1 [Burkholder, Tanya H.; Linton, Garry] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Hoyt, Robert F., Jr.] NHLBI, Bethesda, MD 20892 USA. [Young, Richard] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Burkholder, TH (reprint author), NIH, Div Vet Resources, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. NR 291 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-380921-6; 978-0-12-380920-9 J9 AM COLL LAB PY 2012 BP 529 EP 560 DI 10.1016/B978-0-12-380920-9.00018-3 PG 32 WC Veterinary Sciences SC Veterinary Sciences GA BA2YY UT WOS:000333993900019 ER PT B AU Yao, JH Summers, RM AF Yao, Jianhua Summers, Ronald M. BA Suzuki, K BF Suzuki, K TI Content-Based Image Retrieval for Medical Image Analysis SO MACHINE LEARNING IN COMPUTER-AIDED DIAGNOSIS: MEDICAL IMAGING INTELLIGENCE AND ANALYSIS LA English DT Article; Book Chapter ID NONLINEAR DIMENSIONALITY REDUCTION; CT IMAGES; CLASSIFICATION; DISTANCE; INFORMATION; ALGORITHM; DATABASES; FRAMEWORK; FEATURES; SYSTEMS AB The growing repositories of clinical imaging data generate a need for effective image management and access that demands more than simple text-based queries. Content-Based Image Retrieval (CBIR) is an active research field and has drawn attention in recent years. It is a technique to organize and search image archives by their visual content. iris a multi-discipline field that integrates technologies from computer vision, machine learning, information retrieval, human-machine interaction, database systems, and data mining. CBIR consists of four main components: database and indexing,,feature extraction, query formation and interface, and similarity measures. The applications of CBIR? to the medical field include PACS integration, image annotation/codification, computer-aided diagnosis, case-based reasoning, and teaching tools. This chapter intends to disseminate the CBIR techniques to their applications to medical image management and analysis and to attract greater interest from various research communities to advance research in this field. C1 [Yao, Jianhua; Summers, Ronald M.] NIH, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Bethesda, MD 20892 USA. NR 80 TC 1 Z9 1 U1 0 U2 0 PU IGI GLOBAL PI HERSEY PA 701 E CHOCOLATE AVE, STE 200, HERSEY, PA 17033-1240 USA BN 978-1-4666-0060-7; 978-1-4666-0059-1 PY 2012 BP 202 EP 219 DI 10.4018/978-1-4666-0059-1.ch010 D2 10.4018/978-1-4666-0059-1 PG 18 WC Computer Science, Artificial Intelligence; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Radiology, Nuclear Medicine & Medical Imaging GA BD8PW UT WOS:000364182300012 ER PT S AU Reddy, UM AF Reddy, Uma M. BE Berghella, V TI Fetal death SO MATERNAL-FETAL EVIDENCE BASED GUIDELINES, 2ND EDITION SE Series in Maternal-Fetal Medicine LA English DT Article; Book Chapter ID 2ND-TRIMESTER PREGNANCY TERMINATION; INTRAVAGINAL MISOPROSTOL; VAGINAL MISOPROSTOL; RECURRENT STILLBIRTH; CYTOGENETIC ANALYSIS; UNITED-STATES; MATERNAL AGE; RISK-FACTORS; WORK-UP; INDUCTION C1 NICHD, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. RP Reddy, UM (reprint author), NICHD, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. NR 64 TC 1 Z9 1 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL ST, LONDON, EC2A 4LQ, ENGLAND SN 2158-0871 BN 978-1-84184-823-5; 978-1-84184-822-8 J9 SER MATERN FETAL MED PY 2012 BP 390 EP 396 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA BC6XH UT WOS:000354561400056 ER PT J AU Keim, PS AF Keim, Paul S. TI The NSABB Recommendations: Rationale, Impact, and Implications SO MBIO LA English DT Editorial Material AB The National Science Advisory Board for Biosecurity (NSABB) has recommended that two scientific papers concerning the laboratory adaptation of avian H5N1 influenza virus to mammal-to-mammal respiratory transmission restrict their content to prevent others from replicating their work. After hearing from experts in the field of influenza research and public health, the benefits of the research were deemed less important than the potential negative consequences. The evaluation followed established NSABB procedures and prior policy recommendations for identifying dual use research of concern (DURC). This recommendation was received by the United States Government, endorsed and forwarded to the research teams and scientific journals involved with the publications. C1 [Keim, Paul S.] NIH, Natl Sci Advisory Board Biosecur, Off Biotechnol Act, Bethesda, MD 20892 USA. [Keim, Paul S.] Translat Genom Res Inst, Phoenix, AZ USA. [Keim, Paul S.] No Arizona Univ, Ctr Microbial Genet & Genom, Flagstaff, AZ 86011 USA. RP Keim, PS (reprint author), NIH, Natl Sci Advisory Board Biosecur, Off Biotechnol Act, Bldg 10, Bethesda, MD 20892 USA. EM paul.keim@nau.edu NR 0 TC 6 Z9 7 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2012 VL 3 IS 1 AR e00021-12 DI 10.1128/mBio.00021-12 PG 2 WC Microbiology SC Microbiology GA 933AK UT WOS:000303331400005 ER PT S AU Bagci, U Udupa, JK Yao, JH Mollura, DJ AF Bagci, Ulas Udupa, Jayaram K. Yao, Jianhua Mollura, Daniel J. BE Ayache, N Delingette, H Golland, P Mori, K TI Co-segmentation of Functional and Anatomical Images SO MEDICAL IMAGE COMPUTING AND COMPUTER-ASSISTED INTERVENTION - MICCAI 2012, PT III SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 15th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) CY OCT 01-05, 2012 CL Nice, FRANCE SP GE HealthCare, Philips, Siemens, Canon Median, ERC MedYMA, Medtronic, Aviesan, Dosisoft, IHU Strasbourg, IRCAD France, Kitware, Microsoft Res DE Joint Segmentation; PET-CT; Random Walk; Object Detection ID PET VOLUMES AB This paper presents a novel method for segmenting functional and anatomical structures simultaneously. The proposed method unifies domains of anatomical and functional images (PET-CT), represents them in a product lattice, and performs simultaneous delineation of regions based on a random walk image segmentation. In addition, we propose a simple yet efficient object/background seed localization method, where background and foreground object cues are automatically obtained from PET images and propagated onto the corresponding anatomical images (CT). In our experiments, abnormal anatomies on PET-CT images from human subjects are segmented synergistically by the proposed fully automatic co-segmentation method with high precision (mean DSC of 91.44%) in seconds (avg. 40 seconds). C1 [Bagci, Ulas; Yao, Jianhua; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Udupa, Jayaram K.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Bagci, U (reprint author), NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. OI Bagci, Ulas/0000-0001-7379-6829 NR 6 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 978-3-642-33454-2; 978-3-642-33453-5 J9 LECT NOTES COMPUT SC PY 2012 VL 7512 BP 459 EP 467 PG 9 WC Computer Science, Artificial Intelligence; Computer Science, Theory & Methods; Medical Informatics; Robotics; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Medical Informatics; Robotics; Radiology, Nuclear Medicine & Medical Imaging GA BE3WH UT WOS:000371317400057 ER PT S AU Yao, JH Burns, JE Munoz, H Summers, RM AF Yao, Jianhua Burns, Joseph E. Munoz, Hector Summers, Ronald M. BE Ayache, N Delingette, H Golland, P Mori, K TI Detection of Vertebral Body Fractures Based on Cortical Shell Unwrapping SO MEDICAL IMAGE COMPUTING AND COMPUTER-ASSISTED INTERVENTION - MICCAI 2012, PT III SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 15th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) CY OCT 01-05, 2012 CL Nice, FRANCE SP GE HealthCare, Philips, Siemens, Canon Median, ERC MedYMA, Medtronic, Aviesan, Dosisoft, IHU Strasbourg, IRCAD France, Kitware, Microsoft Res AB Assessment of trauma patients with multiple injuries can be one of the most clinically challenging situations dealt with by the radiologist. We propose a fully automated method to detect acute vertebral body fractures on trauma CT studies. The spine is first segmented and partitioned into vertebrae. Then the cortical shell of the vertebral body is extracted using deformable dual-surface models. The extracted cortical shell is unwrapped onto a 2D map effectively converting a complex 3D fracture detection problem into a pattern recognition problem of fracture lines on a 2D plane. Twenty-eight features are computed for each fracture line and sent to a committee of support vector machines for classification. The system was tested on 18 trauma CT datasets and achieved 95.3% sensitivity and 1.7 false positives per case by leave-one-out cross validation. C1 [Yao, Jianhua; Munoz, Hector; Summers, Ronald M.] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Burns, Joseph E.] Univ Calif Irvine, Sch Med, Dept Radiol Sci, Irvine, CA 92717 USA. RP Yao, JH (reprint author), NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 978-3-642-33454-2; 978-3-642-33453-5 J9 LECT NOTES COMPUT SC PY 2012 VL 7512 BP 509 EP 516 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Theory & Methods; Medical Informatics; Robotics; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Medical Informatics; Robotics; Radiology, Nuclear Medicine & Medical Imaging GA BE3WH UT WOS:000371317400063 ER PT S AU Wang, SJ Liu, P Turkbey, B Choyke, P Pinto, P Summers, RM AF Wang, Shijun Liu, Peter Turkbey, Baris Choyke, Peter Pinto, Peter Summers, Ronald M. BE Ayache, N Delingette, H Golland, P Mori, K TI Gaussian Process Inference for Estimating Pharmacokinetic Parameters of Dynamic Contrast-Enhanced MR Images SO MEDICAL IMAGE COMPUTING AND COMPUTER-ASSISTED INTERVENTION - MICCAI 2012, PT III SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 15th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) CY OCT 01-05, 2012 CL Nice, FRANCE SP GE HealthCare, Philips, Siemens, Canon Median, ERC MedYMA, Medtronic, Aviesan, Dosisoft, IHU Strasbourg, IRCAD France, Kitware, Microsoft Res DE DCE-MRI; Gaussian Stochastic Process; Pharmacokinetic Model; Bayesian Inference; Coordinate Descent Optimization ID DCE-MRI AB In this paper, we propose a new pharmacokinetic model for parameter estimation of dynamic contrast-enhanced (DCE) MRI by using Gaussian process inference. Our model is based on the Tofts dual-compartment model for the description of tracer kinetics and the observed time series from DCE-MRI is treated as a Gaussian stochastic process. The parameter estimation is done through a maximum likelihood approach and we propose a variant of the coordinate descent method to solve this likelihood maximization problem. The new model was shown to outperform a baseline method on simulated data. Parametric maps generated on prostate DCE data with the new model also provided better enhancement of tumors, lower intensity on false positives, and better boundary delineation when compared with the baseline method. New statistical parameter maps from the process model were also found to be informative, particularly when paired with the PK parameter maps. C1 [Wang, Shijun; Liu, Peter; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10,Room 1C224, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter; Pinto, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Wang, SJ (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10,Room 1C224, Bethesda, MD 20892 USA. EM wangshi@cc.nih.gov; liupr@cc.nih.gov; Ismail_Turkbey@nih.gov; pchoyke@nih.gov; peter_pinto@nih.gov; rms@nih.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 978-3-642-33454-2; 978-3-642-33453-5 J9 LECT NOTES COMPUT SC PY 2012 VL 7512 BP 582 EP 589 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Theory & Methods; Medical Informatics; Robotics; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Medical Informatics; Robotics; Radiology, Nuclear Medicine & Medical Imaging GA BE3WH UT WOS:000371317400072 ER PT S AU Wei, ZS Yao, JH Wang, SJ Liu, JM Summers, RM AF Wei, Zhuoshi Yao, Jianhua Wang, Shijun Liu, Jiamin Summers, Ronald M. BE VanGinneken, B Novak, CL TI Computer-aided Marginal Artery Detection on Computed Tomographic Colonography SO MEDICAL IMAGING 2012: COMPUTER-AIDED DIAGNOSIS SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Computer-Aided Diagnosis CY FEB 07-09, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments Inc, eMagin, Isuzu Glass Co Ltd, Medtron, Inc, Ocean Thin Films Inc DE CT colonography; Marginal artery; Hessian matrix; Teniae coli AB Computed tomographic colonography (CTC) is a minimally invasive technique for colonic polyps and cancer screening. The marginal artery of the colon, also known as the marginal artery of Drummond, is the blood vessel that connects the inferior mesenteric artery with the superior mesenteric artery. The marginal artery runs parallel to the colon for its entire length, providing the blood supply to the colon. Detecting the marginal artery may benefit computer-aided detection (CAD) of colonic polyp. It can be used to identify teniae coli based on their anatomic spatial relationship. It can also serve as an alternative marker for colon localization, in case of colon collapse and inability to directly compute the endoluminal centerline. This paper proposes an automatic method for marginal artery detection on CTC. To the best of our knowledge, this is the first work presented for this purpose. Our method includes two stages. The first stage extracts the blood vessels in the abdominal region. The eigenvalue of Hessian matrix is used to detect line-like structures in the images. The second stage is to reduce the false positives in the first step. We used two different masks to exclude the false positive vessel regions. One is a dilated colon mask which is obtained by colon segmentation. The other is an eroded visceral fat mask which is obtained by fat segmentation in the abdominal region. We tested our method on a CTC dataset with 6 cases. Using ratio-of-overlap with manual labeling of the marginal artery as the standard-of-reference, our method yielded true positive, false positive and false negative fractions of 89%, 33%, 11%, respectively. C1 [Wei, Zhuoshi; Yao, Jianhua; Wang, Shijun; Liu, Jiamin; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Dianosis Lab, Ctr Clin, Bethesda, MD 20892 USA. RP Wei, ZS (reprint author), NIH, Imaging Biomarkers & Comp Aided Dianosis Lab, Ctr Clin, Bethesda, MD 20892 USA. EM rms@nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8964-7 J9 PROC SPIE PY 2012 VL 8315 AR 83150Z DI 10.1117/12.911850 PG 6 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BAT32 UT WOS:000305454600034 ER PT S AU Zhang, WD Liu, JM Yao, JH Nguyen, T Louie, A Wank, S Summers, RM AF Zhang, Weidong Liu, Jiamin Yao, Jianhua Tan Nguyen Louie, Adeline Wank, Stephen Summers, Ronald M. BE VanGinneken, B Novak, CL TI Computer-aided mesenteric vasculature segmentation on high-resolution 3D contrast-enhanced CT angiography scans SO MEDICAL IMAGING 2012: COMPUTER-AIDED DIAGNOSIS SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Computer-Aided Diagnosis CY FEB 07-09, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments Inc, eMagin, Isuzu Glass Co Ltd, Medtron, Inc, Ocean Thin Films Inc DE Vessel segmentation; vessel tracing; maximum intensity projection; Hessian matrix AB Segmentation of the mesenteric vasculature has important applications for evaluation of the small bowel. In particular, it may be useful for small bowel path reconstruction and precise localization of small bowel tumors such as carcinoid. Segmentation of the mesenteric vasculature is very challenging, even for manual labeling, because of the low contrast and tortuosity of the small blood vessels. Many vessel segmentation methods have been proposed. However, most of them are designed for segmenting large vessels. We propose a semi-automated method to extract the mesenteric vasculature on contrast-enhanced abdominal CT scans. First, the internal abdominal region of the body is automatically identified. Second, the major vascular branches are segmented using a multi-linear vessel tracing method. Third, small mesenteric vessels are segmented using multi-view multi-scale vesselness enhancement filters. The method is insensitive to image contrast, variations of vessel shape and small occlusions due to overlapping. The method could automatically detect mesenteric vessels with diameters as small as 1 mm. Compared with the standard-of-reference manually labeled by an expert radiologist, the segmentation accuracy (recall rate) for the whole mesenteric vasculature was 82.3% with a 3.6% false positive rate. C1 [Zhang, Weidong; Liu, Jiamin; Yao, Jianhua; Tan Nguyen; Summers, Ronald M.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Zhang, WD (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. EM rms@nih.gov FU National Institute of Health; Clinical Center; NIDDK FX This research was supported by the intramural research programs of the National Institute of Health, Clinical Center and NIDDK NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8964-7 J9 PROC SPIE PY 2012 VL 8315 AR 83151T DI 10.1117/12.911841 PG 6 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BAT32 UT WOS:000305454600064 ER PT B AU Makowski, L Makarov, OA Xu, SL Fischetti, RF AF Makowski, Lee Makarov, Oleg A. Xu, Shenglan Fischetti, Robert F. BE Tschesche, H TI Wide-angle X-ray solution scattering (WAXS) SO METHODS IN PROTEIN BIOCHEMISTRY LA English DT Article; Book Chapter ID PHOSPHOLIPID-BILAYER NANODISCS; STRUCTURAL DYNAMICS; BIOLOGICAL MACROMOLECULES; BETA-LACTOGLOBULIN; FLEXIBLE PROTEINS; HEMOGLOBIN; CRYSTALLOGRAPHY; CONFORMATIONS; DIVERSITY; ENSEMBLES C1 [Makowski, Lee] Northeastern Univ, Dana Res Ctr, Chem Chem Biol, Boston, MA 02115 USA. [Makarov, Oleg A.] Natl Inst Gen Med Sci, Argonne, IL 60439 USA. [Makarov, Oleg A.; Xu, Shenglan] NCI, Collaborat Access Team, Biosci Div, Argonne Natl Lab, Argonne, IL 60439 USA. [Fischetti, Robert F.] Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. RP Makowski, L (reprint author), Northeastern Univ, Dana Res Ctr, Chem Chem Biol, Boston, MA 02115 USA. EM rfischetti@anl.gov NR 45 TC 0 Z9 0 U1 0 U2 0 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY BN 978-3-11-025236-1; 978-3-11-025233-0 PY 2012 BP 165 EP 185 PG 21 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BD9ET UT WOS:000364538900011 ER PT B AU Veetil, JV Ravindranathan, S Jin, S Ye, KM AF Veetil, Jithesh V. Ravindranathan, Sruthi Jin, Sha Ye, Kaiming BE Demirci, U Khademhosseini, A Langer, R Blander, J TI Microfluidic Glucose Sensors SO MICROFLUIDIC TECHNOLOGIES FOR HUMAN HEALTH LA English DT Article; Book Chapter ID PAPER-BASED MICROFLUIDICS; CARBON NANOTUBE ARRAYS; ON-A-CHIP; ELECTROCHEMICAL DETECTION; BIOSENSOR ARRAY; LAB; PROBE; ASSAY C1 [Veetil, Jithesh V.] NIH, Sect Cellular Biophoton, Bethesda, MD 20892 USA. [Veetil, Jithesh V.; Ravindranathan, Sruthi; Jin, Sha; Ye, Kaiming] Univ Arkansas, Biomed Engn Program, Coll Engn, Fayetteville, AR 72701 USA. RP Ye, KM (reprint author), Univ Arkansas, Biomed Engn Program, Coll Engn, 203 Engn Hall, Fayetteville, AR 72701 USA. EM kye@uark.edu NR 53 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4405-52-2; 978-981-4405-51-5 PY 2012 BP 47 EP 67 PG 21 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA BB1RK UT WOS:000341306800004 ER PT J AU Aimon, S Toombes, G Callan-Jones, A Bassereau, P AF Aimon, S. Toombes, G. Callan-Jones, A. Bassereau, P. TI Membrane curvature-induced sorting of transmembrane proteins. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Aimon, S.; Bassereau, P.] Inst Curie, PhysicoChim Curie, Paris, France. [Toombes, G.] NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Callan-Jones, A.] Univ Montpellier 2, Lab Charles Coulomb, Montpellier, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 947 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348603135 ER PT J AU Artym, VV Petrie, RJ Yamada, KM AF Artym, V. V. Petrie, R. J. Yamada, K. M. TI Extracellular matrix guides tumor cell invadopodia formation by modulating beta 1-integrin signaling. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Artym, V. V.; Petrie, R. J.; Yamada, K. M.] NIDCR, LCDB, NIH, Bethesda, MD USA. [Artym, V. V.] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 858 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348603047 ER PT J AU Barzik, M Fujiwara, I Petralia, RS Yang, Y Sellers, JR Hammer, JA AF Barzik, M. Fujiwara, I. Petralia, R. S. Yang, Y. Sellers, J. R. Hammer, J. A. TI Myosin 18A-alpha is highly concentrated in the dendritic spines of mouse cerebellar Purkinje neurons: possible implications for spine morphogenesis and function. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Barzik, M.; Fujiwara, I.; Yang, Y.; Sellers, J. R.; Hammer, J. A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Petralia, R. S.] NIDCD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 400 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602035 ER PT J AU Billington, N Guzik-Lendrum, S Heissler, S Takagi, Y Yang, Y Homsher, E Knight, PJ Seller, JR AF Billington, N. Guzik-Lendrum, S. Heissler, S. Takagi, Y. Yang, Y. Homsher, E. Knight, P. J. Seller, J. R. TI Characterization of full-length mammalian myosin-18A. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Billington, N.; Guzik-Lendrum, S.; Heissler, S.; Takagi, Y.; Yang, Y.; Seller, J. R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Homsher, E.] Univ Calif Los Angeles, CHS, Los Angeles, CA USA. [Knight, P. J.] Univ Leeds, Leeds, W Yorkshire, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 199 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601199 ER PT J AU Bui, M Dalal, Y AF Bui, M. Dalal, Y. TI Cell-Cycle-Dependent Structural Transitions in the Human CENP-A Nucleosome In Vivo. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Bui, M.; Dalal, Y.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 563 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602198 ER PT J AU Burnette, DT Shao, L Ott, C Fiolka, R Davidson, MW Waterman, C Betzig, E Lippincott-Schwartz, J AF Burnette, D. T. Shao, L. Ott, C. Fiolka, R. Davidson, M. W. Waterman, C. Betzig, E. Lippincott-Schwartz, J. TI Live cell, 3-D SIM reveals a myosin II-based, actin arc contractile system operating on the dorsal surface of migrating cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Burnette, D. T.; Ott, C.; Lippincott-Schwartz, J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. [Shao, L.; Fiolka, R.; Betzig, E.] Howard Hughes Med Insitute, Ashburn, VA USA. [Davidson, M. W.] Florida State Univ, Natl High Magnet Field Lab, Talllahassee, FL USA. [Davidson, M. W.] Florida State Univ, Dept Biol Sci, Talllahassee, FL USA. [Waterman, C.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1047 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348603233 ER PT J AU Canzio, D Liao, M Naber, N Pate, E Larson, A Wu, S Cooke, R Schuck, P Narlikar, G AF Canzio, D. Liao, M. Naber, N. Pate, E. Larson, A. Wu, S. Cooke, R. Schuck, P. Narlikar, G. TI A conformational switch in HP1 allows conditional activation and drives assembly of the minimal heterochromatin unit. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Canzio, D.; Liao, M.; Naber, N.; Larson, A.; Wu, S.; Cooke, R.; Narlikar, G.] UCSF, Biochem & Biophys, San Francisco, CA USA. [Pate, E.] Washington State Univ, Pullman, WA 99164 USA. [Schuck, P.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 736 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602369 ER PT J AU Case, LB Shtenge, G Hess, HF Waterman, CM AF Case, L. B. Shtenge, G. Hess, H. F. Waterman, C. M. TI Specific protein-interactions regulate the three-dimensional nanoscale organization of vinculin within focal adhesions. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Case, L. B.; Waterman, C. M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Case, L. B.] Univ N Carolina, Chapel Hill, NC USA. [Shtenge, G.; Hess, H. F.] HHMI Janelia Farm, Ashburn, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2124 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607011 ER PT J AU Case, LB Gutierrez, N Higgins, C Gao, L Waterman, CM AF Case, L. B. Gutierrez, N. Higgins, C. Gao, L. Waterman, C. M. TI The role of actin polymerization in regulating endothelial cell barrier function. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Case, L. B.; Gutierrez, N.; Higgins, C.; Gao, L.; Waterman, C. M.] MBL, Physiol Course, Woods Hole, MA USA. [Case, L. B.; Waterman, C. M.] NIH, Bethesda, MD 20892 USA. [Gutierrez, N.] Rutgers State Univ, Newark, NJ 07102 USA. [Higgins, C.] Univ N Carolina, Chapel Hill, NC USA. [Gao, L.] HHMI Janelia Farm, Ashburn, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 240 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601240 ER PT J AU Chabaud, M Heuze, M Solanes, P Terriac, E Adelstein, R Zhang, Y Jacobelli, J Piel, M Lennon-Dumenil, AM AF Chabaud, M. Heuze, M. Solanes, P. Terriac, E. Adelstein, R. Zhang, Y. Jacobelli, J. Piel, M. Lennon-Dumenil, A-M TI Coupling cell function with cell migration: the example of dendritic cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Chabaud, M.; Heuze, M.; Solanes, P.; Lennon-Dumenil, A-M] Inst Curie, U932, Paris, France. [Terriac, E.; Piel, M.] Inst Curie, UMR144, Paris, France. [Adelstein, R.; Zhang, Y.] NIH, Bethesda, MD 20892 USA. [Jacobelli, J.] NJH, Denver, CO USA. RI Lennon-Dumenil, Ana-Maria/I-6716-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1272 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348604088 ER PT J AU Chandrasekar, I Huettner, JE Goeckeler, ZM Wysolmerski, RB Turney, SG Adelstein, RS Wang, PR Jalalizadeh, R Bridgman, PC AF Chandrasekar, I. Huettner, J. E. Goeckeler, Z. M. Wysolmerski, R. B. Turney, S. G. Adelstein, R. S. Wang, P. R. Jalalizadeh, R. Bridgman, P. C. TI Novel functional roles of non-muscle myosin II in clathrin-mediated endocytosis and synaptic transmission. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Chandrasekar, I.; Wang, P. R.; Jalalizadeh, R.; Bridgman, P. C.] Washington Univ, Sch Med, Anat & Neurobiol, St Louis, MO USA. [Huettner, J. E.] Washington Univ, Sch Med, Cell Biol & Physiol, St Louis, MO USA. [Goeckeler, Z. M.; Wysolmerski, R. B.] W Virginia Univ, Sch Med, Neurobiol & Anat, Morgantown, WV 26506 USA. [Turney, S. G.] Harvard Univ, Mol & Cellular Biol, Cambridge, MA 02138 USA. [Adelstein, R. S.] NHLBI, Mol Cardiol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 586 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602220 ER PT J AU Chang, J Lee, S Blackstone, C AF Chang, J. Lee, S. Blackstone, C. TI Protrudin/ZFYVE27 acts antagonistically to atlastin GTPases in tubular ER network formation. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Chang, J.; Lee, S.; Blackstone, C.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2184 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607071 ER PT J AU Chen, WC Wu, PH Phillip, JM Khatau, SB Choi, J Dallas, MR Konstantopoulos, K Sun, SX Lee, JS Hodzic, D Wirtz, D AF Chen, W-C Wu, P-H Phillip, J. M. Khatau, S. B. Choi, J. Dallas, M. R. Konstantopoulos, K. Sun, S. X. Lee, J. S. Hodzic, D. Wirtz, D. TI Functional interplay between cell cycle and cell phenotypes. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Chen, W-C; Phillip, J. M.; Khatau, S. B.; Choi, J.; Dallas, M. R.; Konstantopoulos, K.; Wirtz, D.] Johns Hopkins Univ, Chem & Biomol Engn, Baltimore, MD USA. [Chen, W-C; Wu, P-H] Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD USA. [Sun, S. X.] Johns Hopkins Univ, Mech Engn, Baltimore, MD USA. [Lee, J. S.] NCI, Ctr Strateg Sci Initiat, Bethesda, MD 20892 USA. [Hodzic, D.] Washington Univ, Sch Med, Ophthalmol, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1749 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605117 ER PT J AU Cullinane, AR Merideth, MA Pan, J Curry, JA White, JG Huizing, M Gahl, WA AF Cullinane, A. R. Merideth, M. A. Pan, J. Curry, J. A. White, J. G. Huizing, M. Gahl, W. A. TI Rab11FIP1 interacts with the BLOC-1 complex to retrieve melanogenic proteins from the recycling pathway and a dominant negative mutation in RAB11FIP1 causes Hermanksy-Pudlak Syndrome Type 10 (HPS-10). SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Cullinane, A. R.; Merideth, M. A.; Pan, J.; Curry, J. A.; Huizing, M.; Gahl, W. A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [White, J. G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 543 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602178 ER PT J AU Elliott, HL Fischer, R Waterman, C Danuser, G AF Elliott, H. L. Fischer, R. Waterman, C. Danuser, G. TI Local shape control by myosin II guides endothelial cell morphology and migration in 3D environments. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Elliott, H. L.; Danuser, G.] Harvard Univ, Sch Med, Cell Biol, Boston, MA USA. [Fischer, R.; Waterman, C.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1262 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348604078 ER PT J AU Fischer, RS Waterman, C AF Fischer, R. S. Waterman, C. TI VASP highlights endothelial tip cell dynamics in vivo. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Fischer, R. S.; Waterman, C.] NHLBI, Cell Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2060 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348606169 ER PT J AU Fujiwara, I Remmert, K Piszczek, G Hammer, JA AF Fujiwara, I. Remmert, K. Piszczek, G. Hammer, J. A. TI A CARMIL and V-1/Myotrophin-Dependent Regulatory Cycle for Capping Protein May Potentiate Actin Polymerization at the Plasma Membrane: Cytosol Interface SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Fujiwara, I.; Remmert, K.; Hammer, J. A.] NHLBI, LCB, NIH, Bethesda, MD 20892 USA. [Piszczek, G.] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RI Fujiwara, Ikuko/H-5717-2016 OI Fujiwara, Ikuko/0000-0002-9361-636X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 257 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601257 ER PT J AU Galletta, BJ Fagerstrom, CJ Guillen, RX Slep, KC Rusan, NM AF Galletta, B. J. Fagerstrom, C. J. Guillen, R. X. Slep, K. C. Rusan, N. M. TI Dissecting the interactions of the centrosome. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Galletta, B. J.; Fagerstrom, C. J.; Guillen, R. X.; Rusan, N. M.] NIH, Cell Biol & Physiol Ctr, Bethesda, MD 20892 USA. [Slep, K. C.] Univ N Carolina, Biol, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 288 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601288 ER PT J AU Gao, L Shao, L Higgins, CD Poulton, JS Peifer, M Davidson, MW Wu, X Goldstein, B Betzig, E AF Gao, L. Shao, L. Higgins, C. D. Poulton, J. S. Peifer, M. Davidson, M. W. Wu, X. Goldstein, B. Betzig, E. TI Noninvasive Imaging of Three-Dimensional Dynamics in Thickly Fluorescent Specimens Beyond the Diffraction Limit. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Gao, L.; Shao, L.; Betzig, E.] HHMI, Ashburn, VA USA. [Gao, L.; Shao, L.; Betzig, E.] Janelia Farm Res Campus, Ashburn, VA USA. [Higgins, C. D.; Poulton, J. S.; Peifer, M.; Goldstein, B.] Univ N Carolina, Dept Biol, Chapel Hill, NC USA. [Davidson, M. W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32306 USA. [Davidson, M. W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Wu, X.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1702 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605070 ER PT J AU Ghosh, S Swaminathan, V Nordenfelt, P Gross, P Prevo, B Springer, T Waterman, C Mayor, S AF Ghosh, S. Swaminathan, V. Nordenfelt, P. Gross, P. Prevo, B. Springer, T. Waterman, C. Mayor, S. TI Analysis of integrin organization and dynamics during focal adhesion formation and turnover using fluorescence anisotropy imaging. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Ghosh, S.; Mayor, S.] Natl Ctr Biol Sci, Bangalore, Karnataka, India. [Swaminathan, V.; Nordenfelt, P.; Gross, P.; Prevo, B.] Marine Biol Lab, Physiol Course, Woods Hole, MA 02543 USA. [Swaminathan, V.; Waterman, C.] NHLBI, Bethesda, MD 20892 USA. [Nordenfelt, P.; Springer, T.] Harvard Univ, Sch Med, Boston, MA USA. [Gross, P.] Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany. [Prevo, B.] Vrije Univ Amsterdam, Fac Sci, Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 473 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602108 ER PT J AU Giovinazzi, S Morozov, VM Summers, MK Reinhold, WC Ishov, AM AF Giovinazzi, S. Morozov, V. M. Summers, M. K. Reinhold, W. C. Ishov, A. M. TI USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora A kinase. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Giovinazzi, S.; Morozov, V. M.; Ishov, A. M.] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL USA. [Summers, M. K.] Lerner Res Inst, Dept Canc Biol, Cleveland, OH USA. [Reinhold, W. C.] NCI, Genom & Bioinformat Grp, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 879 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348603068 ER PT J AU Goyal, U Renvoise, BR Chang, J Blackstone, C AF Goyal, U. Renvoise, B. R. Chang, J. Blackstone, C. TI Centrosomal role of spastin-NA14 interaction in the pathogenesis of hereditary spastic paraplegia SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Goyal, U.] Loma Linda Univ, Loma Linda, CA 92350 USA. [Renvoise, B. R.; Chang, J.; Blackstone, C.] NINDS, CNU, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1214 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348604029 ER PT J AU Guo, M Zhou, E Mackintosh, F Fredberg, J Lippincott-Schwartz, J Weitz, D AF Guo, M. Zhou, E. Mackintosh, F. Fredberg, J. Lippincott-Schwartz, J. Weitz, D. TI Cell stiffness correlates with cell volume. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Guo, M.; Weitz, D.] Harvard Univ, SEAS, Cambridge, MA 02138 USA. [Zhou, E.; Fredberg, J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Mackintosh, F.] Vrije Univ Amsterdam, Phys, Amsterdam, Netherlands. [Lippincott-Schwartz, J.] NIH, Cell Biol & Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1280 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348604096 ER PT J AU Guo, M Zhou, E Mackintosh, F Fredberg, J Lippincott-Schwartz, J Weitz, D AF Guo, M. Zhou, E. Mackintosh, F. Fredberg, J. Lippincott-Schwartz, J. Weitz, D. TI Cell stiffness correlates with cell volume. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Guo, M.; Weitz, D.] Harvard Univ, SEAS, Cambridge, MA 02138 USA. [Zhou, E.; Fredberg, J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Mackintosh, F.] Vrije Univ Amsterdam, Phys, Amsterdam, Netherlands. [Lippincott-Schwartz, J.] NIH, Cell Biol & Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 15 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601015 ER PT J AU Hammond, G Machner, M Balla, T AF Hammond, G. Machner, M. Balla, T. TI Dissecting the role of PI4P in PI(4,5)P2 synthesis at the plasma membrane. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Hammond, G.; Balla, T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, NIH, Bethesda, MD USA. [Machner, M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Microbial Pathogenesis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 518 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602153 ER PT J AU Hong, A Sellers, JR AF Hong, A. Sellers, J. R. TI Characterization of Drosophila myosin 7a and M7BP in the eyes. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Hong, A.; Sellers, J. R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 195 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601195 ER PT J AU Hornick, JE Duncan, FE Sun, M Marko, JF Woodruff, TK AF Hornick, J. E. Duncan, F. E. Sun, M. Marko, J. F. Woodruff, T. K. TI Micromechanical properties of mammalian meiotic chromosomes: a high frequency model of genomic instability. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Hornick, J. E.; Duncan, F. E.; Woodruff, T. K.] Northwestern Univ, Dept Ob Gyn, Chicago, IL 60611 USA. [Sun, M.; Marko, J. F.] Northwestern Univ, Dept Mol Biosci, Evanston, IL USA. [Marko, J. F.] Northwestern Univ, Dept Phys & Astron, Evanston, IL USA. [Marko, J. F.] Northwestern Univ, NCI, Phys Sci & Oncol Ctr, Evanston, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1533 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348604349 ER PT J AU Jaqaman, K Galbraith, J Davidson, M Danuser, G Galbraith, C AF Jaqaman, K. Galbraith, J. Davidson, M. Danuser, G. Galbraith, C. TI Functional linkages between single-molecule integrin dynamics and edge protrusion in motile cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Jaqaman, K.; Danuser, G.] Harvard Univ, Sch Med, Boston, MA USA. [Galbraith, J.; Galbraith, C.] NIH, Bethesda, MD 20892 USA. [Davidson, M.] Florida State Univ, Tallahassee, FL 32306 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2062 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348606171 ER PT J AU Jolly, C Winfree, S Starr, T Steele-Mortimer, O AF Jolly, C. Winfree, S. Starr, T. Steele-Mortimer, O. TI AHNAK is Required for the Formation of Salmonella-Induced Plasma Membrane Ruffles During Invasion of Nonphagocytic Cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Jolly, C.; Winfree, S.; Starr, T.; Steele-Mortimer, O.] NIAID, Salmonella Host Cell Interact Sect, NIH, Rocky Mt Labs,LICP, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2458 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607344 ER PT J AU Jung, G Hammer, JA AF Jung, G. Hammer, J. A. TI The Over Expression of Myotrophin/V-1, a Negative Regulator of Capping Protein, Enhances Actin Polymerization and Filopodia Formation in Dictyostelium SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Jung, G.; Hammer, J. A.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 258 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601258 ER PT J AU Kim, K Nam, J Mukouyamal, YS Kawamoto, S AF Kim, K. Nam, J. Mukouyamal, Y-S. Kawamoto, S. TI Rbfox3-regulated Alternative Splicing of Numb Promotes Neuronal Differentiation during Development. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Kim, K.; Nam, J.; Mukouyamal, Y-S.; Kawamoto, S.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2347 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607234 ER PT J AU Klootwijk, ED Reichold, M Helip-Wooley, A Stanescu, H Bockenhauer, D Gahl, W Warth, R Kleta, R AF Klootwijk, E. D. Reichold, M. Helip-Wooley, A. Stanescu, H. Bockenhauer, D. Gahl, W. Warth, R. Kleta, R. TI Mitochondrial mistargeting causes autosomal dominant renal Fanconi syndrome. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Klootwijk, E. D.; Stanescu, H.; Bockenhauer, D.; Kleta, R.] LEG, UCL Ctr Nephrol, London, England. [Reichold, M.; Warth, R.] Univ Regensburg, D-93053 Regensburg, Germany. [Helip-Wooley, A.; Gahl, W.] NHGRI, Bethesda, MD 20892 USA. RI Warth, Richard/N-7119-2014 OI Warth, Richard/0000-0001-6084-0659 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607092 ER PT J AU Kotlyanskaya, L Nowotarski, S Peifer, M Giniger, E AF Kotlyanskaya, L. Nowotarski, S. Peifer, M. Giniger, E. TI Enabled antagonizes Actin Capping Protein function to regulate growth of motor nerves in the Drosophila embryo. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Kotlyanskaya, L.; Giniger, E.] NINDS, NIH, Bethesda, MD 20892 USA. [Kotlyanskaya, L.] Univ N Carolina, Neurobiol Curriculum, Chapel Hill, NC USA. [Nowotarski, S.; Peifer, M.] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1044 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348603230 ER PT J AU Kraft, LJ Han, B Baucum, AJ Nguyen, TA Vogel, SS Kenworthy, AK AF Kraft, L. J. Han, B. Baucum, A. J. Nguyen, T. A. Vogel, S. S. Kenworthy, A. K. TI LC3 constitutively associates with a high molecular weight complex in both the cytoplasm and nucleus. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Kraft, L. J.; Kenworthy, A. K.] Vanderbilt Univ Sch Med, Chem & Phys Biol Program, Nashville, TN USA. [Han, B.; Baucum, A. J.; Kenworthy, A. K.] Vanderbilt Univ Sch Med, Mol Physiol & Biophys, Nashville, TN USA. [Nguyen, T. A.; Vogel, S. S.] NIAAA, NIH, Rockville, MD 20852 USA. [Kenworthy, A. K.] Vanderbilt Univ Sch Med, Cell & Dev Biol, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1600 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348604416 ER PT J AU Lahin, S Chao, JT Young, BP Tavassoli, S Loewen, CJ Prinz, WA AF Lahin, S. Chao, J. T. Young, B. P. Tavassoli, S. Loewen, C. J. Prinz, W. A. TI A conserved ER-membrane protein complex facilitates phospholipid exchange between the ER and mitochondria. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Lahin, S.; Prinz, W. A.] NIDDK, LCMB, Bethesda, MD 20892 USA. [Chao, J. T.; Young, B. P.; Tavassoli, S.; Loewen, C. J.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1384 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348604200 ER PT J AU Lerit, DA Rusan, NM AF Lerit, D. A. Rusan, N. M. TI Asymmetry in centrosome activity is generated by blocking centrosome maturation. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Lerit, D. A.; Rusan, N. M.] NIH, Cell Biol & Physiol Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1877 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605245 ER PT J AU Lin, X Ruiz, J Bajraktari, I Banerjee, S Robertson, J Gribble, K Griggs, RC Fischbeck, KH Mankodi, A AF Lin, X. Ruiz, J. Bajraktari, I. Banerjee, S. Robertson, J. Gribble, K. Griggs, R. C. Fischbeck, K. H. Mankodi, A. TI ZASP mutations trigger disassembly of F-actin bundles in myofibrillar myopathy. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Lin, X.; Ruiz, J.; Bajraktari, I.; Banerjee, S.; Gribble, K.; Fischbeck, K. H.; Mankodi, A.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Robertson, J.] NIST, Div Semicond Elect, Gaithersburg, MD 20899 USA. [Griggs, R. C.] Univ Rochester, Neurol, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 234 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601234 ER PT J AU Ling, SC Parone, P Da Cruz, S Ilieva, H Platoshyn, O Salazar, D Tokunaga, S Swing, D Tessarollo, L Marsala, M Shaw, CE Cleveland, DW AF Ling, S-C Parone, P. Da Cruz, S. Ilieva, H. Platoshyn, O. Salazar, D. Tokunaga, S. Swing, D. Tessarollo, L. Marsala, M. Shaw, C. E. Cleveland, D. W. TI Dose-dependent and mutant-enhanced neurotoxicity in mice expressing wild type or ALS-linked mutants of FUS/TLS SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Ling, S-C; Parone, P.; Da Cruz, S.; Ilieva, H.; Salazar, D.; Tokunaga, S.; Cleveland, D. W.] Univ Calif San Diego, Ludwig Inst, La Jolla, CA 92093 USA. [Ling, S-C; Cleveland, D. W.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Platoshyn, O.; Marsala, M.] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA. [Swing, D.; Tessarollo, L.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. [Shaw, C. E.] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 68 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601068 ER PT J AU Liu, X Lee, DY Cai, S Hong, MS Shu, S Levine, RL Korn, ED AF Liu, X. Lee, D-Y. Cai, S. Hong, M-S. Shu, S. Levine, R. L. Korn, E. D. TI Regulation of the actin-activated MgATPase activity of Acanthamoeba myosin II by phosphorylation of serine 639 in motor domain loop 2. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Liu, X.; Lee, D-Y.; Cai, S.; Hong, M-S.; Shu, S.; Levine, R. L.; Korn, E. D.] NHLBI, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1755 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605123 ER PT J AU Lu, Q Rahajeng, J Ott, C Lipincott-Schwartz, J Caplan, S Jackson, P Westlake, C AF Lu, Q. Rahajeng, J. Ott, C. Lipincott-Schwartz, J. Caplan, S. Jackson, P. Westlake, C. TI EHD1 shapes developing primary cilia and influences transport from the ciliary pocket. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Lu, Q.; Westlake, C.] NCI, Frederick, MD 21701 USA. [Rahajeng, J.; Caplan, S.] Univ Nebraska, Omaha, NE 68182 USA. [Ott, C.; Lipincott-Schwartz, J.] NICHD, NIH, Bethesda, MD USA. [Jackson, P.] Genentech Inc, San Francisco, CA 94080 USA. RI Lu, Quanlong/M-4436-2015 OI Lu, Quanlong/0000-0002-4261-5121 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2232 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607119 ER PT J AU Ma, X Kovacs, M Adelstein, RS AF Ma, X. Kovacs, M. Adelstein, R. S. TI Vertebrate Cytokinesis: Nonmuscle Myosin II Exerts Tension but does not Translocate Actin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Ma, X.; Adelstein, R. S.] NHLBI, LMC, NIH, Bethesda, MD 20892 USA. [Kovacs, M.] Eotvos Lorand Univ, Dept Biochem, Budapest, Hungary. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 339 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601339 ER PT J AU Malide, D Metais, JY Dunbar, CE AF Malide, D. Metais, J-Y. Dunbar, C. E. TI Clonal analysis of hematopoietic stem and progenitor cells marked by five fluorescent proteins using confocal and multiphoton microscopy SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Malide, D.] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Metais, J-Y.; Dunbar, C. E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 798 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602430 ER PT J AU Manoussaki, D Shin, W Gavara, NC Chadwick, RS Waterman, C AF Manoussaki, D. Shin, W. Gavara, N. C. Chadwick, R. S. Waterman, C. TI A hybrid confocal & atomic force microscope for probing biophysical properties of migrating cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Manoussaki, D.; Chadwick, R. S.] NIDCD, NIH, Bethesda, MD USA. [Manoussaki, D.] Tech Univ Crete, Hania, Greece. [Shin, W.; Waterman, C.] NHLBI, NIH, Bethesda, MD 20892 USA. [Gavara, N. C.] Univ Goettingen, Fac Phys, Gottingen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1712 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605080 ER PT J AU Martina, J Puertollano, R AF Martina, J. Puertollano, R. TI Lysosomes as novel regulators of gene expression, organelle biogenesis, and autophagy induction SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Martina, J.; Puertollano, R.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 62 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601062 ER PT J AU Masedunskas, A Milberg, O Porat-Shliom, N Weigert, R AF Masedunskas, A. Milberg, O. Porat-Shliom, N. Weigert, R. TI Regulated exocytosis in the exocrine glands: the multiple roles of the actomyosin complex revelaed by intravital microscopy. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Masedunskas, A.; Milberg, O.; Porat-Shliom, N.; Weigert, R.] Natl Inst Dent & Craniofacial Res, OPCB, IMTU, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 626 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602260 ER PT J AU Mukherjee, K Bane, SL Sackett, DL AF Mukherjee, K. Bane, S. L. Sackett, D. L. TI Posttranslational Incorporation of 3-Formyltyrosine in alpha-Tubulin Inhibits Cell Proliferation without Altering Microtubule Morphology SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Mukherjee, K.; Bane, S. L.] SUNY Binghamton, Chem, Binghamton, NY USA. [Sackett, D. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Integrat & Med Biophys, Program Phys Biol, NIH, Bethesda, MD USA. RI Bane, Susan/C-1414-2013 OI Bane, Susan/0000-0002-4270-6314 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 268 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601268 ER PT J AU Nicholson, JM Mattingly, A Wangsa, D Camps, J Ried, T Cimini, D AF Nicholson, J. M. Mattingly, A. Wangsa, D. Camps, J. Ried, T. Cimini, D. TI Aneuploidy causes chromosome mis-segregation and karyotype-dependent phenotypes in cancer cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Nicholson, J. M.; Mattingly, A.; Cimini, D.] Virginia Tech, Biol Sci, Blacksburg, VA USA. [Wangsa, D.; Camps, J.; Ried, T.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1938 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348606048 ER PT J AU Pasapera, AM Fischer, RS Plotnikov, SV Egelhoff, T Waterman, CM AF Pasapera, A. M. Fischer, R. S. Plotnikov, S. V. Egelhoff, T. Waterman, C. M. TI Rac1 induces PCK-dependent myosin IIA heavy chain phosphorylation to regulate association with focal adhesions and cell migration SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Pasapera, A. M.; Fischer, R. S.; Plotnikov, S. V.; Waterman, C. M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Egelhoff, T.] Cleveland Clin, Cell Biol, Lerner Res Inst, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 636 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602270 ER PT J AU Patel, SS Atkin, SD Holtzclaw, LA Weerth, SH Pickel, J Russell, JT AF Patel, S. S. Atkin, S. D. Holtzclaw, L. A. Weerth, S. H. Pickel, J. Russell, J. T. TI Action potentials induce Ca2+ signals in Schwann cells in myelinated axons: dynamic measurements using transgenically targeted YC 3.60 cameleon Ca2+ indicator. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Patel, S. S.; Atkin, S. D.; Holtzclaw, L. A.; Weerth, S. H.; Russell, J. T.] NICHD, NIH, Bethesda, MD USA. [Pickel, J.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2283 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607170 ER PT J AU Peckham, M Takagi, Y Ushakov, D Ma, X Temprine, K Shroff, H AF Peckham, M. Takagi, Y. Ushakov, D. Ma, X. Temprine, K. Shroff, H. TI 3D PALM shows distinct distributions of Z-disc proteins with the Z-discs in cardiomyocytes. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Peckham, M.; Ushakov, D.] Univ Leeds, Leeds, W Yorkshire, England. [Takagi, Y.; Ma, X.; Temprine, K.; Shroff, H.] NIH, Bethesda, MD 20892 USA. RI Shroff, Hari/E-7247-2016 OI Shroff, Hari/0000-0003-3613-8215 NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1048 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348603234 ER PT J AU Petrie, R Gavara, N Chadwick, RS Yamada, KM AF Petrie, R. Gavara, N. Chadwick, R. S. Yamada, K. M. TI Actomyosin cytoskeletal organization distinguishes lobopodia from lamellipodia. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Petrie, R.; Yamada, K. M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Gavara, N.; Chadwick, R. S.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2026 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348606135 ER PT J AU Plotnikov, SV Pasapera, A Sabass, B Waterman, CM AF Plotnikov, S. V. Pasapera, A. Sabass, B. Waterman, C. M. TI Force Fluctuations within Focal Adhesions Mediate ECM Rigidity Sensing to Guide Directed Cell Migration. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Plotnikov, S. V.; Pasapera, A.; Waterman, C. M.] NHLBI, Lab Cell & Tissue Morphodynam, NIH, Bethesda, MD 20892 USA. [Sabass, B.] Univ Stuttgart, Inst Theoret Phys 2, D-70174 Stuttgart, Germany. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2016 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348606125 ER PT J AU Porat-Shliom, N Masedunskas, A Weigert, R AF Porat-Shliom, N. Masedunskas, A. Weigert, R. TI Coordination of mitochondrial activity across the rat salivary glands epithelium imaged by intravital two-photon microscopy. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Porat-Shliom, N.; Masedunskas, A.; Weigert, R.] NIDCR, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 506 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602141 ER PT J AU Purvis, J Karhohs, K Mock, C Batchelor, E Loewer, A Lahav, G AF Purvis, J. Karhohs, K. Mock, C. Batchelor, E. Loewer, A. Lahav, G. TI Encoding cellular information through p53 dynamics in individual cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Purvis, J.; Karhohs, K.; Mock, C.; Lahav, G.] Harvard Univ, Sch Med, Syst Biol, Boston, MA USA. [Batchelor, E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Loewer, A.] Max Delbrueck Ctr Mol Med, Berlin Inst Med Syst Biol, Berlin, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 42 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601042 ER PT J AU Ray, NA Dimitriadis, EK AF Ray, N. A. Dimitriadis, E. K. TI Intrinsic, temporal mechanical oscillations of COS-7 cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Ray, N. A.; Dimitriadis, E. K.] BEPS NIBIB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1738 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605106 ER PT J AU Ruiz, J Lin, X Bajraktari, I Banerjee, S Robertson, J Fischbeck, KH Mankodi, A AF Ruiz, J. Lin, X. Bajraktari, I. Banerjee, S. Robertson, J. Fischbeck, K. H. Mankodi, A. TI Characterization of ZASP-skeletal actin interaction and its role in a myofibrillar myopathy. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Ruiz, J.; Lin, X.; Bajraktari, I.; Banerjee, S.; Fischbeck, K. H.; Mankodi, A.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Robertson, J.] NIST, Div Semicond Elect, Gaithersburg, MD 20899 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 235 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601235 ER PT J AU Siththanandan, V Yang, Y Zhang, F Hong, A Billington, N Wu, X Sellers, JR AF Siththanandan, V. Yang, Y. Zhang, F. Hong, A. Billington, N. Wu, X. Sellers, J. R. TI Myosin 7a Binding Protein. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Siththanandan, V.; Yang, Y.; Zhang, F.; Hong, A.; Billington, N.; Wu, X.; Sellers, J. R.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 194 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601194 ER PT J AU Skau, CT Waterman, CM AF Skau, C. T. Waterman, C. M. TI Formin INF2 localizes to focal adhesions and is critical for coordination of adhesion and contraction SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Skau, C. T.; Waterman, C. M.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1791 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605159 ER PT J AU Sladewski, TE Bookwalter, CS Hong, MS Trybus, KM AF Sladewski, T. E. Bookwalter, C. S. Hong, M-S Trybus, K. M. TI RNA on the move: Single molecule reconstitution of ASH1 mRNA transport by a class V myosin from budding yeast. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Sladewski, T. E.; Bookwalter, C. S.; Trybus, K. M.] Univ Vermont, Dept Mol Physiol & Biophys, Burlington, VT USA. [Hong, M-S] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 30 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601030 ER PT J AU Smith, GH Boulanger, CA Anderson, LH Bruno, RD Lydon, JP AF Smith, G. H. Boulanger, C. A. Anderson, L. H. Bruno, R. D. Lydon, J. P. TI Functional rescue of PR null mammary epithelium by redirected testicular cells in vivo. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Smith, G. H.; Boulanger, C. A.; Anderson, L. H.; Bruno, R. D.] NCI, Bethesda, MD 20892 USA. [Lydon, J. P.] Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 786 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602418 ER PT J AU Tanner, K Orellana, W Chen, E Bissell, MJ AF Tanner, K. Orellana, W. Chen, E. Bissell, M. J. TI Regulation of cell- generated forces during phenotypic reversion by a novel laminin chain in 3D culture of human breast tumor cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Tanner, K.; Orellana, W.; Bissell, M. J.] LBNL, Life Sci, Berkeley, CA USA. [Tanner, K.; Orellana, W.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, E.] SUNY Stony Brook, Dept Pharmacol Sci, Sch Med, Stony Brook, NY 11794 USA. [Chen, E.] SUNY Stony Brook, Sch Med, Prote Ctr, Stony Brook, NY 11794 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2144 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607031 ER PT J AU Thievessen, I Berlemont, S Plevock, KM Plotnikov, SV Thompson, PM Zemljic-Harpf, A Ross, RS Davidson, MW Danuser, G Campbell, SL Waterman, CM AF Thievessen, I. Berlemont, S. Plevock, K. M. Plotnikov, S. V. Thompson, P. M. Zemljic-Harpf, A. Ross, R. S. Davidson, M. W. Danuser, G. Campbell, S. L. Waterman, C. M. TI Vinculin-actin interaction mediates engagement of actin retrograde flow to focal adhesions, but is dispensable for actin-dependent focal adhesion maturation. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Thievessen, I.; Plotnikov, S. V.; Waterman, C. M.] NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Thievessen, I.] Univ Erlangen Nurnberg, Biophys Grp, Ctr Med Phys & Technol, D-91054 Erlangen, Germany. [Berlemont, S.; Danuser, G.] Harvard Univ, Sch Med, Lab Computat Cell Biol, Dept Cell Biol, Boston, MA USA. [Plevock, K. M.] Univ N Carolina, Natl Inst Hlth Grad Partnership Program, Capel Hill, NC USA. [Thompson, P. M.; Campbell, S. L.] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Zemljic-Harpf, A.; Ross, R. S.] Univ Calif San Diego, Sch Med, Dept Med, Div Cardiol, San Diego, CA 92103 USA. [Davidson, M. W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32306 USA. [Davidson, M. W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2126 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607013 ER PT J AU Toulmay, A Prinz, W AF Toulmay, A. Prinz, W. TI Direct imaging of sterol-enriched micro-domains that segregate vacuolar membrane proteins. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Toulmay, A.; Prinz, W.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 166 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348601166 ER PT J AU Venugopalan, G Tanner, K Orellana, W Reber, CD Bissell, MJ Fletcher, DA AF Venugopalan, G. Tanner, K. Orellana, W. Reber, C. D. Bissell, M. J. Fletcher, D. A. TI Externally applied forces can phenotypically revert malignant breast epithelial structures. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Venugopalan, G.; Reber, C. D.; Fletcher, D. A.] Univ Calif Berkeley, Bioengn, Berkeley, CA 94720 USA. [Tanner, K.; Orellana, W.; Bissell, M. J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Tanner, K.; Orellana, W.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fletcher, D. A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA. NR 3 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1673 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605042 ER PT J AU Wang, A Zhang, Y Liu, C Adelstein, R AF Wang, A. Zhang, Y. Liu, C. Adelstein, R. TI Identification and Applications of a Genome Locus with High Homologous Recombination Frequency in Mouse Embryonic Stem cells. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Wang, A.; Zhang, Y.; Adelstein, R.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Liu, C.] NHLBI, Transgen Mouse Core Facil, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2364 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607250 ER PT J AU Wang, C Youle, R AF Wang, C. Youle, R. TI Genetic interaction between mitochondrial fission and fusion factors. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Wang, C.; Youle, R.] NINDS, SNB, NIH, Bethesda, MD 20892 USA. RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2196 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607083 ER PT J AU Williamson, CD Eyster, C Cole, N Donaldson, J AF Williamson, C. D. Eyster, C. Cole, N. Donaldson, J. TI The MARCH8 E3 ubiquitin ligase N-terminus plays an important role in CD44 specificity SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Williamson, C. D.; Eyster, C.; Cole, N.; Donaldson, J.] NHLBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2384 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607270 ER PT J AU Xavier, CP Melikova, M Saffo, S Rubin, JS AF Xavier, C. P. Melikova, M. Saffo, S. Rubin, J. S. TI sFRP1 Potentiation vs. Inhibition of Wnt3a/[beta]-catenin Signaling: Mechanistic and Structure-Function Analysis. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Xavier, C. P.; Melikova, M.; Saffo, S.; Rubin, J. S.] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 700 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348602333 ER PT J AU Yamashita, RA Marchler-Bauer, A Chitsaz, F Derbyshire, MK Gonzales, NR Gwadz, M Hurwitz, DI Lanczycki, CJ Lu, F Marchler, GH Song, JS Thanki, N Zheng, C Bryant, SH AF Yamashita, R. A. Marchler-Bauer, A. Chitsaz, F. Derbyshire, M. K. Gonzales, N. R. Gwadz, M. Hurwitz, D. I. Lanczycki, C. J. Lu, F. Marchler, G. H. Song, J. S. Thanki, N. Zheng, C. Bryant, S. H. TI The Conserved Domain Database (CDD) at NCBI. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Yamashita, R. A.; Marchler-Bauer, A.; Chitsaz, F.; Derbyshire, M. K.; Gonzales, N. R.; Gwadz, M.; Hurwitz, D. I.; Lanczycki, C. J.; Lu, F.; Marchler, G. H.; Song, J. S.; Thanki, N.; Zheng, C.; Bryant, S. H.] NCBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 967 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348603154 ER PT J AU Yi, J Shan, K Wu, X Kapoor, T Chen, JK Hammer, J AF Yi, J. Shan, K. Wu, X. Kapoor, T. Chen, J. K. Hammer, J. TI The Dynein Inhibitor Ciliobrevin D Does Not Inhibit T Cell Microcluster Movement SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Yi, J.; Shan, K.; Wu, X.; Hammer, J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Kapoor, T.] Rockefeller Univ, Lab Chem & Cell Biol, New York, NY 10021 USA. [Chen, J. K.] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1778 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605146 ER PT J AU Zhang, Y Ma, X Adelstein, RS AF Zhang, Y. Ma, X. Adelstein, R. S. TI Genetic Replacement of Nonmuscle Myosin (NM) IIA with NM IIC1-GFP In Vivo. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Zhang, Y.; Ma, X.; Adelstein, R. S.] NHLBI, LMC, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 1758 PG 2 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348605126 ER PT J AU Zhu, PP Blackstone, C AF Zhu, P-P Blackstone, C. TI Atlastin-1 mutant P342S, a new mutation causing SPG3A, disrupts the ER network. SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Zhu, P-P; Blackstone, C.] NINDS, CNU, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2012 VL 23 MA 2185 PG 1 WC Cell Biology SC Cell Biology GA V38MX UT WOS:000209348607072 ER PT J AU Nilsson, RH Tedersoo, L Abarenkov, K Ryberg, M Kristiansson, E Hartmann, M Schoch, CL Nylander, JAA Bergsten, J Porter, TM Jumpponen, A Vaishampayan, P Ovaskainen, O Hallenberg, N Bengtsson-Palme, J Eriksson, KM Larsson, KH Larsson, E Koljalg, U AF Nilsson, R. Henrik Tedersoo, Leho Abarenkov, Kessy Ryberg, Martin Kristiansson, Erik Hartmann, Martin Schoch, Conrad L. Nylander, Johan A. A. Bergsten, Johannes Porter, Teresita M. Jumpponen, Ari Vaishampayan, Parag Ovaskainen, Otso Hallenberg, Nils Bengtsson-Palme, Johan Eriksson, K. Martin Larsson, Karl-Henrik Larsson, Ellen Koljalg, Urmas TI Five simple guidelines for establishing basic authenticity and reliability of newly generated fungal ITS sequences SO MYCOKEYS LA English DT Article DE ITS; sequence reliability; sequence quality control; fungi; databases; barcoding AB Molecular data form an important research tool in most branches of mycology. A non-trivial proportion of the public fungal DNA sequences are, however, compromised in terms of quality and reliability, contributing noise and bias to sequence-borne inferences such as phylogenetic analysis, diversity assessment, and barcoding. In this paper we discuss various aspects and pitfalls of sequence quality assessment. Based on our observations, we provide a set of guidelines to assist in manual quality management of newly generated, near-full-length (Sanger-derived) fungal ITS sequences and to some extent also sequences of shorter read lengths, other genes or markers, and groups of organisms. The guidelines are intentionally non-technical and do not require substantial bioinformatics skills or significant computational power. Despite their simple nature, we feel they would have caught the vast majority of the severely compromised ITS sequences in the public corpus. Our guidelines are nevertheless not infallible, and common sense and intuition remain important elements in the pursuit of compromised sequence data. The guidelines focus on basic sequence authenticity and reliability of the newly generated sequences, and the user may want to consider additional resources and steps to accomplish the best possible quality control. A discussion on the technical resources for further sequence quality management is therefore provided in the supplementary material. C1 [Nilsson, R. Henrik; Hallenberg, Nils; Eriksson, K. Martin; Larsson, Ellen] Univ Gothenburg, Dept Biol & Environm Sci, S-40530 Gothenburg, Sweden. [Tedersoo, Leho; Abarenkov, Kessy; Koljalg, Urmas] Univ Tartu, Inst Ecol & Earth Sci, EE-50090 Tartu, Estonia. [Tedersoo, Leho; Koljalg, Urmas] Univ Tartu, Nat Hist Museum, EE-50090 Tartu, Estonia. [Ryberg, Martin] Univ Tennessee, Dept Ecol & Evolutionary Biol, Knoxville, TN 37996 USA. [Kristiansson, Erik] Chalmers, Dept Math Stat, S-41296 Gothenburg, Sweden. [Hartmann, Martin] Mol Ecol Agroscope Reckenholz Tanikon Res Stn ART, Zurich, Switzerland. [Hartmann, Martin] Swiss Fed Res Inst WSL, Forest Soils & Biogeochem, Birmensdorf, Switzerland. [Schoch, Conrad L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. [Nylander, Johan A. A.] Swedish Museum Nat Hist, Dept Biodivers Informat, S-10405 Stockholm, Sweden. [Bergsten, Johannes] Swedish Museum Nat Hist, Dept Entomol, S-10405 Stockholm, Sweden. [Porter, Teresita M.] McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. [Jumpponen, Ari] Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. [Vaishampayan, Parag] CALTECH, Jet Prop Lab, Biotechnol & Planetary Protect Grp, Pasadena, CA USA. [Ovaskainen, Otso] Univ Helsinki, Dept Biosci, FI-00014 Helsinki, Finland. [Bengtsson-Palme, Johan] Univ Gothenburg, Sahlgrenska Acad, Dept Neurosci & Physiol, S-40530 Gothenburg, Sweden. [Larsson, Karl-Henrik] Univ Oslo, Nat Hist Museum, Dept Res & Collect, N-0318 Oslo, Norway. RP Nilsson, RH (reprint author), Univ Gothenburg, Dept Biol & Environm Sci, Box 461, S-40530 Gothenburg, Sweden. EM henrik.nilsson@bioenv.gu.se RI Ovaskainen, Otso/D-9119-2012; Hartmann, Martin/M-9371-2016; Eriksson, Karl/D-7811-2015 OI Ovaskainen, Otso/0000-0001-9750-4421; Hartmann, Martin/0000-0001-8069-5284; Eriksson, Karl/0000-0001-7437-7175 FU Swedish Research Council of Environment, Agricultural Sciences, and Spatial Planning (FORMAS) [215-2011-498]; ETF [8235, 9286]; FIBIR; Life Science Area of Advance at Chalmers University of Technology; Swedish Research Council (VR); FORMAS; Intramural Research Program of the NIH, National Library of Medicine; Government of Canada through Genome Canada; Ontario Genomics Institute [OGI-050]; Department of Energy's Biological and Environmental Research Program [ER65000]; Gothenburg Bioinformatics Network FX RHN acknowledges financial support from Swedish Research Council of Environment, Agricultural Sciences, and Spatial Planning (FORMAS, 215-2011-498). LT and UK received financial support from ETF grants 8235, 9286, and FIBIR. EK acknowledges support from the Life Science Area of Advance at Chalmers University of Technology, the Swedish Research Council (VR), and FORMAS. CLS was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. TMP acknowledges financial support from the Government of Canada through Genome Canada and the Ontario Genomics Institute through the Biomonitoring 2.0 project (OGI-050). AJ acknowledges financial support from Department of Energy's Biological and Environmental Research Program (Award #ER65000). Yann Bertrand and Chris Quince are acknowledged for valuable input on the manuscript. Support from the Gothenburg Bioinformatics Network is gratefully acknowledged. NR 53 TC 36 Z9 38 U1 2 U2 10 PU PENSOFT PUBL PI SOFIA PA GEO MILEV STR 13A, SOFIA, 1111, BULGARIA SN 1314-4057 EI 1314-4049 J9 MYCOKEYS JI MycoKeys PY 2012 IS 4 BP 37 EP 63 DI 10.3897/mycokeys.4.3606 PG 27 WC Mycology SC Mycology GA V39TU UT WOS:000209434100004 ER PT J AU Elia, J Glessner, JT Wang, K Takahashi, N Shtir, CJ Hadley, D Sleiman, PMA Zhang, HT Kim, CE Robison, R Lyon, GJ Flory, JH Bradfield, JP Imielinski, M Hou, CP Frackelton, EC Chiavacci, RM Sakurai, T Rabin, C Middleton, FA Thomas, KA Garris, M Mentch, F Freitag, CM Steinhausen, HC Todorov, AA Reif, A Rothenberger, A Franke, B Mick, EO Roeyers, H Buitelaar, J Lesch, KP Banaschewski, T Ebstein, RP Mulas, F Oades, RD Sergeant, J Sonuga-Barke, EJS Renner, TJ Romanos, M Romanos, J Warnke, A Walitza, S Meyer, J Palmason, H Seitz, C Loo, SK Smalley, SL Biederman, J Kent, L Asherson, P Anney, RJL Gaynor, JW Shaw, P Devoto, M White, PS Grant, SFA Buxbaum, JD Rapoport, JL Williams, NM Nelson, SF Faraone, SV Hakonarson, H AF Elia, Josephine Glessner, Joseph T. Wang, Kai Takahashi, Nagahide Shtir, Corina J. Hadley, Dexter Sleiman, Patrick M. A. Zhang, Haitao Kim, Cecilia E. Robison, Reid Lyon, Gholson J. Flory, James H. Bradfield, Jonathan P. Imielinski, Marcin Hou, Cuiping Frackelton, Edward C. Chiavacci, Rosetta M. Sakurai, Takeshi Rabin, Cara Middleton, Frank A. Thomas, Kelly A. Garris, Maria Mentch, Frank Freitag, Christine M. Steinhausen, Hans-Christoph Todorov, Alexandre A. Reif, Andreas Rothenberger, Aribert Franke, Barbara Mick, Eric O. Roeyers, Herbert Buitelaar, Jan Lesch, Klaus-Peter Banaschewski, Tobias Ebstein, Richard P. Mulas, Fernando Oades, Robert D. Sergeant, Joseph Sonuga-Barke, Edmund J. S. Renner, Tobias J. Romanos, Marcel Romanos, Jasmin Warnke, Andreas Walitza, Susanne Meyer, Jobst Palmason, Haukur Seitz, Christiane Loo, Sandra K. Smalley, Susan L. Biederman, Joseph Kent, Lindsey Asherson, Philip Anney, Richard J. L. Gaynor, J. William Shaw, Philip Devoto, Marcella White, Peter S. Grant, Struan F. A. Buxbaum, Joseph D. Rapoport, Judith L. Williams, Nigel M. Nelson, Stanley F. Faraone, Stephen V. Hakonarson, Hakon TI Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder SO NATURE GENETICS LA English DT Article ID SPONTANEOUSLY HYPERTENSIVE-RAT; AUTISM SPECTRUM DISORDERS; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; DEFICIT/HYPERACTIVITY-DISORDER; MICE LACKING; CHILDREN; ADHD; REPLICATION; LINKAGE AB Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 x 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 x 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in similar to 10% of the cases (P = 4.38 x 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts. C1 [Glessner, Joseph T.; Wang, Kai; Hadley, Dexter; Sleiman, Patrick M. A.; Zhang, Haitao; Kim, Cecilia E.; Flory, James H.; Bradfield, Jonathan P.; Imielinski, Marcin; Hou, Cuiping; Frackelton, Edward C.; Chiavacci, Rosetta M.; Thomas, Kelly A.; Garris, Maria; Mentch, Frank] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Elia, Josephine] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Elia, Josephine] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat, Philadelphia, PA 19104 USA. [Takahashi, Nagahide; Sakurai, Takeshi; Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Psychiat, Lab Mol Neuropsychiat, New York, NY USA. [Shtir, Corina J.] Univ Calif Los Angeles, Dept Human Genet & Psychiat, Los Angeles, CA USA. [Robison, Reid; Lyon, Gholson J.] Univ Utah, Dept Psychiat, Salt Lake City, UT USA. [Rabin, Cara; Shaw, Philip] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Middleton, Frank A.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. [Freitag, Christine M.] Goethe Univ Frankfurt, Dept Child & Adolescent Psychiat Psychosom & psyc, Frankfurt, Germany. [Steinhausen, Hans-Christoph; Asherson, Philip] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Steinhausen, Hans-Christoph] Aarhus Univ Hosp, Aalborg Psychiat Hosp, DK-8000 Aarhus, Denmark. [Steinhausen, Hans-Christoph] Univ Basel, Inst Psychol, Basel, Switzerland. [Todorov, Alexandre A.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Reif, Andreas; Lesch, Klaus-Peter] Univ Wurzburg, Attent Deficit Hyperact Disorder Clin Res Network, Unit Mol Psychiat, Dept Psychiat Psychosomat & Psychotherapy, D-97070 Wurzburg, Germany. [Rothenberger, Aribert] Univ Gottingen, Gottingen, Germany. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Inst Brain Cognit & Behav,Ctr Neurosci, NL-6525 ED Nijmegen, Netherlands. [Mick, Eric O.; Biederman, Joseph] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Roeyers, Herbert] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Buitelaar, Jan] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, NL-6525 ED Nijmegen, Netherlands. [Banaschewski, Tobias] Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, D-6800 Mannheim, Germany. [Ebstein, Richard P.] Natl Univ Singapore, Dept Psychol, Queenstown, Singapore. [Mulas, Fernando] La Fe Univ Hosp, Fac Med, Dept Neuropaediat, Valencia, Spain. [Oades, Robert D.] Univ Duisburg Essen, Clin Child & Adolescent Psychiat, Essen, Germany. [Sergeant, Joseph] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Sch Psychol, Inst Disorder Impulse & Attent, Southampton, Hants, England. [Sonuga-Barke, Edmund J. S.] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Sonuga-Barke, Edmund J. S.] NYU, Ctr Child Study, New York, NY USA. [Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne] Univ Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, Wurzburg, Germany. [Romanos, Marcel] Univ Hosp Munich, Dept Child & Adolescent Psychiat Psychosomat & Ps, Munich, Germany. [Meyer, Jobst; Palmason, Haukur] Univ Trier, Dept Neurobehav Genet, Inst Psychobiol, Trier, Germany. [Seitz, Christiane] Univ Saarland, Dept Child & Adolescent Psychiat, D-6650 Homburg, Germany. [Loo, Sandra K.; Smalley, Susan L.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Kent, Lindsey] Bute Med Sch, St Andrews, Fife, Scotland. [Anney, Richard J. L.] St James Hosp, Dept Psychiat, Trinity Ctr Hlth Sci, Dublin 8, Ireland. [Gaynor, J. William; Hakonarson, Hakon] Childrens Hosp Philadelphia, Div Cardiothorac Surg, Philadelphia, PA 19104 USA. [Devoto, Marcella; Grant, Struan F. A.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Div Genet, Philadelphia, PA 19104 USA. [Devoto, Marcella; Grant, Struan F. A.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Devoto, Marcella] Univ Roma La Sapienza, Dipartimento Med Sperimentale, Rome, Italy. [Devoto, Marcella] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [White, Peter S.] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [White, Peter S.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Williams, Nigel M.] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Div Pulm Med, Philadelphia, PA 19104 USA. RP Hakonarson, H (reprint author), Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. EM hakonarson@email.chop.edu RI Lyon, Gholson/D-2765-2014; Renner, Tobias/I-2120-2013; Franke, Barbara/D-4836-2009; Nelson, Stanley/D-4771-2009; Sonuga-Barke, Edmund/D-9137-2011; Buitelaar, Jan/E-4584-2012; Lesch, Klaus-Peter/J-4906-2013; Romanos, Marcel/D-7695-2017; OI Lyon, Gholson/0000-0002-5869-0716; Kent, Lindsey/0000-0002-5315-3399; Mick, Eric/0000-0001-8505-8145; Buxbaum, Joseph/0000-0001-8898-8313; Franke, Barbara/0000-0003-4375-6572; Buitelaar, Jan/0000-0001-8288-7757; Lesch, Klaus-Peter/0000-0001-8348-153X; Walitza, Susanne/0000-0002-8161-8683; Anney, Richard/0000-0002-6083-407X; Faraone, Stephen/0000-0002-9217-3982 FU US National Institutes of Health (NIH) [R01MH62873]; NIH [K23MH066275]; Pfizer; CHOP; University of Pennsylvania National Center for Research Resources [UL1-RR-024134]; Cotswold Foundation; US Department of Health and Human Services [1RC2MH089924]; Seaver Foundation; NIMH [P50MH066392]; Deutsche Forschungsgemeinschaft [KFO 125, SFB 581, SFB TRR 58, ME 1923/5-1, ME 1923/5-3]; Bundesministerium fur Bildung und Forschung (BMBF) [01GV0605] FX We thank the IMAGE, IMAGE II and PUWMa consortium investigators and the NIMH for making the genotype data available. Funding support for International Multi-Center ADHD Genetics (IMAGE) and IMAGE II Projects was provided by US National Institutes of Health (NIH) grant R01MH62873 to S. V. F., and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The dataset used for the IMAGE analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP), which is found at http://www.ncbi.nlm.nih.gov/gap, through dbGaP accession numbers phs000016.v2.p2 (ADHD IMAGE), phs000020.v2.p1 (depression) and phs000019.v1.p1 (psoriasis). Samples and associated phenotype data for the GAIN Major Depression: Stage 1 Genome-wide Association In Population Based Samples Study (principal investigator, P. F. Sullivan, University of North Carolina) were provided by D. I. Boomsma and E. de Geus, Vrije Universiteit Amsterdam (principal investigators, Netherlands Twin Register); B. W. Penninx, Vrije Universiteit Medical Center Amsterdam; F. Zitman, Leiden University Medical Center, Leiden; and W. Nolen, University Medical Center Groningen (principal investigators and site principal investigators, Netherlands Study of Depression and Anxiety). Samples and associated phenotype data for the Collaborative Association Study of Psoriasis were provided by J.T. Elder (University of Michigan, Ann Arbor, Michigan), G. G. Krueger (University of Utah, Salt Lake City, Utah), A. Bowcock (Washington University, St. Louis, Missouri) and G. R. Abecasis (University of Michigan, Ann Arbor, Michigan). Samples and associated phenotype data for the International Multi-Center ADHD Genetics Project were provided by the following investigators: S. V. F. (principal investigator), R.J.L.A., P. A., J.S., R. P. E., B. F., M. Gill, A. Miranda, F. Mulas, R. D. O., H. R., A. Rothenberger, T. B., J. Buitelaar, E. Sonuga-Barke and H.-C. S. (site principal investigators), M. Daly, C. Lange, N. Laird, J. Su and B. Neale (statistical analysis team). Samples and associated phenotype data were accessed through an authorized data access request by H. H. and S. F. A. G. Data collection for the PUWMa sample was supported by NIH grants to S. V. F., J. Biederman, S. Smalley, R. Todd and A. A. T. GWAS genotyping of the PUWMa samples was completed by Genizon and was provided through a grant for genotyping services to S. V. F. The PUWMa consortium represents a Pfizer-funded collaboration among the University of California Los Angeles, Washington University and Massachussetts General Hospital. We thank M. C. O'Donovan, M. Gill, M. J. Owen, P. A. Holmans, A. Thapar, B. M. Neale and A. Miranda for contributing DNA samples and phenotypes to the study and for editing the manuscript. We thank G. DePalma, T. Topner, A. Guiney and H. Zhang for providing samples for the qRT-PCR CNV validation.; The study was supported by an Institutional Development Award to the Center for Applied Genomics from CHOP (H. H.), which funded all of the discovery genome-wide genotyping for this study. This work was additionally supported in part by NIH grant K23MH066275 (J. E.), University of Pennsylvania National Center for Research Resources Clinical and Translational Science Awards grant UL1-RR-024134 (J. E.), by a Research Development Award from the Cotswold Foundation (H. H. and S. F. A. G.) and by US Department of Health and Human Services grant 1RC2MH089924 (H. H.). N. T., T. S. and J. D. B. received support from the Seaver Foundation and a Conte Center for Neuroscience of Mental Disorders grant from the NIMH (P50MH066392).; Sample and phenotype data collection of parts of the IMAGE II cohort was supported by the Deutsche Forschungsgemeinschaft (KFO 125, SFB 581 and SFB TRR 58 to K.-P.L. and A. Reif, ME 1923/5-1 and ME 1923/5-3 to C.M.F. and J.M.) and the Bundesministerium fur Bildung und Forschung (BMBF 01GV0605 to K.-P.L.). NR 58 TC 110 Z9 111 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JAN PY 2012 VL 44 IS 1 BP 78 EP U113 DI 10.1038/ng.1013 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 870JA UT WOS:000298664000018 PM 22138692 ER PT B AU Raghavachari, N AF Raghavachari, Nalini BE Barh, D Blum, K Madigan, MA TI Overview of Omics SO OMICS: BIOMEDICAL PERSPECTIVES AND APPLICATIONS LA English DT Editorial Material; Book Chapter ID AUTOIMMUNE THYROID-DISEASE; RENAL-ALLOGRAFT REJECTION; ACUTE-PHASE PROTEINS; GENE-EXPRESSION; MASS-SPECTROMETRY; MAGNETIC-RESONANCE; PROTEOMIC ANALYSIS; MICROARRAY ANALYSIS; ULCERATIVE-COLITIS; ALZHEIMERS-DISEASE C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Raghavachari, N (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 127 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-5009-1; 978-1-4398-5008-4 PY 2012 BP 1 EP 19 PG 19 WC Biology; Engineering, Biomedical SC Life Sciences & Biomedicine - Other Topics; Engineering GA BD6HO UT WOS:000362221500003 ER PT B AU Chatterjee, B AF Chatterjee, Bishwanath BE Barh, D Blum, K Madigan, MA TI Forward Genetics Approach in Genomics Functional Identification of Unknown Genes SO OMICS: BIOMEDICAL PERSPECTIVES AND APPLICATIONS LA English DT Editorial Material; Book Chapter ID ETHYL-N-NITROSOUREA; ENU-INDUCED MUTATIONS; EMBRYONIC STEM-CELLS; DROSOPHILA-MELANOGASTER; MOUSE MUTAGENESIS; ETHYLNITROSOUREA MUTAGENESIS; CAENORHABDITIS-ELEGANS; MIDBLASTULA TRANSITION; PHENOTYPE-DRIVEN; MATERNAL CONTROL C1 NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chatterjee, B (reprint author), NHLBI, Dev Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 90 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-5009-1; 978-1-4398-5008-4 PY 2012 BP 227 EP 239 PG 13 WC Biology; Engineering, Biomedical SC Life Sciences & Biomedicine - Other Topics; Engineering GA BD6HO UT WOS:000362221500014 ER PT B AU Smock, JA Herrmann, J Fisher, VS Damis, BJ AF Smock, Jennifer A. Herrmann, Jack Fisher, V. Scott Damis, Bryan J. BE Dietz, JE Black, DR TI Pandemic Planning for Local Health Departments SO PANDEMIC PLANNING LA English DT Article; Book Chapter DE Local Health Department; Pandemic Influenza; H1N1; Communication; Mass Prophylaxis; Immunization; Quarantine and Isolation; Non-Pharmaceutical Interventions; Volunteer Management; Tabletop Exercise AB The public health initiatives encapsulated in the Public Health Service Act, Public Health Security and Bioterrorism Preparedness and Response Act, and the Pandemic and All-Hazards Preparedness Act (PAHPA) enacted by Congress have helped to establish an infrastructure to build upon public health preparedness efforts at the local, state, and federal levels. These laws facilitated the enhancement of the capacity to detect and respond effectively to significant public health threats. One of the more significant preparedness initiatives pertains to planning for and responding to an influenza pandemic. Within the development of a pandemic plan, much consideration needs to be focused within the areas of communication, mass prophylaxis and immunization, quarantine, isolation, social distancing, and volunteer management. To ensure continual improvement and identify vulnerabilities, plans must be tested with well-designed exercises. The 2009-2010 H1N1 pandemic event gave local health departments (LHDs) the opportunity to implement their pandemic plans within their communities on a large scale. Similar to an exercise, the real event unveiled strengths and improvement needs at the local level. This chapter provides considerations on how to develop and exercise pandemic plans along with providing the lessons learned from the 2009-2010 H1N1 pandemic based on experiences in the field. Through continuous improvement of pandemic plans, LHDs will ultimately empower communities to be more resilient during the next pandemic event. C1 [Smock, Jennifer A.] Natl Assoc Cty & City Officials, Washington, DC 20036 USA. [Smock, Jennifer A.] Natl Assoc Cty & City Officials NACCHO, PPHR, Washington, DC USA. [Smock, Jennifer A.; Fisher, V. Scott] NACCHO, Washington, DC USA. [Smock, Jennifer A.] PHSI, New York, NY USA. [Smock, Jennifer A.] Purdue Campus Emergency Preparedness & Planning O, W Lafayette, IN USA. [Herrmann, Jack; Damis, Bryan J.] Natl Assoc Cty & City Hlth Officials NACCHO, Publ Hlth Preparedness, Washington, DC USA. [Fisher, V. Scott] Preparedness Programs, New York, NY USA. [Fisher, V. Scott] NIH, Bethesda, MD USA. [Damis, Bryan J.] Soc Publ Hlth Educ SOPHE, Washington, DC USA. RP Smock, JA (reprint author), Natl Assoc Cty & City Officials, Washington, DC 20036 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-5767-0; 978-1-4398-5765-6 PY 2012 BP 95 EP 106 D2 10.1201/b11779 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA BC8IS UT WOS:000355700100007 ER PT J AU Perrone, JA Krauzlis, RJ AF Perrone, J. A. Krauzlis, R. J. TI Redundancy reduction: A possible explanation for the inhomogeneous patterns of antagonistic surrounds found in Middle Temporal (MT/V5) neurons SO PERCEPTION LA English DT Meeting Abstract C1 [Perrone, J. A.] Univ Waikato, Hamilton, New Zealand. [Krauzlis, R. J.] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD USA. EM jpnz@waikato.ac.nz NR 0 TC 0 Z9 0 U1 0 U2 0 PU PION LTD PI LONDON PA 207 BRONDESBURY PARK, LONDON NW2 5JN, ENGLAND SN 0301-0066 EI 1468-4233 J9 PERCEPTION JI Perception PY 2012 VL 41 SU S BP 57 EP 58 PG 2 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA V31WA UT WOS:000208912500178 ER PT B AU Reis, JP Gibbs, BB AF Reis, Jared P. Gibbs, Bethany Barone BE Ainsworth, BE Macera, CA TI Physical Activity in Chronic Disease Prevention SO PHYSICAL ACTIVITY AND PUBLIC HEALTH PRACTICE LA English DT Article; Book Chapter ID ENDOMETRIAL CANCER-RISK; CORONARY-ARTERY CALCIFICATION; NIH-AARP DIET; CARDIORESPIRATORY FITNESS; BLOOD-PRESSURE; LUNG-CANCER; CARDIOVASCULAR-DISEASE; SEDENTARY BEHAVIOR; COLORECTAL-CANCER; PROSTATE-CANCER C1 [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Gibbs, Bethany Barone] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. RP Reis, JP (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 46 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-4952-1; 978-1-4398-4951-4 PY 2012 BP 53 EP 73 D2 10.1201/b11718 PG 21 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA BC8KG UT WOS:000355754400005 ER PT B AU Troiano, RP Buchner, DM AF Troiano, Richard P. Buchner, David M. BE Ainsworth, BE Macera, CA TI National Guidelines for Physical Activity SO PHYSICAL ACTIVITY AND PUBLIC HEALTH PRACTICE LA English DT Article; Book Chapter ID AMERICAN-HEART-ASSOCIATION; OF-SPORTS-MEDICINE; PUBLIC-HEALTH; OLDER-ADULTS; RECOMMENDATION; EXERCISE C1 [Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, Risk Factor Monitoring & Methods Branch, Appl Res Program, Bethesda, MD 20892 USA. [Buchner, David M.] Univ Illinois, Dept Kinesiol & Community Hlth, Urbana, IL 61801 USA. RP Troiano, RP (reprint author), NCI, Div Canc Control & Populat Sci, Risk Factor Monitoring & Methods Branch, Appl Res Program, Bethesda, MD 20892 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-4952-1; 978-1-4398-4951-4 PY 2012 BP 195 EP 209 D2 10.1201/b11718 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA BC8KG UT WOS:000355754400013 ER PT J AU Clauser, S Haffer, C Ambs, A Hays, R Malinoff, R Giordano, L AF Clauser, Steven Haffer, Chris Ambs, Anita Hays, Ron Malinoff, Rochelle Giordano, Laura TI Using the SEER-MHOS Database to Evaluate the HRQOL of Medicare Advantage Beneficiaries with and without Cancer SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Clauser, Steven; Ambs, Anita] NCI, Bethesda, MD 20892 USA. [Haffer, Chris] Ctr Medicare Serv, Baltimore, MD USA. [Haffer, Chris] Ctr Medicaid Serv, Baltimore, MD USA. [Hays, Ron] Univ Calif Los Angeles, Los Angeles, CA USA. [Malinoff, Rochelle; Giordano, Laura] Hlth Serv Advisory Grp, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD JAN PY 2012 VL 20 SU 1 MA 386 BP 37 EP 37 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QV UT WOS:000209358800081 ER PT J AU Flynn, K Lin, L Dombeck, C Fawzy, M Abernethy, A Bruner, DW Reese, J Reeve, B Smith, A Weinfurt, K AF Flynn, Kathryn Lin, Li Dombeck, Carrie Fawzy, Maria Abernethy, Amy Bruner, Deborah Watkins Reese, Jennifer Reeve, Bryce Smith, Ashley Weinfurt, Kevin TI Validating the PROMIS (R) Sexual Function Brief Profile Measures SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Flynn, Kathryn; Lin, Li; Dombeck, Carrie; Fawzy, Maria; Weinfurt, Kevin] Duke Clin Res Inst, Durham, NC USA. [Abernethy, Amy] Duke Univ, Med Ctr, Durham, NC USA. [Bruner, Deborah Watkins] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Reese, Jennifer] Johns Hopkins Univ, Sch Med, Bethesda, MD USA. [Reeve, Bryce; Smith, Ashley] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD JAN PY 2012 VL 20 SU 1 MA 317 BP 38 EP 38 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QV UT WOS:000209358800085 ER PT J AU Jensen, RE Sulayman, N Hamilton, AS Potosky, AL Arora, NK AF Jensen, Roxanne E. Sulayman, Nadiyah Hamilton, Ann S. Potosky, Arnold L. Arora, Neeraj K. TI Assessment of Cancer Survivors Willingness to Communicate Health-related Quality of Life Problems With their Doctors (CP) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Jensen, Roxanne E.; Sulayman, Nadiyah; Potosky, Arnold L.] Lombardi Comprehens Canc Ctr, Washington, DC USA. [Hamilton, Ann S.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Arora, Neeraj K.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD JAN PY 2012 VL 20 SU 1 MA 1032/394 BP 51 EP 52 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QV UT WOS:000209358800119 ER PT S AU Roy, CJ Song, KJ Sivasubramani, SK Gardner, DJ Pincus, SH AF Roy, Chad J. Song, Kejing Sivasubramani, Satheesh K. Gardner, Donald J. Pincus, Seth H. BE Mantis, NJ TI Animal Models of Ricin Toxicosis SO RICIN AND SHIGA TOXINS: PATHOGENESIS, IMMUNITY, VACCINES AND THERAPEUTICS SE Current Topics in Microbiology and Immunology LA English DT Review; Book Chapter ID PSEUDOMONAS-AERUGINOSA EXOTOXIN; RAT SMALL-INTESTINE; ORAL TOXICITY; BALB/C MICE; KAPPA-B; INHALATION; HEPATOTOXICITY; HYPOGLYCEMIA; INTOXICATION; ABSORPTION AB Animal models of ricin toxicosis are necessary for testing the efficacy of therapeutic measures, as well studying the mechanisms by which ricin exerts its toxicity in intact animals. Because ricin can serve as a particularly well-characterized model of tissue damage, and the host response to that damage, studies of the mechanisms of ricin toxicity may have more general applicability. For example, our studies of the molecular mechanisms underlying the development of ricin-induced hypoglycemia may help elucidate the relationship of type II diabetes, insulin resistance, and inflammation. Studies in non-human primates are most relevant for testing and developing agents having clinical utility. But these animals are expensive and limited in quantity, and so rodents are used for most mechanistic studies. C1 [Roy, Chad J.; Sivasubramani, Satheesh K.] Tulane Sch Med, Tulane Natl Primate Res Ctr, New Orleans, LA 70112 USA. [Song, Kejing; Pincus, Seth H.] Childrens Hosp, LSU Hlth Sci Ctr, New Orleans, LA 70118 USA. [Gardner, Donald J.] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Roy, CJ (reprint author), Tulane Sch Med, Tulane Natl Primate Res Ctr, New Orleans, LA 70112 USA. EM croy@tulane.edu; ssiua@tulane.edu; spincus@chnola-research.org FU NCRR NIH HHS [P51 RR000164]; NIAID NIH HHS [R01 AI059376, U54 AI057156]; NIH HHS [P51 OD011104] NR 29 TC 13 Z9 13 U1 1 U2 6 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0070-217X BN 978-3-642-27470-1; 978-3-642-27469-5 J9 CURR TOP MICROBIOL JI Curr.Top.Microbiol.Immunol. PY 2012 VL 357 BP 243 EP 257 DI 10.1007/82_2011_173 D2 10.1007/978-3-642-27470-1 PG 15 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BJT95 UT WOS:000330361400010 PM 21956160 ER PT J AU Farina, NH Hausburg, M Dalla Betta, N Pulliam, C Srivastava, D Cornelison, DDW Olwin, BB AF Farina, Nicholas H. Hausburg, Melissa Dalla Betta, Nicole Pulliam, Crystal Srivastava, Deepak Cornelison, D. D. W. Olwin, Bradley B. TI A role for RNA post-transcriptional regulation in satellite cell activation SO SKELETAL MUSCLE LA English DT Article DE Satellite cell; RNA post-transcriptional regulation; microRNA AB Background: Satellite cells are resident skeletal muscle stem cells responsible for muscle maintenance and repair. In resting muscle, satellite cells are maintained in a quiescent state. Satellite cell activation induces the myogenic commitment factor, MyoD, and cell cycle entry to facilitate transition to a population of proliferating myoblasts that eventually exit the cycle and regenerate muscle tissue. The molecular mechanism involved in the transition of a quiescent satellite cell to a transit-amplifying myoblast is poorly understood. Methods: Satellite cells isolated by FACS from uninjured skeletal muscle and 12 h post-muscle injury from wild type and Syndecan-4 null mice were probed using Affymetrix 430v2 gene chips and analyzed by Spotfire(tm) and Ingenuity Pathway analysis to identify gene expression changes and networks associated with satellite cell activation, respectively. Additional analyses of target genes identify miRNAs exhibiting dynamic changes in expression during satellite cell activation. The function of the miRNAs was assessed using miRIDIAN hairpin inhibitors. Results: An unbiased gene expression screen identified over 4,000 genes differentially expressed in satellite cells in vivo within 12 h following muscle damage and more than 50% of these decrease dramatically. RNA binding proteins and genes involved in post-transcriptional regulation were significantly over-represented whereas splicing factors were preferentially downregulated and mRNA stability genes preferentially upregulated. Furthermore, six computationally identified miRNAs demonstrated novel expression through muscle regeneration and in satellite cells. Three of the six miRNAs were found to regulate satellite cell fate. Conclusions: The quiescent satellite cell is actively maintained in a state poised to activate in response to external signals. Satellite cell activation appears to be regulated by post-transcriptional gene regulation. C1 [Farina, Nicholas H.; Dalla Betta, Nicole; Pulliam, Crystal; Olwin, Bradley B.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Hausburg, Melissa] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Srivastava, Deepak] Univ San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. [Cornelison, D. D. W.] Univ Missouri, Biol Sci & Bond Life Sci Ctr, Columbia, MO 65211 USA. RP Cornelison, DDW (reprint author), Univ Missouri, Biol Sci & Bond Life Sci Ctr, Columbia, MO 65211 USA. EM cornelisond@missouri.edu; bradley.olwin@colorado.edu OI Farina, Nicholas/0000-0002-6061-590X; DALLA BETTA, NICOLE/0000-0002-6380-9486; Pulliam, Crystal/0000-0002-9467-9821; Cornelison, DDW/0000-0003-4287-7524 FU National Institutes of Health [AR049446]; Muscular Dystrophy Association; Muscular Dystrophy Association Development Grant FX We thank Tiffany Antwine for technical assistance and members of the Olwin laboratory for critical discussion of this manuscript. The project described was supported by the National Institutes of Health grant AR049446 to B. B. Olwin, a grant from the Muscular Dystrophy Association to B. B. Olwin and a Muscular Dystrophy Association Development Grant to D.D.W. Cornelison. NR 68 TC 13 Z9 14 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2044-5040 J9 SKELET MUSCLE JI Skeletal Muscle PY 2012 VL 2 AR UNSP 21 DI 10.1186/2044-5040-2-21 PG 21 WC Cell Biology SC Cell Biology GA V39PM UT WOS:000209422900020 PM 23046558 ER PT J AU Garraffo, HM Andriamaharavo, NR Vaira, M Quiroga, MF Heit, C Spande, TF AF Garraffo, H. Martin Andriamaharavo, Nirina R. Vaira, Marcos Quiroga, Maria F. Heit, Cecilia Spande, Thomas F. TI Alkaloids from single skins of the Argentinian toad Melanophryniscus rubriventris (ANURA, BUFONIDAE): An unexpected variability in alkaloid profiles and a profusion of new structures SO SPRINGERPLUS LA English DT Article DE Alkaloids; Gas chromatography-mass spectrometry; Melanophryniscus Toads; Reproduction; Sequestration AB GC-MS analysis of single-skins of ten Melanophryniscus rubriventris toads (five collections of two toads each) captured during their breeding season in NW Argentina has revealed a total of 127 alkaloids of which 56 had not been previously detected in any frog or toad. Included among these new alkaloids are 23 new diastereomers of previously reported alkaloids. What is particularly distinguishing about the alkaloid profiles of these ten collections is the occurrence of many of the alkaloids, whether known or new to us, in only one of the ten skins sampled, despite two skins being obtained from each breeding site of the five populations. Many of the alkaloids are of classes known to have structures with branched-chains (e.g. pumiliotoxins and tricyclic structures) that are considered to derive from dietary mites. A large number of previously reported and new alkaloids are also of unclassified structures. Only a very few 3,5-disubstituted-indolizidine or -pyrrolizidine alkaloids are observed that have a straight-chain carbon skeleton and are likely derived from ant prey. The possible relationship of these collections made during the toad's brief breeding episodes to sequestration of dietary arthropods and individual alkaloid profiles is discussed. C1 [Garraffo, H. Martin; Andriamaharavo, Nirina R.; Spande, Thomas F.] NIDDK, Lab Bioorgan Chem, NIH, DHHS, Bethesda, MD 20892 USA. [Vaira, Marcos] Univ Nacl Jujuy, Fac Ingn, CIBA, RA-4600 San Salvador De Jujuy, Argentina. [Vaira, Marcos] Univ Nacl Salta, Inst Bio & Geociencias NOA, RA-2 Mendoza, Salta, Argentina. [Quiroga, Maria F.] Univ Nacl Jujuy, Fac Ciencias Agr, RA-47 Alberdi, Jujuy, Argentina. [Heit, Cecilia] Lab Analisis Residuos & Trazas LAnaRT, RA-2170 Zorrilla De San Martin, Jujuy, Argentina. RP Garraffo, HM (reprint author), NIDDK, Lab Bioorgan Chem, NIH, DHHS, Bethesda, MD 20892 USA. EM garraffo@helix.nih.gov OI Vaira, Marcos/0000-0002-3651-5108 FU NIDDK; NIH; HHS; Universidad Nacional de Jujuy; Secter-UNJu grant [D-037] FX HMG, NRA and TFS wish to thank NIDDK, NIH, HHS for support. Part of the project was supported by a research fellowship from Universidad Nacional de Jujuy to MFQ, and was supported also by a Secter-UNJu grant #D-037. Permits for sample collection of the species were provided by the Delegacion Tecnica de Parques Nacionales, Regional Noroeste and Direccion Provincial de Politicas Ambientales y Recursos Naturales, Jujuy. NR 37 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PY 2012 VL 1 AR 51 DI 10.1186/2193-1801-1-51 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V40DJ UT WOS:000209459000051 PM 23596558 ER PT J AU Knosp, WM Knox, SM Hoffman, MP AF Knosp, Wendy M. Knox, Sarah M. Hoffman, Matthew P. TI Salivary gland organogenesis SO WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY LA English DT Article AB Our understanding of vertebrate salivary gland organogenesis has been largely informed by the study of the developing mouse submandibular gland (SMG), which will be the major focus of this review. The mouse SMG has been historically used as a model system to study epithelial mesenchymal interactions, growth factor extracellular matrix (ECM) interactions, and branching morphogenesis. SMG organogenesis involves interactions between a variety of cell types and their stem/progenitor cells, including the epithelial, neuronal, and mesenchymal cells, and their ECM microenvironment, or niche. Here, we will review recent literature that provides conceptual advances in understanding the molecular mechanisms of salivary gland development. We will describe SMG organogenesis, introduce the model systems used to study development, and outline the key signaling pathways and cellular processes involved. We will also review recent research focusing on the identification of stem/progenitor cells in the SMG and how they are directed along a series of cell fate decisions to form a functional gland. The mechanisms that drive SMG organogenesis provide a template to regenerate functional salivary glands in patients who suffer from salivary hypofunction due to irreversible glandular damage after irradiation or removal of tumors. Additionally, these mechanisms may also control growth and development of other organ systems. (C) 2011 Wiley Periodicals, Inc. C1 [Knosp, Wendy M.; Knox, Sarah M.; Hoffman, Matthew P.] NIDCR, Matrix & Morphogenesis Sect, LCDB, NIH, Bethesda, MD 20892 USA. RP Hoffman, MP (reprint author), NIDCR, Matrix & Morphogenesis Sect, LCDB, NIH, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov OI Knox, Sarah/0000-0002-7567-083X NR 81 TC 19 Z9 19 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-7684 EI 1759-7692 J9 WIRES DEV BIOL JI Wiley Interdiscip. Rev.-Dev. Biol. PD JAN-FEB PY 2012 VL 1 IS 1 BP 69 EP 82 DI 10.1002/wdev.4 PG 14 WC Developmental Biology SC Developmental Biology GA V31EH UT WOS:000208866400006 PM 23801668 ER PT B AU D'Amico, L Li, CQ Glaze, E Davis, M Seng, WL AF D'Amico, Louis Li, Chunqi Glaze, Elizabeth Davis, Myrtle Seng, Wen Lin BE McGrath, P TI Zebrafish: A Predictive Model for Assessing Cancer Drug-Induced Organ Toxicity SO ZEBRAFISH: METHODS FOR ASSESSING DRUG SAFETY AND TOXICITY LA English DT Article; Book Chapter C1 [D'Amico, Louis; Li, Chunqi; Seng, Wen Lin] Phylonix, Cambridge, MA 02139 USA. [Glaze, Elizabeth; Davis, Myrtle] NCI, NIH, Bethesda, MD 20892 USA. RP D'Amico, L (reprint author), Phylonix, Cambridge, MA 02139 USA. NR 1 TC 1 Z9 1 U1 1 U2 1 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND BN 978-1-118-10216-9; 978-0-470-42513-8 PY 2012 BP 135 EP 149 PG 15 WC Toxicology; Veterinary Sciences; Virology SC Toxicology; Veterinary Sciences; Virology GA BA6HP UT WOS:000337144400012 ER PT J AU Heim, N Snijder, MB Goodpaster, BH Harris, TB Hue, TF Ritchevsky, SB Newman, AB Gudnason, V Ferrucci, L Deeg, DJH Seidell, JC Visser, M AF Heim, N. Snijder, M. B. Goodpaster, B. H. Harris, T. B. Hue, T. F. Ritchevsky, S. B. Newman, A. B. Gudnason, V. Ferrucci, L. Deeg, D. J. H. Seidell, J. C. Visser, M. TI CROSS-VALIDATION OF NEW CUT-OFF VALUES FOR HIGH-RISK WAIST CIRCUMFERENCE IN OLDER ADULTS: RESULTS FROM FOUR COHORT STUDIES SO AGE AND AGEING LA English DT Meeting Abstract C1 [Heim, N.; Snijder, M. B.; Seidell, J. C.; Visser, M.] Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands. [Heim, N.; Snijder, M. B.; Seidell, J. C.; Visser, M.] Vrije Univ Amsterdam, Fac Earth & Life Sci, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Heim, N.] Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands. [Goodpaster, B. H.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hue, T. F.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Ritchevsky, S. B.] Wake Forest Sch Med, Sticht Ctr Aging A, Winston Salem, NC USA. [Newman, A. B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Gudnason, V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Ferrucci, L.] NIA, Clin Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Deeg, D. J. H.; Seidell, J. C.; Visser, M.] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Dept Epidemiol & Biostat, Amsterdam, Netherlands. RI seidell, jacob/N-7427-2013; Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD JAN PY 2012 VL 41 SU 1 BP 38 EP 38 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 859EN UT WOS:000297859100039 ER PT J AU Hosgood, HD Chapman, RS Wei, H He, XZ Tian, LW Liu, LZ Lai, H Engel, LS Chen, W Rothman, N Lan, Q AF Hosgood, H. Dean, III Chapman, Robert S. Wei, Hu He, Xingzhou Tian, Linwei Liu, Larry Z. Lai, Hong Engel, Lawrence S. Chen, Wei Rothman, Nathaniel Lan, Qing TI Coal mining is associated with lung cancer risk in Xuanwei, China SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE coal mining; lung cancer; occupation; Xuanwei; China ID UNITED-STATES; MINE DUST; MORTALITY; EXPOSURE; OCCUPATION; WORKERS AB Background Xuanwei, China, experiences some of the highest rates of lung cancer in China. While lung cancer risk has been linked to the household use of bituminous coal, no study has comprehensively evaluated the risk of lung cancer associated with the mining of this coal in Xuanwei. In Xuanwei, coal is typically extracted from underground mines, without ventilation, and transported to the surface using carts powered by manpower or electricity. C1 [Hosgood, H. Dean, III] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Chapman, Robert S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. [He, Xingzhou] Chinese Ctr Dis Control & Prevent, Inst Environm Hlth & Engn, Beijing, Peoples R China. [Tian, Linwei] Chinese Univ Hong Kong, Sch Publ Hlth, Stanley Ho Ctr Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China. [Liu, Larry Z.] Cornell Univ, Weill Med Coll, Dept Publ Hlth, New York, NY 10021 USA. [Lai, Hong] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Engel, Lawrence S.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Chen, Wei] Forest Labs Inc, Harborside Financial Ctr, Jersey City, NJ USA. RP Hosgood, HD (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,DHHS, 6120 Execut Blvd,EPS 8120,MCS 7240, Bethesda, MD 20892 USA. EM hosgoodd@mail.nih.gov RI Tian, Linwei/A-9736-2009; Hu, Wei/M-3524-2013; OI Tian, Linwei/0000-0002-4739-1534; Engel, Lawrence/0000-0001-9268-4830 FU Chinese Academy of Preventive Medicine; Yunnan Province Antiepidemic Station; U.S. Environmental Protection Agency; National Institutes of Health FX Contract grant sponsor: Chinese Academy of Preventive Medicine.; Contract grant sponsor: Yunnan Province Antiepidemic Station.; Contract grant sponsor: U.S. Environmental Protection Agency.; Contract grant sponsor: Intramural Research Program of the National Institutes of Health. NR 21 TC 6 Z9 10 U1 1 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JAN PY 2012 VL 55 IS 1 BP 5 EP 10 DI 10.1002/ajim.21014 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 857TH UT WOS:000297742700002 PM 21987405 ER PT J AU Viola, G Bortolozzi, R Hamel, E Moro, S Brun, P Castagliuolo, I Ferlin, MG Basso, G AF Viola, Giampietro Bortolozzi, Roberta Hamel, Ernest Moro, Stefano Brun, Paola Castagliuolo, Ignazio Ferlin, Maria Grazia Basso, Giuseppe TI MG-2477, a new tubulin inhibitor, induces autophagy through inhibition of the Akt/mTOR pathway and delayed apoptosis in A549 cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Autophagy; Apoptosis; Microtubule inhibitors; Cell cycle analysis; Akt/mTOR ID MALIGNANT GLIOMA-CELLS; BREAST-CANCER CELLS; MAMMALIAN TARGET; DEATH; MICROTUBULES; AGENTS; RAPAMYCIN; FUSION; AKT; MITOCHONDRIA AB We previously demonstrated that MG-2477 (3-cyclopropylmethyl-7-phenyl-3H-pyrrolo[3,2-f]quinolin-9(6H)-one) inhibits the growth of several cancer cell lines in vitro. Here we show that MG-2477 inhibited tubulin polymerization and caused cells to arrest in metaphase. The detailed mechanism of action of MG-2477 was investigated in a non-small cell lung carcinoma cell line (A549). Treatment of A549 cells with MG-2477 caused the cells to arrest in the G2/M phase of the cell cycle, with a concomitant accumulation of cyclin B. Moreover, the compound induced autophagy, which was followed at later times by apoptotic cell death. Autophagy was detected as early as 12 h by the conversion of microtubule associated protein 1 light chain 3 (LC3-I) to LC3-II, following cleavage and lipid addition to LC3-I. After 48 h of MG-2477 exposure, phosphatidylserine externalization on the cell membrane, caspase-3 activation, and PARP cleavage occurred, revealing that apoptotic cell death had begun. Pharmacological inhibition of autophagy with 3-methyladenine or bafilomycin A1 increased apoptotic cell death, suggesting that the autophagy caused by MG-2477 played a protective role and delayed apoptotic cell death. Additional studies revealed that MG-2477 inhibited survival signaling by blocking activation of Akt and its downstream targets, including mTOR, and FHKR. Treatment with MG-2477 also reduced phosphorylation of mTOR downstream targets p70 ribosomal S6 kinase and 4E-BP1. Overexpression of Akt by transfection with a Myr-Akt vector decreased MG-2477 induced autophagy, indicating that Akt is involved. Taken together, these results indicated that the autophagy induced by MG-2477 delayed apoptosis by exerting an adaptive response following microtubule damage. (C) 2011 Elsevier Inc. All rights reserved. C1 [Viola, Giampietro; Bortolozzi, Roberta; Basso, Giuseppe] Univ Padua, Dept Pediat, Lab Oncohematol, I-35100 Padua, Italy. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Moro, Stefano; Ferlin, Maria Grazia] Univ Padua, Dept Pharmaceut Sci, I-35100 Padua, Italy. [Brun, Paola; Castagliuolo, Ignazio] Univ Padua, Dept Histol Microbiol & Med Biotechnol, I-35100 Padua, Italy. RP Viola, G (reprint author), Univ Padua, Dept Pediat, Lab Oncohematol, I-35100 Padua, Italy. EM giampietro.viola.1@unipd.it RI Moro, Stefano/A-2979-2012; Viola, Giampietro/I-4095-2012; Bortolozzi, Roberta/D-4950-2015; CASTAGLIUOLO, IGNAZIO/K-9963-2016; OI Moro, Stefano/0000-0002-7514-3802; Viola, Giampietro/0000-0001-9329-165X; Bortolozzi, Roberta/0000-0002-3357-4815; CASTAGLIUOLO, IGNAZIO/0000-0001-9888-7030; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Intramural NIH HHS [Z99 CA999999] NR 51 TC 53 Z9 53 U1 2 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JAN 1 PY 2012 VL 83 IS 1 BP 16 EP 26 DI 10.1016/j.bcp.2011.09.017 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856QP UT WOS:000297658800003 PM 21964343 ER PT J AU Schwaninger, AE Meyer, MR Barnes, AJ Kolbrich-Spargo, EA Gorelick, DA Goodwin, RS Huestis, MA Maurer, HH AF Schwaninger, Andrea E. Meyer, Markus R. Barnes, Allan J. Kolbrich-Spargo, Erin A. Gorelick, David A. Goodwin, Robert S. Huestis, Marilyn A. Maurer, Hans H. TI Stereoselective urinary MDMA (ecstasy) and metabolites excretion kinetics following controlled MDMA administration to humans SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE MDMA; Phase I metabolites; Phase II metabolites; Urine; Chiral; Controlled administration ID MASS-SPECTROMETRIC ASSAY; GC-NICI-MS; DESIGNER DRUGS; MAIN METABOLITES; 3,4-METHYLENEDIOXYMETHAMPHETAMINE ECSTASY; STEREOCHEMICAL ANALYSIS; PHASE-I; AMPHETAMINE; ENANTIOMERS; TOXICOLOGY AB The R- and S-enantiomers of racemic 3,4-methylenedioxymethamphetamine (MDMA) exhibit different dose-concentration curves. In plasma, S-MDMA was eliminated at a higher rate, most likely due to stereoselective metabolism. Similar data were shown in various in vitro experiments. The aim of the present study was the in vivo investigation of stereoselective elimination of MDMA's phase I and phase II metabolites in human urine following controlled oral MDMA administration. Urine samples from 10 participants receiving 1.0 and 1.6 mg/kg MDMA separated by at least one week were analyzed blind by liquid chromatography-high resolution-mass spectrometry and gas chromatography-mass spectrometry after chiral derivatization with S-heptafluorobutyrylprolyl chloride. R/S ratios at C(max) were comparable after low and high doses with ratios >1 for MDMA, free DHMA, and HMMA sulfate, and with ratios <1 for MDA, free HMMA, DHMA sulfate and HMMA glucuronide. In the five days after the high MDMA dose, a median of 21% of all evaluated compounds were excreted as R-stereoisomers and 17% as S-stereoisomers. Significantly greater MDMA, DHMA, and HMMA sulfate R-enantiomers and HMMA and HMMA glucuronide S-stereoisomers were excreted. No significant differences were observed for MDA and DHMA sulfate stereoisomers. Changes in R/S ratios could be observed over time for all analytes, with steady increases in the first 48 h. R/S ratios could help to roughly estimate time of MDMA ingestion and therefore, improve interpretation of MDMA and metabolite urinary concentrations in clinical and forensic toxicology. (C) 2011 Elsevier Inc. All rights reserved. C1 [Schwaninger, Andrea E.; Meyer, Markus R.; Maurer, Hans H.] Univ Saarland, Dept Expt & Clin Toxicol, Inst Expt & Clin Pharmacol & Toxicol, D-66421 Homburg, Saar, Germany. [Barnes, Allan J.; Kolbrich-Spargo, Erin A.; Gorelick, David A.; Goodwin, Robert S.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kolbrich-Spargo, Erin A.] SW Inst Forens Sci, Dallas, TX USA. RP Maurer, HH (reprint author), Univ Saarland, Dept Expt & Clin Toxicol, Inst Expt & Clin Pharmacol & Toxicol, D-66421 Homburg, Saar, Germany. EM hans.maurer@uks.eu RI Meyer, Markus/B-9293-2009; OI Steuer, Andrea Eva/0000-0001-8983-2353 FU Thermo Fisher; HOMFOR; Medical Faculty, Saarland University, Homburg; National Institutes of Health, National Institute on Drug Abuse FX The authors would like to thank Carsten Schroder, Armin Weber, and Gabriele Ulrich from the Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University and Frank T. Peters from Schiller University Jena for their assistance and helpful discussions and Thermo Fisher for their support. Funding was provided by HOMFOR 2010, the research fund of the Medical Faculty, Saarland University, Homburg and the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse. NR 36 TC 10 Z9 10 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JAN 1 PY 2012 VL 83 IS 1 BP 131 EP 138 DI 10.1016/j.bcp.2011.09.023 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856QP UT WOS:000297658800015 PM 21983032 ER PT J AU Singh, UP Singh, NP Singh, B Hofseth, LJ Taub, DD Price, RL Nagarkatti, M Nagarkatti, PS AF Singh, Udai P. Singh, Narendra P. Singh, Balwan Hofseth, Lorne J. Taub, Dennis D. Price, Robert L. Nagarkatti, Mitzi Nagarkatti, Prakash S. TI Role of resveratrol-induced CD11b(+) Gr-1(+) myeloid derived suppressor cells (MDSCs) in the reduction of CXCR3(+) T cells and amelioration of chronic colitis in IL-10(-/-) mice SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Inflammation; Resveratrol; Colitis; CXCR3; CD11b(+) and Gr-1(+); MDSCs ID INFLAMMATORY-BOWEL-DISEASE; IMMUNE-RESPONSES; CHEMOKINE RECEPTORS; CROHNS-DISEASE; EXPRESSION; CANCER; ACTIVATION; MECHANISMS; INDUCTION; TOLERANCE AB Resveratrol, a naturally occurring polyphenol has received significant attention as a potent anti-inflammatory agent. Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce proinflammatory cytokines. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population characterized by the co-expression of CD11b(+) and Gr-1(+) and have long been known for their immunosuppressive function. We report that resveratrol effectively attenuated overall clinical scores as well as various pathological markers of colitis in IL-10(-/-) mice by down regulating Th1 responses. Resveratrol lessened the colitis-associated decrease in body weight and increased levels of serum amyloid A (SAA), CXCL10 and colon TNF-alpha, IL-6, RANTES, IL-12 and IL-beta concentrations. After resveratrol treatment, the percentage of CXCR3 expressing T cells was decreased in the spleen, mesenteric lymph nodes (MLN), and intestinal lamina propria (LP). However, the percentage and absolute numbers of CD11b(+) and Gr-1(+) cells in the lamina propria (LP) and spleen were increased after resveratrol treatment as compared with the vehicle treatment. Co-culture of resveratrol-induced CD11b(+) Gr-1(+) cells with T cells, attenuated T cell proliferation, and most importantly reduced IFN-gamma and GM-CSF production by LP derived T cells from vehicle treated IL-10(-/-) mice with chronic colitis. The current study suggests that administration of resveratrol into IL-10(-/-) mice induces immunosuppressive CD11b(+) Gr-1(+). MDSCs in the colon, which correlates with reversal of established chronic colitis, and down regulation of mucosal and systemic CXCR3(+) expressing effector T cells as well as inflammatory cytokines in the colon. The induction of immunosuppressive CD11b(+) Gr-1(+) cells by resveratrol during colitis is unique, and suggests an as-yet-unidentified mode of anti-inflammatory action of this plant polyphenol. Published by Elsevier Inc. C1 [Singh, Udai P.; Singh, Narendra P.; Nagarkatti, Mitzi; Nagarkatti, Prakash S.] Univ S Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA. [Singh, Balwan] Emory Univ, Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Hofseth, Lorne J.] Univ S Carolina, Dept Pharmaceut & Biomed Sci, S Carolina Coll Pharm, Columbia, SC 29208 USA. [Taub, Dennis D.] NIA IRP, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Price, Robert L.] Univ S Carolina, Dept Cell & Dev Biol, Columbia, SC 29208 USA. RP Nagarkatti, PS (reprint author), Univ S Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA. EM Prakash.Nagarkatti@uscmed.sc.edu FU NIH [ES09098, ES019313, P01AT003961]; NIA, NIH FX This study was supported in part by grants from NIH ES09098, ES019313, P01AT003961 and the Intramural Research Program, NIA, NIH. NR 52 TC 25 Z9 27 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD JAN PY 2012 VL 26 IS 1 BP 72 EP 82 DI 10.1016/j.bbi.2011.07.236 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 855AC UT WOS:000297534900010 PM 21807089 ER PT J AU Chuang, SC Jenab, M Heck, JE Bosetti, C Talamini, R Matsuo, K Castellsague, X Franceschi, S Herrero, R Winn, DM La Vecchia, C Morgenstern, H Zhang, ZF Levi, F Dal Maso, L Kelsey, K McClean, MD Vaughan, T Lazarus, P Muscat, J Ramroth, H Chen, C Schwartz, SM Eluf-Neto, J Hayes, RB Purdue, M Boccia, S Cadoni, G Zaridze, D Koifman, S Curado, MP Ahrens, W Benhamou, S Matos, E Lagiou, P Szeszenia-Dabrowska, N Olshan, AF Fernandez, L Menezes, A Agudo, A Daudt, AW Merletti, F Macfarlane, GJ Kjaerheim, K Mates, D Holcatova, I Schantz, S Yu, GP Simonato, L Brenner, H Mueller, H Conway, DI Thomson, P Fabianova, E Znaor, A Rudnai, P Healy, CM Ferro, G Brennan, P Boffetta, P Hashibe, M AF Chuang, Shu-Chun Jenab, Mazda Heck, Julia E. Bosetti, Cristina Talamini, Renato Matsuo, Keitaro Castellsague, Xavier Franceschi, Silvia Herrero, Rolando Winn, Deborah M. La Vecchia, Carlo Morgenstern, Hal Zhang, Zuo-Feng Levi, Fabio Dal Maso, Luigino Kelsey, Karl McClean, Michael D. Vaughan, Thomas Lazarus, Philip Muscat, Joshua Ramroth, Heribert Chen, Chu Schwartz, Stephen M. Eluf-Neto, Jose Hayes, Richard B. Purdue, Mark Boccia, Stefania Cadoni, Gabriella Zaridze, David Koifman, Sergio Curado, Maria Paula Ahrens, Wolfgang Benhamou, Simone Matos, Elena Lagiou, Pagona Szeszenia-Dabrowska, Neonilla Olshan, Andrew F. Fernandez, Leticia Menezes, Ana Agudo, Antonio Daudt, Alexander W. Merletti, Franco Macfarlane, Gary J. Kjaerheim, Kristina Mates, Dana Holcatova, Ivana Schantz, Stimson Yu, Guo-Pei Simonato, Lorenzo Brenner, Hermann Mueller, Heiko Conway, David I. Thomson, Peter Fabianova, Eleonora Znaor, Ariana Rudnai, Peter Healy, Claire M. Ferro, Gilles Brennan, Paul Boffetta, Paolo Hashibe, Mia TI Diet and the risk of head and neck cancer: a pooled analysis in the INHANCE consortium SO CANCER CAUSES & CONTROL LA English DT Article DE Diet; Head and neck cancer; Fruit and vegetable; Red meat; Processed meat ID UPPER-AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMA; RED MEAT INTAKE; PHARYNGEAL CANCER; INTERNATIONAL HEAD; LARYNGEAL-CANCER; ORAL-CANCER; EPIDEMIOLOGY CONSORTIUM; FOOD GROUPS; SEXUAL PRACTICES AB We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97). C1 [Hashibe, Mia] Univ Utah, Sch Med, Div Publ Hlth, Dept Family & Prevent Med,Huntsman Canc Inst, Salt Lake City, UT 84108 USA. [Chuang, Shu-Chun] Univ London Imperial Coll Sci Technol & Med, London, England. [Chuang, Shu-Chun; Jenab, Mazda; Franceschi, Silvia; Curado, Maria Paula; Ferro, Gilles; Brennan, Paul; Hashibe, Mia] Int Agcy Res Canc, F-69372 Lyon, France. [Heck, Julia E.; Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Bosetti, Cristina; La Vecchia, Carlo] Ist Ric Farmacol Mario Negri, Milan, Italy. [Talamini, Renato; Dal Maso, Luigino] Aviano Canc Ctr, I-33081 Aviano, Italy. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Nagoya, Aichi 464, Japan. [Castellsague, Xavier] Inst Catala Oncol, Barcelona, Spain. [Herrero, Rolando] Inst Invest Epidemiol, San Jose, Costa Rica. [Winn, Deborah M.; Purdue, Mark] NCI, Bethesda, MD USA. [La Vecchia, Carlo] Univ Milan, Dept Occupat Hlth, Milan, Italy. [Morgenstern, Hal] Univ Michigan, Dept Epidemiol & Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Levi, Fabio] Inst Univ Med Sociale & Prevent, CH-1005 Lausanne, Switzerland. [Kelsey, Karl] Brown Univ, Providence, RI 02912 USA. [McClean, Michael D.] Boston Univ Publ Hlth, Boston, MA USA. [Vaughan, Thomas; Chen, Chu; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Lazarus, Philip; Muscat, Joshua] Pen State Coll Med, Philadelphia, PA USA. [Ramroth, Heribert] Univ Heidelberg, Heidelberg, Germany. [Eluf-Neto, Jose] Univ Sao Paulo, Dept Prevent Med, Sao Paulo, Brazil. [Hayes, Richard B.] NYU, Sch Med, New York, NY USA. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Inst Hyg, Rome, Italy. [Boccia, Stefania] IRCCS San Raffaele Pisana, Rome, Italy. [Cadoni, Gabriella] Univ Cattolica Sacro Cuore, Inst Otorhinolaryngol, I-00168 Rome, Italy. [Zaridze, David] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Koifman, Sergio] Escola Nacl Saude Publica, Rio De Janeiro, Brazil. [Ahrens, Wolfgang] Bermen Inst Prevent Res & Social Med, Bermen, Germany. [Benhamou, Simone] INSERM, Paris, France. [Matos, Elena] Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Lagiou, Pagona] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Szeszenia-Dabrowska, Neonilla] Inst Occupat Med, Lodz, Poland. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Fernandez, Leticia] Inst Oncol & Radiol, Havana, Cuba. [Menezes, Ana] Univ Fed Pelotas, Fac Med, Pelotas, Brazil. [Agudo, Antonio] Hosp Llobregat, Catalan Inst Oncol ICO, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain. [Daudt, Alexander W.] Hosp Clin Porto Allegre, Porto Alegre, RS, Brazil. [Merletti, Franco] Canc Epidemiol Unit, Turin, Italy. [Macfarlane, Gary J.] Univ Aberdeen, Sch Med & Dent, Aberdeen AB9 1FX, Scotland. [Kjaerheim, Kristina] Canc Registry Norway, Oslo, Norway. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Holcatova, Ivana] Inst Hyg & Epidemiol, CR-10042 Prague, Czech Republic. [Schantz, Stimson; Yu, Guo-Pei] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Simonato, Lorenzo] Univ Padua, Sch Med, Dept Environm Med & Publ Hlth, Padua, Italy. [Brenner, Hermann; Mueller, Heiko] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Conway, David I.] Univ Glasgow, Sch Dent, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland. [Thomson, Peter] Univ Newcastle, Sch Dent, Newcastle, NSW 2300, Australia. [Fabianova, Eleonora] Specialized State Hlth Inst, Banska Bystrica, Slovakia. [Znaor, Ariana] Croatian Natl Canc Registry, Zagreb, Croatia. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Healy, Claire M.] Trinity Coll Dublin, Sch Dent Sci, Dublin, Ireland. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Hashibe, M (reprint author), Univ Utah, Sch Med, Div Publ Hlth, Dept Family & Prevent Med,Huntsman Canc Inst, 375 Chipeta Way,Suite A, Salt Lake City, UT 84108 USA. EM Mia.Hashibe@utah.edu RI Brenner, Hermann/B-4627-2017; Curado, Maria Paula/M-6200-2013; Thomson, Peter/L-7719-2016; Inca, Inct/K-2204-2013; Zaridze, David/K-5605-2013; Heck, Julia/B-5230-2009; Agudo, Antonio/J-1805-2016; Benhamou, Simone/K-6554-2015; Epidemiologicas, Centro de pesquisas /D-4561-2013; Chuang, Shu-Chun/N-3358-2013; Menezes, Ana/G-7266-2012; Macfarlane, Gary/I-9521-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; McClean, Michael/J-2934-2015; Castellsague Pique, Xavier/N-5795-2014; Eluf-Neto, Jose/B-2522-2009 OI Hayes, Richard/0000-0002-0918-661X; Schwartz, Stephen/0000-0001-7499-8502; Healy, Claire M/0000-0001-7940-4611; Matsuo, Keitaro/0000-0003-1761-6314; Ahrens, Wolfgang/0000-0003-3777-570X; Brenner, Hermann/0000-0002-6129-1572; Curado, Maria Paula/0000-0001-8172-2483; McClean, Michael/0000-0002-3902-8823; Agudo, Antonio/0000-0001-9900-5677; mates, dana/0000-0002-6219-9807; dal maso, luigino/0000-0001-6163-200X; Thomson, Peter/0000-0002-2007-7975; La Vecchia, Carlo/0000-0003-1441-897X; Kjaerheim, Kristina/0000-0003-0691-3735; Heck, Julia/0000-0001-8713-8413; Macfarlane, Gary/0000-0003-2322-3314; Castellsague Pique, Xavier/0000-0002-0802-3595; Eluf-Neto, Jose/0000-0001-7504-2115 FU International Agency for Research on Cancer; US National Institutes of Health (NIH), National Cancer Institute (NCI) [R03CA113157]; National Institute for Dental and Craniofacial Research (NIDCR) [R03DE016611]; Italian Association for Research on Cancer (AIRC); Italian League against Cancer; Italian Ministry of Research; Swiss League against Cancer [KFS1069-09-2000]; Fribourg League against Cancer [FOR381.88]; Swiss Cancer Research [AKT 617]; Gustave-Roussy Institute [88D28]; Swiss Research against Cancer/Oncosuisse [KFS-700, OCS-1633]; World Cancer Research Fund; European Commission [IC15-CT98-0332, IC18-CT97-0222, QLK1-2001-00182]; National Institutes of Health (NIH) US [R01CA048996, R01DE012609, R01CA61188, P01CA068384, K07CA104231, R01DE13158, P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667, R01CA078609, R01CA100679]; National Institute of Environmental Health Sciences [P30ES010126]; UCLA Jonsson Comprehensive Cancer Center; National Institutes of Health (NCI) US; NIDCR; Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina; IMIM (Barcelona); Fundacao de Amparo a Pesquisa no. Estado de Sao Paulo (FAPESP) [01/01768-2]; Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013]; International Union Against Cancer (UICC); Yamagiwa-Yoshida Memorial International Cancer Study Grant; AIRC (Italian Agency for Research on Cancer); National Cancer Institute, National Institutes of Health, USA; NIH [R01CA51845, R01CA30022]; Italian Association for Cancer Research; Compagnia di San Paolo/FIRMS; Region Piemonte; Padova University [CPDA057222]; Ministry of Science, Research and Arts Baden-Wurttemberg; German Ministry of Education and Research [01GB9702/3]; Ministry of Education, Science, Sports, Culture and Technology of Japan [17015052]; Ministry of Health, Labor and Welfare of Japan [H20-002] FX Shu-Chun Chuang worked on this study during the tenure of a Special Training Award from the International Agency for Research on Cancer. This INHANCE Consortium was supported by a grant from the US National Institutes of Health (NIH), National Cancer Institute (NCI), (R03CA113157) and National Institute for Dental and Craniofacial Research (NIDCR; R03DE016611). The individual studies were funded by the following grants: Milan study: Italian Association for Research on Cancer (AIRC). Aviano: Italian Association for Research on Cancer (AIRC), Italian League against Cancer and Italian Ministry of Research. France study: Swiss League against Cancer (KFS1069-09-2000), Fribourg League against Cancer (FOR381.88), Swiss Cancer Research (AKT 617), and Gustave-Roussy Institute (88D28). Italy Multicenter study: Italian Association for Research on Cancer (AIRC), Italian League against Cancer and Italian Ministry of Research. Swiss study: Swiss League against Cancer and the Swiss Research against Cancer/Oncosuisse (KFS-700, OCS-1633). Central Europe study: World Cancer Research Fund and the European Commission's INCO-COPERNICUS Program (Contract No. IC15-CT98-0332). Seattle study: National Institutes of Health (NIH) US (R01CA048996, R01DE012609). North Carolina study: National Institutes of Health (NIH) US (R01CA61188), and in part by a grant from the National Institute of Environmental Health Sciences (P30ES010126). Tampa study: National Institutes of Health (NIH) US (P01CA068384, K07CA104231, R01DE13158). Los Angeles study: National Institute of Health (NIH) US (P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667) and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center. Puerto Rico study: jointly funded by National Institutes of Health (NCI) US and NIDCR intramural programs. Latin America study: Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina, IMIM (Barcelona), Fundacao de Amparo a Pesquisa no. Estado de Sao Paulo (FAPESP) (No 01/01768-2), and European Commission (IC18-CT97-0222). IARC Multicenter study: Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government (FIS 97/0024, FIS 97/0662, BAE 01/5013), International Union Against Cancer (UICC), and Yamagiwa-Yoshida Memorial International Cancer Study Grant. Boston study: National Institutes of Health (NIH) US (R01CA078609, R01CA100679). Rome study: AIRC (Italian Agency for Research on Cancer). US Multicenter study: The Intramural Program of the National Cancer Institute, National Institutes of Health, USA. MSKCC study: NIH (R01CA51845). Seattle-LEO study: NIH(R01CA30022). Western Europe Study: European Commission's 5th Framework Program (Contract No. QLK1-2001-00182), Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (Contract No. CPDA057222). Saarland study: Ministry of Science, Research and Arts Baden-Wurttemberg. Heidelberg study: Grant No. 01GB9702/3 from the German Ministry of Education and Research. Japan study: Scientific Research grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan (17015052) and grant for the Third-Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan (H20-002). NR 70 TC 35 Z9 35 U1 2 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JAN PY 2012 VL 23 IS 1 BP 69 EP 88 DI 10.1007/s10552-011-9857-x PG 20 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 857XG UT WOS:000297757400008 PM 22037906 ER PT J AU Toledo, RA Sekiya, T Horvath, A Faucz, F Fragoso, MCBV Longuini, VC Lourenco, DM Toledo, SPA Stratakis, CA AF Toledo, Rodrigo A. Sekiya, Tomoko Horvath, Anelia Faucz, Fabio Fragoso, Maria C. B. V. Longuini, Viviane C. Lourenco, Delmar M., Jr. Toledo, Sergio P. A. Stratakis, Constantine A. TI Assessing the emerging oncogene protein kinase C epsilon as a candidate gene in families with Carney complex-2 SO CLINICAL ENDOCRINOLOGY LA English DT Letter ID TUMORS C1 [Toledo, Rodrigo A.; Sekiya, Tomoko; Faucz, Fabio; Longuini, Viviane C.; Lourenco, Delmar M., Jr.; Toledo, Sergio P. A.] Univ Sao Paulo, Sch Med, Dept Endocrinol, Endocrine Genet Unit LIM 25, Sao Paulo, Brazil. [Horvath, Anelia; Stratakis, Constantine A.] NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Fragoso, Maria C. B. V.] Univ Sao Paulo, Dept Endocrinol, Adrenal Unit LIM42, Sch Med, Sao Paulo, Brazil. RP Toledo, RA (reprint author), Univ Sao Paulo, Sch Med, Dept Endocrinol, Endocrine Genet Unit LIM 25, Sao Paulo, Brazil. EM toledorodrigo@usp.br RI Lourenco , Delmar/B-8832-2012; Fragoso, Maria Candida/I-4572-2013; Toledo, Rodrigo/N-4078-2013 OI Toledo, Rodrigo/0000-0003-3070-6795 NR 5 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JAN PY 2012 VL 76 IS 1 BP 147 EP 148 DI 10.1111/j.1365-2265.2011.04144.x PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 857SN UT WOS:000297739700023 PM 21649687 ER PT J AU Budde, MD Gold, E Jordan, EK Frank, JA AF Budde, Matthew D. Gold, Eric Jordan, E. Kay Frank, Joseph A. TI Differential microstructure and physiology of brain and bone metastases in a rat breast cancer model by diffusion and dynamic contrast enhanced MRI SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Magnetic resonance imaging; Apparent diffusion coefficient; Brain metastasis; Vessel co-option; Dynamic contrast enhancement; Breast cancer; Biomarker ID PHASE-II TRIAL; IN-VIVO; IMAGING BIOMARKER; TREATMENT RESPONSE; TUMOR PROGRESSION; PROSTATE-CANCER; MOUSE MODEL; GROWTH; GLUTAMATE; CELLS AB Pharmacological approaches to treat breast cancer metastases in the brain have been met with limited success. In part, the impermeability of the blood brain barrier (BBB) has hindered delivery of chemotherapeutic agents to metastatic tumors in the brain. BBB-permeable chemotherapeutic drugs are being developed, and noninvasively assessing the efficacy of these agents will be important in both preclinical and clinical settings. In this regard, dynamic contrast enhanced (DCE) and diffusion weighted imaging (DWI) are magnetic resonance imaging (MRI) techniques to monitor tumor vascular permeability and cellularity, respectively. In a rat model of metastatic breast cancer, we demonstrate that brain and bone metastases develop with distinct physiological characteristics as measured with MRI. Specifically, brain metastases have limited permeability of the BBB as assessed with DCE and an increased apparent diffusion coefficient (ADC) measured with DWI compared to the surrounding brain. Microscopically, brain metastases were highly infiltrative, grew through vessel co-option, and caused extensive edema and injury to the surrounding neurons and their dendrites. By comparison, metastases situated in the leptomenengies or in the bone had high vascular permeability and significantly lower ADC values suggestive of hypercellularity. On histological examination, tumors in the bone and leptomenengies were solid masses with distinct tumor margins. The different characteristics of these tissue sites highlight the influence of the microenvironment on metastatic tumor growth. In light of these results, the suitability of DWI and DCE to evaluate the response of chemotherapeutic and anti-angiogenic agents used to treat co-opted brain metastases, respectively, remains a formidable challenge. C1 [Budde, Matthew D.; Gold, Eric; Jordan, E. Kay; Frank, Joseph A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Budde, MD (reprint author), NIH, Ctr Clin, 9000 Rockville Pike,Bldg 10,B1N256, Bethesda, MD 20892 USA. EM buddem@mail.nih.gov FU Clinical Center at the National Institutes of Health FX This study was supported by the Intramural Research Program of the Clinical Center at the National Institutes of Health. We thank Molly Resnick for assistance with data analysis. NR 56 TC 13 Z9 13 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD JAN PY 2012 VL 29 IS 1 BP 51 EP 62 DI 10.1007/s10585-011-9428-2 PG 12 WC Oncology SC Oncology GA 859BD UT WOS:000297848200006 PM 22042553 ER PT J AU Rees, MG Wincovitch, S Schultz, J Waterstradt, R Beer, NL Baltrusch, S Collins, FS Gloyn, AL AF Rees, M. G. Wincovitch, S. Schultz, J. Waterstradt, R. Beer, N. L. Baltrusch, S. Collins, F. S. Gloyn, A. L. TI Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk SO DIABETOLOGIA LA English DT Article DE Association study; Genetics; Glucokinase; Molecular mechanism ID GLUCOKINASE REGULATORY PROTEIN; RAT PRIMARY HEPATOCYTES; FRUCTOSE 1-PHOSPHATE; LIVER GLUCOKINASE; NUCLEAR EXPORT; IMAGE-ANALYSIS; GLUCOSE; LOCI; TRANSLOCATION; TRIGLYCERIDE AB Translation of genetic association signals into molecular mechanisms for diabetes has been slow. The glucokinase regulatory protein (GKRP; gene symbol GCKR) P446L variant, associated with inverse modulation of glucose- and lipid-related traits, has been shown to alter the kinetics of glucokinase (GCK) inhibition. As GCK inhibition is associated with nuclear sequestration, we aimed to determine whether this variant also alters the direct interaction between GKRP and GCK and their intracellular localisation. Fluorescently tagged rat and human wild-type (WT)- or P446L-GCKR and GCK were transiently transfected into HeLa cells and mouse primary hepatocytes. Whole-cell and nuclear fluorescence was quantified in individual cells exposed to low- or high-glucose conditions (5.5 or 25 mmol/l glucose, respectively). Interaction between GCK and GKRP was measured by sensitised emission-based fluorescence resonance energy transfer (FRET) efficiency. P446L-GKRP had a decreased degree of nuclear localisation, ability to sequester GCK and direct interaction with GCK as measured by FRET compared with WT-GKRP. Decreased interaction was observed between WT-GKRP and GCK at high compared with low glucose, but not between P446L-GKRP and GCK. Rat WT-GKRP and P446L-GKRP behaved quite differently: both variants responded to high glucose by diminished sequestration of GCK but showed no effect of the P446L variant on nuclear localisation or GCK sequestration. Our study suggests the common human P446L-GKRP variant protein results in elevated hepatic glucose uptake and disposal by increasing active cytosolic GCK. This would increase hepatic lipid biosynthesis but decrease fasting plasma glucose concentrations and provides a potential mechanism for the protective effect of this allele on type 2 diabetes risk. C1 [Rees, M. G.; Beer, N. L.; Gloyn, A. L.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Rees, M. G.; Wincovitch, S.; Collins, F. S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Schultz, J.; Waterstradt, R.; Baltrusch, S.] Univ Rostock, Inst Med Biochem & Mol Biol, Rostock, Germany. RP Gloyn, AL (reprint author), Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, S Parks Rd, Oxford OX3 7LJ, England. EM anna.gloyn@drl.ox.ac.uk FU NIH Division of Intramural Research; NHGRI [Z01-HG000024]; Oxford by the Medical Research Council [81696]; Wellcome Trust [095101/Z/10/Z]; German Diabetes Association (DDG) FX This study was supported by the NIH Division of Intramural Research and NHGRI project number Z01-HG000024 (F.S. Collins). This study was funded in Oxford by the Medical Research Council (81696) and the Wellcome Trust (095101/Z/10/Z). A.L. Gloyn is a Wellcome Trust Senior Research Fellow in Basic and Biomedical Science. This study was funded in Rostock by the German Diabetes Association (DDG). NR 29 TC 42 Z9 43 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JAN PY 2012 VL 55 IS 1 BP 114 EP 122 DI 10.1007/s00125-011-2348-5 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 857SI UT WOS:000297739000018 PM 22038520 ER PT J AU Peluso, M Munnia, A Piro, S Jedpiyawongse, A Sangrajrang, S Giese, RW Ceppi, M Boffetta, P Srivatanakul, P AF Peluso, Marco Munnia, Armelle Piro, Sara Jedpiyawongse, Adisorn Sangrajrang, Suleeporn Giese, Roger W. Ceppi, Marcello Boffetta, Paolo Srivatanakul, Petcharin TI Fruit and vegetable and fried food consumption and 3-(2-deoxy-beta-D-erythro-pentafuranosyl)pyrimido[1,2-alpha] purin-10(3H)-one deoxyguanosine adduct formation SO FREE RADICAL RESEARCH LA English DT Review DE fruit and vegetables; fried food; free radicals; oxidative stress; lipid peroxidation; M(1)dG ID MALONDIALDEHYDE-DNA-ADDUCTS; OXIDATIVE DAMAGE; DIETARY-INTAKE; BETA-CAROTENE; IN-VITRO; THAILAND; CELLS; BIOMARKERS; CANCER; PLANTS AB Diet has been shown to modulate M(1)dG adduct, a biomarker of oxidative stress and lipid peroxidation. Thus, we analysed the association between diet and M(1)dG in 120 controls and 67 Map Ta Phut industrial estate workers in Rayong, Thailand, to evaluate the influence of fruit and vegetables, and fried and charcoal-grilled/barbecued food consumption on M(1)dG. M(1)dG was decreased in controls reporting to consume 14-17 servings/week of fruit and vegetables (mean ratio [MR] = 0.35, CI 0.18-0.69, p < 0.05). Conversely, a non-statistically significant M(1)dG increment was detected in controls consuming 9-18 servings/week of fried food (MR = 1.33, CI 0.88-2.00, p = 0.168). No effect of charcoal-grilled/barbecued food was found. No effect of diet was observed in workers. An association with smoking was observed in controls (MR = 1.88, CI 1.14-3.10, p < 0.05), but not in workers. M(1)dG can induce mutations and/or methylation changes within the promoter regions of cancer-related genes, thus promotion of healthy eating practices should be recommended. C1 [Peluso, Marco] ISPO Canc Prevent & Res Inst, Analyt & Biomol Cytol Unit, Canc Risk Factor Branch, I-50139 Florence, Italy. [Jedpiyawongse, Adisorn; Sangrajrang, Suleeporn; Srivatanakul, Petcharin] Natl Canc Inst, Div Res, Mol Epidemiol Unit, Bangkok, Thailand. [Giese, Roger W.] Northeastern Univ, Barnett Inst, Bouve Coll Hlth Sci, Dept Pharmaceut Sci, Boston, MA 02115 USA. [Ceppi, Marcello] Natl Canc Inst, Mol Epidemiol Unit, Genoa, Italy. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Peluso, M (reprint author), ISPO Canc Prevent & Res Inst, Analyt & Biomol Cytol Unit, Canc Risk Factor Branch, Via Cosimo il Vecchio 2, I-50139 Florence, Italy. EM m.peluso@ispo.toscana.it OI PIRO, SARA/0000-0003-4198-7035 FU NCI, Bangkok, Thailand; 'Associazione Italiana per la Ricerca sul Cancro', Milan, Italy; NIEHS [P42ES017198] FX This project was supported by the NCI, Bangkok, Thailand, and, in part, by the 'Associazione Italiana per la Ricerca sul Cancro', Milan, Italy and by Award Number P42ES017198 from NIEHS. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. NR 39 TC 7 Z9 7 U1 2 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1071-5762 J9 FREE RADICAL RES JI Free Radic. Res. PD JAN PY 2012 VL 46 IS 1 BP 85 EP 92 DI 10.3109/10715762.2011.640676 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 858PV UT WOS:000297814900011 PM 22081860 ER PT J AU Tasevska, N Jiao, L Cross, AJ Kipnis, V Subar, AF Hollenbeck, A Schatzkin, A Potischman, N AF Tasevska, Natasa Jiao, Li Cross, Amanda J. Kipnis, Victor Subar, Amy F. Hollenbeck, Albert Schatzkin, Arthur Potischman, Nancy TI Sugars in diet and risk of cancer in the NIH-AARP Diet and Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE sugars; added sugars; diet; cancer; AARP study ID MILK EXTRINSIC SUGARS; GROWTH-FACTOR-I; GLYCEMIC LOAD; PANCREATIC-CANCER; COLORECTAL-CANCER; PROSPECTIVE COHORT; UNITED-STATES; NATIONAL-INSTITUTES; CARBOHYDRATE INTAKE; MULTIETHNIC COHORT AB Prospective epidemiologic data on the effects of different types of dietary sugars on cancer incidence have been limited. In this report, we investigated the association of total sugars, sucrose, fructose, added sugars, added sucrose and added fructose in the diet with risk of 24 malignancies. Participants (n = 435,674) aged 50-71 years from the NIH-AARP Diet and Health Study were followed for 7.2 years. The intake of individual sugars was assessed using a 124-item food frequency questionnaire (FFQ). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariable models adjusted for confounding factors pertinent to individual cancers. We identified 29,099 cancer cases in men and 13,355 cases in women. In gender-combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma (HRQ5 vs. Q1 : 1.62, 95% CI: 1.07-2.45; p(trend) = 0.01), added fructose was associated with risk of small intestine cancer (HRQ5 vs. Q1 : 2.20, 95% CI: 1.16-4.16; p(trend) = 0.009) and all investigated sugars were associated with increased risk of pleural cancer. In women, all investigated sugars were inversely associated with ovarian cancer. We found no association between dietary sugars and risk of colorectal or any other major cancer. Measurement error in FFQ-reported dietary sugars may have limited our ability to obtain more conclusive findings. Statistically significant associations observed for the rare cancers are of interest and warrant further investigation. C1 [Tasevska, Natasa; Subar, Amy F.; Potischman, Nancy] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Tasevska, Natasa; Jiao, Li; Cross, Amanda J.; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kipnis, Victor] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Hollenbeck, Albert] Amer Assoc Retired Persons, Washington, DC USA. RP Tasevska, N (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 3121, Bethesda, MD 20892 USA. EM tasevskan@gmail.com FU Intramural NIH HHS [ZIA CP010196-05] NR 50 TC 24 Z9 26 U1 8 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 1 PY 2012 VL 130 IS 1 BP 159 EP 169 DI 10.1002/ijc.25990 PG 11 WC Oncology SC Oncology GA 859CG UT WOS:000297851300017 PM 21328345 ER PT J AU Day, CP Carter, J Bonomi, C Hollingshead, M Merlino, G AF Day, Chi-Ping Carter, John Bonomi, Carrie Hollingshead, Melinda Merlino, Glenn TI Preclinical therapeutic response of residual metastatic disease is distinct from its primary tumor of origin SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE metastasis; recurrence; preclinical model; adjuvant chemotherapy; cell labeling; bioluminescence; luciferase; disease-free survival; overall survival; growth kinetics ID CELL LUNG-CANCER; SURROGATE END-POINT; IN-VIVO; FLUORESCENT-PROTEIN; BREAST-CANCER; SOLID TUMORS; COLON-CANCER; NUDE-MICE; MODELS; CHEMOTHERAPY AB Cancer-related deaths are caused principally by recurrence and metastasis arising from residual disease, whose therapeutic responses has been suggested to be substantially different from primary tumors. However, experimental animal models designed for evaluating the therapeutic responses of residual disease are mostly lacking. To overcome this deficiency, we have developed a preclinical model that recapitulates the progression for advanced nonsmall cell lung cancer (NSCLC). An archived Lewis lung carcinoma mouse tumor, propagated only through serial in vivo transplantation and never adapted to cell culture, was stably labeled using lentivirus-encoded biomarkers, consistently expressed through an RNA polymerase II promoter. Labeled tumors were inoculated into syngeneic immunocompetent mice to ensure superior tumor-host interactions. Primary tumors were resected on reaching a predetermined size, followed by treatment in a setting akin to postsurgical first-line adjuvant chemotherapy and routine imaging to monitor the progression of pulmonary metastasis. We discovered that efficacious treatment, instead of reducing disease growth rates, significantly prolonged disease-free survival and overall survival. As in the clinic, cisplatin-based regimes were more effective in this model. However, the response of metastases to specific agents could not be predicted from, and often opposed, their effects on subcutaneous "primary" tumors, possibly due to their distinct growth kinetics and host interactions. We here introduce a clinically relevant model of residual metastatic disease that may more accurately predict the therapeutic response of recurrent, metastatic disease. C1 [Day, Chi-Ping; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Carter, John; Bonomi, Carrie] NCI, Dev Therapeut Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Hollingshead, Melinda] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Merlino, G (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bldg 37,Room 5002,37 Convent Dr, Bethesda, MD 20892 USA. EM hollingm@mail.nih.gov; gmerlino@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NCI FX This study is a US government work supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.. C-PD is a recipient of the 2007 NCI Director's Innovation Award. The authors wish to thank Drs. Chand Khanna (Pediatric Oncology Branch, NCI, NIH), Elise Kohn and Phillip Dennis (Medical Oncology Branch, NCI, NIH) for useful discussions and Drs. Betty Conde-Ortiz and Dominic Esposito (Advanced Technology Program, NCI-Frederick) for producing lentiviral vectors. The authors also thank Drs. Josh Webster and Mark Simpson (Laboratory of Cancer Biology and Genetics, NCI, NIH) and Dr. Agnes Holczbauer (Laboratory of Experimental Carcinogenesis, NCI, NIH) for kind help in pathological image analysis. NR 42 TC 14 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 1 PY 2012 VL 130 IS 1 BP 190 EP 199 DI 10.1002/ijc.25978 PG 10 WC Oncology SC Oncology GA 859CG UT WOS:000297851300020 PM 21312195 ER PT J AU Janssens, ACJW Henneman, L Detmar, SB Khoury, MJ Steyerberg, EW Eijkemans, MJC Mushkudiani, N Oostra, B van Duijn, CM Mackenbach, JP AF Janssens, A. Cecile J. W. Henneman, Lidewij Detmar, Symone B. Khoury, Muin J. Steyerberg, Ewout W. Eijkemans, Marinus J. C. Mushkudiani, Nino Oostra, Ben A. van Duijn, Cornelia M. Mackenbach, Johan P. TI Accuracy of self-reported family history is strongly influenced by the accuracy of self-reported personal health status of relatives SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Family history; Accuracy; Self-report assessment; Diabetes; Obesity; Hypertension ID NUTRITION EXAMINATION SURVEY; COMMON CHRONIC DISEASES; PRIMARY-CARE; NATIONAL-HEALTH; PUBLIC-HEALTH; HYPERTENSION; RISK; POPULATION; TOOL; VALIDATION AB Objective: We investigated the accuracy of self-reported family history for diabetes, hypertension, and overweight against two reference standards-family history based on physician-assessed health status of relatives and on self-reported personal health status of relatives. Study Design and Setting: Subjects were participants from the Erasmus Rucphen Family study, an extended family study among descendants of 20 couples who lived between 1850 and 1900 in a southwest region of the Netherlands and their relatives (n = 1,713). Sensitivity and specificity of self-reported family history were calculated. Results: Sensitivity of self-reported family history was 89.2% for diabetes, 92.2% for hypertension, and 78.4% for overweight when family history based on relatives' self-reported personal health status was used as reference and 70.8% for diabetes, 67.4% for hypertension, and 77.3% for overweight when physician-assessed health status of relatives was used. Sensitivity and specificity of self-reported personal health status were 76.8% and 98.8% for diabetes, 38.9% and 98.0% for hypertension, and 80.9% and 75.7% for overweight, respectively. Conclusion: The accuracy of self-reported family history of diabetes and hypertension is strongly influenced by the accuracy of self-reported personal health status of relatives. Raising awareness of personal health status is crucial to ensure the utility of family history for the assessment of risk and disease prevention. (C) 2012 Elsevier Inc. All rights reserved. C1 [Janssens, A. Cecile J. W.; Steyerberg, Ewout W.; Eijkemans, Marinus J. C.; Mushkudiani, Nino; Mackenbach, Johan P.] Erasmus Univ, Med Ctr, Dept Publ Hlth, NL-3015 GE Rotterdam, Netherlands. [Henneman, Lidewij] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Dept Publ & Occupat Hlth, NL-1081 BT Amsterdam, Netherlands. [Detmar, Symone B.] TNO Qual Life, NL-2333 AL Leiden, Netherlands. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Khoury, Muin J.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. [Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Clin Genet, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. RP Janssens, ACJW (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM a.janssens@erasmusmc.nl RI janssens, cecile/L-1075-2015; OI Janssens, A Cecile/0000-0002-6153-4976; Steyerberg, Ewout/0000-0002-7787-0122 FU Centre for Medical Systems Biology in the framework of the Netherlands Genomics Initiative; Netherlands Organisation for Scientific Research; Erasmus Medical Center; Netherlands Diabetes Foundation; Netherlands Kidney foundation FX The Erasmus Rucphen Family study was supported by grants from the Centre for Medical Systems Biology in the framework of the Netherlands Genomics Initiative, the Netherlands Organisation for Scientific Research, Erasmus Medical Center, and grants from the Netherlands Diabetes Foundation and the Netherlands Kidney foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 9 Z9 9 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD JAN PY 2012 VL 65 IS 1 BP 82 EP 89 DI 10.1016/j.jclinepi.2011.05.003 PG 8 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 859VH UT WOS:000297903400012 PM 21889309 ER PT J AU Kamasaki, Y Nakamura, T Yoshizaki, K Iwamoto, T Yamada, A Fukumoto, E Maruya, Y Iwabuchi, K Furukawa, K Fujiwara, T Fukumoto, S AF Kamasaki, Y. Nakamura, T. Yoshizaki, K. Iwamoto, T. Yamada, A. Fukumoto, E. Maruya, Y. Iwabuchi, K. Furukawa, K. Fujiwara, T. Fukumoto, S. TI Glycosphingolipids Regulate Ameloblastin Expression in Dental Epithelial Cells SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE cell differentiation; enamel; developmental biology; tooth development; cell signaling; gene expression ID GANGLIOSIDE BIOSYNTHESIS; LIPID RAFTS; NERVE; P75; DIFFERENTIATION; PROLIFERATION; RECEPTOR; FAMILY AB Neurotrophin 4 (NT-4) and its receptors regulate the differentiation of ameloblasts in tooth development. Gangliosides, sialic acids that contain glycosphingolipids (GSLs), are involved in a variety of membrane-associated cell physiological functions such as ligand-receptor signal transmission. However, the expression patterns and functions of GSLs during tooth development remain unclear. In this study, we identified strong expressions of GM3 and LacCer in dental epithelium, which give rise to differentiation into enamel-secreting ameloblasts. Exogenous GM3 and LacCer in dental epithelial cells induced the expression of ameloblastin (Ambn), while it was also interesting that GM3 synergistically exerted enhancement of NT-4-mediated Ambn expression. In addition, consistently exogenous GM3 and LacCer in dental epithelial cells induced distinct activation of extracellular signal-regulated kinase 1/2 (ERK1/2), an event upstream of the expression of Ambn. Furthermore, depletion of GSLs from dental epithelial cells by D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) inhibited Ambn expression as well as phosphorylation of ERK1/2. In contrast, exogenous addition of GM3 or LacCer rescued the phosphorylation of ERK1/2 repressed by pre-treatment with D-PDMP. Taken together, these results suggest that GM3 and LacCer are essential for NT-4-mediated Ambn expression, and contribute to dental epithelial cell differentiation into ameloblasts. C1 [Nakamura, T.; Iwamoto, T.; Yamada, A.; Fukumoto, E.; Maruya, Y.; Fukumoto, S.] Tohoku Univ, Grad Sch Dent, Div Pediat Dent, Dept Oral Hlth & Dev Sci, Sendai, Miyagi 9808575, Japan. [Kamasaki, Y.; Fujiwara, T.] Nagasaki Univ, Grad Sch Biomed Sci, Unit Translat Med, Dept Pediat Dent, Nagasaki 8528588, Japan. [Yoshizaki, K.] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Iwabuchi, K.] Juntendo Univ, Grad Sch Med, Inst Environm & Gender Specif Med, Chiba 2790023, Japan. [Furukawa, K.] Nagoya Univ, Sch Med, Dept Biochem 2, Nagoya, Aichi 4660065, Japan. RP Nakamura, T (reprint author), Tohoku Univ, Grad Sch Dent, Div Pediat Dent, Dept Oral Hlth & Dev Sci, Sendai, Miyagi 9808575, Japan. EM taka@dent.tohoku.ac.jp; fukumoto@dent.tohoku.ac.jp RI Nakamura, Takashi/P-7796-2016 OI Nakamura, Takashi/0000-0001-9904-1037 FU Japan Society for the Promotion of Science from the Ministry of Education [20592405, 17689058, 20679006] FX This work was supported by grants-in-aid for Research Fellows of the Japan Society for the Promotion of Science from the Ministry of Education [20592405 (YK), 17689058 and 20679006 (SF)]. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 24 TC 5 Z9 5 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JAN PY 2012 VL 91 IS 1 BP 78 EP 83 DI 10.1177/0022034511424408 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 858XI UT WOS:000297836100012 PM 21979133 ER PT J AU Schrama, D Buck, CB Houben, R Becker, JC AF Schrama, David Buck, Chris B. Houben, Roland Becker, Juergen C. TI No Evidence for Association of HPyV6 or HPyV7 with Different Skin Cancers SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID MERKEL CELL POLYOMAVIRUS; CARCINOMA; VIRUS C1 [Schrama, David; Becker, Juergen C.] Med Univ Graz, Dept Dermatol, Graz, Austria. [Schrama, David; Houben, Roland] Univ Hosp Wuerzburg, Dept Dermatol, Wurzburg, Germany. [Buck, Chris B.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Schrama, D (reprint author), Med Univ Graz, Dept Dermatol, Graz, Austria. EM david.schrama@medunigraz.at OI Buck, Christopher/0000-0003-3165-8094; Houben, Roland/0000-0003-4538-2324 NR 12 TC 10 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JAN PY 2012 VL 132 IS 1 BP 239 EP 241 DI 10.1038/jid.2011.261 PG 3 WC Dermatology SC Dermatology GA 864JT UT WOS:000298237000033 PM 21900949 ER PT J AU Hahn, NM Bonney, PL Dhawan, D Jones, DR Balch, C Guo, ZM Hartman-Frey, C Fang, F Parker, HG Kwon, EM Ostrander, EA Nephew, KP Knapp, DW AF Hahn, Noah M. Bonney, Patty L. Dhawan, Deepika Jones, David R. Balch, Curtis Guo, Zhongmin Hartman-Frey, Corie Fang, Fang Parker, Heidi G. Kwon, Erika M. Ostrander, Elaine A. Nephew, Kenneth P. Knapp, Deborah W. TI Subcutaneous 5-Azacitidine Treatment of Naturally Occurring Canine Urothelial Carcinoma: A Novel Epigenetic Approach to Human Urothelial Carcinoma Drug Development SO JOURNAL OF UROLOGY LA English DT Article DE urinary bladder; urothelium; carcinoma; azacitidine; dogs ID TRANSITIONAL-CELL-CARCINOMA; BLADDER-CANCER; URINARY-BLADDER; DNA METHYLATION; SOLID TUMORS; AZACITIDINE; CISPLATIN; PROGRESSION; PATHWAYS; PROMOTER AB Purpose: We determined the efficacy, biological activity, pharmacokinetics and safety of the hypomethylating agent 5-azacitidine (Celgene Corp., Summit, New Jersey) in dogs with naturally occurring invasive urothelial carcinoma. Materials and Methods: We performed a preclinical phase I trial in dogs with naturally occurring invasive urothelial carcinoma to examine once daily subcutaneous administration of 5-azacitidine in 28-day cycles at doses of 0.10 to 0.30 mg/kg per day according to 2 dose schedules, including days 1 to 5 (28-day cohort) or days 1 to 5 and 15 to 19 (14-day cohort). Clinical efficacy was assessed by serial cystosonography, radiography and cystoscopy. Urinary 5-azacitidine pharmacokinetic analysis was also done. Pretreatment and posttreatment peripheral blood mononuclear cell and invasive urothelial carcinoma DNA, respectively, was analyzed for global and gene specific [CDKN2A (p14ARF)] methylation changes. Results: Enrolled in the study were 19 dogs with naturally occurring invasive urothelial carcinoma. In the 28-day cohort the maximum tolerated dose was 0.20 mg/ kg per day with higher doses resulting in grade 3 or 4 neutropenia in 4 of 6 dogs. In the 14-day cohort the maximum tolerated dose was 0.10 mg/ kg per day with grade 3 or 4 neutropenia seen in 2 of 3 dogs treated at higher doses. No grade 3 or 4 nonhematological toxicity was observed during either dosing schedule. Of 18 dogs evaluable for tumor response partial remission, stable disease and progressive disease were observed in 4 (22.2%), 9 (50.0%) and 4 (22.2%), respectively. Consistent 5-azacitidine levels (205 to 857 ng/ml) were detected in urine. Pretreatment and posttreatment methylation analysis revealed no significant correlation with clinical response. Conclusions: Subcutaneous 5-azacitidine showed promising clinical activity in a canine invasive urothelial carcinoma model, thus meriting further development in humans with urothelial carcinoma. C1 [Hahn, Noah M.; Jones, David R.; Balch, Curtis; Guo, Zhongmin; Nephew, Kenneth P.] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Bonney, Patty L.; Dhawan, Deepika; Knapp, Deborah W.] Purdue Univ, Sch Vet Med, W Lafayette, IN 47907 USA. [Knapp, Deborah W.] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA. [Balch, Curtis; Guo, Zhongmin; Hartman-Frey, Corie; Fang, Fang; Nephew, Kenneth P.] Indiana Univ, Med Sci Program, Bloomington, IN USA. [Parker, Heidi G.; Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Kwon, Erika M.] Johns Hopkins Univ, Sch Med, Program Human Genet & Mol Biol, Baltimore, MD USA. RP Hahn, NM (reprint author), Indiana Univ, Melvin & Bren Simon Canc Ctr, Indiana Univ Canc Pavil Room RT445,535 Barnhill D, Indianapolis, IN 46202 USA. EM nhahn@iupui.edu OI Ostrander, Elaine/0000-0001-6075-9738 FU Indiana University Melvin; Bren Simon Cancer Center; Celgene Corp., Summit, New Jersey; National Cancer Institute [P30 CA082709] FX Supported by Indiana University Melvin and Bren Simon Cancer Center Translational Research Acceleration Collaboration grant funding, Celgene Corp., Summit, New Jersey and National Cancer Institute Grant P30 CA082709. NR 29 TC 12 Z9 12 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JAN PY 2012 VL 187 IS 1 BP 302 EP 309 DI 10.1016/j.juro.2011.09.010 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 863FK UT WOS:000298148000113 PM 22099988 ER PT J AU Nussinov, R AF Nussinov, Ruth TI How do dynamic cellular signals travel long distances? SO MOLECULAR BIOSYSTEMS LA English DT Editorial Material ID PROTEIN-PROTEIN INTERACTIONS; CONFORMATIONAL ENSEMBLES; MOLECULAR RECOGNITION; DISORDERED PROTEINS; INTRINSIC DISORDER; DRUG DISCOVERY; ALLOSTERY; COOPERATIVITY; SIZE; MECHANISM AB Communication is essential. It is vital between cells in multi-cellular organisms, and within cells. A signaling molecule binds to a receptor protein, and initiates a cascade of dynamic events. Signaling is a multistep pathway, which allows signal amplification: if some of the molecules in a pathway transmit the signal to multiple molecules, the result can be a large number of activated molecules across the cell and multiple reactions. That is how a small number of extracellular signaling molecules can produce a major cellular response. The pathway can relay signals from the extracellular space to the nucleus. How do signals travel efficiently over long-distances across the cell? Here we argue that evolution has utilized three properties: a modular functional organization of the cellular network; sequences in some key regions of proteins, such as linkers or loops, which were pre-encoded by evolution to facilitate signaling among domains; and compact interactions between proteins which is achieved via conformational disorder. C1 [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Bldg 469,Rm 151, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov FU Intramural NIH HHS; PHS HHS [HHSN261200800001E] NR 87 TC 21 Z9 21 U1 1 U2 21 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1742-206X J9 MOL BIOSYST JI Mol. Biosyst. PY 2012 VL 8 IS 1 BP 22 EP 26 DI 10.1039/c1mb05205e PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 855JZ UT WOS:000297561600002 PM 21766126 ER PT J AU Fong, JH Shoemaker, BA Panchenko, AR AF Fong, Jessica H. Shoemaker, Benjamin A. Panchenko, Anna R. TI Intrinsic protein disorder in human pathways SO MOLECULAR BIOSYSTEMS LA English DT Article ID UNSTRUCTURED PROTEINS; TRANSCRIPTION FACTORS; INTERACTION NETWORKS; COILED-COIL; UNFOLDOMICS; DISEASES; REGIONS; BINDING; PHOSPHORYLATION; PREDICTION AB We analyze human-specific KEGG pathways trying to understand the functional role of intrinsic disorder in proteins. Pathways provide a comprehensive picture of biological processes and allow better understanding of a protein's function within the specific context of its surroundings. Our study pinpoints a few specific pathways significantly enriched in disorder-containing proteins and identifies the role of these proteins within the framework of pathway relationships. Three major categories of relations are shown to be significantly enriched in disordered proteins: gene expression, protein binding and to a lesser degree, protein phosphorylation. Finally we find that relations involving protein activation and to some extent inhibition are characterized by low disorder content. C1 [Fong, Jessica H.; Shoemaker, Benjamin A.; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Fong, JH (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM fongj@ncbi.nlm.nih.gov; panch@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 48 TC 8 Z9 8 U1 0 U2 7 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1742-206X J9 MOL BIOSYST JI Mol. Biosyst. PY 2012 VL 8 IS 1 BP 320 EP 326 DI 10.1039/c1mb05274h PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 855JZ UT WOS:000297561600031 PM 22012032 ER PT J AU Lee, JY Shin, JY Kim, HS Heo, JI Kho, YJ Kang, HJ Park, SH Lee, JY AF Lee, Ji-Young Shin, Jong-Yeon Kim, Hyun-Seok Heo, Jee-In Kho, Yoon-Jung Kang, Hong-Jun Park, Seong-Hoon Lee, Jae-Yong TI Effect of combined treatment with progesterone and tamoxifen on the growth and apoptosis of human ovarian cancer cells SO ONCOLOGY REPORTS LA English DT Article DE ovarian cancer cell line; progesterone; tamoxifen; apoptosis; growth arrest ID CARCINOMA; THERAPY; P53; TRANSACTIVATION; SURVIVAL; HZF AB Progesterone has a potential protective effect against ovarian carcinoma induced by estrogen. Progesterone is also known to cause apoptosis while tamoxifen induces growth arrest. Therefore, we attempted to determine whether combined treatment with progesterone and tamoxifen has a synergistic effect on anti-cancer activity. Although progesterone is known to cause apoptosis while tamoxifen induces growth arrest in many cancer cells, the detailed action of progesterone and tamoxifen and the anticancer effect of combined treatment have not been tested in ovarian cancer cells. Therefore, we tested the growth and apoptosis activity of progesterone and tamoxifen and the anticancer effect of combined treatment of progesterone and tamoxifen in ovarian cancer cells. Ovarian cancer cells, PA-1, were treated with progesterone, tamoxifen, or a combination of progesterone and tamoxifen. The anti-cancer effects were investigated by use of flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, DNA fragmentation analysis, and Western blot analysis. We found that 100 mu M progesterone induced typical apoptosis in PA-1 cells. Treatment of PA-1 cells with 10 mu M tamoxifen resulted in an increase in the levels of p21, p27, p16 and phospho-pRb, indicating typical G, arrest. Co-treatment of PA-1 cells with 100 mu M progesterone and 10 mu M tamoxifen resulted in typical apoptosis, similar to that induced by treatment with 100 mu M progesterone alone. These results indicate that progesterone caused apoptosis and tamoxifen induced G, arrest. Combined treatment with tamoxifen and progesterone caused apoptosis similar to that induced by treatment with progesterone alone and had no additional anti-cancer effect in ovarian cancer cells. C1 [Heo, Jee-In; Park, Seong-Hoon; Lee, Jae-Yong] Hallym Univ, Dept Biochem, Coll Med, Chunchon 200702, Gangwon Do, South Korea. [Heo, Jee-In; Kho, Yoon-Jung; Lee, Jae-Yong] Hallym Univ, Inst Nat Med, Coll Med, Chunchon 200702, Gangwon Do, South Korea. [Lee, Ji-Young] SUNY Buffalo, Dept Obstet & Gynecol, Sisters Char Hosp, Buffalo, NY 14214 USA. [Shin, Jong-Yeon] Seoul Natl Univ, Genom Med Inst, Med Res Ctr, Seoul, South Korea. [Kim, Hyun-Seok; Park, Seong-Hoon] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kang, Hong-Jun] NIDDK, Genet Dis Res Sect, NIH, Bethesda, MD 20892 USA. RP Lee, JY (reprint author), Hallym Univ, Dept Biochem, Coll Med, 1 Okcheon Dong, Chunchon 200702, Gangwon Do, South Korea. EM jyolee@hallym.ac.kr; jyolee@hallym.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2010-0029642] FX This study was supported by Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0029642). NR 19 TC 5 Z9 6 U1 0 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JAN PY 2012 VL 27 IS 1 BP 87 EP 93 DI 10.3892/or.2011.1460 PG 7 WC Oncology SC Oncology GA 853AB UT WOS:000297397500012 PM 21922150 ER PT J AU Topaloglu, R Vilboux, T Coskun, T Ozaltin, F Tinloy, B Gunay-Aygun, M Bakkaloglu, A Besbas, N van den Heuvel, L Kleta, R Gahl, WA AF Topaloglu, Rezan Vilboux, Thierry Coskun, Turgay Ozaltin, Fatih Tinloy, Brad Gunay-Aygun, Meral Bakkaloglu, Aysin Besbas, Nesrin van den Heuvel, Lambert Kleta, Robert Gahl, William A. TI Genetic basis of cystinosis in Turkish patients: a single-center experience SO PEDIATRIC NEPHROLOGY LA English DT Article DE Cystinosis; CTNS gene; Turkish patients; Genetic basis; New mutations ID NEPHROPATHIC CYSTINOSIS; CTNS MUTATIONS; CYSTEAMINE THERAPY; IDENTIFICATION AB We report the molecular findings for the CTNS gene in 12 Turkish cystinosis patients aged 7-29 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Cystinosis was diagnosed at age 1 month to 9 years. Seven patients reached end-stage renal failure at ages ranging from 6.5 to 15 years. Whereas three of the remaining five have renal Fanconi syndrome with proteinuria, two have had kidney failure of varying degrees. Molecular analyses involved an initial multiplex polymerase chain reaction (PCR) to determine the presence or absence of the 57-kb northern European founder deletion in CTNS, followed by sequencing of the ten coding exons of CTNS. Comprehensive mutation analysis verified that none of the 12 patients carried the common 57-kb deletion. We identified four previously reported nucleotide variations associated with cystinosis and five new variants: a 10-kb deletion, three missense variants, and a nucleotide substitution in a potential branch point site of intron 4. This study is the first molecular analysis of Turkish cystinosis patients and provides guidance for the molecular diagnosis of cystinosis in this population. C1 [Topaloglu, Rezan; Ozaltin, Fatih; Bakkaloglu, Aysin; Besbas, Nesrin] Hacettepe Univ, Fac Med, Dept Pediat Nephrol, TR-06100 Ankara, Turkey. [Vilboux, Thierry; Tinloy, Brad; Gunay-Aygun, Meral; Kleta, Robert; Gahl, William A.] NHGRI, NIH, MGB, Bethesda, MD 20892 USA. [Coskun, Turgay] Hacettepe Univ, Fac Med, Dept Pediat Metab Dis, TR-06100 Ankara, Turkey. [van den Heuvel, Lambert] Acad Hosp Leuven, Dept Pediat, B-3000 Louvain, Belgium. RP Topaloglu, R (reprint author), Hacettepe Univ, Fac Med, Dept Pediat Nephrol, TR-06100 Ankara, Turkey. EM rezantopaloglu@hacettepe.edu.tr RI Heuvel, L.P.W.J./H-8044-2014 FU Hacettepe University [06A101008] FX We gratefully acknowledge Prof. Dr. Elena Levtchenko for her advice and help in completing the genetic analysis and the critical reading of the manuscript. Hacettepe University Nephrogenetics Laboratory was established by Hacettepe University Infrastructure Project (Project No: 06A101008) NR 26 TC 10 Z9 11 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JAN PY 2012 VL 27 IS 1 BP 115 EP 121 DI 10.1007/s00467-011-1942-6 PG 7 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 855EG UT WOS:000297546000016 PM 21786142 ER PT J AU McDermott, CL Blough, DK Fedorenko, CR Arora, NK Zeliadt, SB Fairweather, ME Oakley-Girvan, I Van den Eeden, SK Ramsey, SD AF McDermott, Cara L. Blough, David K. Fedorenko, Catherine R. Arora, Neeraj K. Zeliadt, Steven B. Fairweather, Megan E. Oakley-Girvan, Ingrid Van den Eeden, Stephen K. Ramsey, Scott D. TI Complementary and alternative medicine use among newly diagnosed prostate cancer patients SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Prostatic neoplasms; Complementary medicine; Alternative medicine; Patient satisfaction ID QUALITY-OF-LIFE; MEN; MANAGEMENT; SURVIVORS; ASSOCIATION; VALIDATION; THERAPIES; DECISIONS; OUTCOMES; SCALE AB We surveyed prostate cancer patients about complementary and alternative medicine (CAM) use and evaluated patient factors that correlated with CAM use 6 months following diagnosis. The Prostate CAncer Therapy Selection study was a prospective, observational multi-site study of men's treatment decision-making process after a diagnosis of local stage prostate cancer. Recruitment occurred in community urology practices in Washington State, hospital-based urology clinics affiliated with the University of Southern California, and Kaiser Permanente in Northern California. Eligible study participants included men over age 21 diagnosed with local stage prostate cancer between May 1, 2005 and December 31, 2006. Fifty-two percent of survey respondents (379) reported using one or more types of CAM. Of the patients, 51% used one CAM method, 26% used two methods, and 23% used three or more methods. The most commonly reported category was mind-body therapies (65%). Only 43% of patients discussed their CAM use with a health professional; of those, 20% informed their primary care physician and 30% told the doctor managing their prostate cancer care. Less than half thought the CAM they used was "very helpful", but a majority thought it was somewhat helpful for their condition. Further research is needed to characterize the goals prostate cancer patients have for CAM, whether the treatments met those goals, and how this translates into the perceived helpfulness of these therapies. The implications of patients not discussing CAM use with health professionals at the time of prostate cancer treatment need further studies. C1 [McDermott, Cara L.; Fedorenko, Catherine R.; Zeliadt, Steven B.; Fairweather, Megan E.; Ramsey, Scott D.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Blough, David K.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Zeliadt, Steven B.] Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Excellence, VA Puget, Seattle, WA USA. [Oakley-Girvan, Ingrid] Canc Prevent Inst Calif, Fremont, CA USA. [Van den Eeden, Stephen K.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. RP Ramsey, SD (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M3-B232, Seattle, WA 98109 USA. EM sramsey@fhcrc.org FU National Cancer Institute [HHSN261200900582P, N01-PC-35142, N01-PC-35139, N01-PC-35136]; Cancer Surveillance System of the Fred Hutchinson Cancer Research Center; Fred Hutchinson Cancer Research Center; State of Washington FX This publication was supported by the National Cancer Institute contracts HHSN261200900582P, N01-PC-35142, N01-PC-35139, and N01-PC-35136.; This research was also supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by Contract No. N01-PC-35142 from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington. NR 38 TC 8 Z9 8 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JAN PY 2012 VL 20 IS 1 BP 65 EP 73 DI 10.1007/s00520-010-1055-y PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 855DF UT WOS:000297543200007 PM 21120540 ER PT J AU Liu, Z Blasch, E Xue, ZY Zhao, JY Laganiere, R Wu, W AF Liu, Zheng Blasch, Erik Xue, Zhiyun Zhao, Jiying Laganiere, Robert Wu, Wei TI Objective Assessment of Multiresolution Image Fusion Algorithms for Context Enhancement in Night Vision: A Comparative Study SO IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE LA English DT Article DE Night vision; context enhancement; pixel-level image fusion; multiresolution analysis; objective fusion assessment; performance metric; image quality ID INFORMATION MEASURE; MUTUAL INFORMATION; QUALITY; PERFORMANCE; ENTROPY AB Comparison of image processing techniques is critically important in deciding which algorithm, method, or metric to use for enhanced image assessment. Image fusion is a popular choice for various image enhancement applications such as overlay of two image products, refinement of image resolutions for alignment, and image combination for feature extraction and target recognition. Since image fusion is used in many geospatial and night vision applications, it is important to understand these techniques and provide a comparative study of the methods. In this paper, we conduct a comparative study on 12 selected image fusion metrics over six multiresolution image fusion algorithms for two different fusion schemes and input images with distortion. The analysis can be applied to different image combination algorithms, image processing methods, and over a different choice of metrics that are of use to an image processing expert. The paper relates the results to an image quality measurement based on power spectrum and correlation analysis and serves as a summary of many contemporary techniques for objective assessment of image fusion algorithms. C1 [Liu, Zheng; Zhao, Jiying; Laganiere, Robert] Univ Ottawa, Sch Informat Technol & Engn, Ottawa, ON K1N 6N5, Canada. [Liu, Zheng] Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada. [Blasch, Erik] USAF, Res Lab AFRL, AFRL RYAA, Wright Patterson AFB, OH 45433 USA. [Xue, Zhiyun] NIH, Natl Lib Med, Commun Engn Branch, Bethesda, MD 20894 USA. [Wu, Wei] Sichuan Univ, Coll Elect & Informat Engn, Chengdu 610064, Peoples R China. RP Liu, Z (reprint author), Univ Ottawa, Sch Informat Technol & Engn, 800 King Edward Ave, Ottawa, ON K1N 6N5, Canada. EM zheng.liu@ieee.org; erik.blasch@wpafb.af.mil; xuez@mail.nih.gov; jyzhao@site.uottawa.ca; laganier@site.uottawa.ca; wuwei@scu.edu.cn RI Laganiere, Robert/H-9138-2013; OI Laganiere, Robert/0000-0001-9475-8151; Wu, Wei/0000-0001-5769-9340 NR 42 TC 113 Z9 120 U1 3 U2 42 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0162-8828 J9 IEEE T PATTERN ANAL JI IEEE Trans. Pattern Anal. Mach. Intell. PD JAN PY 2012 VL 34 IS 1 BP 94 EP 109 DI 10.1109/TPAMI.2011.109 PG 16 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 848RB UT WOS:000297069900007 PM 21576753 ER PT J AU Patlolla, JMR Zhang, YT Li, Q Steele, VS Rao, CV AF Patlolla, Jagan M. R. Zhang, Yuting Li, Qian Steele, Vernon S. Rao, Chinthalapally V. TI Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE aberrant crypt foci; omeprazole; colon cancer; chemoprevention; apoptosis ID PROTON PUMP INHIBITOR; BCL-2 PROTEIN FAMILY; COLORECTAL CARCINOGENESIS; APOPTOSIS; SURVIVIN; P21(WAF1/CIP1); EXPRESSION; INDUCTION; ORIGIN; GROWTH AB Omeprazole is a proton pump inhibitor, a widely used drug to treat ulcers and gastroesophageal refluxdisease. We have evaluated colon cancer chemopreventive properties of omeprazole using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats and analyzed cell growth inhibition and apoptosis induction in human colon cancer cells. Five-week-old male F344 rats were fed a control or experimental diet containing two doses of omeprazole (200 and 400 ppm). After one week, all animals were s.c. injected with AOM (15 mg/kg body weight, once weekly for two weeks). Rats continued on experimental diets for seven more weeks before being sacrificed. Colons were histopathologically evaluated for ACF. Human colon cancer HCT-116 and HCA-7 cells treated with omeprazole were evaluated for different markers associated with proliferation and apoptotic markers using Western blot technique. Rats fed with 200 and 400 ppm of omeprazole significantly suppressed total colonic ACF formation (similar to 30%, P<0.001) and showed significant suppression of multi-crypt foci (similar to 30-50%, P<0.05-0.001). Omeprazole produced significant dose-response effects on inhibition of multi-crypt foci (>= 4) Omeprazole treatment in human colon cancer cell lines HCT-116 and HCA-7 cells resulted in induction of p21(wafI/cip1) and decreased the expression of anti-apoptotic proteins Bcl-2, Bcl-X-L, and survivin in a dose-dependent manner. Anticancer properties observed in colon cancer cell lines suggest that omeprazole may induce key signaling molecules of antiproliferation and inhibition of anti-apoptotic proteins. C1 [Rao, Chinthalapally V.] OUHSC, OU Canc Inst, Ctr Chemoprevent & Canc Drug Dev, PC Stephenson Oklahoma Canc Ctr,Dept Med,Hem One, Oklahoma City, OK 73104 USA. [Steele, Vernon S.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), OUHSC, OU Canc Inst, Ctr Chemoprevent & Canc Drug Dev, PC Stephenson Oklahoma Canc Ctr,Dept Med,Hem One, 975 NE 10th St,BRC 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU USPHS from the NCI [NO1-CN-53300] FX This study was supported in part by USPHS Grants NO1-CN-53300 from the NCI. We wish to thank Ashley for her help in the editing and preparation of this manuscript. NR 35 TC 3 Z9 3 U1 0 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JAN PY 2012 VL 40 IS 1 BP 170 EP 175 DI 10.3892/ijo.2011.1214 PG 6 WC Oncology SC Oncology GA 853CM UT WOS:000297403800021 PM 21956158 ER PT B AU Kobayashi, SD Rigby, KM DeLeo, FR AF Kobayashi, Scott D. Rigby, Kevin M. DeLeo, Frank R. BE Locht, C Simonet, M TI Bacteria-induced Host Cell Death SO BACTERIAL PATHOGENESIS: MOLECULAR AND CELLULAR MECHANISMS LA English DT Article; Book Chapter ID CYTOLETHAL-DISTENDING TOXIN; NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; CLOSTRIDIUM-DIFFICILE TOXIN; ANTHRAX LETHAL TOXIN; INTESTINAL EPITHELIAL-CELLS; MONOCYTE-DERIVED MACROPHAGES; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS LEUKOTOXIN; PSEUDOMONAS-AERUGINOSA-EXOTOXIN; GROUP-A STREPTOCOCCUS AB The interaction of bacteria with host cells largely dictates the outcome of infection. Whether following a breach in the epithelium or by dissemination from colonized tissues, bacteria interact directly with immune and non-immune host cells. Therefore, it is perhaps not surprising that bacteria implement multiple strategies to circumvent destruction or avoid detection by the host. One such strategy is the ability of bacteria to alter host cell apoptosis or cause other forms of cell death. Although some bacterial pathogens induce or delay cell death and thereby promote disease, bacteria-induced cell death can also be beneficial to the host. This topic is reviewed in the present chapter. C1 [Kobayashi, Scott D.; Rigby, Kevin M.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Kobayashi, SD (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM kobayashis@niaid.nih.gov; rigbyk@niaid.nih.gov; fdeleo@niaid.nih.gov NR 632 TC 3 Z9 3 U1 2 U2 9 PU CAISTER ACADEMIC PRESS PI WYMONDHAM PA 32 HEWITTS LANE, WYMONDHAM NR 18 0JA, ENGLAND BN 978-1-904455-91-2 PY 2012 BP 317 EP 362 PG 46 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA BXD59 UT WOS:000295820000015 ER PT J AU Holley, MM Zhang, YQ Lehrmann, E Wood, WH Becker, KG Kielian, T AF Holley, Monica M. Zhang, Yongqing Lehrmann, Elin Wood, William H. Becker, Kevin G. Kielian, Tammy TI Toll-like receptor 2 (TLR2)-TLR9 crosstalk dictates IL-12 family cytokine production in microglia SO GLIA LA English DT Article DE S; aureus; TLR2; TLR9; microglia; MAPK; JNK; PI3K ID STAPHYLOCOCCUS-AUREUS; BRAIN-ABSCESS; CPG OLIGONUCLEOTIDES; LEPROMATOUS LEPROSY; IMMUNE-RESPONSES; HOST-DEFENSE; RECOGNITION; TLR2; INTERLEUKIN-12; ACTIVATION AB Microglia are the resident mononuclear phagocytes of the CNS parenchyma and represent an initial line of defense against invading microorganisms. Microglia utilize Toll-like receptors (TLRs) for pathogen recognition and TLR2 specifically senses conserved motifs of gram-positive bacteria including lipoproteins, lipoteichoic acids, and peptidoglycan (PGN) leading to cytokine/chemokine production. Interestingly, primary microglia derived from TLR2 knockout (KO) mice over-expressed numerous IL-12 family members, including IL-12p40, IL-12p70, and IL-27 in response to intact S. aureus, but not the less structurally complex TLR2 ligands Pam3CSK4 or PGN. The ability of intact bacteria to augment IL-12 family member expression was specific for gram-positive organisms, since numerous gram-negative strains were unable to elicit exaggerated responses in TLR2 KO microglia. Inhibition of SYK or IRAK4 signaling did not impact heightened IL-12 family member production in S. aureus-treated TLR2 KO microglia, whereas PI3K, MAPK, and JNK inhibitors were all capable of restoring exaggerated cytokine expression to wild type levels. Additionally, elevated IL-12 production in TLR2 KO microglia was ablated by a TLR9 antagonist, suggesting that TLR9 drives IL-12 family member production following exposure to intact bacteria that remains unchecked in the absence of TLR2 signaling. Collectively, these findings indicate crosstalk between TLR2 and TLR9 pathways to regulate IL-12 family member production by microglia. The summation of TLR signals must be tightly controlled to ensure the timely cessation and/or fine tuning of cytokine signaling to avoid nonspecific bystander damage due to sustained IL-12 release. (c) 2011 Wiley Periodicals, Inc. C1 [Holley, Monica M.; Kielian, Tammy] Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Zhang, Yongqing; Lehrmann, Elin; Wood, William H.; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD USA. RP Kielian, T (reprint author), Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, 985900 Nebraska Med Ctr, Omaha, NE 68198 USA. EM tkielian@unmc.edu OI Lehrmann, Elin/0000-0002-9869-9475; Becker, Kevin/0000-0002-6794-6656 FU NIH National Institute of Neurological Disorders and Stroke [RO1 NS055385]; NIH, National Institute on Aging FX Grant sponsor: NIH National Institute of Neurological Disorders and Stroke; Grant number: RO1 NS055385; Grant sponsor: Intramural Research Program of the NIH, National Institute on Aging. NR 61 TC 11 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD JAN PY 2012 VL 60 IS 1 BP 29 EP 42 DI 10.1002/glia.21243 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 850QY UT WOS:000297213400003 PM 21901759 ER PT J AU Kanungo, J Chandrasekharappa, SC AF Kanungo, Jyotshnabala Chandrasekharappa, Settara C. TI Menin induces endodermal differentiation in aggregated P19 stem cells by modulating the retinoic acid receptors SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE Menin; Endodermal differentiation; Stem cells; Retinoic acid receptor; Cytokeratin Endo A ID EMBRYONAL CARCINOMA-CELLS; MULTIPLE ENDOCRINE NEOPLASIA; HISTONE METHYLTRANSFERASE COMPLEX; TUMOR-SUPPRESSOR MENIN; HOX GENE-EXPRESSION; NEURONAL DIFFERENTIATION; CELLULAR AGGREGATION; TRANSCRIPTION FACTOR; SKELETAL MYOGENESIS; TERMINAL KINASE AB Menin, a ubiquitously expressed protein, is the product of the multiple endocrine neoplasia type I (Men1) gene, mutations of which cause tumors primarily of the parathyroid, endocrine pancreas, and anterior pituitary. Menin-null mice display early embryonic lethality, and thus imply a critical role for menin in early development. In this study, using the P19 embryonic carcinoma stem cells, we studied menin's role in cell differentiation. Menin expression is induced in P19 cell aggregates by retinoic acid (RA). Menin over-expressing stable clones proliferated in a significantly reduced rate compared to the empty vector harboring cells. RA induced cell death in aggregated menin over-expressing cells. However, in the absence of RA, specific populations of the aggregated menin over-expressing cells displayed the characteristic of an endodermal phenotype by the acquisition of cytokeratin Endo A expression (TROMA-1), a marker for the primitive endoderm, with a concomitant loss of the stem cell marker SSEA-1. Menin's ability to induce endodermal differentiation in specific populations of the aggregated cells in the absence of RA implied that menin could substitute RA by inducing a set of target genes that are RA responsive. Menin over-expressing cells upon aggregation showed a robust expression of RA receptors (RAR), RAR alpha, beta, and gamma relative to the empty vector-harboring cells. Moreover, endodermal differentiation was inhibited by the pan-RAR antagonist Ro41-5253, suggesting that menin could induce endodermal differentiation of uncommitted cells by functionally modulating the RARs. C1 [Kanungo, Jyotshnabala; Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Kanungo, Jyotshnabala] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Chandrasekharappa, SC (reprint author), NHGRI, Canc Genet Branch, NIH, 50 S Dr,Bldg 50,Room 5232, Bethesda, MD 20892 USA. EM chandra@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health, USA FX This study was supported by Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, USA. NR 48 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD JAN PY 2012 VL 359 IS 1-2 BP 95 EP 104 DI 10.1007/s11010-011-1003-2 PG 10 WC Cell Biology SC Cell Biology GA 850DK UT WOS:000297174700011 PM 21833538 ER PT J AU Sun, JH Kohr, MJ Nguyen, T Aponte, AM Connelly, PS Esfahani, SG Gucek, M Daniels, MP Steenbergen, C Murphy, E AF Sun, Junhui Kohr, Mark J. Tiffany Nguyen Aponte, Angel M. Connelly, Patricia S. Esfahani, Shervin G. Gucek, Marjan Daniels, Mathew P. Steenbergen, Charles Murphy, Elizabeth TI Disruption of Caveolae Blocks Ischemic Preconditioning-Mediated S-Nitrosylation of Mitochondrial Proteins SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID NITRIC-OXIDE SYNTHASE; CARDIAC MYOCYTES; ESTROGEN-RECEPTOR; ENDOTHELIAL-CELLS; CARDIOPROTECTION; HEART; INTERNALIZATION; ACTIVATION; PROTECTION; INJURY AB Aims: Nitric oxide (NO) and protein S-nitrosylation (SNO) play important roles in ischemic preconditioning (IPC)-induced cardioprotection. Mitochondria are key regulators of preconditioning, and most proteins showing an increase in SNO with IPC are mitochondrial. The aim of this study was to address how IPC transduces NO/SNO signaling to mitochondria in the heart. Results: In this study using Langendorff perfused mouse hearts, we found that IPC-induced cardioprotection was blocked by treatment with either N-nitro-L-arginine methyl ester (L-NAME, a constitutive NO synthase inhibitor), ascorbic acid (a reducing agent to decompose SNO), or methyl-beta-cyclodextrin (M beta CD, a cholesterol sequestering agent to disrupt caveolae). IPC not only activated AKT/eNOS signaling but also led to translocation of eNOS to mitochondria. MbCD treatment disrupted caveolar structure, leading to dissociation of eNOS from caveolin-3 and blockade of IPC-induced activation of the AKT/eNOS signaling pathway. A significant increase in mitochondrial SNO was found in IPC hearts compared to perfusion control, and the disruption of caveolae by M beta CD treatment not only abolished IPC-induced cardioprotection, but also blocked the IPC-induced increase in SNO. Innovation: These results provide mechanistic insight into how caveolae/eNOS/NO/SNO signaling mediates cardioprotection induced by IPC. Conclusion: Altogether these results suggest that caveolae transduce eNOS/NO/SNO cardioprotective signaling in the heart. Antioxid. Redox Signal. 16, 45-56. C1 [Sun, Junhui; Kohr, Mark J.; Tiffany Nguyen; Aponte, Angel M.; Gucek, Marjan; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Kohr, Mark J.; Steenbergen, Charles] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Connelly, Patricia S.; Esfahani, Shervin G.; Daniels, Mathew P.] NHLBI, Elect Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Kohr, Mark J.; Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Sun, JH (reprint author), NHLBI, Syst Biol Ctr, NIH, 10 Ctr Dr,Bldg10,Rm8N206, Bethesda, MD 20892 USA. EM sun1@mail.nih.gov RI Sun, Junhui/C-3499-2011; OI Kohr, Mark/0000-0002-6034-5962 FU NIH [1F32HL096142, 5R01HL039752] FX This work was supported by the NIH Intramural Program (JS, TN, AA, PC, SE, MG, MD and EM), NIH grants 1F32HL096142 (MK), and 5R01HL039752 (CS). NR 41 TC 30 Z9 32 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JAN PY 2012 VL 16 IS 1 BP 45 EP 56 DI 10.1089/ars.2010.3844 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 849WH UT WOS:000297155500004 PM 21834687 ER PT J AU Saeed, F Perez-Rathke, A Gwarnicki, J Berger-Wolf, T Khokhar, A AF Saeed, Fahad Perez-Rathke, Alan Gwarnicki, Jaroslaw Berger-Wolf, Tanya Khokhar, Ashfaq TI A high performance multiple sequence alignment system for pyrosequencing reads from multiple reference genomes SO JOURNAL OF PARALLEL AND DISTRIBUTED COMPUTING LA English DT Article DE Multiple sequence alignment; Pyrosequencing; Parallel algorithms; Computational biology; Genome alignment and mapping ID ARABIDOPSIS-THALIANA; DNA; TRANSFORM; ULTRAFAST; DATABASES; PROGRAM; SEARCH AB Genome resequencing with short reads generated from pyrosequencing generally relies on mapping the short reads against a single reference genome. However, mapping of reads from multiple reference genomes is not possible using a pairwise mapping algorithm. In order to align the reads w.r.t each other and the reference genomes, existing multiple sequence alignment(MSA) methods cannot be used because they do not take into account the position of these short reads with respect to the genome, and are highly inefficient for a large number of sequences. In this paper, we develop a highly scalable parallel algorithm based on domain decomposition, referred to as P-Pyro-Align, to align such a large number of reads from single or multiple reference genomes. The proposed alignment algorithm accurately aligns the erroneous reads, and has been implemented on a cluster of workstations using MPI library. Experimental results for different problem sizes are analyzed in terms of execution time, quality of the alignments, and the ability of the algorithm to handle reads from multiple haplotypes. We report high quality multiple alignment of up to 0.5 million reads. The algorithm is shown to be highly scalable and exhibits super-linear speedups with increasing number of processors. (C) 2011 Elsevier Inc. All rights reserved. C1 [Khokhar, Ashfaq] Univ Illinois, Dept Elect & Comp Engn, Chicago, IL 60607 USA. [Perez-Rathke, Alan; Gwarnicki, Jaroslaw; Berger-Wolf, Tanya] Univ Illinois, Dept Comp Sci, Chicago, IL USA. [Saeed, Fahad] NHLBI, NIH, Bethesda, MD 20892 USA. RP Khokhar, A (reprint author), Univ Illinois, Dept Elect & Comp Engn, Chicago, IL 60607 USA. EM ashfaq@uic.edu RI Saeed, Fahad/D-1545-2013; OI Berger-Wolf, Tanya/0000-0001-7610-1412 FU Intramural NIH HHS [Z99 HL999999] NR 52 TC 4 Z9 4 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 0743-7315 EI 1096-0848 J9 J PARALLEL DISTR COM JI J. Parallel Distrib. Comput. PD JAN PY 2012 VL 72 IS 1 BP 83 EP 93 DI 10.1016/j.jpdc.2011.08.001 PG 11 WC Computer Science, Theory & Methods SC Computer Science GA 847UJ UT WOS:000296997700008 PM 23125479 ER PT J AU Lindholm, JSO Autio, H Vesa, L Antila, H Lindemann, L Hoener, MC Skolnick, P Rantamaki, T Castren, E AF Lindholm, Jesse S. O. Autio, Henri Vesa, Liisa Antila, Hanna Lindemann, Lothar Hoener, Marius C. Skolnick, Phil Rantamaki, Tomi Castren, Eero TI The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf(+/-) heterozygous null mice SO NEUROPHARMACOLOGY LA English DT Article DE Brain-derived neurotrophic factor; TrkB; Glutamate; Depression; Ketamine; LY 4516461 ID D-ASPARTATE ANTAGONIST; RESISTANT MAJOR DEPRESSION; NEUROTROPHIC FACTOR BDNF; MOOD DISORDERS; BEHAVIORAL-MODELS; MAMMALIAN TARGET; DEFICIENT MICE; MOUSE-BRAIN; EXPRESSION; TRKB AB Accumulating evidence suggests that biogenic amine-based antidepressants act, at least in part, via regulation of brain-derived neurotrophic factor (BDNF) signaling. Biogenic amine-based antidepressants increase BDNF synthesis and activate its signaling pathway through TrkB receptors. Moreover, the antidepressant-like effects of these molecules are abolished in BDNF deficient mice. Glutamate-based drugs, including the NMDA antagonist ketamine, and the AMPA receptor potentiator LY 451646, mimic the effects of antidepressants in preclinical tests with high predictive validity. In humans, a single intravenous dose of ketamine produces an antidepressant effect that is rapid, robust and persistent. In this study, we examined the role of BDNF in expression of the antidepressant-like effects of ketamine and an AMPA receptor potentiator (LY 451646) in the forced swim test (FST). Ketamine and LY 451646 produced antidepressant-like effects in the FST in mice at 45 min after a single injection, but no effects were observed one week after a single ketamine injection. As previously reported, the effects of imipramine in the forced swim test were blunted in heterozygous BDNF knockout (bdnf(+/-)) mice. However ketamine and LY 451646 produced similar antidepressant-like responses in wildtype and bdnf(+/-) mice. Neither ketamine nor LY 451646 significantly influenced the levels BDNF or TrkB phosphorylation in the hippocampus when assessed at 45 min or 7 days after the drug administration. These data demonstrate that under the conditions tested, neither ketamine nor the AMPA-potentiator LY 451656 activate BDNF signaling, but produce a characteristic antidepressant-like response in heterozygous bdnf(+/-) mice. These data indicate that unlike biogenic amine-based agents, BDNF signaling does not play a pivotal role in the antidepressant effects of glutamate-based compounds. This article is part of a Special Issue entitled 'Anxiety and Depression'. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Castren, Eero] Univ Helsinki, Sigrid Juselius Lab, Ctr Neurosci, FIN-00014 Helsinki, Finland. [Lindholm, Jesse S. O.] Univ Helsinki, Fac Biol & Environm Sci, Dept Biosci Physiol, FIN-00014 Helsinki, Finland. [Lindemann, Lothar; Hoener, Marius C.] F Hoffmann La Roche Ltd, Roche Discovery Neurosci, CH-4070 Basel, Switzerland. [Skolnick, Phil] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. [Castren, Eero] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. RP Castren, E (reprint author), Univ Helsinki, Sigrid Juselius Lab, Ctr Neurosci, POB 56, FIN-00014 Helsinki, Finland. EM eero.castren@helsinki.fi RI Hoener, Marius/I-6464-2012; OI Hoener, Marius/0000-0001-6510-6250; Antila, Hanna/0000-0001-8317-4564; Rantamaki, Tomi/0000-0002-0052-1434; Castren, Eero/0000-0002-1402-2791 FU Academy of Finland Center of Excellence; Sigrid Juselius Foundation FX We thank Dr. Mark D. Lister at Eli Lilly and Company for the generous gift of LY 451646, N. Karpova, O. Nikkila and E. Tiraboschi for technical assistance and S. Pastell for animal care. This work was financially supported by The Academy of Finland Center of Excellence program and the Sigrid Juselius Foundation. NR 54 TC 38 Z9 38 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2012 VL 62 IS 1 SI SI BP 391 EP 397 DI 10.1016/j.neuropharm.2011.08.015 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 845MM UT WOS:000296826800043 PM 21867718 ER PT J AU Ihne, JL Fitzgerald, PJ Hefner, KR Holmes, A AF Ihne, Jessica L. Fitzgerald, Paul J. Hefner, Kathryn R. Holmes, Andrew TI Pharmacological modulation of stress-induced behavioral changes in the light/dark exploration test in male C57BL/6J mice SO NEUROPHARMACOLOGY LA English DT Article DE Fluoxetine; Lithium; Mood; Depression; Animal model ID CHRONIC MILD STRESS; ELEVATED PLUS-MAZE; STRAIN DIFFERENCES; ANIMAL-MODEL; MOUSE STRAIN; ANTIDEPRESSANT TREATMENTS; CHRONIC FLUOXETINE; BALB/CJ MICE; ANXIETY; DEPRESSION AB Psychological stress is a major risk factor for mood and anxiety disorders. However, the phenotypic manifestation of stress effects varies across individuals, likely due, in part, to genetic variation. Modeling the behavioral and neural consequences of stress across genetically diverse inbred mouse strains is a valuable approach to studying gene x stress interactions. Recent work has shown that C57BL/6J mice exposed to ten daily sessions of restraint stress exhibited increased exploration of the aversive light compartment in the light/dark exploration (LDE) test. Here we sought to clarify the nature of this stress-induced phenotype by testing the ability of treatment with various clinically efficacious drugs of different therapeutic classes to rescue it. Ten days of restraint increased light compartment exploration, reduced body weight and sensitized the corticosterone response to swim stress. Subchronic administration (during stress and LDE testing) of fluoxetine, and to a lesser extent, lithium chloride, rescued stress-induced LDE behavior. Chronic fluoxetine treatment prior to (plus during stress and testing) failed to block the LDE stress effect Acute administration of antipsychotic haloperidol, anti-ADHD medication methylphenidate or anxiolytic drug chlordiazepoxide, prior to LDE testing, was also unable to normalize the LDE stress effect. Collectively, these data demonstrate a treatment-selective prophylactic rescue of a restraint stress-induced behavioral abnormality in the C57BL/6J inbred strain. Further work with this novel model could help elucidate genetic and neural mechanisms mediating stress-induced changes in mouse 'emotion-relevant' behaviors and, ultimately, further understanding of the pathophysiology of stress-related neuropsychiatric disorders. This article is part of a Special Issue entitled 'Anxiety and Depression'. Published by Elsevier Ltd. C1 [Ihne, Jessica L.; Fitzgerald, Paul J.; Hefner, Kathryn R.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, Rockville, MD 20852 USA. RP Fitzgerald, PJ (reprint author), NIAAA, Lab Behav & Genom Neurosci, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM fitzpj@mail.nih.gov OI Hefner, Kathryn/0000-0002-5208-7860; Reed, Jessica/0000-0003-0550-7284 FU National Institute on Alcohol Abuse; Alcoholism Intramural Research Program FX We are very grateful to Carolyn Graybeal and Heather Cameron for performing the corticosterone analyses, and to Etienne Sibille and Cara Wellman for valuable discussions. Research was supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. NR 55 TC 24 Z9 26 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2012 VL 62 IS 1 SI SI BP 464 EP 473 DI 10.1016/j.neuropharm.2011.08.045 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 845MM UT WOS:000296826800051 PM 21906605 ER PT J AU Cao, K Yang, X Chen, XJ Zang, YL Liang, JM Tian, J AF Cao, Kai Yang, Xin Chen, Xinjian Zang, Yali Liang, Jimin Tian, Jie TI A novel ant colony optimization algorithm for large-distorted fingerprint matching SO PATTERN RECOGNITION LA English DT Article DE Distortion; Fingerprint matching; Minutiae pairing; Minutia similarity; Ant colony optimization ID IMAGE-ENHANCEMENT; MINUTIAE; SYSTEM; VERIFICATION; MODEL AB Large distortion may be introduced by non-orthogonal finger pressure and 3D-2D mapping during the process of fingerprint capturing. Furthermore, large variations in resolution and geometric distortion may exist among the fingerprint images acquired from different types of sensors. This distortion greatly challenges the traditional minutiae-based fingerprint matching algorithms. In this paper, we propose a novel ant colony optimization algorithm to establish minutiae correspondences in large-distorted fingerprints. First, minutiae similarity is measured by local features, and an assignment graph is constructed by local search. Then, the minutiae correspondences are established by a pseudo-greedy rule and local propagation, and the pheromone matrix is updated by the local and global update rules. Finally, the minutiae correspondences that maximize the matching score are selected as the matching result. To compensate resolution difference of fingerprint images captured from disparate sensors, a common resolution method is adopted. The proposed method is tested on FVC2004 DB1 and a FINGERPASS cross-matching database established by our lab. The experimental results demonstrate that the proposed algorithm can effectively improve the performance of large-distorted fingerprint matching, especially for those fingerprint images acquired from different modes of acquisition. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Cao, Kai; Liang, Jimin; Tian, Jie] Xidian Univ, Life Sci Res Ctr, Sch Life Sci & Technol, Xian 710071, Peoples R China. [Yang, Xin; Zang, Yali; Tian, Jie] Chinese Acad Sci, Inst Automat, Beijing 100190, Peoples R China. [Chen, Xinjian] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Tian, J (reprint author), Xidian Univ, Life Sci Res Ctr, Sch Life Sci & Technol, Xian 710071, Peoples R China. EM tian@ieee.org RI Tian, Jie/H-1190-2011; Tian, Jie/M-5976-2013; Life, FP/M-9555-2013; Liang, Jimin/B-5394-2014; Chen, Xinjian/E-8592-2016 OI Tian, Jie/0000-0003-0498-0432; FU National Natural Science Foundation of China [60902083, 60803151, 60875018]; Beijing Natural Science Fund [4091004]; Fundamental Research Funds for the Central Universities FX This paper is supported by the National Natural Science Foundation of China under Grant nos. 60902083, 60803151, 60875018, Beijing Natural Science Fund under Grant no. 4091004, and the Fundamental Research Funds for the Central Universities. NR 36 TC 12 Z9 12 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 J9 PATTERN RECOGN JI Pattern Recognit. PD JAN PY 2012 VL 45 IS 1 BP 151 EP 161 DI 10.1016/j.patcog.2011.04.016 PG 11 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 831WB UT WOS:000295760700013 ER PT J AU Chen, X Kim, YA Wang, B Wei, W Shi, ZJ Song, Y AF Chen, Xian Kim, Yoo-Ah Wang, Bing Wei, Wei Shi, Zhijie Jerry Song, Yuan TI Fault-tolerant monitor placement for out-of-band wireless sensor network monitoring SO AD HOC NETWORKS LA English DT Article DE Monitoring; Health monitoring; Wireless sensor network; Fault tolerant monitoring; Out-of-band ID COVERAGE AB Monitoring a sensor network to quickly detect faults is important for maintaining the health of the network. Out-of-band monitoring, i.e., deploying dedicated monitors and transmitting monitoring traffic using a separate channel, does not require instrumenting sensor nodes, and hence is flexible (can be added on top of any application) and energy conserving (not consuming resources of the sensor nodes). In this paper, we study fault-tolerant out-of-band monitoring for wireless sensor networks. Our goal is to place a minimum number of monitors in a sensor network so that all sensor nodes are monitored by k distinct monitors, and each monitor serves no more than w sensor nodes. We prove that this problem is NP-hard. For small-scale network, we formulate the problem as an Integer Linear Programming (ILP) problem, and obtain the optimal solution. For large-scale network, the ILP is not applicable, and we propose two algorithms to solve it. The first one is a In(kn) approximation algorithm, where n is the number of sensor nodes. The second is a simple heuristic scheme that has much shorter running time. We evaluate our algorithms using extensive simulation. In small-scale networks, the latter two algorithms provide results close to the optimal solution from the ILP for relatively dense networks. In large-scale networks, the performance of these two algorithms are similar, and for relatively dense networks, the number of monitors required by both algorithms is close to a lower bound. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved. C1 [Chen, Xian; Wang, Bing; Shi, Zhijie Jerry; Song, Yuan] Univ Connecticut, Dept Comp Sci & Engn, Storrs, CT 06269 USA. [Wei, Wei] Univ Massachusetts, Dept Comp Sci, Amherst, MA 01003 USA. [Kim, Yoo-Ah] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Chen, X (reprint author), Univ Connecticut, Dept Comp Sci & Engn, Storrs, CT 06269 USA. EM Xian.Chen@engr.uconn.edu; kimy3@ncbi.nlm.nih.gov; bing@engr.uconn.edu; weiwei@cs.umass.edu; zshi@engr.uconn.edu; Yuan.Song@engr.uconn.edu FU NSF [CNS-0821597, CNS-0709005, 0644188, 0746841]; Qualtech Systems Incorporated FX A preliminary version of this paper appeared in Milcom 2009 [32]. This work was partially supported by NSF awards CNS-0821597, CNS-0709005, NSF CAREER awards 0644188 and 0746841, and Qualtech Systems Incorporated. NR 35 TC 4 Z9 6 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-8705 J9 AD HOC NETW JI Ad Hoc Netw. PD JAN PY 2012 VL 10 IS 1 BP 62 EP 74 DI 10.1016/j.adhoc.2011.05.008 PG 13 WC Computer Science, Information Systems; Telecommunications SC Computer Science; Telecommunications GA 831VF UT WOS:000295758500005 ER PT J AU Knuppel, M Kubicka, S Vogel, A Malek, NP Schneider, M Papendorf, F Greten, T Wedemeyer, J Schneider, A AF Knueppel, M. Kubicka, S. Vogel, A. Malek, N. P. Schneider, M. Papendorf, F. Greten, T. Wedemeyer, J. Schneider, A. TI Combination of Conservative and Interventional Therapy Strategies for Intra- and Extrahepatic Cholangiocellular Carcinoma: A Retrospective Survival Analysis SO GASTROENTEROLOGY RESEARCH AND PRACTICE LA English DT Article ID BILE-DUCT CANCER; NONRESECTABLE HILAR CHOLANGIOCARCINOMA; PHOTODYNAMIC THERAPY; ENDOSCOPIC APPLICATION; GALLBLADDER CARCINOMA; INITIAL-EXPERIENCE; PHASE-II; CHEMOTHERAPY; BILIARY; PALLIATION AB Background. Due to the predominantly advanced stage at the time of diagnosis treatment of cholangiocarcinoma is difficult. Apart from surgical resection, interventional treatment strategies are increasingly used in advanced stage tumours. The aim of the study was a retrospective comparison of the effect of the various forms of treatment on morbidity and mortality. Method. A total of 195 patients, received either chemotherapy or a combination of photodynamic therapy (PDT) or transarterial chemoembolization (TACE) and chemotherapy. Results. The median survival rate for all patients was 15.6 months, 50.8% were still alive 1 year after diagnosis. Patients, who had previously undergone surgery, survived 17.1 months longer than those without surgical treatment (P < .01). Chemotherapy prolonged the survival by 9.2 months (P = .47). Palliative patients under combination of chemotherapy and PDT survived on average 1.8 months longer (P = .28), with chemotherapy and TACE 9.8 months longer (P = .04) compared to chemotherapy alone. Conclusions. It appears that surgical treatment and chemotherapy combined with PDT or TACE may prolong survival. C1 [Knueppel, M.] Hannover Med Sch, Dept Anesthesiol & Intens Care Med, D-30625 Hannover, Germany. [Kubicka, S.; Vogel, A.; Malek, N. P.; Wedemeyer, J.; Schneider, A.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany. [Schneider, M.] Hannover Med Sch, Inst Biometry, Ctr Biometry Med Informat & Med Technol, D-30625 Hannover, Germany. [Papendorf, F.] Hannover Med Sch, Tumour Ctr Hannover, D-30625 Hannover, Germany. [Greten, T.] NCI, Bethesda, MD 20892 USA. RP Knuppel, M (reprint author), Hannover Med Sch, Dept Anesthesiol & Intens Care Med, D-30625 Hannover, Germany. EM m.knueppel@me.com RI huo, hongyao/D-1510-2012; Vogel, Arndt/A-8437-2012; Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 33 TC 4 Z9 4 U1 0 U2 3 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-6121 J9 GASTROENT RES PRACT JI Gastroenterol. Res. Pract. PY 2012 AR 190708 DI 10.1155/2012/190708 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 803GP UT WOS:000293570100001 ER PT J AU Breman, JG Arita, I AF Breman, Joel G. Arita, Isao TI The certification of smallpox eradication and implications for guinea worm, poliomyelitis, and other diseases: Confirming and maintaining a negative SO VACCINE LA English DT Article DE Smallpox eradication; Certification of eradication; Dracunculiasis eradication; Polio; Eradication; WHO Commissions ID VIRUS DESTRUCTION; VACCINE; CONGO AB Rigorous, independent, confirmation of disease eradication is necessary to assure credibility of the claimed accomplishment. The criteria and procedures for formal certification of global disease freedom are based on the biological and epidemiological features of the pathogen and its manifestations. Certification activities by previously endemic and at-risk countries include comprehensive documentation focusing on surveillance, reports of national independent review groups, and special field surveys. National and regional results are reviewed by authoritative International Commissions (ICs) which verify the findings by field visits. The ICs present their results to an independent WHO-convened group ("Global Commission" for smallpox), members of which participate in field visits. When fully satisfied, the Global Commission makes conclusions and recommendations to the World Health Assembly (WHA). Smallpox was confirmed eradicated in 1980 by the WHA less than three years after the last naturally occurring case was detected. Dracunculiasis (guinea worm) freedom has been certified in 187 countries. Regional commissions have certified the Americas, Asia, and Europe polio-free: however, re-establishment of endemic foci in countries previously declared disease-free has created special challenges for completing this program. Post-eradication activities require attention to surveillance, maximum security of the microbial agent, and essential research to assure maintenance of disease freedom. (C) 2011 Published by Elsevier Ltd. C1 [Breman, Joel G.] US Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Arita, Isao] Kumamoto Natl Hosp, Kumamoto, Japan. RP Breman, JG (reprint author), US Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM joel.breman@nih.gov; oiarita@ms2.infobears.ne.jp NR 26 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 30 PY 2011 VL 29 SU 4 BP D41 EP D48 DI 10.1016/j.vaccine.2011.06.018 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 932PN UT WOS:000303303100010 PM 22185832 ER PT J AU Breman, JG Brandling-Bennett, AD AF Breman, Joel G. Brandling-Bennett, A. David TI The challenge of malaria eradication in the twenty-first century: Research linked to operations is the key SO VACCINE LA English DT Article DE Malaria; Eradication; Elimination; Malaria research ID BURDEN AB Interest and support for malaria control, eradication, and research has increased greatly over the past decade. This has resulted from appreciation of the huge medical, social, and economic burden that malaria exacts from endemic populations. Recent breakthroughs in drug development (artemisinin-based combination treatments), preventive interventions (long-lasting, insecticide-treated bed nets), improved diagnosis (rapid diagnostic tests), and community mobilization have resulted in deployment of new antimalarial tools. National programs supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria, the U.S. President's Malaria Initiative, and other donors have resulted in substantial reductions in malaria morbidity and mortality. Bill and Melinda Gates have given great impetus to eradication with support for the development of key research strategies and direct funding of innovative research projects, including malaria vaccine and drug discovery, that could decrease disease and transmission. Linking research to field operations is a strategy that succeeded for smallpox eradication and will be required for the demise of malaria. Published by Elsevier Ltd. C1 [Breman, Joel G.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Brandling-Bennett, A. David] Bill & Melinda Gates Fdn, Global Hlth Program, Seattle, WA 98102 USA. RP Breman, JG (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM joel.breman@nih.gov; David.Brandling-Bennett@gatesfoundation.org NR 29 TC 11 Z9 12 U1 3 U2 29 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 30 PY 2011 VL 29 SU 4 BP D97 EP D103 DI 10.1016/j.vaccine.2011.12.003 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 932PN UT WOS:000303303100020 PM 22284402 ER PT J AU Muyembe-Tamfum, JJ Mulembakani, P Lekie, RB Szczeniowski, M Jezek, Z Doshi, R Hoff, N Rimoin, AW AF Muyembe-Tamfum, Jean-Jacques Mulembakani, Prime Lekie, Rene Botee Szczeniowski, Mark Jezek, Zdenek Doshi, Reena Hoff, Nicole Rimoin, Anne W. TI Smallpox and its eradication in the Democratic Republic of Congo: Lessons learned SO VACCINE LA English DT Article DE Smallpox; Monkeypox; Polio; Eradication; Democratic Republic of Congo; History ID POLIO ERADICATION; HUMAN MONKEYPOX; CAMPAIGN AB Smallpox eradication is considered to be one of the most remarkable accomplishments of the 20th century. Lessons learned from the campaign during the 1960s and 1970s in the Democratic Republic of Congo (DRC) can provide important information for the development of other eradication programs including polio. The DRC is the third largest country in Africa; the population suffers from extreme poverty, deteriorating infrastructure and health systems, and long periods of civil strife. Despite these challenges, DRC's smallpox eradication campaign was successful, eradicating smallpox only 41 months after initiation. DRC had been polio free since 2001; however, in 2006, imported cases were identified in the country. Polio transmission has since been re-established and DRC now has the second greatest number of reported polio cases in the world. Challenges which existed during the smallpox campaign in DRC are still present today; additionally, the polio vaccine itself poses unique challenges which include requiring multiple doses to confer immunity. In the fight against polio in DRC, it will be important to draw from the smallpox eradication experience. A number of important themes emerged during the campaign that could be beneficial to eradicating polio and future eradication programs that may follow. During the smallpox campaign, a standard vaccination program was implemented, surveillance was intensified, and there were strong collaborative programs with community involvement. These successful elements of the smallpox campaign should be adapted and applied in DRC in polio eradication programs. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Muyembe-Tamfum, Jean-Jacques] Natl Inst Biomed Res, Kinshasa, Zaire. [Mulembakani, Prime] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Lekie, Rene Botee] Minist Hlth, Kinshasa, Zaire. [Szczeniowski, Mark; Jezek, Zdenek] WHO, CH-1211 Geneva, Switzerland. [Doshi, Reena; Hoff, Nicole; Rimoin, Anne W.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. [Rimoin, Anne W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Muyembe-Tamfum, JJ (reprint author), Natl Inst Biomed Res, BP 1197 Kinshasa, Kinshasa, Zaire. EM jjmuyembe@yahoo.fr; pmulembakani@gvfi.org; markszczeniowski@wanadoo.fr; zdenek.jezek@post.cz; rhdoshi@ucla.edu; nhoff84@ucla.edu; arimoin@ucla.edu NR 30 TC 4 Z9 4 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 30 PY 2011 VL 29 SU 4 BP D13 EP D18 DI 10.1016/j.vaccine.2011.10.049 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 932PN UT WOS:000303303100005 PM 22188930 ER PT J AU Rimoin, AW Graham, BS AF Rimoin, Anne W. Graham, Barney S. TI Whither monkeypox vaccination SO VACCINE LA English DT Article DE Orthopoxvirus; Vaccine; Biodefense; Smallpox; Variola ID PROTECTIVE IMMUNITY; SMALLPOX VACCINES; PRAIRIE DOGS; VIRUS; CONGO; TRANSMISSION; INFECTION; ERADICATION AB Monkeypox (MPX) is a virulent orthopoxvirus that is endemic in some regions of Central Africa. MPX incidence has been rising since the cessation of routine smallpox immunization. While it causes significant disease, there is limited person-to-person spread, the incidence is still relatively low, and cases are generally restricted to remote areas that are difficult to access. Therefore, initiating vaccine trials or implementing vaccination programs would be challenging. This paper considers the factors that may influence future decisions on whether MPX vaccination should be pursued. Published by Elsevier Ltd. C1 [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Rimoin, Anne W.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC 3017,Bldg 40,Room 2502, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU Intramural NIH HHS [ZIA AI005047-09] NR 22 TC 2 Z9 2 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 30 PY 2011 VL 29 SU 4 BP D60 EP D64 DI 10.1016/j.vaccine.2011.09.004 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 932PN UT WOS:000303303100013 PM 22188935 ER PT J AU Braun, R Leibon, G Pauls, S Rockmore, D AF Braun, Rosemary Leibon, Gregory Pauls, Scott Rockmore, Daniel TI Partition decoupling for multi-gene analysis of gene expression profiling data SO BMC BIOINFORMATICS LA English DT Article ID PROSTATE-CANCER; CLUSTER-ANALYSIS; CLASS DISCOVERY; MICROARRAY; CLASSIFICATION; PATTERNS; INFORMATION; ALGORITHM; SOFTWARE; NETWORK AB Background: Multi-gene interactions likely play an important role in the development of complex phenotypes, and relationships between interacting genes pose a challenging statistical problem in microarray analysis, since the genes involved in these interactions may not exhibit marginal differential expression. As a result, it is necessary to develop tools that can identify sets of interacting genes that discriminate phenotypes without requiring that the classification boundary between phenotypes be convex. Results: We describe an extension and application of a new unsupervised statistical learning technique, known as the Partition Decoupling Method (PDM), to gene expression microarray data. This method may be used to classify samples based on multi-gene expression patterns and to identify pathways associated with phenotype, without relying upon the differential expression of individual genes. The PDM uses iterated spectral clustering and scrubbing steps, revealing at each iteration progressively finer structure in the geometry of the data. Because spectral clustering has the ability to discern clusters that are not linearly separable, it is able to articulate relationships between samples that would be missed by distance-and tree-based classifiers. After projecting the data onto the cluster centroids and computing the residuals ("scrubbing"), one can repeat the spectral clustering, revealing clusters that were not discernible in the first layer. These iterations, each of which provide a partition of the data that is decoupled from the others, are carried forward until the structure in the residuals is indistinguishable from noise, preventing over-fitting. We describe the PDM in detail and apply it to three publicly available cancer gene expression data sets. By applying the PDM on a pathway-by-pathway basis and identifying those pathways that permit unsupervised clustering of samples that match known sample characteristics, we show how the PDM may be used to find sets of mechanistically-related genes that may play a role in disease. An R package to carry out the PDM is available for download. Conclusions: We show that the PDM is a useful tool for the analysis of gene expression data from complex diseases, where phenotypes are not linearly separable and multi-gene effects are likely to play a role. Our results demonstrate that the PDM is able to distinguish cell types and treatments with higher accuracy than is obtained through other approaches, and that the Pathway-PDM application is a valuable technique for identifying disease-associated pathways. C1 [Braun, Rosemary] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Braun, Rosemary] Northwestern Univ, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Braun, Rosemary] NCI, NIH, Bethesda, MD 20892 USA. [Leibon, Gregory; Pauls, Scott; Rockmore, Daniel] Dartmouth Coll, Dept Math, Hanover, NH 03755 USA. [Rockmore, Daniel] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Braun, R (reprint author), Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. EM rosemary.braun@gmail.com OI Braun, Rosemary/0000-0001-9668-9866; Pauls, Scott/0000-0002-0281-2868 FU Cancer Prevention Fellowship Program; National Cancer Institute, NIH FX RB would like to thank Sean Brocklebank (University of Edinburgh) for many fruitful discussions. This work was made possible by the Santa Fe Institute Complex Systems Summer School (2009). RB is supported by the Cancer Prevention Fellowship Program and a Cancer Research Training Award, National Cancer Institute, NIH. NR 47 TC 4 Z9 4 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 30 PY 2011 VL 12 AR 497 DI 10.1186/1471-2105-12-497 PG 19 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 889YN UT WOS:000300112200001 PM 22208906 ER PT J AU Dai, LS Tsai-Morris, CH Sato, H Villar, J Kang, JH Zhang, JB Dufau, ML AF Dai, Lisheng Tsai-Morris, Chon-Hwa Sato, Hisashi Villar, Joaquin Kang, Jung-Hoon Zhang, Jiabao Dufau, Maria L. TI Testis-specific miRNA-469 Up-regulated in Gonadotropin-regulated Testicular RNA Helicase (GRTH/DDX25)-null Mice Silences Transition Protein 2 and Protamine 2 Messages at Sites within Coding Region IMPLICATIONS OF ITS ROLE IN GERM CELL DEVELOPMENT SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA; DROSHA-DGCR8 COMPLEX; MICRORNA BIOGENESIS; CHROMATOID BODY; SELF-RENEWAL; STEM-CELLS; SPERMATOGENESIS; EXPRESSION; GRTH/DDX25; DIFFERENTIATION AB Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a testis-specific member of the DEAD-box family, is an essential post-transcriptional regulator of spermatogenesis. Failure of expression of Transition protein 2 (TP2) and Protamine 2 (Prm2) proteins (chromatin remodelers, essential for spermatid elongation and completion of spermatogenesis) with preservation of their mRNA expression was observed in GRTH-null mice (azoospermic due to failure of spermatids to elongate). These were identified as target genes for the testis-specific miR-469, which is increased in the GRTH-null mice. Further analysis demonstrated that miR-469 repressed TP2 and Prm2 protein expression at the translation level with minor effect on mRNA degradation, through binding to the coding regions of TP2 and Prm2 mRNAs. The corresponding primary-microRNAs and the expression levels of Drosha and DGCR8 (both mRNA and protein) were increased significantly in the GRTH-null mice. miR-469 silencing of TP2 and Prm2 mRNA in pachytene spermatocytes and round spermatids is essential for their timely translation at later times of spermiogenesis, which is critical to attain mature sperm. Collectively, these studies indicate that GRTH, a multifunctional RNA helicase, acts as a negative regulator of miRNA-469 biogenesis and consequently their function during spermatogenesis. C1 [Dai, Lisheng; Tsai-Morris, Chon-Hwa; Sato, Hisashi; Villar, Joaquin; Kang, Jung-Hoon; Dufau, Maria L.] Eunice Kennedy Shriver NICHD, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Dai, Lisheng; Zhang, Jiabao] Jilin Univ, Lab Anim Ctr, Coll Anim Sci & Vet Med, Changchun 130062, Jilin, Peoples R China. RP Dufau, ML (reprint author), Eunice Kennedy Shriver NICHD, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bldg 49,Rm 6A-36, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported, in whole or in part, by National Institutes of Health Intramural Program through the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 57 TC 24 Z9 27 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 30 PY 2011 VL 286 IS 52 BP 44306 EP 44318 DI 10.1074/jbc.M111.282756 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 870CA UT WOS:000298645500002 PM 22086916 ER PT J AU Hooten, NN Kompaniez, K Barnes, J Lohani, A Evans, MK AF Hooten, Nicole Noren Kompaniez, Kari Barnes, Janice Lohani, Althaf Evans, Michele K. TI Poly(ADP-ribose) Polymerase 1 (PARP-1) Binds to 8-Oxoguanine-DNA Glycosylase (OGG1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; OXIDATIVE DNA-DAMAGE; MAMMALIAN-CELLS; GENETIC POLYMORPHISMS; HUMAN HOMOLOG; LUNG-CANCER; COMET ASSAY; IN-VIVO; CLONING; HOGG1 AB Human 8-oxoguanine-DNA glycosylase (OGG1) plays a major role in the base excision repair pathway by removing 8-oxoguanine base lesions generated by reactive oxygen species. Here we report a novel interaction between OGG1 and Poly( ADP-ribose) polymerase 1 (PARP-1), a DNA-damage sensor protein involved in DNA repair and many other cellular processes. We found that OGG1 binds directly to PARP-1 through the N-terminal region of OGG1, and this interaction is enhanced by oxidative stress. Furthermore, OGG1 binds to PARP-1 through its BRCA1 C-terminal (BRCT) domain. OGG1 stimulated the poly(ADP-ribosyl)ation activity of PARP-1, whereas decreased poly(ADP-ribose) levels were observed in OGG1(-/-) cells compared with wild-type cells in response to DNA damage. Importantly, activated PARP-1 inhibits OGG1. Although the OGG1 polymorphic variant proteins R229Q and S326C bind to PARP-1, these proteins were defective in activating PARP-1. Furthermore, OGG1(-/-) cells were more sensitive to PARP inhibitors alone or in combination with a DNA-damaging agent. These findings indicate that OGG1 binding to PARP-1 plays a functional role in the repair of oxidative DNA damage. C1 [Hooten, Nicole Noren; Kompaniez, Kari; Barnes, Janice; Lohani, Althaf; Evans, Michele K.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIA, Lab Mol Biol & Immunol, NIH, 251 Bayview Bld, Baltimore, MD 21224 USA. EM me42v@nih.gov OI Noren Hooten, Nicole/0000-0002-1683-3838 FU National Institutes of Health National Institute on Aging (NIA) FX This work was supported by the National Institutes of Health National Institute on Aging, Intramural Research Program (NIA). NR 60 TC 21 Z9 22 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 30 PY 2011 VL 286 IS 52 BP 44679 EP 44690 DI 10.1074/jbc.M111.255869 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 870CA UT WOS:000298645500038 ER PT J AU Airavaara, M Pletnikova, O Doyle, ME Zhang, YE Troncoso, JC Liu, QR AF Airavaara, Mikko Pletnikova, Olga Doyle, Maire E. Zhang, Yong E. Troncoso, Juan C. Liu, Qing-Rong TI Identification of Novel GDNF Isoforms and cis-Antisense GDNFOS Gene and Their Regulation in Human Middle Temporal Gyrus of Alzheimer Disease SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEURONS IN-VIVO; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; NUCLEUS-ACCUMBENS; HUMAN BRAIN; BDNF GENES; EXPRESSION; SURVIVAL; MOUSE; IMMUNOREACTIVITY AB Primate-specific genes and isoforms could provide insight into human brain diseases. Our bioinformatic analysis revealed that there are possibly five isoforms of human GDNF gene with different pre- and pro-regions by inter- and intra-exon splicing. By using TaqMan primer probe sets, designed between exons, we verified the expression of all isoforms. Furthermore, a novel GDNFOS gene was found to be transcribed from the opposite strand of GDNF gene. GDNFOS gene has four exons that are spliced into different isoforms. GDNFOS1 and GDNFOS2 are long noncoding RNAs, and GDNFOS3 encodes a protein of 105 amino acids. To study human GDNF and GDNFOS regulation in neurodegenerative diseases, the protein and mRNA levels were measured by Western blot and RT-quantitative PCR, respectively, in postmortem middle temporal gyrus (MTG) of Alzheimer disease (AD) and Huntington disease (HD) patients in comparison with those of normal controls. In the MTG of AD patients, the mature GDNF peptide was down-regulated; however, the transcript of GDNF isoform from human exon 2 was up-regulated, whereas that of the conserved isoform from exon 1 remained unchanged in comparison with those of normal controls. In contrast, the mature GDNF peptide and the isoform mRNA levels were not changed in the MTG of HD. The findings of novel GDNF and GDNFOS isoforms and differences in tissue expression patterns dysregulated in AD brains may further reveal the role of endogenous GDNF in human brain diseases. C1 [Liu, Qing-Rong] NIDA, Behav Neurosci Branch, IRP, NIH,DHSS, Baltimore, MD 21224 USA. [Airavaara, Mikko] NIDA, Neural Protect & Regenerat Sect, IRP, NIH,DHSS, Baltimore, MD 21224 USA. [Pletnikova, Olga; Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Div Neuropathol, Dept Pathol, Baltimore, MD 21205 USA. [Doyle, Maire E.] Johns Hopkins Med Inst, Div Endocrinol, Baltimore, MD 21224 USA. [Zhang, Yong E.] Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China. RP Liu, QR (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHSS, 251 Bayview Blvd,Ste 200, Baltimore, MD 21224 USA. EM qliu@intra.nida.nih.gov RI Zhang, Yong/A-7855-2011; Liu, Qing-Rong/A-3059-2012; OI Liu, Qing-Rong/0000-0001-8477-6452; Airavaara, Mikko/0000-0002-2026-1609 FU National Institutes of Health NIDA; Johns Hopkins University Alzheimer's Disease Research Center (NIA) [P50AG051460]; Huntington's Research Center without Walls (NINDS) [PO1NS16375]; Integrated Islet Distribution Program; NIDDK; JDRF; Alzheimer's Association [IIRG-09-134090] FX This work was supported, in whole or in part, by National Institutes of Health NIDA intramural research program. This work was also supported by the Johns Hopkins University Alzheimer's Disease Research Center (NIA P50AG051460), the Huntington's Research Center without Walls (NINDS PO1NS16375), the Integrated Islet Distribution Program, funded by the NIDDK and the JDRF.; Supported by a Juvenile Diabetes Research Foundation career award from the Sanford Project (Sioux Falls, SD).; Recipient of a grant from the Alzheimer's Association (IIRG-09-134090). NR 55 TC 26 Z9 29 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 30 PY 2011 VL 286 IS 52 BP 45093 EP 45102 DI 10.1074/jbc.M111.310250 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 870CA UT WOS:000298645500076 PM 22081608 ER PT J AU Marsh, AA Finger, EC Fowler, KA Jurkowitz, ITN Schechter, JC Yu, HH Pine, DS Blair, RJR AF Marsh, Abigail A. Finger, Elizabeth C. Fowler, Katherine A. Jurkowitz, Ilana T. N. Schechter, Julia C. Yu, Henry H. Pine, Daniel S. Blair, R. J. R. TI Reduced amygdala-orbitofrontal connectivity during moral judgments in youths with disruptive behavior disorders and psychopathic traits SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Conduct disorder; Psychopathy; Moral reasoning; fMRI ID VENTROMEDIAL PREFRONTAL CORTEX; CALLOUS-UNEMOTIONAL TRAITS; COMMON STEREOTACTIC SPACE; PURE CONDUCT DISORDER; ANTERIOR CINGULATE; CRIMINAL PSYCHOPATHS; PREDICTIVE-VALIDITY; CHILDREN; BOYS; ABNORMALITIES AB We used functional magnetic resonance imaging (fMRI) to investigate dysfunction in the amygdala and orbitofrontal cortex in adolescents with disruptive behavior disorders and psychopathic traits during a moral judgment task. Fourteen adolescents with psychopathic traits and 14 healthy controls were assessed using fMRI while they categorized illegal and legal behaviors in a moral judgment implicit association task. fMRI data were then analyzed using random-effects analysis of variance and functional connectivity. Youths with psychopathic traits showed reduced amygdala activity when making judgments about legal actions and reduced functional connectivity between the amygdala and orbitofrontal cortex during task performance. These results suggest that psychopathic traits are associated with amygdala and orbitofrontal cortex dysfunction. This dysfunction may relate to previous findings of disrupted moral judgment in this population. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Marsh, Abigail A.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. [Marsh, Abigail A.; Fowler, Katherine A.; Jurkowitz, Ilana T. N.; Yu, Henry H.; Pine, Daniel S.; Blair, R. J. R.] NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. [Finger, Elizabeth C.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. [Schechter, Julia C.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. RP Marsh, AA (reprint author), Georgetown Univ, Dept Psychol, 37th & O St NW, Washington, DC 20057 USA. EM aam72@georgetown.edu RI Finger, Elizabeth/B-6453-2015 FU NIH: NIMH FX This research was supported by the Intramural Research Program of the NIH: NIMH. We wish to thank Andy Speer and Marguerite Reid for their assistance in conducting this research. NR 51 TC 47 Z9 50 U1 7 U2 41 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD DEC 30 PY 2011 VL 194 IS 3 BP 279 EP 286 DI 10.1016/j.pscychresns.2011.07.008 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 868KQ UT WOS:000298522600011 PM 22047730 ER PT J AU Brittain, E Follmann, D AF Brittain, Erica Follmann, Dean TI A hierarchical rank test for crossover trials with censored data SO STATISTICS IN MEDICINE LA English DT Article DE crossover trials; Cox regression; subjective rankings; survival times ID SUBJECTIVE RANKINGS; CLINICAL-TRIALS AB We propose an approach to analyze survival time in a crossover clinical trial by performing a primary ranking on whether events occur and a secondary ranking on event times. This hierarchical ranking method is meant to reflect the idea that the goal of therapy is to prevent a clinical event and, failing that, to delay the occurrence of the event, hopefully for a substantial amount of time. We compare our approach with other methods including one method proposed by Feingold and Gillespie, a recommended procedure. The power is similar in many settings, but the hierarchical ranking can have substantially greater power under certain censoring patterns and also under a cure model, or models where treatment induces a substantial delay in some fraction of patients. We additionally feel that the hierarchical ranking method should be more clinically relevant in many settings. The method can also be applied to continuous outcomes censored by a limit of detection, such as HIV viremia. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Brittain, Erica; Follmann, Dean] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Brittain, E (reprint author), NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. EM ebrittain@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 19 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 30 PY 2011 VL 30 IS 30 BP 3507 EP 3519 DI 10.1002/sim.4398 PG 13 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 860YY UT WOS:000297986300004 PM 22139739 ER PT J AU Berger, VW AF Berger, Vance W. TI Can objective endpoints be manipulated in unmasked trials? SO STATISTICS IN MEDICINE LA English DT Letter C1 [Berger, Vance W.] Natl Canc Inst, Biometry Res Grp, Bethesda, MD 20892 USA. UMBC, Baltimore, MD 21250 USA. RP Berger, VW (reprint author), Natl Canc Inst, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 30 PY 2011 VL 30 IS 30 BP 3573 EP 3574 DI 10.1002/sim.4312 PG 2 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 860YY UT WOS:000297986300009 PM 22161953 ER PT J AU Kuehn, HS Jung, MY Beaven, MA Metcalfe, DD Gilfillan, AM AF Kuehn, Hye Sun Jung, Mi-Yeon Beaven, Michael A. Metcalfe, Dean D. Gilfillan, Alasdair M. TI Distinct PGE(2)-responder and non-responder phenotypes in human mast cell populations: "All or nothing" enhancement of antigen-dependent mediator release SO IMMUNOLOGY LETTERS LA English DT Article DE Mast cells; PGE(2); Degranulation; Cytokine release; Signaling ID FC-EPSILON-RI; PROSTAGLANDIN E-2; KIT ACTIVATION; RECEPTORS; PHOSPHORYLATION; DEGRANULATION; AGGREGATION; MECHANISMS; RESPONSES; 3-KINASE AB Reports indicate that prostaglandin (PG)E-2 markedly enhances antigen-mediated degranulation in mouse bone marrow-derived mast cells (BMMCs) but not in human mast cells (HuMCs). We have examined the underlying mechanism(s) for this disparity in HuMCs derived from the peripheral blood of multiple donors in addition to mouse BMMCs. HuMCs from half of these donors failed to respond to PGE(2) and the PGE(2) EP3 receptor agonist, sulprostone. However. HuMCs from the remaining donors and the LAD2 human MC line responded to PGE(2) and sulprostone with marked enhancement of antigen-mediated degranulation and IL-8 production in a similar manner to that observed in mouse BMMCs. The EP2 agonist, butaprost, failed to modulate antigen-mediated responses in any type of MCs. These distinct phenotypes could not be explained by differences in EP2 or EP3 expression nor by differences in the ability of PGE2 to elevate levels of cAMP, a signal recognized to down-regulate mast cell activation. Moreover, both responder and non-responder HuMC populations exhibited similar activation of phosphatidylinositol 3-kinase, and MAP kinases. However, translocation of PLC gamma(1) to the cell membrane and the associated calcium signal were enhanced only in the responder HuMC population indicating that the link between EP3 and PLC gamma is impaired in the non-responder HuMCs. Conclusions: These data provide a cautionary note for the translating of observations in the mouse to human mast cell-dependent disorders, but may also provide a basis for examining the effects of co-activating receptors in patients susceptible to allergic conditions. Published by Elsevier B.V. C1 [Kuehn, Hye Sun; Jung, Mi-Yeon; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C206,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov FU Division of Intramural Research of NIAID; NHLBI within the National Institutes of Health FX Financial support for this work was provided by the Division of Intramural Research of NIAID and NHLBI within the National Institutes of Health. NR 33 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD DEC 30 PY 2011 VL 141 IS 1 BP 45 EP 54 DI 10.1016/j.imlet.2011.07.002 PG 10 WC Immunology SC Immunology GA 859JC UT WOS:000297871700006 PM 21798286 ER PT J AU Gwamaka, M Fried, M Domingo, G Duffy, PE AF Gwamaka, Moses Fried, Michal Domingo, Gonzalo Duffy, Patrick E. TI Early and extensive CD55 loss from red blood cells supports a causal role in malarial anaemia SO MALARIA JOURNAL LA English DT Article ID PERCOLL DENSITY GRADIENTS; DECAY-ACCELERATING FACTOR; PLASMODIUM-FALCIPARUM MALARIA; CIRCULATING IMMUNE-COMPLEXES; ERYTHROCYTE FRACTIONATION; COMPLEMENT; CR-1; MECHANISM; CHILDREN; BINDING AB Background: Levels of complement regulatory proteins (CrP) on the surface of red blood cells (RBC) decrease during severe malarial anaemia and as part of cell ageing process. It remains unclear whether CrP changes seen during malaria contribute to the development of anaemia, or result from an altered RBC age distribution due to suppressive effects of malaria on erythropoiesis. Methods: A cross sectional study was conducted in the north-east coast of Tanzania to investigate whether the changes in glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins (CD55 and CD59) contributes to malaria anaemia. Blood samples were collected from a cohort of children under intensive surveillance for Plasmodium falciparum parasitaemia and illness. Levels of CD55 and CD59 were measured by flow cytometer and compared between anaemic (8.08 g/dl) and non-anaemic children (11.42 g/dl). Results: Levels of CD55 and CD59 decreased with increased RBC age. CD55 levels were lower in anaemic children and the difference was seen in RBC of all ages. Levels of CD59 were lower in anaemic children, but these differences were not significant. CD55, but not CD59, levels correlated positively with the level of haemoglobin in anaemic children. Conclusion: The extent of CD55 loss from RBC of all ages early in the course of malarial anaemia and the correlation of CD55 with haemoglobin levels support the hypothesis that CD55 may play a causal role in this disorder. C1 [Gwamaka, Moses; Fried, Michal; Domingo, Gonzalo; Duffy, Patrick E.] Muheza Designated Dist Hosp, Mother Offspring Malaria Studies Project, Muheza, Tanzania. [Gwamaka, Moses] Sokoine Univ Agr, Morogoro, Tanzania. [Gwamaka, Moses] IHI, Biomed & Environm Themat Grp, Ifakara, Tanzania. [Fried, Michal; Duffy, Patrick E.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20892 USA. [Domingo, Gonzalo] PATH, Seattle, WA 98121 USA. RP Gwamaka, M (reprint author), Muheza Designated Dist Hosp, Mother Offspring Malaria Studies Project, Muheza, Tanzania. EM mgwamaka@ihi.or.tz FU Grand Challenges in Global Health/Foundation for NIH [1364]; National Institutes of Health [R01AI52059]; Fogarty International Center (FIC)/NIH [D43 TW005509] FX The authors gratefully acknowledge the participation of the mothers and their children in the MOMS Project, and the work of the MOMS Project staff, including assistant medical officers, nurses, village health workers, laboratory technicians, microscopists, and data entry personnel. Also, the IHI core funding which paid for MG time while preparing this paper is acknowledged. This work was supported by funds to PED from the Grand Challenges in Global Health/Foundation for NIH Grant 1364, the National Institutes of Health Grant R01AI52059, and the Fogarty International Center (FIC)/NIH Grant D43 TW005509. This publication is solely the responsibility of the authors and does not necessarily represent the official views of the FIC. NR 31 TC 12 Z9 12 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD DEC 29 PY 2011 VL 10 AR 386 DI 10.1186/1475-2875-10-386 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 909VT UT WOS:000301594700002 PM 22206234 ER PT J AU Hansen, L Kim, NK Marino-Ramirez, L Landsman, D AF Hansen, Loren Kim, Nak-Kyeong Marino-Ramirez, Leonardo Landsman, David TI Analysis of Biological Features Associated with Meiotic Recombination Hot and Cold Spots in Saccharomyces cerevisiae SO PLOS ONE LA English DT Article ID DOUBLE-STRAND BREAKS; GENE-EXPRESSION DATA; CHROMATIN-STRUCTURE; FEATURE-SELECTION; INITIATION SITES; FISSION YEAST; DNA BREAKS; NUCLEOSOME ORGANIZATION; SAMPLE CLASSIFICATION; HISTONE MODIFICATIONS AB Meiotic recombination is not distributed uniformly throughout the genome. There are regions of high and low recombination rates called hot and cold spots, respectively. The recombination rate parallels the frequency of DNA double-strand breaks (DSBs) that initiate meiotic recombination. The aim is to identify biological features associated with DSB frequency. We constructed vectors representing various chromatin and sequence-based features for 1179 DSB hot spots and 1028 DSB cold spots. Using a feature selection approach, we have identified five features that distinguish hot from cold spots in Saccharomyces cerevisiae with high accuracy, namely the histone marks H3K4me3, H3K14ac, H3K36me3, and H3K79me3; and GC content. Previous studies have associated H3K4me3, H3K36me3, and GC content with areas of mitotic recombination. H3K14ac and H3K79me3 are novel predictions and thus represent good candidates for further experimental study. We also show nucleosome occupancy maps produced using next generation sequencing exhibit a bias at DSB hot spots and this bias is strong enough to obscure biologically relevant information. A computational approach using feature selection can productively be used to identify promising biological associations. H3K14ac and H3K79me3 are novel predictions of chromatin marks associated with meiotic DSBs. Next generation sequencing can exhibit a bias that is strong enough to lead to incorrect conclusions. Care must be taken when interpreting high throughput sequencing data where systematic biases have been documented. C1 [Hansen, Loren; Marino-Ramirez, Leonardo; Landsman, David] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Hansen, Loren] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Kim, Nak-Kyeong] Old Dominion Univ, Dept Math & Stat, Norfolk, VA 23529 USA. [Marino-Ramirez, Leonardo] PanAmerican Bioinformat Inst, Santa Marta, Magdalena, Colombia. RP Marino-Ramirez, L (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM marino@ncbi.nlm.nih.gov RI Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU National Institutes of Health; National Library of Medicine; National Center for Biotechnology Information FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine and National Center for Biotechnology Information. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 6 Z9 6 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 29 PY 2011 VL 6 IS 12 AR e29711 DI 10.1371/journal.pone.0029711 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 897SP UT WOS:000300677000057 PM 22242140 ER PT J AU Ohnishi, T Yamada, K Watanabe, A Ohba, H Sakaguchi, T Honma, Y Iwayama, Y Toyota, T Maekawa, M Watanabe, K Detera-Wadleigh, SD Wakana, S Yoshikawa, T AF Ohnishi, Tetsuo Yamada, Kazuo Watanabe, Akiko Ohba, Hisako Sakaguchi, Toru Honma, Yota Iwayama, Yoshimi Toyota, Tomoko Maekawa, Motoko Watanabe, Kazutada Detera-Wadleigh, Sevilla D. Wakana, Shigeharu Yoshikawa, Takeo TI Ablation of Mrds1/Ofcc1 Induces Hyper-gamma-Glutamyl Transpeptidasemia without Abnormal Head Development and Schizophrenia-Relevant Behaviors in Mice SO PLOS ONE LA English DT Article ID PEDIGREE DISEQUILIBRIUM TEST; GENE DTNBP1; COMMON VARIANTS; 6P22.3 GENE; ASSOCIATION; IDENTIFICATION; DYSBINDIN; LINKAGE; RISK; MORPHOGENESIS AB Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as "the Japan Mouse Clinic". No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum c-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-c-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-c-glutamyl transpeptidasemia and schizophrenia. C1 [Ohnishi, Tetsuo; Yamada, Kazuo; Watanabe, Akiko; Ohba, Hisako; Sakaguchi, Toru; Honma, Yota; Iwayama, Yoshimi; Toyota, Tomoko; Maekawa, Motoko; Yoshikawa, Takeo] RIKEN Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama, Japan. [Sakaguchi, Toru; Honma, Yota; Watanabe, Kazutada] Nagaoka Univ Technol, Dept Bioengn, Nagaoka, Niigata 94021, Japan. [Detera-Wadleigh, Sevilla D.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Wakana, Shigeharu] RIKEN BioResource Ctr, Technol & Dev Team Mouse Phenotype Anal, Tsukuba, Ibaraki, Japan. RP Ohnishi, T (reprint author), RIKEN Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama, Japan. EM tohnishi@brain.riken.jp FU RIKEN BSI FX This study was supported mainly by the RIKEN BSI Funds. A part of this study is the result of "Development of Biomarker Candidates for Social Behavior" carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 29 PY 2011 VL 6 IS 12 AR e29499 DI 10.1371/journal.pone.0029499 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 897SP UT WOS:000300677000041 PM 22242126 ER PT J AU Carson, JL Terrin, ML Noveck, H Sanders, DW Chaitman, BR Rhoads, GG Nemo, G Dragert, K Beaupre, L Hildebrand, K Macaulay, W Lewis, C Cook, DR Dobbin, G Zakriya, KJ Apple, FS Horney, RA Magaziner, J AF Carson, Jeffrey L. Terrin, Michael L. Noveck, Helaine Sanders, David W. Chaitman, Bernard R. Rhoads, George G. Nemo, George Dragert, Karen Beaupre, Lauren Hildebrand, Kevin Macaulay, William Lewis, Courtland Cook, Donald Richard Dobbin, Gwendolyn Zakriya, Khwaja J. Apple, Fred S. Horney, Rebecca A. Magaziner, Jay CA FOCUS Investigators TI Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CRITICALLY-ILL; TRIAL AB BACKGROUND The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. METHODS We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. RESULTS A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. CONCLUSIONS A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.) C1 [Carson, Jeffrey L.; Noveck, Helaine; Dragert, Karen] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, Div Gen Internal Med, New Brunswick, NJ 08903 USA. [Terrin, Michael L.; Magaziner, Jay] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Zakriya, Khwaja J.] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. [Sanders, David W.] Univ Western Ontario, Div Orthopaed Surg, London, ON, Canada. [Beaupre, Lauren] Univ Alberta, Dept Phys Therapy & Surg, Edmonton, AB, Canada. [Beaupre, Lauren] Univ Alberta, Div Orthopaed Surg, Edmonton, AB, Canada. [Hildebrand, Kevin] Univ Calgary, Div Orthoped Surg, Calgary, AB, Canada. [Cook, Donald Richard] Univ Calgary, Dept Med, Calgary, AB, Canada. [Dobbin, Gwendolyn] QEII Hlth Sci Ctr, Dept Orthoped Surg, Halifax, NS, Canada. [Chaitman, Bernard R.] St Louis Univ, Sch Med, Dept Med, St Louis, MO 63103 USA. [Rhoads, George G.] Univ Med & Dent New Jersey, Sch Publ Hlth, Dept Epidemiol, Piscataway, NJ 08854 USA. [Nemo, George] NHLBI, Transfus Med & Cellular Therapeut Branch, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Horney, Rebecca A.] Vet Affairs Med Ctr, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Macaulay, William] Columbia Univ, Dept Orthoped Surg, New York Presbyterian Hosp, New York, NY USA. [Lewis, Courtland] Hartford Hosp, Hartford, CT 06115 USA. [Apple, Fred S.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Apple, Fred S.] Minneapolis Med Res Fdn Inc, Hennepin Cty Med Ctr, Minneapolis, MN USA. RP Carson, JL (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, Div Gen Internal Med, 125 Paterson St, New Brunswick, NJ 08903 USA. EM carson@umdnj.edu RI Naudie, Douglas /B-5779-2015; Hildebrand, Kevin/N-8394-2015 OI Hildebrand, Kevin/0000-0001-8786-9021 FU National Heart, Lung, and Blood Institute [U01 HL073958, U01 HL074815]; Amgen; Orthopaedic Associates of Hartford; Abbott Diagnostics; Ortho Clinical Diagnostics; Instrumentation Laboratories; Siemens; Roche Diagnostics; BioRad; Response Biomedical; Radiometer; BRAHMS; Alere; Eli Lily; Sanofi-Aventis; Novartis; Merck FX Supported in part by grants from the National Heart, Lung, and Blood Institute (U01 HL073958 and U01 HL074815).; Dr. Carson reports receiving grant support to his institution from Amgen; Dr. Lewis, receiving a salary from the Orthopaedic Associates of Hartford, receiving a stipend for serving as president of the Hartford County Medical Association, and providing expert testimony representing the American Academy of Orthopaedic Surgery on the Medicare Evidence Development and Coverage Advisory Committee; Dr. Apple, serving as a scientific advisory board member for Abbott Laboratories, Alere, Beckman Coulter, Ortho Clinical Diagnostics, and Instrumentation Laboratories, receiving consulting fees from Abbott Diagnostics, Ortho Clinical Diagnostics, and Instrumentation Laboratories, receiving grant support to his institution from Abbott Diagnostics, Siemens, Ortho Clinical Diagnostics, Roche Diagnostics, BioRad, Response Biomedical, Radiometer, and BRAHMS, and receiving lecture fees and travel expenses from Abbott Diagnostics and Alere; Dr. Magazine, serving as a board member for Amgen, Novartis, and GlaxoSmithKline and receiving consulting fees from Eli Lily, Sanofi-Aventis, and Amgen, grant support to his institution from Novartis, Merck, and Eli Lilly, and lecture fees from Novartis. No other potential conflict of interest relevant to this article was reported. NR 14 TC 456 Z9 474 U1 0 U2 29 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 DEC 29 PY 2011 VL 365 IS 26 BP 2453 EP 2462 DI 10.1056/NEJMoa1012452 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 868SD UT WOS:000298544600006 PM 22168590 ER PT J AU Tang, LY Zhang, YE AF Tang, Liu-Ya Zhang, Ying E. TI Non-degradative ubiquitination in Smad-dependent TGF-beta signaling SO CELL AND BIOSCIENCE LA English DT Review ID SQUAMOUS-CELL CARCINOMA; RECEPTOR; LIGASE; TARGETS; E3; PHOSPHORYLATION; HOMEOSTASIS; PATHWAYS; POLARITY; CANCER AB Transforming growth factor-beta (TGF-beta) signaling is tightly regulated at the level of post-translational modification to transmit quantitative difference in ligand concentration into proportional transcriptional output. Ubiquitination is one such modification with several E3 ubiquitin ligases implicated in TGF-beta signaling in marking crucial pathway components for proteasomal degradation. However, ubiquitination, particularly in the mono-or oligo-ubiquitin modifying form, is also known to regulate incorporation of substrate proteins into signaling complexes that involved in DNA repair, kinase activation, and endocytosis. This review focuses on recent advances in understanding the role of such non-degradative ubiquitination in TGF-beta signaling. C1 [Tang, Liu-Ya; Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhang, YE (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM zhangyin@mail.nih.gov RI Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 FU US National Institutes of Health, US National Cancer Institute, Center for Cancer Research FX Research in Y.E. Zhang's group is supported by the intramural research program of the US National Institutes of Health, US National Cancer Institute, Center for Cancer Research. NR 34 TC 9 Z9 10 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD DEC 28 PY 2011 VL 1 AR 43 DI 10.1186/2045-3701-1-43 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982QQ UT WOS:000307060900005 PM 22204598 ER PT J AU Zhang, YE AF Zhang, Ying E. TI A special issue on TGF-beta signaling and biology SO CELL AND BIOSCIENCE LA English DT Editorial Material C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zhang, YE (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ZhangYin@mail.nih.gov RI Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 NR 5 TC 4 Z9 4 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD DEC 28 PY 2011 VL 1 AR 39 DI 10.1186/2045-3701-1-39 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982QQ UT WOS:000307060900001 PM 22204389 ER PT J AU Goodman, AL Blagborough, AM Biswas, S Wu, YM Hill, AV Sinden, RE Draper, SJ AF Goodman, Anna L. Blagborough, Andrew M. Biswas, Sumi Wu, Yimin Hill, Adrian V. Sinden, Robert E. Draper, Simon J. TI A Viral Vectored Prime-Boost Immunization Regime Targeting the Malaria Pfs25 Antigen Induces Transmission-Blocking Activity SO PLOS ONE LA English DT Article ID SUBUNIT VACCINE IMMUNOGENICITY; MEROZOITE SURFACE PROTEIN-1; PLASMODIUM-FALCIPARUM; FUNCTIONAL IMMUNOGENICITY; ADJUVANT VACCINES; SEXUAL STAGE; IN-VITRO; ANTIBODIES; CANDIDATE; IMMUNITY AB The ookinete surface protein Pfs25 is a macrogamete-to-ookinete/ookinete stage antigen of Plasmodium falciparum, capable of exerting high-level anti-malarial transmission-blocking activity following immunization with recombinant protein-in-adjuvant formulations. Here, this antigen was expressed in recombinant chimpanzee adenovirus 63 (ChAd63), human adenovirus serotype 5 (AdHu5) and modified vaccinia virus Ankara (MVA) viral vectored vaccines. Two immunizations were administered to mice in a heterologous prime-boost regime. Immunization of mice with AdHu5 Pfs25 at week 0 and MVA Pfs25 at week 10 (Ad-MVA Pfs25) resulted in high anti-Pfs25 IgG titers, consisting of predominantly isotypes IgG1 and IgG2a. A single priming immunization with ChAd63 Pfs25 was as effective as AdHu5 Pfs25 with respect to ELISA titers at 8 weeks post-immunization. Sera from Ad-MVA Pfs25 immunized mice inhibited the transmission of P. falciparum to the mosquito both ex vivo and in vivo. In a standard membrane-feeding assay using NF54 strain P. falciparum, oocyst intensity in Anopheles stephensi mosquitoes was significantly reduced in an IgG concentration-dependent manner when compared to control feeds (96% reduction of intensity, 78% reduction in prevalence at a 1 in 5 dilution of sera). In addition, an in vivo transmission-blocking effect was also demonstrated by direct feeding of immunized mice infected with Pfs25DR3, a chimeric P. berghei line expressing Pfs25 in place of endogenous Pbs25. In this assay the density of Pfs25DR3 oocysts was significantly reduced when mosquitoes were fed on vaccinated as compared to control mice (67% reduction of intensity, 28% reduction in prevalence) and specific IgG titer correlated with efficacy. These data confirm the utility of the adenovirus-MVA vaccine platform for the induction of antibodies with transmission-blocking activity, and support the continued development of this alternative approach to transmission-blocking malaria subunit vaccines. C1 [Goodman, Anna L.; Biswas, Sumi; Hill, Adrian V.; Sinden, Robert E.; Draper, Simon J.] Univ Oxford, Jenner Inst, Oxford, England. [Blagborough, Andrew M.; Sinden, Robert E.] Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, London, England. [Wu, Yimin] NIAID, Lab Malaria Immunol & Vaccinol, Rockville, MD USA. RP Goodman, AL (reprint author), Univ Oxford, Jenner Inst, Oxford, England. EM anna.goodman@nhs.net RI Draper, Simon/F-1758-2011 OI Draper, Simon/0000-0002-9415-1357 FU Medical Research Council [G0600424]; Transmolbloc (EU); BBSRC [LDAD_P15820] FX This work was supported primarily by grant G0600424 from the Medical Research Council (ALG) and in addition by Transmolbloc (EU FP7) and BBSRC (award number LDAD_P15820). SJD and AVH are Jenner Investigators. SJD is a MRC Career Development Fellow. AVH is a Wellcome Trust Principal Research Fellow. ALG was an MRC clinical training fellow whilst she undertook this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. http://www.mrc.ac.uk/index.htm. http://www.bbsrc.ac.uk/. http://www.wellcome.ac.uk/. NR 57 TC 25 Z9 26 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 28 PY 2011 VL 6 IS 12 AR e29428 DI 10.1371/journal.pone.0029428 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 897SK UT WOS:000300676300059 PM 22216279 ER PT J AU Wehby, GL Castilla, EE Goco, N Rittler, M Cosentino, V Javois, L Kindem, M Chakraborty, H Dutra, G Lopez-Camelo, JS Orioli, IM Murray, JC AF Wehby, George L. Castilla, Eduardo E. Goco, Norman Rittler, Monica Cosentino, Viviana Javois, Lorette Kindem, Mark Chakraborty, Hrishikesh Dutra, Graca Lopez-Camelo, Jorge S. Orioli, Ieda M. Murray, Jeffrey C. TI The effect of systematic pediatric care on neonatal mortality and hospitalizations of infants born with oral clefts SO BMC PEDIATRICS LA English DT Article ID OROFACIAL CLEFTS; FOLLOW-UP; 1ST-YEAR MORTALITY; BIRTH-DEFECTS; OF-LIFE; LIP; PALATE; SURVIVAL; CHILDREN; ASSOCIATION AB Background: Cleft lip and/or palate (CL/P) increase mortality and morbidity risks for affected infants especially in less developed countries. This study aimed at assessing the effects of systematic pediatric care on neonatal mortality and hospitalizations of infants with cleft lip and/or palate (CL/P) in South America. Methods: The intervention group included live-born infants with isolated or associated CL/P in 47 hospitals between 2003 and 2005. The control group included live-born infants with CL/P between 2001 and 2002 in the same hospitals. The intervention group received systematic pediatric care between the 7th and 28th day of life. The primary outcomes were mortality between the 7th and 28th day of life and hospitalization days in this period among survivors adjusted for relevant baseline covariates. Results: There were no significant mortality differences between the intervention and control groups. However, surviving infants with associated CL/P in the intervention group had fewer hospitalization days by about six days compared to the associated control group. Conclusions: Early systematic pediatric care may significantly reduce neonatal hospitalizations of infants with CL/P and additional birth defects in South America. Given the large healthcare and financial burden of CL/P on affected families and the relatively low cost of systematic pediatric care, improving access to such care may be a cost-effective public policy intervention. C1 [Murray, Jeffrey C.] Univ Iowa, Coll Med, Dept Pediat, Iowa City, IA 52242 USA. [Wehby, George L.] Univ Iowa, Coll Publ Hlth, Dept Hlth Management & Policy, Iowa City, IA USA. [Castilla, Eduardo E.; Lopez-Camelo, Jorge S.] Cemic, ECLAMC Latin Amer Collaborat Study Congenital Mal, Buenos Aires, DF, Argentina. [Castilla, Eduardo E.; Dutra, Graca] Inst Oswaldo Cruz, ECLAMC, BR-20001 Rio De Janeiro, Brazil. [Castilla, Eduardo E.; Dutra, Graca; Orioli, Ieda M.] INAGEMP Natl Inst Populat Med Genet, ECLAMC, Porto Alegre, RS, Brazil. [Goco, Norman; Kindem, Mark] RTI Int, Div Stat Res, Res Triangle Pk, NC USA. [Rittler, Monica] Maternidad Ramon Sarda, ECLAMC, Buenos Aires, DF, Argentina. [Cosentino, Viviana; Kindem, Mark] Cemic, ECLAMC, Buenos Aires, DF, Argentina. [Javois, Lorette] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Biol Genet & Teratol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD USA. [Chakraborty, Hrishikesh] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Lopez-Camelo, Jorge S.] Imbice, ECLAMC, La Plata, Buenos Aires, Argentina. [Orioli, Ieda M.] Univ Fed Rio de Janeiro, Dept Genet, ECLAMC, Rio De Janeiro, Brazil. RP Murray, JC (reprint author), Univ Iowa, Coll Med, Dept Pediat, Iowa City, IA 52242 USA. EM jeff-murray@uiowa.edu RI Inagemp, Inct/J-9451-2013 FU NIH [U01HD04056, R37 DE08559, 1 R03 DE018394]; CDC [1R01DD000295]; University of Iowa; ECLAMC; RTI FX This study was funded by NIH U01HD04056 and NIH R37 DE08559. Data analysis was in part supported by NIH 1 R03 DE018394 and CDC 1R01DD000295. The authors thank the participating families and the ECLAMC study pediatricians. Written consent for publication was obtained from the study subjects or their relatives. The authors acknowledge the research support and input of staff at the University of Iowa (Sandra Daack-Hirsch; Carol Guarnizo Herreno), ECLAMC (Alejandra Mariona), and RTI (Tyler Hartwell, Hillary Harris, Stephen Litavecz). NR 39 TC 5 Z9 5 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD DEC 28 PY 2011 VL 11 AR 121 DI 10.1186/1471-2431-11-121 PG 12 WC Pediatrics SC Pediatrics GA 891XJ UT WOS:000300249800001 PM 22204448 ER PT J AU Parsons, HM Tuttle, TM Virnig, BA AF Parsons, Helen M. Tuttle, Todd M. Virnig, Beth A. TI Lymph Node Evaluation for Colon Cancer Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Parsons, Helen M.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Virnig, Beth A.] Univ Minnesota, Div Hlth Policy & Management, Minneapolis, MN USA. [Tuttle, Todd M.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. RP Parsons, HM (reprint author), NCI, Appl Res Program, Bethesda, MD 20892 USA. EM helen.parsons@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 28 PY 2011 VL 306 IS 24 BP 2669 EP 2669 DI 10.1001/jama.2011.1883 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 867VX UT WOS:000298484000013 ER PT J AU Shaw, P AF Shaw, Philip TI ADHD Medications and Cardiovascular Risk Some Heartening News SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CARDIAC SAFETY; ADULTS; METHYLPHENIDATE; ADOLESCENTS; CHILDREN; PREVALENCE; DISEASE; DRUGS C1 NHGRI, Bethesda, MD 20892 USA. RP Shaw, P (reprint author), NHGRI, Bldg 31,Room B1B37, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov NR 15 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 28 PY 2011 VL 306 IS 24 BP 2723 EP 2724 DI 10.1001/jama.2011.1866 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 867VX UT WOS:000298484000026 PM 22161945 ER PT J AU Abedi-Ardekani, B Kamangar, F Sotoudeh, M Villar, S Islami, F Aghcheli, K Nasrollahzadeh, D Taghavi, N Dawsey, SM Abnet, CC Hewitt, SM Fahimi, S Saidi, F Brennan, P Boffetta, P Malekzadeh, R Hainaut, P AF Abedi-Ardekani, Behnoush Kamangar, Farin Sotoudeh, Masoud Villar, Stephanie Islami, Farhad Aghcheli, Karim Nasrollahzadeh, Dariush Taghavi, Noushin Dawsey, Sanford M. Abnet, Christian C. Hewitt, Stephen M. Fahimi, Saman Saidi, Farrokh Brennan, Paul Boffetta, Paolo Malekzadeh, Reza Hainaut, Pierre TI Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran SO PLOS ONE LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; HIGH-RISK AREA; NORTHEASTERN IRAN; DNA-DAMAGE; TOBACCO-SMOKE; NORTHERN IRAN; P53 MUTATIONS; CANCER; POPULATION; CHINA AB Background: Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. Methodology/Principal Findings: Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. Conclusion/Significance: ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis. C1 [Abedi-Ardekani, Behnoush; Sotoudeh, Masoud; Islami, Farhad; Aghcheli, Karim; Nasrollahzadeh, Dariush; Taghavi, Noushin; Fahimi, Saman; Saidi, Farrokh; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Abedi-Ardekani, Behnoush; Villar, Stephanie; Islami, Farhad; Brennan, Paul; Hainaut, Pierre] Int Agcy Res Canc, F-69372 Lyon, France. [Abedi-Ardekani, Behnoush] Social Secur Org, Tehran, Iran. [Kamangar, Farin; Dawsey, Sanford M.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Nasrollahzadeh, Dariush] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Fahimi, Saman] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Abedi-Ardekani, B (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. EM hainaut@iarc.fr RI Abnet, Christian/C-4111-2015; Abedi-Ardekani, Behnoush/O-7829-2016; Hainaut, Pierre/B-6018-2012; OI Abnet, Christian/0000-0002-3008-7843; Abedi-Ardekani, Behnoush/0000-0002-0980-0587; Hewitt, Stephen/0000-0001-8283-1788; Hainaut, Pierre/0000-0002-1303-1610; Malekzadeh, Reza/0000-0003-1043-3814 FU Division of Cancer Epidemiology; Genetics of the National Cancer Institute at the National Institutes of Health, Bethesda, Maryland, USA; International Agency for Research on Cancer, Lyon, France; Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran FX This work was supported by intramural funds of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute at the National Institutes of Health, Bethesda, Maryland, USA and by regular budgets from the International Agency for Research on Cancer, Lyon, France and the Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 12 Z9 12 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 27 PY 2011 VL 6 IS 12 AR e29488 DI 10.1371/journal.pone.0029488 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 897SB UT WOS:000300674900040 PM 22216294 ER PT J AU Fang, F Chen, HL Wirdefeldt, K Ronnevi, LO Al-Chalabi, A Peters, TL Kamel, F Ye, WM AF Fang, Fang Chen, Honglei Wirdefeldt, Karin Ronnevi, Lars-Olof Al-Chalabi, Ammar Peters, Tracy L. Kamel, Freya Ye, Weimin TI Infection of the Central Nervous System, Sepsis and Amyotrophic Lateral Sclerosis SO PLOS ONE LA English DT Article ID MOTOR-NEURON DISEASE; INFLAMMATORY RESPONSE; UNITED-STATES; ALS PATIENTS; SPINAL-CORD; DEATH; MORTALITY; NEURODEGENERATION; PROGRESSION; MICROGLIA AB Background: Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients. Methodology and Principal Findings: The present study included 4,004 ALS patients identified from the Swedish Patient Register during 1991-2007 and 20,020 age and sex matched general population controls. Conditional logistic regression was used to estimate the odds ratios (ORs) of ALS given a previous hospitalization for CNS infection or sepsis. Cox models were used to estimate the hazard ratios (HRs) of hospitalization for CNS infection or sepsis after ALS diagnosis. Overall, previous CNS infection (OR: 1.3, 95% confidence interval [CI]: 0.8, 2.4) or sepsis (OR: 1.2, 95% CI: 0.9, 1.6) was not associated with ALS risk. However, compared to ALS free individuals, ALS cases were more likely to be hospitalized for sepsis after diagnosis (HR: 2.6, 95% CI: 1.9, 3.5). We did not observe a higher risk of CNS infection after ALS diagnosis. Conclusions/Significance: Our results suggest that acute and severe infections unlikely contribute to the development of ALS; however, ALS patients are at a higher risk of sepsis after diagnosis, compared to ALS free individuals. C1 [Fang, Fang; Wirdefeldt, Karin; Peters, Tracy L.; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Chen, Honglei; Kamel, Freya] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Wirdefeldt, Karin; Ronnevi, Lars-Olof] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Al-Chalabi, Ammar] Kings Coll London, MRC Ctr Neurodegenerat Res, Inst Psychiat, London, England. RP Fang, F (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM fang.fang@ki.se RI Al-Chalabi, Ammar/E-5361-2010; OI Al-Chalabi, Ammar/0000-0002-4924-7712; Fang, Fang/0000-0002-3310-6456; Kamel, Freya/0000-0001-5052-6615; Chen, Honglei/0000-0003-3446-7779 FU Swedish Research Council (SIMSAM) [80748301]; Hjarnfonden; Svenska Sallskapet for Medicinsk Forskning (SSMF); National Institutes of Health, the National Institute of Environmental Health Sciences of the United States; European Community [FP7/2007-2013, 259867] FX This work was supported by Swedish Research Council (SIMSAM grant number 80748301). Drs. Fang Fang and Karin Wirdefeldt were supported by Hjarnfonden and the Svenska Sallskapet for Medicinsk Forskning (SSMF). Drs. Honglei Chen and Freya Kamel were supported by the intramural research program of National Institutes of Health, the National Institute of Environmental Health Sciences of the United States. We also thank the NIHR specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry, King's College London. The research leading to these results also received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259867. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 10 Z9 10 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 27 PY 2011 VL 6 IS 12 AR e29749 DI 10.1371/journal.pone.0029749 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 897SB UT WOS:000300674900058 PM 22216353 ER PT J AU Zaal, KJM Reid, E Mousavi, K Zhang, T Mehta, A Bugnard, E Sartorelli, V Ralston, E AF Zaal, Kristien J. M. Reid, Ericka Mousavi, Kambiz Zhang, Tan Mehta, Amisha Bugnard, Elisabeth Sartorelli, Vittorio Ralston, Evelyn TI Who Needs Microtubules? Myogenic Reorganization of MTOC, Golgi Complex and ER Exit Sites Persists Despite Lack of Normal Microtubule Tracks SO PLOS ONE LA English DT Article ID MUSCLE-CELL DIFFERENTIATION; HAMSTER OVARY CELLS; ENDOPLASMIC-RETICULUM; SKELETAL-MUSCLE; LIVING CELLS; CENTROSOME PROTEINS; ORGANIZING CENTERS; SIGNALING PATHWAY; BINDING-PROTEIN; MANNOSIDASE-II AB A wave of structural reorganization involving centrosomes, microtubules, Golgi complex and ER exit sites takes place early during skeletal muscle differentiation and completely remodels the secretory pathway. The mechanism of these changes and their functional implications are still poorly understood, in large part because all changes occur seemingly simultaneously. In an effort to uncouple the reorganizations, we have used taxol, nocodazole, and the specific GSK3-beta inhibitor DW12, to disrupt the dynamic microtubule network of differentiating cultures of the mouse skeletal muscle cell line C2. Despite strong effects on microtubules, cell shape and cell fusion, none of the treatments prevented early differentiation. Redistribution of centrosomal proteins, conditional on differentiation, was in fact increased by taxol and nocodazole and normal in DW12. Redistributions of Golgi complex and ER exit sites were incomplete but remained tightly linked under all circumstances, and conditional on centrosomal reorganization. We were therefore able to uncouple microtubule reorganization from the other events and to determine that centrosomal proteins lead the reorganization hierarchy. In addition, we have gained new insight into structural and functional aspects of the reorganization of microtubule nucleation during myogenesis. C1 [Zaal, Kristien J. M.; Reid, Ericka; Zhang, Tan; Mehta, Amisha; Bugnard, Elisabeth; Ralston, Evelyn] NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. [Mousavi, Kambiz; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Bugnard, Elisabeth] Ctr Univ Orsay, Inst Curie, F-91405 Orsay, France. RP Zaal, KJM (reprint author), NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. EM zaalk@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This work was funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 9 Z9 9 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 27 PY 2011 VL 6 IS 12 AR e29057 DI 10.1371/journal.pone.0029057 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 897SB UT WOS:000300674900009 PM 22216166 ER PT J AU Schellenberg, MJ Williams, RS AF Schellenberg, Matthew J. Williams, R. Scott TI DNA end processing by polynucleotide kinase/phosphatase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID STRAND BREAK REPAIR; NEURODEGENERATIVE DISEASE; SUBSTRATE RECOGNITION; KINASE-ACTIVITY; PHOSPHORYLATION; PHOSPHATASE; MECHANISM; LIGATION; ENZYME; DAMAGE C1 [Schellenberg, Matthew J.; Williams, R. Scott] NIEHS, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Williams, RS (reprint author), NIEHS, Struct Biol Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov RI Williams, Robert/A-6059-2015 FU Intramural NIH HHS [ZIA ES102765-02]; NIEHS NIH HHS [1Z01-ES102765-01] NR 18 TC 6 Z9 6 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 27 PY 2011 VL 108 IS 52 BP 20855 EP 20856 DI 10.1073/pnas.1118214109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 867UI UT WOS:000298479900006 PM 22184240 ER PT J AU Burnette, DT Sengupta, P Dai, YH Lippincott-Schwartz, J Kachar, B AF Burnette, Dylan T. Sengupta, Prabuddha Dai, Yuhai Lippincott-Schwartz, Jennifer Kachar, Bechara TI Bleaching/blinking assisted localization microscopy for superresolution imaging using standard fluorescent molecules SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nanoscopy; diffraction limit; immunofluorescence; subcellular localization; GFP ID OPTICAL RECONSTRUCTION MICROSCOPY; SUBDIFFRACTION-RESOLUTION; EXCITATION MICROSCOPY; ELECTRON-MICROSCOPY; CELLS; PROBES; NANOSCOPY; LIGHT; FLUOROPHORES; IMPROVEMENT AB Superresolution imaging techniques based on the precise localization of single molecules, such as photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM), achieve high resolution by fitting images of single fluorescent molecules with a theoretical Gaussian to localize them with a precision on the order of tens of nanometers. PALM/STORM rely on photoactivated proteins or photoswitching dyes, respectively, which makes them technically challenging. We present a simple and practical way of producing point localization-based superresolution images that does not require photoactivatable or photoswitching probes. Called bleaching/blinking assisted localization microscopy (BaLM), the technique relies on the intrinsic bleaching and blinking behaviors characteristic of all commonly used fluorescent probes. To detect single fluorophores, we simply acquire a stream of fluorescence images. Fluorophore bleach or blink-off events are detected by subtracting from each image of the series the subsequent image. Similarly, blink-on events are detected by subtracting from each frame the previous one. After image subtractions, fluorescence emission signals from single fluorophores are identified and the localizations are determined by fitting the fluorescence intensity distribution with a theoretical Gaussian. We also show that BaLM works with a spectrum of fluorescent molecules in the same sample. Thus, BaLM extends single molecule-based superresolution localization to samples labeled with multiple conventional fluorescent probes. C1 [Burnette, Dylan T.; Sengupta, Prabuddha; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Dai, Yuhai; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov; kacharb@nidcd.nih.gov FU National Institute of Deafness and Other Communication Disorders; National Institute of Child Health and Human Development; National Institute of General Medical Sciences, National Institutes of Health FX We thank Uri Manor, Ronald Petralia, Stephan Brenowitz, and the members of the B. K. and J.L.-S. laboratories for comments on the manuscript; and Robert Adelstein for the generous gift of the myosin IIC-EGFP construct. This research was supported by the Intramural Programs of the National Institute of Deafness and Other Communication Disorders and the National Institute of Child Health and Human Development. D. T. B. was supported by a Pharmacology Research Associate Fellowship from the National Institute of General Medical Sciences, National Institutes of Health during the course of these studies. NR 44 TC 90 Z9 94 U1 3 U2 61 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 27 PY 2011 VL 108 IS 52 BP 21081 EP 21086 DI 10.1073/pnas.1117430109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 867UI UT WOS:000298479900046 PM 22167805 ER PT J AU Wu, J Jiao, YC Dal Molin, M Maitra, A de Wilde, RF Wood, LD Eshleman, JR Goggins, MG Wolfgang, CL Canto, MI Schulick, RD Edil, BH Choti, MA Adsay, V Klimstra, DS Offerhaus, GJA Klein, AP Kopelovich, L Carter, H Karchin, R Allen, PJ Schmidt, CM Naito, Y Diaz, LA Kinzler, KW Papadopoulos, N Hruban, RH Vogelstein, B AF Wu, Jian Jiao, Yuchen Dal Molin, Marco Maitra, Anirban de Wilde, Roeland F. Wood, Laura D. Eshleman, James R. Goggins, Michael G. Wolfgang, Christopher L. Canto, Marcia I. Schulick, Richard D. Edil, Barish H. Choti, Michael A. Adsay, Volkan Klimstra, David S. Offerhaus, G. Johan A. Klein, Alison P. Kopelovich, Levy Carter, Hannah Karchin, Rachel Allen, Peter J. Schmidt, C. Max Naito, Yoshiki Diaz, Luis A., Jr. Kinzler, Kenneth W. Papadopoulos, Nickolas Hruban, Ralph H. Vogelstein, Bert TI Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LINDAU TUMOR-SUPPRESSOR; BETA-CATENIN; DIFFERENTIAL-DIAGNOSIS; COLORECTAL-CANCER; FLUID ANALYSIS; MANAGEMENT; LESIONS; PROTEIN; DISEASE; PREVALENCE AB More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 +/- 4.6, 27 +/- 12, 16 +/- 7.6, and 2.9 +/- 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel-Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (beta-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors. C1 [Dal Molin, Marco; Maitra, Anirban; de Wilde, Roeland F.; Wood, Laura D.; Eshleman, James R.; Goggins, Michael G.; Klein, Alison P.; Hruban, Ralph H.] Johns Hopkins Med Inst, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21231 USA. [Goggins, Michael G.; Canto, Marcia I.] Johns Hopkins Med Inst, Sol Goldman Pancreat Canc Res Ctr, Dept Med, Baltimore, MD 21231 USA. [Wolfgang, Christopher L.; Schulick, Richard D.; Edil, Barish H.; Choti, Michael A.] Johns Hopkins Med Inst, Sol Goldman Pancreat Canc Res Ctr, Dept Surg, Baltimore, MD 21231 USA. [Wu, Jian; Jiao, Yuchen; Diaz, Luis A., Jr.; Kinzler, Kenneth W.; Papadopoulos, Nickolas; Vogelstein, Bert] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet, Baltimore, MD 21231 USA. [Wu, Jian; Jiao, Yuchen; Diaz, Luis A., Jr.; Kinzler, Kenneth W.; Papadopoulos, Nickolas; Vogelstein, Bert] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD 21231 USA. [Adsay, Volkan] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. [Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Allen, Peter J.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Offerhaus, G. Johan A.] Univ Med Ctr Utrecht, Dept Pathol, NL-3508 GA Utrecht, Netherlands. [Kopelovich, Levy] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Kopelovich, Levy; Karchin, Rachel] Johns Hopkins Univ, Dept Biomed Engn, Inst Computat Med, Baltimore, MD USA. [Schmidt, C. Max] Indiana Univ, Dept Surg, Indianapolis, IN 46202 USA. [Schmidt, C. Max] Indiana Univ, Dept Biochem, Indianapolis, IN 46202 USA. [Schmidt, C. Max] Indiana Univ, Dept Mol Biol, Indianapolis, IN 46202 USA. [Naito, Yoshiki] Kurume Univ, Sch Med, Dept Pathol, Kurume, Fukuoka 8300011, Japan. RP Hruban, RH (reprint author), Johns Hopkins Med Inst, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21231 USA. EM rhruban@jhmi.edu; bertvog@gmail.com RI Karchin, Rachel/A-3385-2010; Papadopoulos, Nickolas/K-7272-2012 FU Lustgarten Foundation for Pancreatic Cancer Research; Virginia and D. K. Ludwig Fund for Cancer Research; The Sol Goldman Pancreatic Cancer Research Center; Joseph L. Rabinowitz Fund; Michael Rolfe Foundation; Stringer Foundation; family of Ted and Julie Smith; Indiana Genomics Initiative of Indiana University; Lilly Endowment, Inc.; J. C. Monastra Foundation; Swim Across America; National Science Foundation [DBI-1845275]; National Institutes of Health [CA 62924, CA 57345, CA 152432, CA 43460]; National Cancer Institute [N01-CN-43302, N01-CN-43309, P01CA134292] FX We thank J. Schaeffer, J. Ptak, N. Silliman, M. Whalen, and L. Dobbyn for expert technical assistance. This work was supported by the Lustgarten Foundation for Pancreatic Cancer Research; the Virginia and D. K. Ludwig Fund for Cancer Research; The Sol Goldman Pancreatic Cancer Research Center; the Joseph L. Rabinowitz Fund; the Michael Rolfe Foundation; the Stringer Foundation; the family of Ted and Julie Smith; the Indiana Genomics Initiative of Indiana University, which is supported, in part, by Lilly Endowment, Inc.; the J. C. Monastra Foundation; Swim Across America; National Science Foundation Grant DBI-1845275; National Institutes of Health Grants CA 62924, CA 57345, CA 152432, and CA 43460; and National Cancer Institute Contracts N01-CN-43302, N01-CN-43309, and NCI grant P01CA134292. NR 73 TC 196 Z9 199 U1 0 U2 19 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 27 PY 2011 VL 108 IS 52 BP 21188 EP 21193 DI 10.1073/pnas.1118046108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 867UI UT WOS:000298479900064 PM 22158988 ER PT J AU Lu, J Yang, CZ Chen, M Ye, DY Lonser, RR Brady, RO Zhuang, ZP AF Lu, Jie Yang, Chunzhang Chen, Masako Ye, Donald Y. Lonser, Russell R. Brady, Roscoe O. Zhuang, Zhengping TI Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEAT-SHOCK RESPONSE; ACID BETA-GLUCOSIDASE; ISOFAGOMINE INCREASES; CHEMICAL CHAPERONES; MOLECULAR-BASIS; PROTEIN; ENZYME; MUTANT; FIBROBLASTS; DEFICIENCY AB Gaucher disease (GD) is caused by a spectrum of genetic mutations within the gene encoding the lysosomal enzyme glucocerebrosidase (GCase). These mutations often lead to misfolded proteins that are recognized by the unfolded protein response system and are degraded through the ubiquitin-proteasome pathway. Modulating this pathway with histone deacetylase inhibitors (HDACis) has been shown to improve protein stability in other disease settings. To identify the mechanisms involved in the regulation of GCase and determine the effects of HDACis on protein stability, we investigated the most prevalent mutations for nonneuronopathic (N370S) and neuronopathic (L444P) GD in cultured fibroblasts derived from GD patients and HeLa cells transfected with these mutations. The half-lives of mutant GCase proteins correspond to decreases in protein levels and enzymatic activity. GCase was found to bind to Hsp70, which directed the protein to TCP1 for proper folding, and to Hsp90, which directed the protein to the ubiquitin-proteasome pathway. Using a known HDACi (SAHA) and a unique small-molecule HDACi (LB-205), GCase levels increased rescuing enzymatic activity in mutant cells. The increase in the quantity of protein can be attributed to increases in protein half-life that correspond primarily with a decrease in degradation rather than an increase in chaperoned folding. HDACis reduce binding to Hsp90 and prevent subsequent ubiquitination and proteasomal degradation without affecting binding to Hsp70 or TCP1. These findings provide insight into the pathogenesis of GD and indicate a potent therapeutic potential of HDAC inhibitors for the treatment of GD and other human protein misfolding disorders. C1 [Brady, Roscoe O.] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lu, Jie; Yang, Chunzhang; Chen, Masako; Ye, Donald Y.; Lonser, Russell R.; Zhuang, Zhengping] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. EM bradyr@ninds.nih.gov; zhuangp@ninds.nih.gov FU National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS) FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS). NR 42 TC 40 Z9 41 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 DEC 27 PY 2011 VL 108 IS 52 BP 21200 EP 21205 DI 10.1073/pnas.1119181109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 867UI UT WOS:000298479900066 PM 22160715 ER PT J AU Sam, WJ Chamberlain, CE Lee, SJ Goldstein, JA Hale, DA Mannon, RB Kirk, AD Hon, YY AF Sam, Wai-Johnn Chamberlain, Christine E. Lee, Su-Jun Goldstein, Joyce A. Hale, Douglas A. Mannon, Roslyn B. Kirk, Allan D. Hon, Yuen Yi TI Associations of ABCB1 3435C > T and IL-10-1082G > A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients SO TRANSPLANTATION LA English DT Article DE Sirolimus; ABCB1; CYP3A5; Pharmacogenetics; Pharmacokinetics ID KIDNEY-TRANSPLANTATION; GENETIC POLYMORPHISMS; CYTOCHROME-P450 3A4; MESSENGER-RNA; IN-VIVO; EXPRESSION; CYP3A5; TACROLIMUS; RECIPIENTS; INDUCTION AB Backgrounds. Sirolimus (SRL) absorption and metabolism are affected by p-glycoprotein-mediated transport and CYP3A enzyme activity, which are further under the influences of cytokine concentrations. This retrospective study determined the associations of adenosine triphosphate-binding cassette, subfamily B, member 1 (ABCB1) 1236C>T, 2677 G>T/A, and 3435C>T, cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) -392A>G, cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) 6986A>G and 14690G>A, interleukin (IL)-10 -1082G>A, and tumor necrosis factor (TNF) -308G>A polymorphisms with SRL dose-adjusted, weight-normalized trough concentrations (C/D) at 7 days, and at 1, 3, 6, and 12 months after initiation of SRL. Methods. Genotypes for 86 renal transplant patients who received SRL-based maintenance immunosuppressive therapy were determined using polymerase chain reaction followed by chip-based mass spectrometry. The changes of log-transformed C/D over the days posttransplantation were analyzed using a linear mixed-effects model, with adjustments for body mass index and weight-normalized doses of tacrolimus, prednisone, clotrimazole, and statins. Results. ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with log C/D (P=0.0016 and 0.0394, respectively). Mean SRL C/D was 48% higher in patients with ABCB1 3435CT/TT genotype than those with 3435CC genotype, and was 24% higher in IL-10-1082GG compared with -1082AG/AA. Conclusions. ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with long-term SRL dose requirements. Genetics can play a significant role in SRL dosing and may be useful in therapeutic monitoring of SRL in renal transplantation. Future replication studies are needed to confirm these associations. C1 [Hon, Yuen Yi] NIH, Clin Pharmacokinet Res Lab, Clin Ctr Pharm Dept, Bethesda, MD 20892 USA. [Lee, Su-Jun; Goldstein, Joyce A.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Hale, Douglas A.; Mannon, Roslyn B.; Kirk, Allan D.] NIDDK, Transplantat Branch, Bethesda, MD USA. RP Hon, YY (reprint author), NIH, Clin Pharmacokinet Res Lab, Clin Ctr Pharm Dept, Bldg 10,Room 1C240,10 Ctr Dr, Bethesda, MD 20892 USA. EM chon@cc.nih.gov RI Goldstein, Joyce/A-6681-2012; Kirk, Allan/B-6905-2012 FU NIH Clinical Center Pharmacy Department; National Institute of Diabetes and Digestive and Kidney Diseases Transplantation Branch; National Institute of Environmental Health Sciences [Z01ES02124] FX This study was supported by the Intramural Research Program of the NIH Clinical Center Pharmacy Department, National Institute of Diabetes and Digestive and Kidney Diseases Transplantation Branch, and National Institute of Environmental Health Sciences grant Z01ES02124. NR 37 TC 10 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD DEC 27 PY 2011 VL 92 IS 12 BP 1342 EP 1347 DI 10.1097/TP.0b013e3182384ae2 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 863FW UT WOS:000298149200013 PM 22094953 ER PT J AU Zeng, W Wan, R Zheng, YH Singh, SR Wei, YY AF Zeng, Wen Wan, Rong Zheng, Yuehuan Singh, Shree Ram Wei, Yiyong TI Hypoxia, stem cells and bone tumor SO CANCER LETTERS LA English DT Review DE Hypoxia; Hypoxia inducible factors; Bone tumor; Bone metastasis; Stem cells; Osteosarcoma ID INDUCIBLE FACTOR-I; HORMONE-RELATED PROTEIN; BREAST-CANCER CELLS; KAPPA-B ACTIVATION; HUMAN OSTEOSARCOMA; PROSTATE-CANCER; INITIATING CELLS; EWINGS-SARCOMA; GENE-EXPRESSION; FACTOR 1-ALPHA AB Normal oxygen level is critical for niches that together with other components of the niche play vital role in regulating stem or tumor cells behavior. Hypoxia plays an important role in normal development and disease progression, including the growth of solid tumors. The hypoxia inducible factors (HIFs) are the key mediators of the cellular response to hypoxia. In this review, we focused on the role of HIFs on bone tumor formation. Further, we also emphasized how hypoxia, stem cells, and its niches regulate the bone tumorigenesis. Published by Elsevier Ireland Ltd. C1 [Singh, Shree Ram] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Zeng, Wen] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Dept Orthopaed, Shanghai 200080, Peoples R China. [Zeng, Wen; Wan, Rong; Zheng, Yuehuan; Wei, Yiyong] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Orthopaed,Inst Traumatol & Orthopaed, Shanghai 200025, Peoples R China. RP Singh, SR (reprint author), NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov; dr.yiyongwei@yahoo.com RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU National Natural Science Foundation of China [30801164]; Shanghai Municipal Education Commission [09YZ107]; National Institutes of Health, National Cancer Institute FX This work was supported by National Natural Science Foundation of China (No. 30801164), Innovation Program of Shanghai Municipal Education Commission (No. 09YZ107) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 93 TC 17 Z9 18 U1 1 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD DEC 27 PY 2011 VL 313 IS 2 BP 129 EP 136 DI 10.1016/j.canlet.2011.09.023 PG 8 WC Oncology SC Oncology GA 859SJ UT WOS:000297895800002 PM 21999934 ER PT J AU Chang, C Wang, JW Zhao, C Fostel, J Tong, WD Bushel, PR Deng, YP Pusztai, L Symmans, WF Shi, TL AF Chang, Chang Wang, Junwei Zhao, Chen Fostel, Jennifer Tong, Weida Bushel, Pierre R. Deng, Youping Pusztai, Lajos Symmans, W. Fraser Shi, Tieliu TI Maximizing biomarker discovery by minimizing gene signatures SO BMC GENOMICS LA English DT Article ID SUPPORT VECTOR MACHINES; PRIMARY BREAST-CANCER; EXPRESSION PROFILES; MICROARRAY ANALYSIS; ESTROGEN; CLASSIFICATION; CHEMOTHERAPY; PREDICTION; ALPHA; SENSITIVITY AB Background: The use of gene signatures can potentially be of considerable value in the field of clinical diagnosis. However, gene signatures defined with different methods can be quite various even when applied the same disease and the same endpoint. Previous studies have shown that the correct selection of subsets of genes from microarray data is key for the accurate classification of disease phenotypes, and a number of methods have been proposed for the purpose. However, these methods refine the subsets by only considering each single feature, and they do not confirm the association between the genes identified in each gene signature and the phenotype of the disease. We proposed an innovative new method termed Minimize Feature's Size (MFS) based on multiple level similarity analyses and association between the genes and disease for breast cancer endpoints by comparing classifier models generated from the second phase of MicroArray Quality Control (MAQC-II), trying to develop effective meta-analysis strategies to transform the MAQC-II signatures into a robust and reliable set of biomarker for clinical applications. Results: We analyzed the similarity of the multiple gene signatures in an endpoint and between the two endpoints of breast cancer at probe and gene levels, the results indicate that disease-related genes can be preferably selected as the components of gene signature, and that the gene signatures for the two endpoints could be interchangeable. The minimized signatures were built at probe level by using MFS for each endpoint. By applying the approach, we generated a much smaller set of gene signature with the similar predictive power compared with those gene signatures from MAQC-II. Conclusions: Our results indicate that gene signatures of both large and small sizes could perform equally well in clinical applications. Besides, consistency and biological significances can be detected among different gene signatures, reflecting the studying endpoints. New classifiers built with MFS exhibit improved performance with both internal and external validation, suggesting that MFS method generally reduces redundancies for features within gene signatures and improves the performance of the model. Consequently, our strategy will be beneficial for the microarray-based clinical applications. C1 [Chang, Chang; Wang, Junwei; Zhao, Chen; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Ctr Bioinformat, Shanghai 200241, Peoples R China. [Chang, Chang; Wang, Junwei; Zhao, Chen; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai 200241, Peoples R China. [Fostel, Jennifer] NIEHS, SRA Global Hlth Sect, Res Triangle Pk, NC 27709 USA. [Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Bushel, Pierre R.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Deng, Youping] Rush Univ, Med Ctr, Dept Internal Med, Ctr Canc, Chicago, IL 60612 USA. [Pusztai, Lajos; Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77230 USA. [Pusztai, Lajos; Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77230 USA. RP Shi, TL (reprint author), E China Normal Univ, Sch Life Sci, Ctr Bioinformat, 500 Dongchuan Rd, Shanghai 200241, Peoples R China. EM tlshi@sibs.ac.cn FU State Key Program of Basic Research of China [2010CB945401, 2007CB108800]; National High Technology Research, Development Program of China (863 project) [2006AA02Z313]; National Natural Science Foundation of China [30870575]; Research Platform of Cell Signaling Networks from the Science and Technology Commission of Shanghai Municipality [11DZ2260300]; NIH; NIEHS; Division of Intramural Research of the NIEHS [HHSN273200700046U] FX We are grateful to the MAQC Consortium to provide the datasets. This research was supported by the State Key Program of Basic Research of China grants (2010CB945401 and 2007CB108800), the National High Technology Research, Development Program of China (863 project) (Grant No. 2006AA02Z313), National Natural Science Foundation of China grants (30870575) and Research Platform of Cell Signaling Networks from the Science and Technology Commission of Shanghai Municipality (11DZ2260300). This research was also supported, in part by, the Intramural Research Program of the NIH and NIEHS. JF was supported by the Division of Intramural Research of the NIEHS under contract HHSN273200700046U. NR 40 TC 4 Z9 4 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 23 PY 2011 VL 12 SU 5 AR S6 DI 10.1186/1471-2164-12-S5-S6 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 940WB UT WOS:000303922700007 PM 22369133 ER PT J AU Wu, X Li, P Wang, N Gong, P Perkins, EJ Deng, YP Zhang, CY AF Wu, Xi Li, Peng Wang, Nan Gong, Ping Perkins, Edward J. Deng, Youping Zhang, Chaoyang TI State Space Model with hidden variables for reconstruction of gene regulatory networks SO BMC SYSTEMS BIOLOGY LA English DT Article AB Background: State Space Model (SSM) is a relatively new approach to inferring gene regulatory networks. It requires less computational time than Dynamic Bayesian Networks (DBN). There are two types of variables in the linear SSM, observed variables and hidden variables. SSM uses an iterative method, namely Expectation-Maximization, to infer regulatory relationships from microarray datasets. The hidden variables cannot be directly observed from experiments. How to determine the number of hidden variables has a significant impact on the accuracy of network inference. In this study, we used SSM to infer Gene regulatory networks (GRNs) from synthetic time series datasets, investigated Bayesian Information Criterion (BIC) and Principle Component Analysis (PCA) approaches to determining the number of hidden variables in SSM, and evaluated the performance of SSM in comparison with DBN. Method: True GRNs and synthetic gene expression datasets were generated using GeneNetWeaver. Both DBN and linear SSM were used to infer GRNs from the synthetic datasets. The inferred networks were compared with the true networks. Results: Our results show that inference precision varied with the number of hidden variables. For some regulatory networks, the inference precision of DBN was higher but SSM performed better in other cases. Although the overall performance of the two approaches is compatible, SSM is much faster and capable of inferring much larger networks than DBN. Conclusion: This study provides useful information in handling the hidden variables and improving the inference precision. C1 [Wu, Xi; Wang, Nan; Zhang, Chaoyang] Univ So Mississippi, Sch Comp, Hattiesburg, MS 39406 USA. [Li, Peng] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Gong, Ping] SpecPro Inc, Environm Serv, San Antonio, TX 78216 USA. [Perkins, Edward J.] USA, Environm Lab, Engineer Res & Dev Ctr, Vicksburg, MS 39180 USA. [Deng, Youping] Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA. RP Zhang, CY (reprint author), Univ So Mississippi, Sch Comp, Hattiesburg, MS 39406 USA. EM chaoyang.zhang@usm.edu FU US Army Corps of Engineers Environmental Quality [W912HZ-08-2-0011]; NSF EPSCoR [EPS-0903787] FX This work was supported by the US Army Corps of Engineers Environmental Quality Program under contract #W912HZ-08-2-0011 and the NSF EPSCoR project "Modeling and Simulation of Complex Systems" (NSF #EPS-0903787). Permission was granted by the Chief of Engineers to publish this information. NR 18 TC 5 Z9 5 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD DEC 23 PY 2011 VL 5 SU 3 AR S3 DI 10.1186/1752-0509-5-S3-S3 PG 6 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 929FL UT WOS:000303046600004 PM 22784622 ER PT J AU Trcek, T Larson, DR Moldon, A Query, CC Singer, RH AF Trcek, Tatjana Larson, Daniel R. Moldon, Alberto Query, Charles C. Singer, Robert H. TI Single-Molecule mRNA Decay Measurements Reveal Promoter-Regulated mRNA Stability in Yeast SO CELL LA English DT Article ID CELL-CYCLE PROGRESSION; SACCHAROMYCES-CEREVISIAE; PROTEIN-KINASE; BUDDING YEAST; IN-VIVO; TRANSCRIPTION; GENE; DBF2; VISUALIZATION; DEGRADATION AB Messenger RNA decay measurements are typically performed on a population of cells. However, this approach cannot reveal sufficient complexity to provide information on mechanisms that may regulate mRNA degradation, possibly on short timescales. To address this deficiency, we measured cell cycle-regulated decay in single yeast cells using single-molecule FISH. We found that two genes responsible for mitotic progression, SWI5 and CLB2, exhibit a mitosis-dependent mRNA stability switch. Their transcripts are stable until mitosis, when a precipitous decay eliminates the mRNA complement, preventing carryover into the next cycle. Remarkably, the specificity and timing of decay is entirely regulated by their promoter, independent of specific cis mRNA sequences. The mitotic exit network protein Dbf2p binds to SWI5 and CLB2 mRNAs cotranscriptionally and regulates their decay. This work reveals the promoter-dependent control of mRNA stability, a regulatory mechanism that could be employed by a variety of mRNAs and organisms. C1 [Singer, Robert H.] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, Bronx, NY 10461 USA. [Larson, Daniel R.] NCI, NIH, Bethesda, MD 20892 USA. RP Singer, RH (reprint author), Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM robert.singer@einstein.yu.edu RI Larson, Daniel/B-9829-2008 OI Larson, Daniel/0000-0001-9253-3055 FU EMBO [GM57829, GM57071] FX We would like to thank Drs. Jeffrey Chao and Kevin Czaplinski for helpful discussion of the project and Xiuhua Meng for her help with cloning. We thank Drs. Ian Willis, Michael Keogh, and Angelika Amon for sharing Delta SWI5 (TT012), Pab1p-TAP (TT065) strains, and Dbf2p-kinase dead plasmid with us, respectively. This work was supported by an EMBO fellowship awarded to A.M., GM57829 to C.C.Q., and GM57071 to R.H.S. NR 47 TC 113 Z9 114 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 23 PY 2011 VL 147 IS 7 BP 1484 EP 1497 DI 10.1016/j.cell.2011.11.051 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 866SP UT WOS:000298403400014 PM 22196726 ER PT J AU Shao, SC Hegde, RS AF Shao, Sichen Hegde, Ramanujan S. TI A Calmodulin-Dependent Translocation Pathway for Small Secretory Proteins SO CELL LA English DT Article ID SIGNAL RECOGNITION PARTICLE; PREPRO-ALPHA-FACTOR; MAMMALIAN ENDOPLASMIC-RETICULUM; IN-VIVO; INTRACELLULAR CALCIUM; SEC PROTEINS; ER MEMBRANE; TRANSPORT; MICROSOMES; COMPLEX AB Metazoans secrete an extensive array of small proteins essential for intercellular communication, defense, and physiologic regulation. Their synthesis takes mere seconds, leaving minimal time for recognition by the machinery for cotranslational protein translocation into the ER. The pathway taken by these substrates to enter the ER is not known. Here, we show that both in vivo and in vitro, small secretory proteins can enter the ER posttranslationally via a transient cytosolic intermediate. This intermediate contained calmodulin selectively bound to the signal peptides of small secretory proteins. Calmodulin maintained the translocation competence of small-protein precursors, precluded their aggregation and degradation, and minimized their inappropriate interactions with other cytosolic polypeptide-binding proteins. Acute inhibition of calmodulin specifically impaired small-protein translocation in vitro and in cells. These findings establish a mammalian posttranslational pathway for small-protein secretion and identify an unexpected role for calmodulin in chaperoning these precursors safely through the cytosol. C1 [Shao, Sichen; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Shao, Sichen] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Hegde, RS (reprint author), MRC Lab Mol Biol, Hills Rd, Cambridge CB2 0QH, England. EM rhegde@mrc-lmb.cam.ac.uk OI Shao, Sichen/0000-0003-2679-5537; Hegde, Ramanujan/0000-0001-8338-852X FU JHU-NIH; NICHD; Medical Research Council FX We are grateful to M. Mariappan for useful discussions; S. Appathurai for initial experiments and reagents; A. Sharma for technical help; other Hegde lab members for support; and K. Strub for sharing results prior to publication. This work was supported by the JHU-NIH Graduate Partnership Program, the Intramural Research Program of the NICHD, and the Medical Research Council. NR 47 TC 34 Z9 36 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 23 PY 2011 VL 147 IS 7 BP 1576 EP 1588 DI 10.1016/j.cell.2011.11.048 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 866SP UT WOS:000298403400021 PM 22196732 ER PT J AU Layre, E Sweet, L Hong, S Madigan, CA Desjardins, D Young, DC Cheng, TY Armand, JW Kim, K Shamputa, IC McConnell, MJ Debono, CA Behar, SM Minnaard, AJ Murray, M Barry, CE Matsunaga, I Moody, DB AF Layre, Emilie Sweet, Lindsay Hong, Sunhee Madigan, Cressida A. Desjardins, Danielle Young, David C. Cheng, Tan-Yun Armand, John W. Kim, Keunpyo Shamputa, Isdore C. McConnell, Matthew J. Debono, C. Anthony Behar, Samuel M. Minnaard, Adriaan J. Murray, Megan Barry, Clifton E., III Matsunaga, Isamu Moody, D. Branch TI A Comparative Lipidomics Platform for Chemotaxonomic Analysis of Mycobacterium tuberculosis SO CHEMISTRY & BIOLOGY LA English DT Article ID TANDEM MASS-SPECTROMETRY; OUTER-MEMBRANE; STRAINS; LIPIDS; INFECTION; VIRULENCE; IDENTIFICATION; REVEALS; COMPLEX; PHENOLGLYCOLIPIDS AB The lipidic envelope of Mycobacterium tuberculosis promotes virulence in many ways, so we developed a lipidomics platform for a broad survey of cell walls. Here we report two new databases (MycoMass, MycoMap), 30 lipid fine maps, and mass spectrometry datasets that comprise a static lipidome. Further, by rapidly regenerating lipidomic datasets during biological processes, comparative lipidomics provides statistically valid, organism-wide comparisons that broadly assess lipid changes during infection or among clinical strains of mycobacteria. Using stringent data filters, we tracked more than 5,000 molecular features in parallel with few or no false-positive molecular discoveries. The low error rates allowed chemotaxonomic analyses of mycobacteria, which describe the extent of chemical change in each strain and identified particular strain-specific molecules for use as biomarkers. C1 [Layre, Emilie; Sweet, Lindsay; Hong, Sunhee; Madigan, Cressida A.; Desjardins, Danielle; Young, David C.; Cheng, Tan-Yun; Armand, John W.; McConnell, Matthew J.; Debono, C. Anthony; Behar, Samuel M.; Moody, D. Branch] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Kim, Keunpyo] Medimmune Inc, Biostat, Gaithersburg, MD 20878 USA. [Shamputa, Isdore C.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Minnaard, Adriaan J.] Univ Groningen, Stratingh Inst Chem, NL-9747 AG Groningen, Netherlands. [Murray, Megan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Matsunaga, Isamu] Kyoto Univ, Dept Viral Oncol, Lab Cell Regulat, Inst Virus Res, Kyoto 6068507, Japan. RP Moody, DB (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. EM bmoody@rics.bwh.harvard.edu RI Barry, III, Clifton/H-3839-2012; Minnaard, Adriaan/E-9547-2014; OI Kim, Keunpyo/0000-0002-7103-924X; Behar, Samuel/0000-0002-3374-6699 FU National Institutes of Health [U19 AI076217, R01 AI071155, AR048632]; Broad Institute; Burroughs Wellcome Fund for Translational Research FX This work is supported by National Institutes of Health Grants U19 AI076217, R01 AI071155, and AR048632; the Broad Institute; and the Burroughs Wellcome Fund for Translational Research. The authors thank M. Gilleron and C. Rat ledge for providing lipid standards, R.N. Husson for providing M. tuberculosis Beijing strains, and S. Fortune for reading the manuscript. NR 52 TC 52 Z9 53 U1 2 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD DEC 23 PY 2011 VL 18 IS 12 BP 1537 EP 1549 DI 10.1016/j.chembiol.2011.10.013 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873OY UT WOS:000298893900007 PM 22195556 ER PT J AU Nakayamada, S Kanno, Y Takahashi, H Jankovic, D Lu, KT Johnson, TA Sun, HW Vahedi, G Hakim, O Handon, R Schwartzberg, PL Hager, GL O'Shea, JJ AF Nakayamada, Shingo Kanno, Yuka Takahashi, Hayato Jankovic, Dragana Lu, Kristina T. Johnson, Thomas A. Sun, Hong-wei Vahedi, Golnaz Hakim, Ofir Handon, Robin Schwartzberg, Pamela L. Hager, Gordon L. O'Shea, John J. TI Early Th1 Cell Differentiation Is Marked by a Tfh Cell-like Transition SO IMMUNITY LA English DT Article ID CD4(+) T-CELLS; FOLLICULAR HELPER-CELLS; INTERFERON-GAMMA; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSES; LINEAGE; EXPRESSION; PLASTICITY; BET; COMMITMENT AB Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we showed interleukin-12 acting via the transcription factor STAT4 induced both 1121 and BcI6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced the transcription factor T-bet. With ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed BcI6 and other markers of Tfh cells, thereby attenuating the nascent Tfh cell-like phenotype in the late phase of Th1 cell specification. Tfh-like cells were rapidly generated after Toxoplasma gondii infection in mice, but T-bet constrained Tfh cell expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation. C1 [Nakayamada, Shingo; Kanno, Yuka; Takahashi, Hayato; Vahedi, Golnaz; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Lu, Kristina T.; Handon, Robin; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Johnson, Thomas A.; Hakim, Ofir; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. [Sun, Hong-wei] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. RP Nakayamada, S (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. EM nakayamadas@mail.nih.gov RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 FU NIAMS FX We thank J. Simone and J. Lay for technical help with cell sorting and A.C. Poholek for critical review of the manuscript. This research was supported by the Intramural Research Programs of NIAMS. NR 41 TC 161 Z9 166 U1 2 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC 23 PY 2011 VL 35 IS 6 BP 919 EP 931 DI 10.1016/j.immuni.2011.11.012 PG 13 WC Immunology SC Immunology GA 871ZX UT WOS:000298777300011 PM 22195747 ER PT J AU Muranski, P Borman, ZA Kerkar, SP Klebanoff, CA Ji, Y Sanchez-Perez, L Sukumar, M Reger, RN Yu, ZY Kern, SJ Roychoudhuri, R Ferreyra, GA Shen, W Durum, SK Feigenbaum, L Palmer, DC Antony, PA Chan, CC Laurence, A Danner, RL Gattinoni, L Restifo, NP AF Muranski, Pawel Borman, Zachary A. Kerkar, Sid P. Klebanoff, Christopher A. Ji, Yun Sanchez-Perez, Luis Sukumar, Madhusudhanan Reger, Robert N. Yu, Zhiya Kern, Steven J. Roychoudhuri, Rahul Ferreyra, Gabriela A. Shen, Wei Durum, Scott K. Feigenbaum, Lionel Palmer, Douglas C. Antony, Paul A. Chan, Chi-Chao Laurence, Arian Danner, Robert L. Gattinoni, Luca Restifo, Nicholas P. TI Th17 Cells Are Long Lived and Retain a Stem Cell-like Molecular Signature SO IMMUNITY LA English DT Article ID CD8(+) T-CELLS; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; TRANSCRIPTION FACTOR; ESTABLISHED MELANOMA; EFFECTOR FUNCTION; TUMOR-REGRESSION; TELOMERE LENGTH; MEMORY CELLS; T(H)17 CELLS AB Th17 cells have been described as short lived, but this view is at odds with their capacity to trigger protracted damage to normal and transformed tissues. We report that Th17 cells, despite displaying low expression of CD27 and other phenotypic markers of terminal differentiation, efficiently eradicated tumors and caused autoimmunity, were long lived, and maintained a core molecular signature resembling early memory CD8(+) cells with stem cell-like properties. In addition, we found that Th17 cells had high expression of Tcf7, a direct target of the Wnt and beta-catenin signaling axis, and accumulated beta-catenin, a feature observed in stem cells. In vivo, Th17 cells gave rise to Th1-like effector cell progeny and also self-renewed and persisted as IL-17A-secreting cells. Multipotency was required for Th17 cell-mediated tumor eradication because effector cells deficient in IFN-gamma or IL-17A had impaired activity. Thus, Th17 cells are not always short lived and are a less-differentiated subset capable of superior persistence and functionality. C1 [Muranski, Pawel; Borman, Zachary A.; Kerkar, Sid P.; Klebanoff, Christopher A.; Ji, Yun; Sanchez-Perez, Luis; Sukumar, Madhusudhanan; Reger, Robert N.; Yu, Zhiya; Roychoudhuri, Rahul; Palmer, Douglas C.; Gattinoni, Luca; Restifo, Nicholas P.] NCI, Bethesda, MD 20892 USA. [Kern, Steven J.; Ferreyra, Gabriela A.; Danner, Robert L.] NIH, Ctr Clin, Dept Crit Care Med, Funct Genom & Prote Facil, Bethesda, MD 20892 USA. [Shen, Wei; Durum, Scott K.] NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. [Feigenbaum, Lionel] Sci Applicat Int Corp SAIC, NCI, Frederick, MD 21702 USA. [Antony, Paul A.] Univ Maryland, Sch Med, Dept Pathol, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Antony, Paul A.] Univ Maryland, Sch Med, Tumor Immunol & lmmunotherapy Program, Baltimore, MD 21201 USA. [Chan, Chi-Chao] NEI, NIH, Bethesda, MD 20892 USA. [Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, CRC10 Room 3W5816, Bethesda, MD 20892 USA. EM restifon@mail.nih.gov RI Gattinoni, Luca/A-2281-2008; Laurence, Arian/A-8770-2009; Ji, Yun/B-7245-2009; Restifo, Nicholas/A-5713-2008; Palmer, Douglas/B-9454-2008; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Laurence, Arian/0000-0003-0942-8292; Ji, Yun/0000-0001-6340-7009; Palmer, Douglas/0000-0001-5018-5734; Roychoudhuri, Rahul/0000-0002-5392-1853; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [ZIA BC011037-03, ZIA BC010763-05, Z99 CA999999] NR 82 TC 156 Z9 156 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC 23 PY 2011 VL 35 IS 6 BP 972 EP 985 DI 10.1016/j.immuni.2011.09.019 PG 14 WC Immunology SC Immunology GA 871ZX UT WOS:000298777300015 PM 22177921 ER PT J AU Mayer-Barber, KD Andrade, BB Barber, DL Hieny, S Feng, CG Caspar, P Oland, S Gordon, S Sher, A AF Mayer-Barber, Katrin D. Andrade, Bruno B. Barber, Daniel L. Hieny, Sara Feng, Carl G. Caspar, Patricia Oland, Sandy Gordon, Siamon Sher, Alan TI Innate and Adaptive Interferons Suppress IL-1 alpha and IL-1 beta Production by Distinct Pulmonary Myeloid Subsets during Mycobacterium tuberculosis Infection SO IMMUNITY LA English DT Article ID DENDRITIC CELLS; IL-10 PRODUCTION; IFN-GAMMA; IN-VIVO; INTERLEUKIN-1-BETA; MONOCYTES; INFLAMMATION; ACTIVATION; INDUCTION; IMMUNITY AB Interleukin-1 (IL-1) receptor signaling is necessary for control of Mycobacterium tuberculosis (Mtb) infection, yet the role of its two ligands, IL-1 alpha and IL-1 beta, and their regulation in vivo are poorly understood. Here, we showed that both IL-1 alpha and IL-1 beta are critically required for host resistance and identified two multifunctional inflammatory monocyte-macrophage and DC populations that coexpressed both IL-1 species at the single-cell level in lungs of Mtb-infected mice. Moreover, we demonstrated that interferons (IFNs) played important roles in regulating IL-1 production by these cells in vivo. Type I interferons inhibited IL-1 production by both subsets whereas CD4(+) T cell-derived IFN-gamma selectively suppressed monocyte-macrophages. These data provide a cellular basis for both the anti-inflammatory effects of IFNs and probacterial functions of type I IFNs during Mtb infection and reveal differential regulation of IL-1 production by distinct cell populations as an additional layer of complexity in the activity of IL-1 in vivo. C1 [Mayer-Barber, Katrin D.; Andrade, Bruno B.; Barber, Daniel L.; Hieny, Sara; Feng, Carl G.; Caspar, Patricia; Oland, Sandy; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Gordon, Siamon] Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. RP Mayer-Barber, KD (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM mayerk@niaid.nih.gov; asher@niaid.nih.gov RI Andrade, Bruno/J-9111-2012 OI Andrade, Bruno/0000-0001-6833-3811 FU NIAID, NIH; NIAID; NCI FX We are grateful to the NIAD flow cytometry core facility and in particular B. Hague for assistance with the BSL3 FACS sorting and to the staff of the NIAID animal BSL3 facility for excellent technical help. We thank K. Shenderov, G. Trinchieri, Y. Belkaid, and R. Goldzmid for valuable discussion. This research was supported by the Intramural Research Program of the NIAID, NIH. S.G.'s contributions occurred during a sabbatical supported by a stipend from the NIAID and NCI intramural programs. NR 46 TC 143 Z9 145 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC 23 PY 2011 VL 35 IS 6 BP 1023 EP 1034 DI 10.1016/j.immuni.2011.12.002 PG 12 WC Immunology SC Immunology GA 871ZX UT WOS:000298777300019 PM 22195750 ER PT J AU Martin, WJ Glass, RI Balbus, JM Collins, FS AF Martin, William J., II Glass, Roger I. Balbus, John M. Collins, Francis S. TI Cultivating a Demand for Clean Cookstoves Response SO SCIENCE LA English DT Letter C1 [Martin, William J., II; Glass, Roger I.; Balbus, John M.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Martin, WJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjmartin@mail.nih.gov NR 2 TC 0 Z9 0 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 23 PY 2011 VL 334 IS 6063 BP 1637 EP 1637 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865XK UT WOS:000298344000033 ER PT J AU Kim, Y Sharov, AA McDole, K Cheng, M Hao, H Fan, CM Gaiano, N Ko, MSH Zheng, Y AF Kim, Youngjo Sharov, Alexei A. McDole, Katie Cheng, Melody Hao, Haiping Fan, Chen-Ming Gaiano, Nicholas Ko, Minoru S. H. Zheng, Yixian TI Mouse B-Type Lamins Are Required for Proper Organogenesis But Not by Embryonic Stem Cells SO SCIENCE LA English DT Article ID NUCLEAR LAMINA; DIFFERENTIATION; ORGANIZATION; EXPRESSION; GENE; PROLIFERATION; PERIPHERY; DEFECTS AB B-type lamins, the major components of the nuclear lamina, are believed to be essential for cell proliferation and survival. We found that mouse embryonic stem cells (ESCs) do not need any lamins for self-renewal and pluripotency. Although genome-wide lamin-B binding profiles correlate with reduced gene expression, such binding is not directly required for gene silencing in ESCs or trophectoderm cells. However, B-type lamins are required for proper organogenesis. Defects in spindle orientation in neural progenitor cells and migration of neurons probably cause brain disorganizations found in lamin-B null mice. Thus, our studies not only disprove several prevailing views of lamin-Bs but also establish a foundation for redefining the function of the nuclear lamina in the context of tissue building and homeostasis. C1 [Sharov, Alexei A.; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. [Kim, Youngjo; Fan, Chen-Ming; Zheng, Yixian] Carnegie Inst Sci, Dept Embryol, Baltimore, MD 21218 USA. [Kim, Youngjo; McDole, Katie; Zheng, Yixian] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [McDole, Katie; Fan, Chen-Ming; Zheng, Yixian] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Cheng, Melody; Gaiano, Nicholas] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Hao, Haiping] Johns Hopkins Univ, Sch Med, Microarray Core Facil, Baltimore, MD 21205 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@grc.nia.nih.gov; zheng@ciwemb.edu RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU National Institute on Aging; Howard Hughes Medical Institute; [R01 GM056312] FX We thank B. Van Steensel and H. Niwa for reagents, M. Sepanski for electron microscopy, O. Martin for technical support, C. Liu (National Heart, Lung, and Blood Institute) for mouse targeting, and the members of the Zheng lab for critical comments. Supported in part by the Intramural Research Program of National Institute on Aging (A. A. S. and M. S. H. K.) and R01 GM056312 (Y.Z.). Y.Z. is supported by the Howard Hughes Medical Institute. A patent (7510850) regarding the use of Xenopus egg extracts to isolate and study the lamin-B spindle matrix is held by The Carnegie Institution for Science. NR 26 TC 111 Z9 114 U1 4 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 23 PY 2011 VL 334 IS 6063 BP 1706 EP 1710 DI 10.1126/science.1211222 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865XK UT WOS:000298344000068 PM 22116031 ER PT J AU Ren, DB Xie, H Zhang, WH Hassan, F Petralia, RS Yu, SQ Lim, DJ Gu, XX AF Ren, Dabin Xie, Hang Zhang, Wenhong Hassan, Ferdaus Petralia, Ronald S. Yu, Shengqing Lim, David J. Gu, Xin-Xing TI Intranasal Immunization of the Combined Lipooligosaccharide Conjugates Protects Mice from the Challenges with Three Serotypes of Moraxella catarrhalis SO PLOS ONE LA English DT Article ID OUTER-MEMBRANE PROTEIN; BRANHAMELLA-CATARRHALIS; MONOCLONAL-ANTIBODIES; VACCINE CANDIDATES; OTITIS-MEDIA; LIPOPOLYSACCHARIDE; OLIGOSACCHARIDES; INFECTIONS; RESPONSES; ANTIGENS AB Background: There are no licensed vaccines available against Moraxella catarrhalis, a significant human respiratory pathogen. Lipooligosaccharide (LOS) based conjugate vaccines derived from individual serotype M. catarrhalis only showed partial protection coverage. A vaccine combining LOS conjugates of two or three serotypes might provide a broader protection. Methods: Mice were immunized intranasally with the combined conjugates consisting of LOS from serotype A and B or serotype A, B, and C followed by challenge with different M. catarrhalis strains of three serotypes. Mouse lungs, nasal washes, and sera were collected after each challenge for bacterial counts, histological evaluation, cytokine profiles, antibody level and binding activity determinations. Results: Intranasal administration of the combined LOS conjugates not only enhanced pulmonary bacterial clearance of all three serotypes of M. catarrhalis strains in vaccinated mice, but also elevated serotype-specific anti-LOS immunoglobulin (Ig)A and IgG titers in nasal wash and serum respectively. Mice vaccinated with the combined LOS conjugates also showed increased interferon (IFN)-gamma, interleukin (IL)-12, and IL-4 in the lungs after challenges. Compared to the control group, mice immunized with the combined LOS conjugates also showed reduced lung inflammation after M. catarrhalis infections. The hyperimmune sera induced by the combined conjugates exhibited a broad cross-reactivity toward all three serotypes of M. catarrhalis under transmission electron microscopy. Conclusions: The combined vaccine of serotype A and B LOS conjugates provides protection against most M. catarrhalis strains by eliciting humoral and cellular immune responses. C1 [Ren, Dabin; Zhang, Wenhong; Hassan, Ferdaus; Yu, Shengqing; Gu, Xin-Xing] NIDCD, Vaccine Res Sect, NIH, Rockville, MD USA. [Xie, Hang] US FDA, Lab Resp Viral Dis, Off Vaccines Res & Review, Div Viral Prod,Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Petralia, Ronald S.] NIDCD, Sect Neurotransmitter Receptor Biol, NIH, Bethesda, MD USA. [Lim, David J.] House Ear Res Inst, Sect Pathogenesis Ear Dis, Los Angeles, CA USA. RP Ren, DB (reprint author), Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. EM guxx@mail.nih.gov RI Ren, Dabin/H-6263-2013 FU National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America [NIH0010103632] FX This research was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America (#NIH0010103632). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 5 Z9 5 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2011 VL 6 IS 12 AR e29553 DI 10.1371/journal.pone.0029553 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 884DI UT WOS:000299684700068 PM 22216312 ER PT J AU La Regina, G Bai, R Rensen, W Coluccia, A Piscitelli, F Gatti, V Bolognesi, A Lavecchia, A Granata, I Porta, A Maresca, B Soriani, A Iannitto, ML Mariani, M Santoni, A Brancale, A Ferlini, C Dondio, G Varasi, M Mercurio, C Hamel, E Lavia, P Novellino, E Silvestri, R AF La Regina, Giuseppe Bai, Ruoli Rensen, Willeke Coluccia, Antonio Piscitelli, Francesco Gatti, Valerio Bolognesi, Alessio Lavecchia, Antonio Granata, Ilaria Porta, Amalia Maresca, Bruno Soriani, Alessandra Iannitto, Maria Luisa Mariani, Marisa Santoni, Angela Brancale, Andrea Ferlini, Cristiano Dondio, Giulio Varasi, Mario Mercurio, Ciro Hamel, Ernest Lavia, Patrizia Novellino, Ettore Silvestri, Romano TI Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CANCER-CELLS; EFFICIENT SYNTHESIS; ANTICANCER AGENTS; ANTIMITOTIC DRUGS; BREAST-CANCER; MICROTUBULE; COLCHICINE; INDOLES; ANALOGS; TARGET AB New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability. C1 [La Regina, Giuseppe; Coluccia, Antonio; Piscitelli, Francesco; Gatti, Valerio; Silvestri, Romano] Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Rensen, Willeke; Bolognesi, Alessio; Santoni, Angela; Lavia, Patrizia] Sapienza Univ Roma, Inst Mol Biol & Pathol, Natl Res Council, CNR, I-00185 Rome, Italy. [Granata, Ilaria; Porta, Amalia; Maresca, Bruno] Univ Salerno, Sez Biomed, Dipartimento Sci Farmaceut, I-84084 Salerno, Italy. [Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Lavecchia, Antonio; Novellino, Ettore] Univ Naples Federico 2, Dipartirnento Chim Farmaceut & Tossicol, I-80131 Naples, Italy. [Soriani, Alessandra; Iannitto, Maria Luisa; Santoni, Angela] Sapienza Univ Roma, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy. [Mariani, Marisa; Ferlini, Cristiano] Danbury Hosp Res Inst, Tumor Reprod Biol Res Lab, Danbury, CT 06810 USA. [Dondio, Giulio] NiKem Res Srl, I-20021 Milan, Italy. [Varasi, Mario] European Inst Oncol, I-20139 Milan, Italy. [Mercurio, Ciro] DAC SRL, Genextra Grp, I-20139 Milan, Italy. RP Silvestri, R (reprint author), Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, Piazza Aldo Moro 5, I-00185 Rome, Italy. EM romano.silvestri@uniroma1.it RI La Regina, Giuseppe/I-2161-2012; Porta, Amalia/E-9540-2012; Ferlini, Cristiano/K-1339-2013; Brancale, Andrea/N-9445-2014; santoni, angela/K-8997-2016; OI Lavia, Patrizia/0000-0003-3310-6701; La Regina, Giuseppe/0000-0003-3252-1161; /0000-0002-7940-8206; Porta, Amalia/0000-0001-5947-9472; Ferlini, Cristiano/0000-0003-3886-9134; Brancale, Andrea/0000-0002-9728-3419; santoni, angela/0000-0003-1206-7731; SORIANI, Alessandra/0000-0001-5461-9026; Silvestri, Romano/0000-0003-2489-0178 FU Sapienza Universita di Roma; [200879X9N9] FX This research was supported by PRIN 2008 Grant No. 200879X9N9, and Progetti di Ricerca di Universita, Sapienza Universita di Roma. A.C. thanks Istituto Pasteur-Fondazione Cenci Bolognetti for his Borsa di Studio per Ricerche in Italia. NR 40 TC 23 Z9 23 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 22 PY 2011 VL 54 IS 24 BP 8394 EP 8406 DI 10.1021/jm2012886 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 860KD UT WOS:000297946300016 PM 22044164 ER PT J AU Smrz, D Kim, MS Zhang, SL Mock, BA Smrzova, S DuBois, W Simakova, O Maric, I Wilson, TM Metcalfe, DD Gilfillan, AM AF Smrz, Daniel Kim, Mi-Sun Zhang, Shuling Mock, Beverly A. Smrzova, Sarka DuBois, Wendy Simakova, Olga Maric, Irina Wilson, Todd M. Metcalfe, Dean D. Gilfillan, Alasdair M. TI mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells SO BLOOD LA English DT Article ID FC-EPSILON-RI; C-KIT; MEDIATOR RELEASE; COMPLEX 2; RICTOR; GROWTH; ACTIVATION; MASTOCYTOSIS; RAPTOR; PHOSPHORYLATION AB Increased mast cell burden is observed in the inflamed tissues and affected organs and tissues of patients with mast cell proliferative disorders. However, normal mast cells participate in host defense, so approaches to preferentially target clonally expanding mast cells are needed. We found that mammalian target of rapamycin complex 1(mTORC1) and 2(mTORC2) are up-regulated in neoplastic and developing immature mast cells compared with their terminally differentiated counter-parts. Elevated mTOR mRNA was also observed in bone marrow mononuclear cells of patients exhibiting mast-cell hyperplasia. Selective inhibition of mTORC1 and mTORC2 through genetic and pharmacologic manipulation revealed that, whereas mTORC1 may contribute to mast-cell survival, mTORC2 was only critical for homeostasis of neoplastic and dividing immature mast cells. The cytostatic effect of mTORC2 down-regulation in proliferating mast cells was deter-mined to be via inhibition of cell-cycle progression. Because mTORC2 was observed to play little role in the homeostasis of differentiated, nonproliferating, mature mast cells, these data provide a rationale for adopting a targeted approaching selectively inhibiting mTORC2 to effectively reduce the proliferation of mast cells associated with inflammation and disorders of mast cell proliferation while leaving normal differentiated mast cells largely unaffected. (Blood.2011;118(26):6803-6813) C1 [Smrz, Daniel; Kim, Mi-Sun; Smrzova, Sarka; Wilson, Todd M.; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Zhang, Shuling; Mock, Beverly A.; DuBois, Wendy] Ctr Canc Res, Lab Canc Biol & Genet, Bethesda, MD USA. [Simakova, Olga; Maric, Irina] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Rm 11C206,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov RI Mock, Beverly/B-3110-2015; Smrz, Daniel/D-4853-2014 OI Mock, Beverly/0000-0003-2479-4549; Smrz, Daniel/0000-0003-0143-8744 FU Division of Intramural Research of the NIAID; National Cancer Institute, NIH FX Financial support for this work was provided by the Division of Intramural Research of the NIAID and the National Cancer Institute, NIH. NR 44 TC 24 Z9 24 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 22 PY 2011 VL 118 IS 26 BP 6803 EP 6813 DI 10.1182/blood-2011-06-359984 PG 11 WC Hematology SC Hematology GA 866RY UT WOS:000298401000017 PM 22053105 ER PT J AU Sneller, MC Kopp, WC Engelke, KJ Yovandich, JL Creekmore, SP Waldmann, TA Lane, HC AF Sneller, Michael C. Kopp, William C. Engelke, Kory J. Yovandich, Jason L. Creekmore, Stephen P. Waldmann., Thomas A. Lane, H. Clifford TI IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of CD8(+) T effector memory population in peripheral blood SO BLOOD LA English DT Article ID NONHUMAN-PRIMATES; CYTOKINES; CELLS; INTERLEUKIN-15; HOMEOSTASIS; CANCER; TRANS AB IL-15 promotes activation and maintenance of natural killer (NK) and CD8(+) T effector memory (T-EM) cells, making it a potential immunotherapeutic agent for the treatment of cancer and immunodeficiency states. Here we report the immunologic effects of 3 different IL-15 dosing strategies in Rhesus macaques. IL-15 at a dose of 20 mu g/kg/d administered by continuous intravenous infusion for 10 days resulted in a massive (100-fold) expansion of CD8(+) T-EM cells in the peripheral blood. In contrast, the administration of 20-40 mu g/kg/d of IL-15 by subcutaneous injection resulted in a more modest (10-fold) expansion of CD8(+) T-EM cells. NK expansion was similar in both the continuous intravenous and daily subcutaneous treatment groups. The observation that IL-15 administered by continuous intravenous infusion is able to induce markedly greater expansions of CD8(+) T-EM cells than the same dose administered by other routes may have important implications for clinical development of this cytokine. (Blood.2011;118(26):6845-6848) C1 [Sneller, Michael C.; Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, NCI, Bethesda, MD 20892 USA. [Kopp, William C.] SAIC Frederick Inc, Appl Dev Res Directorate, Frederick, MD USA. [Engelke, Kory J.] Avanza Labs, Gaithersburg, MD USA. [Yovandich, Jason L.; Creekmore, Stephen P.] NCI Frederick, Biol Resources Branch, Dev Therapeut Program, Frederick, MD USA. [Waldmann., Thomas A.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Sneller, MC (reprint author), NIAID, Immunoregulat Lab, NIH, NCI, 10 Ctr Dr,MSC 1763, Bethesda, MD 20892 USA. EM msneller@niaid.nih.gov FU National Cancer Institute; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the intramural programs of the National Cancer Institute and the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 13 TC 23 Z9 23 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 22 PY 2011 VL 118 IS 26 BP 6845 EP 6848 DI 10.1182/blood-2011-09-377804 PG 4 WC Hematology SC Hematology GA 866RY UT WOS:000298401000021 PM 22067383 ER PT J AU Farrar, JE Vlachos, A Atsidaftos, E Carlson-Donohoe, H Markello, TC Arceci, RJ Ellis, SR Lipton, JM Bodine, DM AF Farrar, Jason E. Vlachos, Adrianna Atsidaftos, Eva Carlson-Donohoe, Hannah Markello, Thomas C. Arceci, Robert J. Ellis, Steven R. Lipton, Jeffrey M. Bodine, David M. TI Ribosomal protein gene deletions in Diamond-Blackfan anemia SO BLOOD LA English DT Article ID COPY-NUMBER VARIATION; HUMAN GENOME; RPS19 MUTATIONS; S19; RNA; IDENTIFICATION; MICRODELETIONS; HETEROGENEITY; MATURATION; SUBUNITS AB Diamond-Blackfan anemia (DBA) is a congenital BM failure syndrome characterized by hypoproliferative anemia, associated physical abnormalities, and a predisposition to cancer. Perturbations of the ribosome appear to be critically important in DBA; alterations in 9 different ribosomal protein genes have been identified in multiple unrelated families, along with rarer abnormalities of additional ribosomal proteins. However, at present, only 50% to 60% of patients have an identifiable genetic lesion by ribosomal protein gene sequencing. Using genome-wide single-nucleotide polymorphism array to evaluate for regions of recurrent copy variation, we identified deletions at known DBA-related ribosomal protein gene loci in 17% (9 of 51) of patients without an identifiable mutation, including RPS19, RPS17, RPS26, and RPL35A. No recurrent regions of copy variation at novel loci were identified. Because RPS17 is a duplicated gene with 4 copies in a diploid genome, we demonstrate haploinsufficient RPS17 expression and a small subunit ribosomal RNA processing abnormality in patients harboring RPS17 deletions. Finally, we report the novel identification of variable mosaic loss involving known DBA gene regions in 3 patients from 2 kindreds. These data suggest that ribosomal protein gene deletion is more common than previously suspected and should be considered a component of the initial genetic evaluation in cases of suspected DBA. (Blood. 2011;118(26):6943-6951) C1 [Farrar, Jason E.; Arceci, Robert J.] Johns Hopkins Univ, Sch Med, Dept Oncol, Kimmel Comprehens Canc Ctr,Div Pediat Oncol, Baltimore, MD 21205 USA. [Vlachos, Adrianna; Atsidaftos, Eva; Lipton, Jeffrey M.] Feinstein Inst Med Res, Manhasset, NY USA. [Vlachos, Adrianna; Lipton, Jeffrey M.] Steven & Alexandra Cohen Childrens Med Ctr New Yo, Div Hematol Oncol & Stem Cell Transplantat, New Hyde Pk, NY USA. [Carlson-Donohoe, Hannah; Markello, Thomas C.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Ellis, Steven R.] Univ Louisville, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. [Bodine, David M.] NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Farrar, JE (reprint author), 1650 Orleans St,CRB I Rm 209, Baltimore, MD 21231 USA. EM jfarrar4@jhmi.edu; tedyaz@mail.nih.gov OI Farrar, Jason/0000-0003-2148-5839 FU National Institutes of Health [K08HL092224, R01HL079571]; National Heart, Lung, and Blood Institute DNA Resequencing and Genotyping Service [R109 MOHLKE]; Feinstein Institute for Medical Research General Clinical Research Center [M01RR018535]; National Human Genome Research Institute FX This study was supported by grants from the National Institutes of Health (K08HL092224 to J.E.F., R01HL079571 to A.V. and J.M.L.); by the National Heart, Lung, and Blood Institute DNA Resequencing and Genotyping Service (R109 MOHLKE to A.V., J.M.L., J.E.F., R.J.A., and S.R.E.); by the Feinstein Institute for Medical Research General Clinical Research Center (M01RR018535 to A.V. and J.M.L.); and by National Human Genome Research Institute intramural funds (to D.M.B.). NR 39 TC 45 Z9 46 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 22 PY 2011 VL 118 IS 26 BP 6943 EP 6951 DI 10.1182/blood-2011-08-375170 PG 9 WC Hematology SC Hematology GA 866RY UT WOS:000298401000032 PM 22045982 ER PT J AU Malhotra, D McCarthy, S Michaelson, JJ Vacic, V Burdick, KE Yoon, S Cichon, S Corvin, A Gary, S Gershon, ES Gill, M Karayiorgou, M Kelsoe, JR Krastoshevsky, O Krause, V Leibenluft, E Levy, DL Makarov, V Bhandari, A Malhotra, AK McMahon, FJ Nothen, MM Potash, JB Rietschel, M Schulze, TG Sebat, J AF Malhotra, Dheeraj McCarthy, Shane Michaelson, Jacob J. Vacic, Vladimir Burdick, Katherine E. Yoon, Seungtai Cichon, Sven Corvin, Aiden Gary, Sydney Gershon, Elliot S. Gill, Michael Karayiorgou, Maria Kelsoe, John R. Krastoshevsky, Olga Krause, Verena Leibenluft, Ellen Levy, Deborah L. Makarov, Vladimir Bhandari, Abhishek Malhotra, Anil K. McMahon, Francis J. Noethen, Markus M. Potash, James B. Rietschel, Marcella Schulze, Thomas G. Sebat, Jonathan TI High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia SO NEURON LA English DT Article ID GENOME-WIDE ASSOCIATION; COPY-NUMBER VARIATION; SPECTRUM DISORDERS; INCREASE RISK; I DISORDER; DUPLICATIONS; DELETIONS; AUTISM; MICRODELETIONS; INDIVIDUALS AB While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases. C1 [Malhotra, Dheeraj; Michaelson, Jacob J.; Bhandari, Abhishek; Sebat, Jonathan] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA. [Malhotra, Dheeraj; Michaelson, Jacob J.; Kelsoe, John R.; Bhandari, Abhishek; Sebat, Jonathan] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Sebat, Jonathan] Univ Calif San Diego, Dept Cellular Mol & Mol Med, La Jolla, CA 92093 USA. [Kelsoe, John R.; Sebat, Jonathan] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Yoon, Seungtai; Makarov, Vladimir] Mt Sinai Sch Med, Seaver Autism Ctr, New York, NY 10029 USA. [Malhotra, Anil K.] N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Glen Oaks, NY 11004 USA. [Leibenluft, Ellen] Emot & Dev Branch, Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. [Potash, James B.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-370075 Gottingen, Germany. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-53127 Bonn, Germany. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Cichon, Sven] Res Ctr Julich, Inst Neurosci & Med INM 1, D-52425 Julich, Germany. [Rietschel, Marcella] Univ Heidelberg J5, Cent Inst Mental Hlth, D-68159 Mannheim, Germany. [McMahon, Francis J.] NIMH, NIH, Bethesda, MD 20892 USA. [Vacic, Vladimir] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. [Noethen, Markus M.] German Ctr Neurodegenerat Dis DZNE, D-53175 Bonn, Germany. [Corvin, Aiden; Gill, Michael] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Inst Mol Med, Dublin 2, Ireland. [Karayiorgou, Maria] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Corvin, Aiden; Gill, Michael] Trinity Coll Dublin, Dept Psychiat, Dublin 2, Ireland. [Krastoshevsky, Olga; Krause, Verena; Levy, Deborah L.] McLean Hosp, Belmont, MA 02478 USA. [Kelsoe, John R.] Vet Affairs San Diego Healthcare Syst, San Diego, CA 92161 USA. [Gershon, Elliot S.] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Malhotra, Dheeraj; McCarthy, Shane; Vacic, Vladimir; Yoon, Seungtai; Gary, Sydney; Makarov, Vladimir; Bhandari, Abhishek; Sebat, Jonathan] Cold Spring Harbor Lab, Stanley Inst Cognit Genom, Cold Spring Harbor, NY 12824 USA. [Burdick, Katherine E.] Mt Sinai Sch Med, New York, NY 10029 USA. RP Sebat, J (reprint author), Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA. EM jsebat@ucsd.edu RI Burdick, Katherine/G-6124-2012; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; OI Vacic, Vladimir/0000-0001-6571-2293; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Sebat, Jonathan/0000-0002-9087-526X; Corvin, Aiden/0000-0001-6717-4089; Gill, Michael/0000-0003-0206-5337 FU Beyster family foundation, NIH [MH076431, HG04222, MH071523, MH061399]; NARSAD; Wellcome Trust [072894/Z/03/Z]; Science Foundation Ireland [08INIB1916] FX We thank all patients and their families for their participation in this genetic study. Special thanks to James Watson for helpful discussions and support. This study was supported by a gift from Ted and Vada Stanley to the Cold Spring Harbor Laboratory, a gift to J.S. from the Beyster family foundation, NIH grants to J.S. (MH076431, HG04222), D.L.L. (MH071523), and M.K. (MH061399), grants to J.S. and D.L.L. from NARSAD, grants to A.C. and M.G. from the Wellcome Trust (072894/Z/03/Z) and Science Foundation Ireland (08INIB1916), and grants to D.L.L. from the Sidney R. Baer, Jr. Foundation and Essel Foundation. We thank the Genetic Association Information Network (GAIN), Molecular Genetics of Schizophrenia (MGS), and the Bipolar Genome Study (BiGS) for providing data for this study. We thank Roche NimbleGen and Oxford Gene Technology for their expert technical assistance. We thank Lilia M. lakoucheva and Roser Corominas for helpful discussions. NR 38 TC 132 Z9 133 U1 1 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 22 PY 2011 VL 72 IS 6 BP 951 EP 963 DI 10.1016/j.neuron.2011.11.007 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 871XM UT WOS:000298771000010 PM 22196331 ER PT J AU Koelle, K Ratmann, O Rasmussen, DA Pasour, V Mattingly, J AF Koelle, Katia Ratmann, Oliver Rasmussen, David A. Pasour, Virginia Mattingly, Jonathan TI A dimensionless number for understanding the evolutionary dynamics of antigenically variable RNA viruses SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE phylodynamics; infectious disease dynamics; viral evolution; immune escape; antigenic evolution ID INFLUENZA-A H3N2; EPOCHAL EVOLUTION; CROSS-IMMUNITY; PHYLODYNAMICS; PATHOGENS; HISTORY; MODEL; DRIFT; HOST AB Antigenically variable RNA viruses are significant contributors to the burden of infectious disease world-wide. One reason for their ubiquity is their ability to escape herd immunity through rapid antigenic evolution and thereby to reinfect previously infected hosts. However, the ways in which these viruses evolve antigenically are highly diverse. Some have only limited diversity in the long-run, with every emergence of a new antigenic variant coupled with a replacement of the older variant. Other viruses rapidly accumulate antigenic diversity over time. Others still exhibit dynamics that can be considered evolutionary intermediates between these two extremes. Here, we present a theoretical framework that aims to understand these differences in evolutionary patterns by considering a virus's epidemiological dynamics in a given host population. Our framework, based on a dimensionless number, probabilistically anticipates patterns of viral antigenic diversification and thereby quantifies a virus's evolutionary potential. It is therefore similar in spirit to the basic reproduction number, the well-known dimensionless number which quantifies a pathogen's reproductive potential. We further outline how our theoretical framework can be applied to empirical viral systems, using influenza A/H3N2 as a case study. We end with predictions of our framework and work that remains to be done to further integrate viral evolutionary dynamics with disease ecology. C1 [Koelle, Katia; Ratmann, Oliver; Rasmussen, David A.; Pasour, Virginia] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Ratmann, Oliver] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London W2 1PG, England. [Mattingly, Jonathan] Duke Univ, Dept Math, Durham, NC 27708 USA. RP Koelle, K (reprint author), Duke Univ, Dept Biol, POB 90338, Durham, NC 27708 USA. EM katia.koelle@duke.edu OI Ratmann, Oliver/0000-0001-8667-4118 FU James S. McDonnell Foundation [NSF-EF-08-27416]; Sir Henry Wellcome Fellowship [WT092311MF]; NSF; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; [DMS-0616710] FX We thank Greg Sawicki and the Koelle research group for helpful discussions. This work was funded by the James S. McDonnell Foundation and grant NSF-EF-08-27416 to K. K. O.R. was further supported by the Sir Henry Wellcome Fellowship WT092311MF; J.C.M. through grant DMS-0616710; D. R. through an NSF pre-doctoral fellowship; and K. K. by the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 27 TC 5 Z9 5 U1 1 U2 4 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD DEC 22 PY 2011 VL 278 IS 1725 BP 3723 EP 3730 DI 10.1098/rspb.2011.0435 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 846CK UT WOS:000296874600013 PM 21543353 ER PT J AU Geng, HF Whiteley, G Ribbens, J Zheng, W Southall, N Hu, X Marugan, JJ Ferrer, M Maegawa, GHB AF Geng, Haifeng Whiteley, Grace Ribbens, Jameson Zheng, Wei Southall, Noel Hu, Xin Marugan, Juan J. Ferrer, Marc Maegawa, Gustavo H. B. TI Novel Patient Cell-Based HTS Assay for Identification of Small Molecules for a Lysosomal Storage Disease SO PLOS ONE LA English DT Article ID THROUGHPUT SCREENING ASSAYS; METACHROMATIC LEUKODYSTROPHY; ARYLSULFATASE-A; PHARMACOLOGICAL CHAPERONES; BETA-HEXOSAMINIDASE; GAUCHER-DISEASE; ENZYME; INHIBITORS; FIBROBLASTS; DISORDERS AB Small molecules have been identified as potential therapeutic agents for lysosomal storage diseases (LSDs), inherited metabolic disorders caused by defects in proteins that result in lysosome dysfunctional. Some small molecules function assisting the folding of mutant misfolded lysosomal enzymes that are otherwise degraded in ER-associated degradation. The ultimate result is the enhancement of the residual enzymatic activity of the deficient enzyme. Most of the high throughput screening (HTS) assays developed to identify these molecules are single-target biochemical assays. Here we describe a cell-based assay using patient cell lines to identify small molecules that enhance the residual arylsulfatase A (ASA) activity found in patients with metachromatic leukodystrophy (MLD), a progressive neurodegenerative LSD. In order to generate sufficient cell lines for a large scale HTS, primary cultured fibroblasts from MLD patients were transformed using SV40 large T antigen. These SV40 transformed (SV40t) cells showed to conserve biochemical characteristics of the primary cells. Using a specific colorimetric substrate para-nitrocatechol sulfate (pNCS), detectable ASA residual activity were observed in primary and SV40t fibroblasts from a MLD patient (ASA-I179S) cultured in multi-well plates. A robust fluorescence ASA assay was developed in high-density 1,536-well plates using the traditional colorimetric pNCS substrate, whose product (pNC) acts as "plate fluorescence quencher" in white solid-bottom plates. The quantitative cell-based HTS assay for ASA generated strong statistical parameters when tested against a diverse small molecule collection. This cell-based assay approach can be used for several other LSDs and genetic disorders, especially those that rely on colorimetric substrates which traditionally present low sensitivity for assay-miniaturization. In addition, the quantitative cell-based HTS assay here developed using patient cells creates an opportunity to identify therapeutic small molecules in a disease-cellular environment where potentially disrupted pathways are exposed and available as targets. C1 [Geng, Haifeng; Ribbens, Jameson; Maegawa, Gustavo H. B.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. [Maegawa, Gustavo H. B.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Whiteley, Grace; Zheng, Wei; Southall, Noel; Hu, Xin; Marugan, Juan J.; Ferrer, Marc] NIH, NIH Chem Genom Ctr, Rockville, MD USA. RP Geng, HF (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. EM gmaegaw1@jhmmi.edu RI Southall, Noel/H-8991-2012; Geng, Haifeng/A-9681-2012; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757; Maegawa, Gustavo/0000-0001-6933-4138 FU NIH-NINDS [1R21NS071535-01]; National Tay-Sachs and Allied Diseases Association (NTSAD); Kennedy Krieger Intellectual and Developmental Disabilities Research Center (IDDRC) [HD024061] FX This project was supported by funds from NIH-NINDS grant 1R21NS071535-01 and National Tay-Sachs and Allied Diseases Association (NTSAD) Research Grant and Kennedy Krieger Intellectual and Developmental Disabilities Research Center (IDDRC, grant #HD024061). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 7 Z9 7 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 21 PY 2011 VL 6 IS 12 AR e29504 DI 10.1371/journal.pone.0029504 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 876NF UT WOS:000299113600084 PM 22216298 ER PT J AU Karim, S Singh, P Ribeiro, JMC AF Karim, Shahid Singh, Parul Ribeiro, Jose M. C. TI A Deep Insight into the Sialotranscriptome of the Gulf Coast Tick, Amblyomma maculatum SO PLOS ONE LA English DT Article ID RICH SECRETORY PROTEINS; PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN; HEPATOZOON-AMERICANUM APICOMPLEXA; PLATELET-AGGREGATION INHIBITORS; NATURALLY-OCCURRING ANTAGONISTS; SALIVARY-GLAND HYALURONIDASE; THYROGLOBULIN TYPE-1 DOMAINS; FIBRINOGEN-RELATED PROTEINS; VECTOR IXODES-SCAPULARIS; POTASSIUM-ION CHANNELS AB Background: Saliva of blood sucking arthropods contains compounds that antagonize their hosts' hemostasis, which include platelet aggregation, vasoconstriction and blood clotting; saliva of these organisms also has anti-inflammatory and immunomodullatory properties. Perhaps because hosts mount an active immune response against these compounds, the diversity of these compounds is large even among related blood sucking species. Because of these properties, saliva helps blood feeding as well as help the establishment of pathogens that can be transmitted during blood feeding. Methodology/Principal Findings: We have obtained 1,626,969 reads by pyrosequencing a salivary gland cDNA library from adult females Amblyomma maculatum ticks at different times of feeding. Assembly of this data produced 72,441 sequences larger than 149 nucleotides from which 15,914 coding sequences were extracted. Of these, 5,353 had>75% coverage to their best match in the non-redundant database from the National Center for Biotechnology information, allowing for the deposition of 4,850 sequences to GenBank. The annotated data sets are available as hyperlinked spreadsheets. Putative secreted proteins were classified in 133 families, most of which have no known function. Conclusions/Significance: This data set of proteins constitutes a mining platform for novel pharmacologically active proteins and for uncovering vaccine targets against A. maculatum and the diseases they carry. C1 [Karim, Shahid; Singh, Parul] Univ So Mississippi, Dept Biol Sci, Hattiesburg, MS 39406 USA. [Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Karim, S (reprint author), Univ So Mississippi, Dept Biol Sci, Hattiesburg, MS 39406 USA. EM jribeiro@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; OI Ribeiro, Jose/0000-0002-9107-0818 FU United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) [2007-35607-20200]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health-National Center for Research Resources [P20RR016476] FX United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) award (# 2007-35607-20200) to SK. The Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, to JMCR and the National Institutes of Health-National Center for Research Resources award (P20RR016476) to the MS-INBRE facility. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 169 TC 74 Z9 74 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 21 PY 2011 VL 6 IS 12 AR e28525 DI 10.1371/journal.pone.0028525 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 876NF UT WOS:000299113600020 PM 22216098 ER PT J AU Pitisuttithum, P Rerks-Ngarm, S Bussaratid, V Dhitavat, J Maekanantawat, W Pungpak, S Suntharasamai, P Vanijanonta, S Nitayapan, S Kaewkungwal, J Benenson, M Morgan, P O'Connell, RJ Berenberg, J Gurunathan, S Francis, DP Paris, R Chiu, J Stablein, D Michael, NL Excler, JL Robb, ML Kim, JH AF Pitisuttithum, Punnee Rerks-Ngarm, Supachai Bussaratid, Valai Dhitavat, Jittima Maekanantawat, Wirach Pungpak, Swangjai Suntharasamai, Pravan Vanijanonta, Sirivan Nitayapan, Sorachai Kaewkungwal, Jaranit Benenson, Michael Morgan, Patricia O'Connell, Robert J. Berenberg, Jeffrey Gurunathan, Sanjay Francis, Donald P. Paris, Robert Chiu, Joseph Stablein, Donald Michael, Nelson L. Excler, Jean-Louis Robb, Merlin L. Kim, Jerome H. TI Safety and Reactogenicity of Canarypox ALVAC-HIV (vCP1521) and HIV-1 gp120 AIDSVAX B/E Vaccination in an Efficacy Trial in Thailand SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIME-BOOST IMMUNIZATION; IMMUNE-RESPONSES; ANTIRETROVIRAL THERAPY; SUBTYPE-E; T-CELLS; SMALLPOX VACCINATION; HIV-1-INFECTED WOMEN; CANDIDATE VACCINE; RECOMBINANT GP120 AB Background: A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand. Methodology/Principal Findings: Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p<0.001) and were more frequent after ALVAC-HIV than AIDSVAX B/E vaccination. Systemic reactions were more frequent in vaccine than placebo recipients (77.2% vs. 59.8%, p<0.001). Local and systemic reactions were mostly mild to moderate, resolving within 3 days. Conclusions/Significance: The ALVAC-HIV and AIDSVAX B/E vaccine regimen was found to be safe, well tolerated and suitable for potential large-scale use in Thailand. C1 [Pitisuttithum, Punnee; Bussaratid, Valai; Dhitavat, Jittima; Maekanantawat, Wirach; Pungpak, Swangjai; Suntharasamai, Pravan; Vanijanonta, Sirivan; Kaewkungwal, Jaranit] Mahidol Univ, Fac Trop Med, Bangkok, Thailand. [Rerks-Ngarm, Supachai] Minist Publ Hlth, Dept Dis Control, Bangkok, Thailand. [Nitayapan, Sorachai; Benenson, Michael; Morgan, Patricia] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [O'Connell, Robert J.; Michael, Nelson L.; Excler, Jean-Louis; Robb, Merlin L.; Kim, Jerome H.] Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD USA. [Berenberg, Jeffrey] Tripler Army Med Ctr, Dept Med, Honolulu, HI 96859 USA. [Gurunathan, Sanjay] Sanofi Pasteur, Swiftwater, PA USA. [Francis, Donald P.] Global Solut Infect Dis, San Francisco, CA USA. [Paris, Robert] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Chiu, Joseph] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Stablein, Donald] EMMES Corp, Rockville, MD USA. RP Pitisuttithum, P (reprint author), Mahidol Univ, Fac Trop Med, Bangkok, Thailand. EM tmppt@mahidol.ac.th FU U.S. Army Medical Research and Materiel Command [Y1-AI-2642-12]; National Institute of Allergy and Infectious Diseases [W81XWH-07-2-0067]; Henry M. Jackson Foundation for the Advancement of Military Medicine; U.S. Department of Defense; National Institutes of Health, Bethesda, MD, USA; U.S. Military HIV Research Program, Rockville, MD, USA; Department for Disease Control, Bangkok, Thailand; Mahidol University, Bangkok, Thailand; RIMS, Global Solutions for Infectious Diseases, South San Francisco, CA, USA; EMMES Corporation, Rockville MD, USA; Sanofi Pasteur, Swiftwater, PA, USA; Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand FX Supported in part by an Interagency Agreement (Y1-AI-2642-12) between the U.S. Army Medical Research and Materiel Command and the National Institute of Allergy and Infectious Diseases and by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Department of Defense. The U.S. Army was also involved in the planning, funding, execution and analysis of the trial; it was involved in both the preparation of the manuscript and the decision to publish. NIAID was involved in the planning and funding. Sanofi Pasteur provided the ALVAC-HIV vaccine, and Global Solutions for Infectious Diseases (VaxGen) provided the reagents for the immunogenicity assays. The manufacturers were full trial collaborators and were a part of the phase 3 trial steering committee.; We gratefully acknowledge and thank all the participants of the trial and the support rendered by National Institutes of Health, Bethesda, MD, USA; U.S. Military HIV Research Program, Rockville, MD, USA; Department for Disease Control, Bangkok, Thailand; Mahidol University, Bangkok, Thailand, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; RIMS, Global Solutions for Infectious Diseases, South San Francisco, CA, USA; EMMES Corporation, Rockville MD, USA; Sanofi Pasteur, Swiftwater, PA, USA. We thank Elizabeth Adams, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, for helpful comments. NR 60 TC 27 Z9 28 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 21 PY 2011 VL 6 IS 12 AR e27837 DI 10.1371/journal.pone.0027837 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 876NF UT WOS:000299113600004 PM 22205930 ER PT J AU Thambisetty, M Simmons, A Hye, A Campbell, J Westman, E Zhang, Y Wahlund, LO Kinsey, A Causevic, M Killick, R Kloszewska, I Mecocci, P Soininen, H Tsolaki, M Vellas, B Spenger, C Lovestone, S AF Thambisetty, Madhav Simmons, Andrew Hye, Abdul Campbell, James Westman, Eric Zhang, Yi Wahlund, Lars-Olof Kinsey, Anna Causevic, Mirsada Killick, Richard Kloszewska, Iwona Mecocci, Patrizia Soininen, Hilkka Tsolaki, Magda Vellas, Bruno Spenger, Christian Lovestone, Simon CA AddNeuroMed Consortium TI Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease SO PLOS ONE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; CEREBROSPINAL-FLUID BIOMARKERS; CLUSTERIN CONCENTRATION; DEMENTIA; PROTEINS; COMPLEMENT; PROGRESSION; PREDICTION; SEVERITY; TRIALS AB Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods-quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, gamma-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis. C1 [Thambisetty, Madhav; Lovestone, Simon] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Simmons, Andrew; Hye, Abdul; Westman, Eric; Kinsey, Anna; Causevic, Mirsada; Killick, Richard] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Campbell, James] Proteome Sci Plc, Cobham, England. [Zhang, Yi; Spenger, Christian] Karolinska Inst, Div Radiol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Wahlund, Lars-Olof] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Sect Clin Geriatr, Stockholm, Sweden. [Kloszewska, Iwona] Med Univ Lodz, Dept Old Age Psychiat & Psychot Disorders, Lodz, Poland. [Mecocci, Patrizia] Univ Perugia, Dept Clin & Expt Med, Sect Gerontol & Geriatr, I-06100 Perugia, Italy. [Soininen, Hilkka] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Soininen, Hilkka] Univ Eastern Finland, Dept Neurol, Kuopio, Finland. [Tsolaki, Magda] Aristotle Univ Thessaloniki, Dept Neurol, GR-54006 Thessaloniki, Greece. [Vellas, Bruno] Hop Toulouse, Dept Internal & Geriatr Med, Toulouse, France. RP Thambisetty, M (reprint author), NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov RI Simmons, Andrew/B-8848-2008; Westman, Eric/H-5771-2011; OI Simmons, Andrew/0000-0003-2306-5811; Campbell, James/0000-0001-6756-8766; Kinsey, Anna/0000-0001-8987-5353; Killick, Richard/0000-0002-8815-3436; wahlund, lars-olof/0000-0002-9905-8426; Westman, Eric/0000-0002-3115-2977 FU European Union [FP6-2004-LIFESCIHEALTH-5]; Alzheimer's Society at the Institute of Psychiatry, King's College London; National Institute for Health Research Biomedical Research Centre for Mental Health at South London; Maudsley National Health Service Foundation Trust; Institute of Psychiatry, King's College London. FX This study was supported by InnoMed (Innovative Medicines in Europe), an Integrated Project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5, Life Sciences, Genomics and Biotechnology for Health. Madhav Thambisetty held an Alzheimer's Society Research Fellowship at the Institute of Psychiatry, King's College London, and was an Emanoel Lee medical research fellow at St. Cross College, Oxford. AS and SL were supported by funds from the National Institute for Health Research Biomedical Research Centre for Mental Health at South London (www.nihr.ac.uk) and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King's College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 43 Z9 46 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 21 PY 2011 VL 6 IS 12 AR e28527 DI 10.1371/journal.pone.0028527 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 876NF UT WOS:000299113600021 PM 22205954 ER PT J AU Grohman, JK Kottegoda, S Gorelick, RJ Allbritton, NL Weeks, KM AF Grohman, Jacob K. Kottegoda, Sumith Gorelick, Robert J. Allbritton, Nancy L. Weeks, Kevin M. TI Femtomole SHAPE Reveals Regulatory Structures in the Authentic XMRV RNA Genome SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SELECTIVE 2'-HYDROXYL ACYLATION; IMMUNODEFICIENCY-VIRUS TYPE-1; SINGLE NUCLEOTIDE RESOLUTION; PRIMER EXTENSION SHAPE; MURINE LEUKEMIA-VIRUS; CAPILLARY-ELECTROPHORESIS; SECONDARY STRUCTURE; REVERSE TRANSCRIPTION; PRIMARY DETERMINANT; PCR PRIMERS AB Higher-order structure influences critical functions in nearly all noncoding and coding RNAs. Most single-nucleotide resolution RNA structure determination technologies cannot be used to analyze RNA from scarce biological samples, like viral genomes. To make quantitative RNA structure analysis applicable to a much wider array of RNA structure-function problems, we developed and applied high-sensitivity selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) to structural analysis of authentic genomic RNA of the xenotropic murine leukemia virus-related virus (XMRV). For analysis of fluorescently labeled cDNAs generated in high-sensitivity SHAPE experiments, we developed a two-color capillary electrophoresis approach with zeptomole molecular detection limits and subfemtomole sensitivity for complete SHAPE experiments involving hundreds of individual RNA structure measurements. High-sensitivity SHAPE data correlated closely (R = 0.89) with data obtained by conventional capillary electrophoresis. Using high-sensitivity SHAPE, we determined the dimeric structure of the XMRV packaging domain, examined dynamic interactions between the packaging domain RNA and viral nucleocapsid protein inside virion particles, and identified the packaging signal for this virus. Despite extensive sequence differences between XMRV and the intensively studied Moloney murine leukemia virus, architectures of the regulatory domains are similar and reveal common principles of gammaretrovirus RNA genome packaging. C1 [Grohman, Jacob K.; Kottegoda, Sumith; Allbritton, Nancy L.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Gorelick, Robert J.] Sci Applicat Int Corp Frederick Inc, AIDS & Canc Virus Program, NCI Frederick, Frederick, MD 21702 USA. [Allbritton, Nancy L.] N Carolina State Univ, Raleigh, NC 27695 USA. [Allbritton, Nancy L.] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC 27599 USA. RP Weeks, KM (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. EM weeks@unc.edu FU U.S. National Institutes of Health [GM064803, CA139599]; National Cancer Institute, National Institutes of Health [HHSN2612008-00001E]; SAIC-Frederick, Inc. FX We are indebted to Freddy Pinero in the UNC Chemistry Instrument shop for mechanical drawings and construction of custom instrument pieces, Alex Villa for creation of the Labview software, Jenny Mauger for helpful discussions on Labview programming, and Julian W. Bess, Jr., (AIDS and Cancer Virus Program, Biological Products Core) for providing and purifying XMRV stocks for this work. This work was supported by grants from the U.S. National Institutes of Health (GM064803 to K.M.W. and CA139599 to N.L.A.) and has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN2612008-00001E with SAIC-Frederick, Inc. NR 44 TC 8 Z9 8 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 DEC 21 PY 2011 VL 133 IS 50 BP 20326 EP 20334 DI 10.1021/ja2070945 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 871BW UT WOS:000298713600055 PM 22126209 ER PT J AU Brody, H Miller, FG AF Brody, Howard Miller, Franklin G. TI Lessons From Recent Research About the Placebo Effect-From Art to Science SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Brody, Howard] Univ Texas Med Branch, Inst Med Humanities, Dept Family Med, Galveston, TX 77555 USA. [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Brody, H (reprint author), Univ Texas Med Branch, Inst Med Humanities, Dept Family Med, 301 Univ Blvd, Galveston, TX 77555 USA. EM habrody@utmb.edu NR 9 TC 24 Z9 24 U1 0 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 21 PY 2011 VL 306 IS 23 BP 2612 EP 2613 DI 10.1001/jama.2011.1850 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 864YQ UT WOS:000298276800025 PM 22187283 ER PT J AU Anisimova, NYU Kiselevsky, MV Sosnov, AV Sadovnikov, SV Stankov, IN Gakh, AA AF Anisimova, Natalia Y. U. Kiselevsky, Mikhail V. Sosnov, Andrey V. Sadovnikov, Sergey V. Stankov, Ivan N. Gakh, Andrei A. TI Trans-, cis-, and dihydro-resveratrol: a comparative study SO CHEMISTRY CENTRAL JOURNAL LA English DT Article ID PROSTATE-CANCER CELLS; ESTROGEN-RECEPTOR; CYCLE ARREST; ER-BETA; GROWTH; ESTRADIOL; APOPTOSIS; ALCOHOL; ALPHA; WINE AB Background: Recent studies showed that moderate consumption of red or white wines increased the chances of breast cancer, while similar consumption of red wines, rich in trans-resveratrol (trans-R), decreased the rate of prostate cancer. This prompted us to explore the role of various forms of R in cancer proliferation. Results: Trans-R was found to be the most potent antiproliferative agent. Cis-R demonstrated somewhat less potency compared to trans-R. Unlike cis-R and trans-R, dihydro-R exhibits moderate proliferative effect on androgen-independent prostate cancer cell lines PC-3 and DU-145 at picomolar concentrations. At higher concentrations, dihydro-R caused proliferation inhibition, similar to cis-R and trans-R. The proliferative effect of dihydro-R at low concentrations can be reversed by trans-R which acts as a partial antagonist in the presence of dihydro-R. Mixtures of dihydro-R and trans-R demonstrated complex non-monotonic cross-modulation activity patterns. Conclusions: Dihydro-R exhibits proliferative effects in androgen-independent prostate cancer cells at picomolar and nanomolar concentrations. While the exact mechanism of these effects requires further evaluation, our preliminary results point to hormone receptor modulation activity. We also observed strong cross modulation between trans-R and dihydro-R at sub-picomolar concentrations. The role of dihydro-R in cancer proliferation related to moderate consumption of red wine remains an open question because dihydro-R has a very complex activity pattern in the presence of trans-R. C1 [Gakh, Andrei A.] NIDDK, NIH, Bethesda, MD 20892 USA. [Anisimova, Natalia Y. U.; Kiselevsky, Mikhail V.] NN Blokhin Russian Canc Res Ctr RAMS, Moscow, Russia. [Sosnov, Andrey V.] Inst Gen Patol & Pathophysiol, Moscow 125315, Russia. [Sadovnikov, Sergey V.] Chem Div Res Inst, Chimki 141401, Moscow Reg, Russia. RP Gakh, AA (reprint author), NIDDK, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM gakhaa@yahoo.com RI Anisimova, Natalia/A-6640-2014; Kiselevskiy, Mikhail/D-8822-2017 OI Anisimova, Natalia/0000-0002-4370-6578; Kiselevskiy, Mikhail/0000-0002-0132-167X FU Global IPP through the International Science and Technology Center; NIDDK FX The authors are grateful to Dr. M. Yu. Krasavin and M. V. Yudin for the preparation of trans-, cis-, and dihydro-resveratrol samples. This research was supported by the Global IPP program through the International Science and Technology Center. This paper is a contribution from the Discovery Chemistry Project. This effort was supported in part by NIDDK Intramural Research Program. NR 30 TC 3 Z9 5 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-153X J9 CHEM CENT J JI Chem. Cent. J. PD DEC 20 PY 2011 VL 5 AR 88 DI 10.1186/1752-153X-5-88 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 915NY UT WOS:000302035800001 PM 22185600 ER PT J AU Rivero, S Ruiz-Garcia, A Diaz-Guerra, MJM Laborda, J Garcia-Ramirez, JJ AF Rivero, Samuel Ruiz-Garcia, Almudena Diaz-Guerra, Maria J. M. Laborda, Jorge Garcia-Ramirez, Jose J. TI Characterization of a proximal Sp1 response element in the mouse Dlk2 gene promoter SO BMC MOLECULAR BIOLOGY LA English DT Article ID II CORE PROMOTER; HOMEOTIC PROTEIN DLK; DELTA-LIKE DLK; ADIPOCYTE DIFFERENTIATION; TATA-BOX; DNA METHYLATION; REPEAT MOTIFS; HUMAN GENOME; STEM-CELLS; EXPRESSION AB Background: DLK2 is an EGF-like membrane protein, closely related to DLK1, which is involved in adipogenesis. Both proteins interact with the NOTCH1 receptor and are able to modulate its activation. The expression of the gene Dlk2 is coordinated with that of Dlk1 in several tissues and cell lines. Unlike Dlk1, the mouse Dlk2 gene and its locus at chromosome 17 are not fully characterized. Results: The goal of this work was the characterization of Dlk2 mRNA, as well as the analysis of the mechanisms that control its basal transcription. First, we analyzed the Dlk2 transcripts expressed by several mouse cells lines and tissues, and mapped the transcription start site by 5' Rapid Amplification of cDNA Ends. In silico analysis revealed that Dlk2 possesses a TATA-less promoter containing minimal promoter elements associated with a CpG island, and sequences for Inr and DPE elements. Besides, it possesses six GC-boxes, considered as consensus sites for the transcription factor Sp1. Indeed, we report that Sp1 directly binds to the Dlk2 promoter, activates its transcription, and regulates its level of expression. Conclusions: Our results provide the first characterization of Dlk2 transcripts, map the location of the Dlk2 core promoter, and show the role of Sp1 as a key regulator of Dlk2 transcription, providing new insights into the molecular mechanisms that contribute to the expression of the Dlk2 gene. C1 [Rivero, Samuel; Ruiz-Garcia, Almudena; Diaz-Guerra, Maria J. M.; Laborda, Jorge; Garcia-Ramirez, Jose J.] Univ Castilla La Mancha, Fac Med, CRIB, Albacete 02006, Spain. [Rivero, Samuel] NIAID, Samuel Rivero Mol Pathol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Garcia-Ramirez, JJ (reprint author), Univ Castilla La Mancha, Fac Med, CRIB, Calle Almansa 14, Albacete 02006, Spain. EM JoseJavier.GRamirez@uclm.es RI Garcia-Ramirez, Jose/L-2153-2014; Laborda, Jorge/L-5726-2014; Martinez Diaz-Guerra, Maria/M-2855-2014; OI Garcia-Ramirez, Jose/0000-0002-8348-3727; Laborda, Jorge/0000-0002-9210-838X; Martinez Diaz-Guerra, Maria Jose/0000-0003-3843-3912 FU Fundacion para la Investigacion Sanitaria de Castilla-La Mancha [FISCAM PI-2006/12]; Spanish Ministry for Science and Education [BFU2007-61094] FX We greatly appreciate the technical input offered by Dr. Marta Casado, as well as the kind gift of the Sp1 expression and response plasmids. We thank Dr. Paloma Martin-Sanz for kindly providing us with AT3F cells. We greatly appreciate the help of Dr. Elena de la Casa-Esperon in critically reading the manuscript. The work was supported by Fundacion para la Investigacion Sanitaria de Castilla-La Mancha, [FISCAM PI-2006/12], and the Spanish Ministry for Science and Education [BFU2007-61094]. NR 51 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2199 J9 BMC MOL BIOL JI BMC Mol. Biol. PD DEC 20 PY 2011 VL 12 AR 52 DI 10.1186/1471-2199-12-52 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 908IR UT WOS:000301484600001 PM 22185379 ER PT J AU Kilicoglu, H Rosemblat, G Fiszman, M Rindflesch, TC AF Kilicoglu, Halil Rosemblat, Graciela Fiszman, Marcelo Rindflesch, Thomas C. TI Constructing a semantic predication gold standard from the biomedical literature SO BMC BIOINFORMATICS LA English DT Article ID INFORMATION EXTRACTION; CORPUS; TEXT; AGREEMENT; DOMAIN; GENE AB Background: Semantic relations increasingly underpin biomedical text mining and knowledge discovery applications. The success of such practical applications crucially depends on the quality of extracted relations, which can be assessed against a gold standard reference. Most such references in biomedical text mining focus on narrow subdomains and adopt different semantic representations, rendering them difficult to use for benchmarking independently developed relation extraction systems. In this article, we present a multi-phase gold standard annotation study, in which we annotated 500 sentences randomly selected from MEDLINE abstracts on a wide range of biomedical topics with 1371 semantic predications. The UMLS Metathesaurus served as the main source for conceptual information and the UMLS Semantic Network for relational information. We measured interannotator agreement and analyzed the annotations closely to identify some of the challenges in annotating biomedical text with relations based on an ontology or a terminology. Results: We obtain fair to moderate interannotator agreement in the practice phase (0.378-0.475). With improved guidelines and additional semantic equivalence criteria, the agreement increases by 12% (0.415 to 0.536) in the main annotation phase. In addition, we find that agreement increases to 0.688 when the agreement calculation is limited to those predications that are based only on the explicitly provided UMLS concepts and relations. Conclusions: While interannotator agreement in the practice phase confirms that conceptual annotation is a challenging task, the increasing agreement in the main annotation phase points out that an acceptable level of agreement can be achieved in multiple iterations, by setting stricter guidelines and establishing semantic equivalence criteria. Mapping text to ontological concepts emerges as the main challenge in conceptual annotation. Annotating predications involving biomolecular entities and processes is particularly challenging. While the resulting gold standard is mainly intended to serve as a test collection for our semantic interpreter, we believe that the lessons learned are applicable generally. C1 [Kilicoglu, Halil; Rosemblat, Graciela; Fiszman, Marcelo; Rindflesch, Thomas C.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Kilicoglu, Halil] Concordia Univ, Dept Comp Sci & Software Engn, Montreal, PQ, Canada. RP Kilicoglu, H (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. EM kilicogluh@mail.nih.gov FU National Institutes of Health, National Library of Medicine FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 36 TC 11 Z9 11 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 20 PY 2011 VL 12 AR 486 DI 10.1186/1471-2105-12-486 PG 17 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 894KT UT WOS:000300426300001 PM 22185221 ER PT J AU Ichim, T Riordan, NH Stroncek, DF AF Ichim, Thomas Riordan, Neil H. Stroncek, David F. TI The King is Dead, Long Live the King: Entering A New Era of Stem Cell Research and Clinical Development SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material AB In mid November the biopharma industry was shocked by the announcement from Geron that they were ending work on embryonic stem cell research and therapy. For more than 10 years the public image of all stem cell research has been equated with embryonic stem cells. Unfortunately, a fundamentally important medical and financial fact was being ignored: embryonic stem cell therapy is extremely immature. In parallel to efforts in embryonic stem cell research and development, scientists and physicians in the field of adult stem cells realized that the natural role of adult stem cells in the body is to promote healing and to act like endogenous "repair cells" and, as a result, numerous companies have entered the field of adult stem cell therapy with the goal of expanding numbers of adult stem cells for administration to patients with various conditions. In contrast to embryonic stem cells, which are extremely expensive and potentially dangerous, adult cell cells are inexpensive and have an excellent safety record when used in humans. Many studies are now showing that adult stem cells are practical, patient-applicable, therapeutics that are very close to being available for incorporation into the practice of medicine. These events signal the entrance of the field of stem cells into a new era: an era where hype and misinformation no longer triumph over economic and medical realities. C1 [Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Ichim, Thomas] MediStem Inc, San Diego, CA USA. [Riordan, Neil H.] Aidan Fdn, Chandler, AZ USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov NR 0 TC 7 Z9 7 U1 0 U2 3 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 DEC 20 PY 2011 VL 9 AR 218 DI 10.1186/1479-5876-9-218 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 893HI UT WOS:000300346500001 PM 22185188 ER PT J AU Gething, PW Patil, AP Smith, DL Guerra, CA Elyazar, IRF Johnston, GL Tatem, AJ Hay, SI AF Gething, Peter W. Patil, Anand P. Smith, David L. Guerra, Carlos A. Elyazar, Iqbal R. F. Johnston, Geoffrey L. Tatem, Andrew J. Hay, Simon I. TI A new world malaria map: Plasmodium falciparum endemicity in 2010 SO MALARIA JOURNAL LA English DT Article ID ENTOMOLOGICAL INOCULATION RATE; TRANSMISSION INTENSITY; DIAGNOSTIC-TECHNIQUES; SCHISTOSOMA-MANSONI; AFRICAN CHILDREN; ATLAS PROJECT; VIVAX MALARIA; PARASITE RATE; RISK; MODEL AB Background: Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations. Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control. To remain relevant operationally, such maps must be updated frequently. Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010. This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (PfEIR) and the basic reproductive number (PfR). Methods: Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (PfPR) surveys were used in a model-based geostatistical (MBG) prediction to create a continuous contemporary surface of malaria endemicity within these limits. A suite of transmission models were developed that link PfPR to PfEIR and PfR and these were fitted to field data. These models were combined with the PfPR map to create new global predictions of PfEIR and PfR. All output maps included measured uncertainty. Results: An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively. The majority of the endemic world was predicted with a median PfEIR of less than one and a median PfR(c) of less than two. Values of either metric exceeding 10 were almost exclusive to Africa. The uncertainty described in both PfEIR and PfR was substantial in regions of intense transmission. Conclusions: The year 2010 has a particular significance as an evaluation milestone for malaria global health policy. The maps presented here contribute to a rational basis for control and elimination decisions and can serve as a baseline assessment as the global health community looks ahead to the next series of milestones targeted at 2015. C1 [Gething, Peter W.; Patil, Anand P.; Guerra, Carlos A.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Smith, David L.; Tatem, Andrew J.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Smith, David L.] Univ Florida, Dept Biol, Gainesville, FL USA. [Smith, David L.; Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Elyazar, Iqbal R. F.] Eijkman Oxford Clin Res Unit, Jakarta 10430, Indonesia. [Johnston, Geoffrey L.] Columbia Univ, Sch Int & Publ Affairs, New York, NY USA. [Johnston, Geoffrey L.] Columbia Univ, Dept Microbiol & Immunol, Coll Phys & Surg, New York, NY 10032 USA. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. RP Gething, PW (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,S Parks Rd, Oxford, England. EM peter.gething@zoo.ox.ac.uk; simon.i.hay@gmail.com RI Smith, David/L-8850-2013; Hay, Simon/F-8967-2015; OI Smith, David/0000-0003-4367-3849; Hay, Simon/0000-0002-0611-7272; Gething, Peter/0000-0001-6759-5449 FU Wellcome Trust [079091, 091835]; University of Oxford-Li Ka Shing Foundation; Oxford Tropical Network; Bill and Melinda Gates Foundation [49446]; National Science Foundation; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Wellcome Trust, UK; Global Fund FX The large global assembly of parasite prevalence data was critically dependent on the generous contributions of data made by a large number of people in the malaria research and control communities and these individuals are listed on the MAP website (http://www.map.ox.ac.uk/acknowledgements/). Thanks also to Kevin Baird, Thomas Van Boeckel, Peter Horby, Viola Kirui, Bui Manh, Catherine Moyes, Will Temperley and Heiman Wertheim for contributing their expertise, and to Catherine Moyes, Rosalind Howes, Katherine Battle and Jennie Charlton for proof-reading. We thank Professor David Rogers for providing the Fourier-processed remote sensing data. SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#079091), which also supports PWG and CAG. APP is funded by a Biomedical Resources Grant from the Wellcome Trust (#091835). IRFE is funded by grants from the University of Oxford-Li Ka Shing Foundation Global Health Program and the Oxford Tropical Network. DLS and AJT are supported by a grant from the Bill and Melinda Gates Foundation (#49446) (http://www.gatesfoundation.org). GLJ is supported by a National Science Foundation Graduate Research Fellowship. PWG, APP, DLS, AJT and SIH also acknowledge support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov). This work forms part of the output of the Malaria Atlas Project (MAP, http://www.map.ox.ac.uk), principally funded by the Wellcome Trust, UK (http://www.wellcome.ac.uk). MAP also acknowledges the support of the Global Fund to fight AIDS, Tuberculosis, and Malaria (http://www.theglobalfund.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript NR 82 TC 254 Z9 256 U1 10 U2 72 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD DEC 20 PY 2011 VL 10 AR 378 DI 10.1186/1475-2875-10-378 PG 16 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 893KV UT WOS:000300355700001 PM 22185615 ER PT J AU Puri, A Jang, H Yavlovich, A Masood, MA Veenstra, TD Luna, C Aranda-Espinoza, H Nussinov, R Blumenthal, R AF Puri, Anu Jang, Hyunbum Yavlovich, Amichai Masood, M. Athar Veenstra, Timothy D. Luna, Carlos Aranda-Espinoza, Helim Nussinov, Ruth Blumenthal, Robert TI Material Properties of Matrix Lipids Determine the Conformation and Intermolecular Reactivity of Diacetylenic Phosphatidylcholine in the Lipid Bilayer SO LANGMUIR LA English DT Article ID MOLECULAR-DYNAMICS; PHOSPHOLIPID-BILAYER; PHOTO-POLYMERIZATION; MEMBRANE-COMPOSITION; DOMAIN FORMATION; MONOLAYERS; LIPOSOMES; RAFTS; GRAMICIDIN; VESICLES AB Photopolymerizable phospholipid DC(8,9)PC (1,2-bis-(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine) exhibits unique assembly characteristics in the lipid bilayer. Because of the presence of the diacetylene groups, DC(8,9)PC undergoes polymerization upon UV (254 rim) exposure and assumes chromogenic properties. DC(8,9)PC photopolymerization in gel-phase matrix lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monitored by UV-vis absorption spectroscopy occurred within 2 min after UV treatment, whereas no spectral shifts were observed when DC(8,9)PC was incorporated into liquid-phase matrix 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Liquid chromatography-tandem mass spectrometry analysis showed a decrease in the amount of DC(8,9)PC monomer in both DPPC and POPC environments without any change in the matrix lipids in UV-treated samples. Molecular dynamics (MD) simulations of DPPC/DC(8,9)PC and POPC/DC(8,9)PC bilayers indicate that the DC(8,9)PC molecules adjust to the thickness of the matrix lipid bilayer. Furthermore, the motions of DC(8,9)PC in the gel-phase bilayer are more restricted than in the fluid bilayer. The restricted motional flexibility of DC(8,9)PC (in the gel phase) enables the reactive diacetylenes in individual molecules to align and undergo polymerization, whereas the unrestricted motions in the fluid bilayer restrict polymerization because of the lack of appropriate alignment of the DC(8,9)PC fatty acyl chains. Fluorescence microscopy data indicates the homogeneous distribution of lipid probe 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-lissamine rhodamine B sulfonyl ammonium salt (N-Rh-PE) in POPC/DC(8,9)PC monolayers but domain formation in DPPC/DC(8,9)PC monolayers. These results show that the DC(8,9)PC molecules cluster and assume the preferred conformation in the gel-phase matrix for the UV-triggered polymerization reaction. C1 [Puri, Anu; Yavlovich, Amichai; Blumenthal, Robert] Natl Canc Inst Frederick, Membrane Struct & Funct Sect, Frederick, MD 21702 USA. [Jang, Hyunbum] SAIC Frederick Inc, Basic Sci Program, Nanobiol Program, Ctr Canc Res,Natl Canc Inst Frederick, Frederick, MD 21702 USA. [Masood, M. Athar; Veenstra, Timothy D.] SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, Ctr Canc Res,Natl Canc Inst Frederick, Frederick, MD 21702 USA. [Luna, Carlos; Aranda-Espinoza, Helim] Univ Maryland, Fischell Dept Bioengn, College Pk, MD USA. RP Blumenthal, R (reprint author), Natl Canc Inst Frederick, Membrane Struct & Funct Sect, Frederick, MD 21702 USA. EM blumenthalr@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project is funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does its mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. All simulations were performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). We thank Brian Mikolajczyk, Alex Haber, Mylinh Vu, Christopher Connor, and Aamir Akram for their help with the experiments. NR 33 TC 8 Z9 8 U1 0 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD DEC 20 PY 2011 VL 27 IS 24 BP 15120 EP 15128 DI 10.1021/la203453x PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 862UB UT WOS:000298118500049 PM 22053903 ER PT J AU O'Donnell, CJ Kavousi, M Smith, AV Kardia, SLR Feitosa, MF Hwang, SJ Sun, YV Province, MA Aspelund, T Dehghan, A Hoffmann, U Bielak, LF Zhang, QY Eiriksdottir, G van Duijn, CM Fox, CS de Andrade, M Kraja, AT Sigurdsson, S Elias-Smale, SE Murabito, JM Launer, LJ van der Lugt, A Kathiresan, S Krestin, GP Herrington, DM Howard, TD Liu, YM Post, W Mitchell, BD O'Connell, JR Shen, HQ Shuldiner, AR Altshuler, D Elosua, R Salomaa, V Schwartz, SM Siscovick, DS Voight, BF Bis, JC Glazer, NL Psaty, BM Boerwinkle, E Heiss, G Blankenberg, S Zeller, T Wild, PS Schnabel, RB Schillert, A Ziegler, A Munzel, T White, CC Rotter, JI Nalls, M Oudkerk, M Johnson, AD Newman, AB Uitterlinden, AG Massaro, JM Cunningham, J Harris, TB Hofman, A Peyser, PA Borecki, IB Cupples, LA Gudnason, V Witteman, JCM AF O'Donnell, Christopher J. Kavousi, Maryam Smith, Albert V. Kardia, Sharon L. R. Feitosa, Mary F. Hwang, Shih-Jen Sun, Yan V. Province, Michael A. Aspelund, Thor Dehghan, Abbas Hoffmann, Udo Bielak, Lawrence F. Zhang, Qunyuan Eiriksdottir, Gudny van Duijn, Cornelia M. Fox, Caroline S. de Andrade, Mariza Kraja, Aldi T. Sigurdsson, Sigurdur Elias-Smale, Suzette E. Murabito, Joanne M. Launer, Lenore J. van der Lugt, Aad Kathiresan, Sekar Krestin, Gabriel P. Herrington, David M. Howard, Timothy D. Liu, Yongmei Post, Wendy Mitchell, Braxton D. O'Connell, Jeffrey R. Shen, Haiqing Shuldiner, Alan R. Altshuler, David Elosua, Roberto Salomaa, Veikko Schwartz, Stephen M. Siscovick, David S. Voight, Benjamin F. Bis, Joshua C. Glazer, Nicole L. Psaty, Bruce M. Boerwinkle, Eric Heiss, Gerardo Blankenberg, Stefan Zeller, Tanja Wild, Philipp S. Schnabel, Renate B. Schillert, Arne Ziegler, Andreas Muenzel, Thomas White, Charles C. Rotter, Jerome I. Nalls, Michael Oudkerk, Matthijs Johnson, Andrew D. Newman, Anne B. Uitterlinden, Andre G. Massaro, Joseph M. Cunningham, Julie Harris, Tamara B. Hofman, Albert Peyser, Patricia A. Borecki, Ingrid B. Cupples, L. Adrienne Gudnason, Vilmundur Witteman, Jacqueline C. M. CA CARDIoGRAM Consortium TI Genome-Wide Association Study for Coronary Artery Calcification With Follow-Up in Myocardial Infarction SO CIRCULATION LA English DT Article DE cardiac computed tomography; coronary artery calcification; coronary atherosclerosis; genome-wide association studies; myocardial infarction ID BEAM COMPUTED-TOMOGRAPHY; EXPERT CONSENSUS DOCUMENT; ABDOMINAL AORTIC-ANEURYSM; BONE-MINERAL DENSITY; OLD-ORDER AMISH; AMERICAN-COLLEGE; SEQUENCE VARIANT; BLOOD-PRESSURE; HEART-DISEASE; RISK AB Background-Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI. Methods and Results-Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58x10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65x10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). Conclusions-SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events. (Circulation. 2011;124:2855-2864.) C1 [O'Donnell, Christopher J.; Hwang, Shih-Jen; Fox, Caroline S.; Murabito, Joanne M.; Johnson, Andrew D.; Massaro, Joseph M.; Cupples, L. Adrienne] NHLBIs Framingham Heart Study, Framingham, MA 01702 USA. [O'Donnell, Christopher J.; Kardia, Sharon L. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [O'Donnell, Christopher J.; Hwang, Shih-Jen; Fox, Caroline S.; Johnson, Andrew D.] NHLBI, Bethesda, MD 20892 USA. [Kavousi, Maryam; Dehghan, Abbas; van Duijn, Cornelia M.; Elias-Smale, Suzette E.; Uitterlinden, Andre G.; Hofman, Albert; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Elias-Smale, Suzette E.] Erasmus Univ, Dept Radiol, Med Ctr, Rotterdam, Netherlands. [Kavousi, Maryam; Dehghan, Abbas; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Witteman, Jacqueline C. M.] Netherlands Genom Initiat Sponsored Netherlands C, Rotterdam, Netherlands. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Sigurdsson, Sigurdur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur Iceland, Iceland. [Kardia, Sharon L. R.; Sun, Yan V.; Bielak, Lawrence F.; Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Feitosa, Mary F.; Province, Michael A.; Zhang, Qunyuan; Kraja, Aldi T.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Gen, St Louis, MO 63110 USA. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Metab & Diabet,Dept Med, Boston, MA 02115 USA. [de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [van der Lugt, Aad; Krestin, Gabriel P.] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Kathiresan, Sekar; Altshuler, David; Voight, Benjamin F.] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA. [Herrington, David M.; Howard, Timothy D.; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Post, Wendy] Johns Hopkins Univ Hosp, Dept Med & Epidemiol, Baltimore, MD 21287 USA. [Mitchell, Braxton D.; O'Connell, Jeffrey R.; Shen, Haiqing; Shuldiner, Alan R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Baltimore, MD 21218 USA. [Altshuler, David; Voight, Benjamin F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Elosua, Roberto] Inst Municipal Invest Med, Barcelona, Spain. [Elosua, Roberto] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Salomaa, Veikko] Natl Publ Hlth Inst, Chron Dis Epidemiol Unit, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Schwartz, Stephen M.; Siscovick, David S.; Bis, Joshua C.; Glazer, Nicole L.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Schwartz, Stephen M.; Siscovick, David S.; Bis, Joshua C.; Glazer, Nicole L.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Human Genet Ctr, Houston, TX USA. [Boerwinkle, Eric] Inst Mol Med, Houston, TX USA. [Heiss, Gerardo] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27515 USA. [Blankenberg, Stefan; Zeller, Tanja; Wild, Philipp S.; Schnabel, Renate B.; Muenzel, Thomas] Univ Med Ctr Mainz, Dept Med 2, Mainz, Germany. [Schillert, Arne; Ziegler, Andreas] Univ Lubeck, Inst Med Biometrie & Stat, Univ Klinikum Schleswig Holstein, Lubeck, Germany. [White, Charles C.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Nalls, Michael] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Oudkerk, Matthijs] Univ Groningen, Ctr Med Imaging NE Netherlands, Dept Radiol, Univ Med Ctr Groningen, Groningen, Netherlands. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Cunningham, Julie] Mayo Clin, Coll Med, Rochester, MN USA. RP O'Donnell, CJ (reprint author), NHLBIs Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov; ppeyser@umich.edu RI Aspelund, Thor/C-5983-2008; Willenborg, Christina/D-2668-2012; Johnson, Andrew/G-6520-2013; Smith, Albert/K-5150-2015; Feitosa, Mary/K-8044-2012; Altshuler, David/A-4476-2009; Elias-Smale, Suzette/F-2410-2014; Schnabel, Renate/F-6527-2014; Newman, Anne/C-6408-2013; Gudnason, Vilmundur/K-6885-2015; Peters, Annette/A-6117-2011; OI Aspelund, Thor/0000-0002-7998-5433; Willenborg, Christina/0000-0001-5217-6882; Smith, Albert/0000-0003-1942-5845; Feitosa, Mary/0000-0002-0933-2410; Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812; Altshuler, David/0000-0002-7250-4107; Newman, Anne/0000-0002-0106-1150; Gudnason, Vilmundur/0000-0001-5696-0084; ELOSUA, ROBERTO/0000-0001-8235-0095; Cupples, L. Adrienne/0000-0003-0273-7965; Ziegler, Andreas/0000-0002-8386-5397; Mitchell, Braxton/0000-0003-4920-4744; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X FU Intramural NIH HHS [Z01 HL006002-01, Z99 HL999999, ZIA HL006002-04]; NCATS NIH HHS [UL1 TR000005, UL1 TR000124]; NHLBI NIH HHS [R01 HL087647] NR 64 TC 101 Z9 104 U1 0 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 20 PY 2011 VL 124 IS 25 BP 2855 EP U255 DI 10.1161/CIRCULATIONAHA.110.974899 PG 68 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866VS UT WOS:000298414900016 PM 22144573 ER PT J AU Takemura, SY Karuppudurai, T Ting, CY Lu, ZY Lee, CH Meinertzhagen, IA AF Takemura, Shin-ya Karuppudurai, Thangavel Ting, Chun-Yuan Lu, Zhiyuan Lee, Chi-Hon Meinertzhagen, Ian A. TI Cholinergic Circuits Integrate Neighboring Visual Signals in a Drosophila Motion Detection Pathway SO CURRENT BIOLOGY LA English DT Article ID ELEMENTARY MOVEMENT DETECTORS; SYSTEM LIGHT MICROSCOPY; MUSCA-DOMESTICA; OPTIC LOBE; SENSITIVE PATHWAYS; WILD-TYPE; FLY; MELANOGASTER; ORGANIZATION; VISION AB Detecting motion is a feature of all advanced visual systems [1], nowhere more so than in flying animals, like insects [2, 3]. In flies, an influential autocorrelation model for motion detection, the elementary motion detector circuit (EMD; [4, 5]), compares visual signals from neighboring photoreceptors to derive information on motion direction and velocity. This information is fed by two types of interneuron, L1 and L2, in the first optic neuropile, or lamina, to downstream local motion detectors in columns of the second neuropile, the medulla. Despite receiving carefully matched photoreceptor inputs, L1 and L2 drive distinct, separable pathways responding preferentially to moving "on" and "off" edges, respectively [6, 7]. Our serial electron microscopy (EM) identifies two types of transmedulla (Tm) target neurons, Tm1 and Tm2, that receive apparently matched synaptic inputs from L2. Tm2 neurons also receive inputs from two retinotopically posterior neighboring columns via L4, a third type of lamina neuron. Light microscopy reveals that the connections in these L2/L4/Tm2 circuits are highly determinate. Single-cell transcript profiling suggests that nicotinic acetylcholine receptors mediate transmission within the L2/L4/Tm2 circuits, whereas L1 is apparently glutamatergic. We propose that Tm2 integrates signconserving inputs from neighboring columns to mediate the detection of front-to-back motion generated during forward motion. C1 [Karuppudurai, Thangavel; Ting, Chun-Yuan; Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Takemura, Shin-ya; Lu, Zhiyuan; Meinertzhagen, Ian A.] Dalhousie Univ, Dept Psychol & Neurosci, Life Sci Ctr, Halifax, NS B3H 4R2, Canada. [Takemura, Shin-ya; Meinertzhagen, Ian A.] Dalhousie Univ, Dept Biol, Life Sci Ctr, Halifax, NS B3H 4R2, Canada. RP Lee, CH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM leechih@mail.nih.gov; iam@dal.ca RI Lee, Chi-Hon/G-9190-2012; Ting, chun-yuan/F-6448-2013; Karuppudurai, Thangavel/C-4831-2014; OI Takemura, Shin-ya/0000-0003-2400-6426; Meinertzhagen, Ian/0000-0002-6578-4526 FU National Institutes of Health (NIH) [EY-03592]; NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development [H0008776-06] FX This work was supported by National Institutes of Health (NIH) grant EY-03592 (to I.A.M.) and the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant H0008776-06 to C.-H. L.). We are grateful to Matthew Murphey and Satoko Takemura for assistance in making the EM reconstructions; Tara Edwards for executing Figure 4; Christina Dollar for carrying out Rp49 experiments; Claude Desplan, Tzumin Lee, Martin Heisenberg, and Tiffany Cook for reagents and communication; and Alan Hinnebusch and the late Howard Nash for helpful discussions. NR 43 TC 49 Z9 49 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD DEC 20 PY 2011 VL 21 IS 24 BP 2077 EP 2084 DI 10.1016/j.cub.2011.10.053 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 867FK UT WOS:000298440100022 PM 22137471 ER PT J AU Kelly, RJ Petrini, I Rajan, A Wang, YS Giaccone, G AF Kelly, Ronan J. Petrini, Iacopo Rajan, Arun Wang, Yisong Giaccone, Giuseppe TI Thymic Malignancies: From Clinical Management to Targeted Therapies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR; FACTOR-I RECEPTOR; P53 PROTEIN EXPRESSION; OF-THE-LITERATURE; EPITHELIAL TUMORS; INVASIVE THYMOMA; PHASE-II; NEUROTROPHIN RECEPTORS; SOMATOSTATIN RECEPTORS; GENETIC ABERRATIONS AB Purpose A key challenge in the treatment of thymoma and thymic carcinoma (TC) is in improving our understanding of the molecular biology of these relatively rare tumors. In recent years, significant efforts have been made to dissect the molecular pathways involved in their carcinogenesis. Here we discuss the results of large-scale genomic analyses conducted to date and review the most active chemotherapies and targeted treatments. Methods We reviewed the literature for chemotherapeutic trials in the last 20 years and trials involving targeted therapies between 1999 and 2010. The search was supplemented by a review of abstracts presented at the annual meetings of the American Society of Clinical Oncology (from 1999 to 2010), at the first International Conference on Thymic Malignancies in 2009, and at a follow-up meeting of the newly formed International Thymic Malignancies Interest Group in 2010. Results Surgery remains the treatment of choice for operable tumors, whereas chemotherapy is standard in locally advanced and metastatic disease. Thus far, targeted therapies have been developed empirically. Histone deacetylase inhibitors have shown some activity in thymoma whereas sunitinib may be active in TC. There are no data to support the use of HER2- or EGFR-targeted therapies in thymic malignancies. Conclusion Drug development for the treatment of thymic malignancies is difficult because of the rarity of these tumors. Ethnic differences are becoming apparent, with aggressive subtypes being observed in Asians and African Americans. Incremental improvements in our understanding of tumor biology suggest that molecular profiling-directed therapies may be the preferred route of investigation in the future. J Clin Oncol 29: 4820-4827. (C) 2011 by American Society of Clinical Oncology C1 [Kelly, Ronan J.; Petrini, Iacopo; Rajan, Arun; Wang, Yisong; Giaccone, Giuseppe] NCI, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, NIH, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Petrini, Iacopo/K-7316-2016; Giaccone, Giuseppe/E-8297-2017 OI Petrini, Iacopo/0000-0002-7752-6866; Giaccone, Giuseppe/0000-0002-5023-7562 FU National Cancer Institute (NCI), National Institutes of Health (NIH); NIH, Center for Cancer Research, NCI FX Supported by the National Cancer Institute (NCI), National Institutes of Health (NIH) and by the NIH Intramural Research Program, Center for Cancer Research, NCI. NR 102 TC 38 Z9 38 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 20 PY 2011 VL 29 IS 36 BP 4820 EP 4827 DI 10.1200/JCO.2011.36.0487 PG 8 WC Oncology SC Oncology GA 863DD UT WOS:000298142100018 PM 22105817 ER PT J AU Olnes, MJ Scheinberg, P AF Olnes, Matthew J. Scheinberg, Phillip TI Activity of Alemtuzumab in Acute Myelogenous Leukemia and Myelodysplastic Syndrome With Chromosome 7 Aberrations Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CELLS; ABNORMALITIES C1 [Olnes, Matthew J.; Scheinberg, Phillip] NHLBI, NIH, Bethesda, MD 20892 USA. RP Olnes, MJ (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Scheinberg, Phillip/H-5251-2012 NR 9 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 20 PY 2011 VL 29 IS 36 BP 4842 EP 4843 DI 10.1200/JCO.2011.38.6698 PG 3 WC Oncology SC Oncology GA 863DD UT WOS:000298142100023 ER PT J AU Redon, CE Bonner, WM AF Redon, Christophe E. Bonner, William M. TI High salt and DNA double-strand breaks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HIGH NACL; IN-VIVO; REPAIR; GAMMA-H2AX; CELLS; H2AX C1 [Redon, Christophe E.; Bonner, William M.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bonner, WM (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM bonnerw@mail.nih.gov NR 17 TC 2 Z9 3 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 20 PY 2011 VL 108 IS 51 BP 20281 EP 20282 DI 10.1073/pnas.1117713109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865CW UT WOS:000298289400016 PM 22160689 ER PT J AU Castillo, JP De Giorgis, D Basilio, D Gadsby, DC Rosenthal, JJC Latorre, R Holmgren, M Bezanilla, F AF Castillo, Juan P. De Giorgis, Daniela Basilio, Daniel Gadsby, David C. Rosenthal, Joshua J. C. Latorre, Ramon Holmgren, Miguel Bezanilla, Francisco TI Energy landscape of the reactions governing the Na+ deeply occluded state of the Na+/K+-ATPase in the giant axon of the Humboldt squid SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE P-type ATPases; pump currents; thermodynamics ID CURRENT-VOLTAGE RELATIONSHIP; NA/K PUMP CURRENT; PIG VENTRICULAR MYOCYTES; XENOPUS-OOCYTES; CHARGE TRANSLOCATION; TRANSIENT CURRENTS; SPEED LIMIT; NA,K PUMP; DEPENDENCE; KINETICS AB The Na+/K+ pump is a nearly ubiquitous membrane protein in animal cells that uses the free energy of ATP hydrolysis to alternatively export 3Na(+) from the cell and import 2K(+) per cycle. This exchange of ions produces a steady-state outwardly directed current, which is proportional in magnitude to the turnover rate. Under certain ionic conditions, a sudden voltage jump generates temporally distinct transient currents mediated by the Na+/K+ pump that represent the kinetics of extracellular Na+ binding/release and Na+ occlusion/deocclusion transitions. For many years, these events have escaped a proper thermodynamic treatment due to the relatively small electrical signal. Here, taking the advantages offered by the large diameter of the axons from the squid Dosidicus gigas, we have been able to separate the kinetic components of the transient currents in an extended temperature range and thus characterize the energetic landscape of the pump cycle and those transitions associated with the extracellular release of the first Na+ from the deeply occluded state. Occlusion/deocclusion transition involves large changes in enthalpy and entropy as the ion is exposed to the external milieu for release. Binding/unbinding is substantially less costly, yet larger than predicted for the energetic cost of an ion diffusing through a permeation pathway, which suggests that ion binding/unbinding must involve amino acid side-chain rearrangements at the site. C1 [Castillo, Juan P.; De Giorgis, Daniela; Basilio, Daniel; Gadsby, David C.; Rosenthal, Joshua J. C.; Latorre, Ramon; Holmgren, Miguel; Bezanilla, Francisco] Univ Chile, Fac Ciencias, Lab Fisiol Celular, Montemar 2366103, Chile. [Castillo, Juan P.; De Giorgis, Daniela; Latorre, Ramon] Univ Valparaiso, Ctr Interdisciplinario Neurociencia Valparaiso, Valparaiso 2366103, Chile. [Basilio, Daniel] Weill Cornell Med Coll, Dept Anesthesiol, New York, NY 10065 USA. [Gadsby, David C.] Rockefeller Univ, Lab Cardiac Membrane Physiol, New York, NY 10065 USA. [Rosenthal, Joshua J. C.] Univ Puerto Rico, Dept Biochem, San Juan, PR 00901 USA. [Holmgren, Miguel] Natl Inst Neurol Disorders & Stroke, Mol Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Bezanilla, Francisco] Univ Chicago, Dept Biochem & Mol Biol, Gordon Ctr Integrat Sci, Chicago, IL 60637 USA. RP Latorre, R (reprint author), Univ Chile, Fac Ciencias, Lab Fisiol Celular, Montemar 2366103, Chile. EM ramon.latorre@uv.cl; holmgren@ninds.nih.gov; febesanilla@uchaicago.edu RI Basilio, Daniel/A-9350-2009 OI Basilio, Daniel/0000-0002-5346-8921 FU Fogarty International Research Collaboration Award [RO3 TW008351]; National Institutes of Health (NIH) [U54GM087519, R01GM030376, R01NS64259, R01HL36783]; Fondo Nacional de Desarrollo Cientifico y Tecnologico [1110430]; NIH (National Institute of Neurological Disorders and Stroke); Albert Cast Traveling Fellowship FX We kindly thank Francisco Palma, who during the first two experimental seasons participated in the squid collection and performed, in the boat, the first step of the animal dissection. We also thank Professor Mario Luxoro, Alan Neely, Ana Maria Navia, Rodrigo Toro, and Jose Soto for in situ logistics throughout the years that facilitate and maximize our short experimental season in Montemar. We thank the Section on Instrumentation of the National Institute of Mental Health for technical assistance. This work was possible thanks to Fogarty International Research Collaboration Award Grant RO3 TW008351 (to R. L., F. B., and M. H.). F. B. was supported by National Institutes of Health (NIH) (U54GM087519 and R01GM030376). J.J.C.R. was supported by NIH (R01NS64259). R. L. was supported by Fondo Nacional de Desarrollo Cientifico y Tecnologico Grant 1110430. The Centro Interdisciplinario de Neurociencia de Valparaiso is a Scientific Millennium Institute. D. C. G. was supported by NIH (R01HL36783). This study was also partially supported by the Intramural Research Program of the NIH (National Institute of Neurological Disorders and Stroke). D. B. thanks the Albert Cast Traveling Fellowship for providing travel funds to Montemar, Chile (2009 season). NR 41 TC 7 Z9 7 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 DEC 20 PY 2011 VL 108 IS 51 BP 20556 EP 20561 DI 10.1073/pnas.1116439108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865CW UT WOS:000298289400062 PM 22143771 ER PT J AU Sandbulte, MR Westgeest, KB Gao, J Xu, XY Klimov, AI Russell, CA Burke, DF Smith, DJ Fouchier, RAM Eichelberger, MC AF Sandbulte, Matthew R. Westgeest, Kim B. Gao, Jin Xu, Xiyan Klimov, Alexander I. Russell, Colin A. Burke, David F. Smith, Derek J. Fouchier, Ron A. M. Eichelberger, Maryna C. TI Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HONG-KONG INFLUENZA; A VIRUS; ANTIBODY; VACCINE; IMMUNITY; RESISTANCE; EVOLUTION; INFECTION; VARIANTS; SEQUENCE AB Seasonal epidemics caused by influenza virus are driven by antigenic changes (drift) in viral surface glycoproteins that allow evasion from preexisting humoral immunity. Antigenic drift is a feature of not only the hemagglutinin (HA), but also of neuraminidase (NA). We have evaluated the antigenic evolution of each protein in H1N1 and H3N2 viruses used in vaccine formulations during the last 15 y by analysis of HA and NA inhibition titers and antigenic cartography. As previously shown for HA, genetic changes in NA did not always lead to an antigenic change. The noncontinuous pattern of NA drift did not correspond closely with HA drift in either subtype. Although NA drift was demonstrated using ferret sera, we show that these changes also impact recognition by NA-inhibiting antibodies in human sera. Remarkably, a single point mutation in the NA of A/Brisbane/59/2007 was primarily responsible for the lack of inhibition by polyclonal antibodies specific for earlier strains. These data underscore the importance of NA inhibition testing to define antigenic drift when there are sequence changes in NA. C1 [Sandbulte, Matthew R.; Gao, Jin; Eichelberger, Maryna C.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Westgeest, Kim B.; Smith, Derek J.; Fouchier, Ron A. M.] Erasmus MC, Dept Virol, NL-3000 CA Rotterdam, Netherlands. [Xu, Xiyan; Klimov, Alexander I.] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Russell, Colin A.; Burke, David F.; Smith, Derek J.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Smith, Derek J.] NIH, Fogarty & Int Ctr, Bethesda, MD 20892 USA. RP Eichelberger, MC (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM maryna.eichelberger@fda.hhs.gov RI burke, david/C-2091-2013; Fouchier, Ron/A-1911-2014; OI Fouchier, Ron/0000-0001-8095-2869; burke, david/0000-0001-8830-3951; Russell, Colin/0000-0002-2113-162X FU Center for Biologics Evaluation and Research; VICI of the Netherlands Organization for Scientific Research; National Institutes of Health [DP1-OD000490-01]; European Union [223498, 278976]; Human Frontier Science Program [P0050/2008]; Royal Society FX We thank Zhiping Ye and Vladimir Lugovtsev for viruses; Robert Webster for plasmids; Olga Zoueva and Arash Hassantoufighi for technical support in preparing reassortant viruses; Theo Bestebroer and Stefan van der Vliet for excellent technical assistance with hemagglutination inhibition assays; and Timothy Straight for provision of human sera. This study used the CamGrid distributed computing resource and was supported by Center for Biologics Evaluation and Research Pandemic Influenza funds (to M.C.E.); a VICI grant of the Netherlands Organization for Scientific Research (to R.A.M.F.); a National Institutes of Health Director's Pioneer Award (DP1-OD000490-01 to D.J.S.), European Union FP7 programs EMPERIE (223498 to D.J.S.) and ANTIGONE (278976 to D.J.S.), a Human Frontier Science Program grant (P0050/2008 to D.J.S.), and a University Research Fellowship from the Royal Society (to C.A.R.). NR 32 TC 51 Z9 52 U1 0 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 20 PY 2011 VL 108 IS 51 BP 20748 EP 20753 DI 10.1073/pnas.1113801108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865CW UT WOS:000298289400095 PM 22143798 ER PT J AU Dmitrieva, NI Cui, KR Kitchaev, DA Zhao, KJ Burg, MB AF Dmitrieva, Natalia I. Cui, Kairong Kitchaev, Daniil A. Zhao, Keji Burg, Maurice B. TI DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hypertonicity; salt; DNA damage; kidney; mIMCD3 cells ID COMET ASSAY; DAMAGE RESPONSE; OSMOTIC-STRESS; CELLS; GAMMA-H2AX; REPAIR; CHECKPOINT; EVOLUTION; CHROMATIN; KINASE AB High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. The exact nature of the breaks, and their location, has not been entirely clear, and it has not been evident how cells survive, replicate, and maintain genome integrity in environments like the renal inner medulla in which cells are constantly exposed to high NaCl concentration. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (gamma H2AX), which occurs around DNA double-strand breaks and contributes to their repair. Here, we confirm by specific comet assay and pulsed-field electrophoresis that cells adapted to high NaCl have increased levels of double-strand breaks. Importantly,gamma H2AX foci that occur during repair of the breaks are nonrandomly distributed in the mouse genome. By chromatin immunoprecipitation using anti-gamma H2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of double-strand breaks induced by high NaCl,gamma H2AX is predominantly localized to regions of the genome devoid of genes ("gene deserts"), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation, and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes. C1 [Dmitrieva, Natalia I.; Burg, Maurice B.] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kitchaev, Daniil A.] CALTECH, Dept Chem Engn, Pasadena, CA 91125 USA. RP Dmitrieva, NI (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov; maurice_burg@nih.gov RI Dmitrieva, Natalia/A-2924-2013; OI Dmitrieva, Natalia/0000-0001-8074-6950; /0000-0003-2309-3644 FU National Institutes of Health, NHLBI FX We thank Drs. Chris Combs and Daniela Malide at the National Heart, Lung, and Blood Institute (NHLBI) Light Microscopy Core Facility for help with microscopy and images processing and Dr. Iouri Chepelev at the NHLBI Laboratory of Molecular Immunology for assistance with sequencing data analysis. This research was supported by the Intramural Research Programs of the National Institutes of Health, NHLBI. NR 37 TC 13 Z9 14 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 20 PY 2011 VL 108 IS 51 BP 20796 EP 20801 DI 10.1073/pnas.1114677108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865CW UT WOS:000298289400103 PM 22106305 ER PT J AU Das, SR Hensley, SE David, A Schmidt, L Gibbs, JS Puigbo, P Ince, WL Bennink, JR Yewdell, JW AF Das, Suman R. Hensley, Scott E. David, Alexandre Schmidt, Loren Gibbs, James S. Puigbo, Pere Ince, William L. Bennink, Jack R. Yewdell, Jonathan W. TI Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antigenic drift; viral evolution ID A/PR/8/34 HEMAGGLUTININ; MONOCLONAL-ANTIBODIES; ANTIGENIC STRUCTURE; BALB/C MICE; CARBOHYDRATE; MOLECULE; NEUTRALIZATION; GLYCOPROTEIN; TRANSPORT; EPITOPE AB Here, we address the question of why the influenza A virus hemagglutinin (HA) does not escape immunity by hyperglycosylation. Uniquely among dozens of monoclonal antibodies specific for A/Puerto Rico/8/34, escape from H28-A2 neutralization requires substitutions introducing N-linked glycosylation at residue 131 or 144 in the globular domain. This escape decreases viral binding to cellular receptors, which must be compensated for by additional substitutions in HA or neuraminidase that enable viral replication. Sequence analysis of circulating H1 influenza viruses confirms the in vivo relevance of our findings: natural occurrence of glycosylation at residue 131 is always accompanied by a compensatory mutation known to increase HA receptor avidity. In vaccinated mice challenged with WT vs. H28-A2 escape mutants, the selective advantage conferred by glycan-mediated global reduction in antigenicity is trumped by the costs of diminished receptor avidity. These findings show that, although N-linked glycosylation can broadly diminish HA antigenicity, fitness costs restrict its deployment in immune evasion. C1 [Das, Suman R.; Hensley, Scott E.; David, Alexandre; Schmidt, Loren; Gibbs, James S.; Ince, William L.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Das, Suman R.] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Puigbo, Pere] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012; Puigbo, Pere/A-2214-2008; Das, Suman/C-8760-2009; OI David, Alexandre/0000-0003-3365-1339 FU National Institutes of Health/NIAID [U19-AI057266, U19 AI057266-06S2]; Intramural Research National Institute of Allergy and Infectious Diseases (NIAID) FX We thank Glennys Reynoso for providing outstanding technical assistance. This work was generously supported by the Division of Intramural Research National Institute of Allergy and Infectious Diseases (NIAID). S.R.D. is currently supported by National Institutes of Health/NIAID Grant U19-AI057266 with American Recovery and Reinvestment Act Supplement Funding Grant U19 AI057266-06S2. NR 23 TC 41 Z9 41 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 20 PY 2011 VL 108 IS 51 BP E1417 EP E1422 DI 10.1073/pnas.1108754108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865CW UT WOS:000298289400008 PM 22106257 ER PT J AU Polis, MA AF Polis, Michael A. TI Early antiretroviral therapy reduced HIV-1 transmission in serodiscordant couples SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 NIAID, Bethesda, MD 20892 USA. RP Polis, MA (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 20 PY 2011 VL 155 IS 12 AR JC6-8 DI 10.7326/0003-4819-155-12-201112200-02008 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 864ZU UT WOS:000298280500007 PM 22184709 ER PT J AU Johnson, RF Dodd, LE Yellayi, S Gu, WJ Cann, JA Jett, C Bernbaum, JG Ragland, DR St Claire, M Byrum, R Paragas, J Blaney, JE Jahrling, PB AF Johnson, Reed F. Dodd, Lori E. Yellayi, Srikanth Gu, Wenjuan Cann, Jennifer A. Jett, Catherine Bernbaum, John G. Ragland, Dan R. St Claire, Marisa Byrum, Russell Paragas, Jason Blaney, Joseph E. Jahrling, Peter B. TI Simian hemorrhagic fever virus infection of rhesus macaques as a model of viral hemorrhagic fever: Clinical characterization and risk factors for severe disease SO VIROLOGY LA English DT Article DE Hemorrhagic fever virus; Animal model; Pathogenesis; Simian hemorrhagic fever virus; Arterivirus; Coagulopathy; Emerging pathogens; Virus; Hemorrhagic disease ID EBOLA-VIRUS; ENDOTHELIAL-CELLS; MONKEYS; PATHOGENESIS; COAGULATION; LASSA; TRANSMISSION; REPLICATION; ACTIVATION; ARENAVIRUS AB Simian Hemorrhagic Fever Virus (SHFV) has caused sporadic outbreaks of hemorrhagic fevers in macaques at primate research facilities. SHFV is a BSL-2 pathogen that has not been linked to human disease; as such, investigation of SHFV pathogenesis in non-human primates (NHPs) could serve as a model for hemorrhagic fever viruses such as Ebola, Marburg, and Lassa viruses. Here we describe the pathogenesis of SHFV in rhesus macaques inoculated with doses ranging from 50 PFU to 500,000 PFU. Disease severity was independent of dose with an overall mortality rate of 64% with signs of hemorrhagic fever and multiple organ system involvement Analyses comparing survivors and non-survivors were performed to identify factors associated with survival revealing differences in the kinetics of viremia, immunosuppression, and regulation of hemostasis. Notable similarities between the pathogenesis of SHFV in NHPs and hemorrhagic fever viruses in humans suggest that SHFV may serve as a suitable model of BSL-4 pathogens. Published by Elsevier Inc. C1 [Johnson, Reed F.; Blaney, Joseph E.; Jahrling, Peter B.] NIAID, NIH, EVPS, Bethesda, MD 20892 USA. [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Frederick, MD 21702 USA. [Yellayi, Srikanth; Cann, Jennifer A.; Jett, Catherine; Bernbaum, John G.; Ragland, Dan R.; St Claire, Marisa; Byrum, Russell; Paragas, Jason; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Gu, Wenjuan] NCI, SAIC Frederick Inc, Biostat Res Branch, Frederick, MD 21702 USA. RP Johnson, RF (reprint author), NIAID, NIH, EVPS, Bldg 33 Rm 2E19A,33 North Dr, Bethesda, MD 20892 USA. EM johnsonreed@mail.nih.gov FU NIAID; NIAID Division of Intramural Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work, in part, was supported by the NIAID and NIAID Division of Intramural Research. We are grateful to Cindy Allan, Krisztina Janosko, Abigail Lara, Erika Zommer, Rebecca Kurnat, Nicholas Oberlander, Isis Alexander, Bernardo Rosa, Oscar Rojas, Haifeng Song, and Kurt Cooper for their contributions to these studies. We thank Sharon Altmann, Stacy Agar, James Lawler, Laura Bollinger, and Fabian De Kok Mercado for their critical review and contribution to the preparation of this manuscript. We would also like to thank Patrick Murray for his assistance with blood culture and bacterial identification.; This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 47 TC 13 Z9 14 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 2011 VL 421 IS 2 BP 129 EP 140 DI 10.1016/j.virol.2011.09.016 PG 12 WC Virology SC Virology GA 850GU UT WOS:000297183900006 PM 22014505 ER PT J AU Jiang, JY Ablan, SD Derebail, S Hercik, K Soheilian, F Thomas, JA Tang, SX Hewlett, I Nagashima, K Gorelick, RJ Freed, EO Levin, JG AF Jiang, Jiyang Ablan, Sherimay D. Derebail, Suchitra Hercik, Kamil Soheilian, Ferri Thomas, James A. Tang, Shixing Hewlett, Indira Nagashima, Kunio Gorelick, Robert J. Freed, Eric O. Levin, Judith G. TI The interdomain linker region of HIV-1 capsid protein is a critical determinant of proper core assembly and stability SO VIROLOGY LA English DT Article DE HIV-1 capsid protein; HIV-1 assembly; HIV-1 cores; VSV-G pseudotyping; Interdomain linker; In vitro assembly; TRIM5 proteins; Host restriction; Virus disassembly; Reverse transcription ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; VESICULAR STOMATITIS-VIRUS; REVERSE TRANSCRIPTION COMPLEXES; FUSION INHIBITOR T-20; ROUS-SARCOMA-VIRUS; N-TERMINAL DOMAIN; IN-VITRO; NUCLEOCAPSID PROTEIN; TRIM5-ALPHA PROTEIN AB The HIV-1 capsid protein consists of two independently folded domains connected by a flexible peptide linker (residues 146-150), the function of which remains to be defined. To investigate the role of this region in virus replication, we made alanine or leucine substitutions in each linker residue and two flanking residues. Three classes of mutants were identified: (i) S146A and T148A behave like wild type (WT); (ii) Y145A, 1150A, and L151A are noninfectious, assemble unstable cores with aberrant morphology, and synthesize almost no viral DNA; and (iii) P147L and S149A display a poorly infectious, attenuated phenotype. Infectivity of P147L and S149A is rescued specifically by pseudotyping with vesicular stomatitis virus envelope glycoprotein. Moreover, despite having unstable cores, these mutants assemble WT-like structures and synthesize viral DNA, although less efficiently than WT. Collectively, these findings demonstrate that the linker region is essential for proper assembly and stability of cores and efficient replication. Published by Elsevier Inc. C1 [Jiang, Jiyang; Derebail, Suchitra; Hercik, Kamil; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Soheilian, Ferri; Nagashima, Kunio] NCI, Image Anal Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Thomas, James A.; Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Tang, Shixing; Hewlett, Indira] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bldg 6B,Room 216,6 Ctr Dr, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov OI Thomas, James/0000-0002-2509-490X FU National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development); National Cancer Institute, Center for Cancer Research; Office of Science and Health Coordination, Food and Drug Administration, National Heart, Lung, and Blood Institute, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; SAIC-Frederick, Inc. FX We thank Christopher Aiken for his generous gift of OMK cells and the HIV-1-GFP reporter construct as well as for helpful advice regarding the TRIMCyp assay, Michael Summers for kindly providing a CA construct and protocol for bacterial expression and purification of HIV-1 CA, Jane Burns for the VSV-G expression vector (pHCMV-Genv), and the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH for antisera, cells, and plasmids, as detailed in the text. We are also indebted to Angela M. Gronenborn and In-Ja L. Byeon for valuable discussion. This work was supported in part by the Intramural Research Program at the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development [J.J., S.D., K.H., and J.G.L.] and the National Cancer Institute, Center for Cancer Research S.D.A. and E.O.F.]) and in part by the Office of Science and Health Coordination, Food and Drug Administration, National Heart, Lung, and Blood Institute, National Institutes of Health (S.T. and I.H.). This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with SAIC-Frederick, Inc. (F.S., K.N., J.A.T., and R.J.G.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 113 TC 20 Z9 20 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 2011 VL 421 IS 2 BP 253 EP 265 DI 10.1016/j.virol.2011.09.012 PG 13 WC Virology SC Virology GA 850GU UT WOS:000297183900019 PM 22036671 ER PT J AU Chagas, AC Calvo, E Pimenta, PFP Ribeiro, JMC AF Chagas, Andrezza C. Calvo, Eric Pimenta, Paulo F. P. Ribeiro, Jose M. C. TI An insight into the sialome of Simulium guianense (DIPTERA:SIMulIIDAE), the main vector of River Blindness Disease in Brazil SO BMC GENOMICS LA English DT Article ID ADULT FEMALE MOSQUITO; SALIVARY-GLAND TRANSCRIPTOME; INDUCED PLATELET-AGGREGATION; ABUNDANT SECRETED PROTEINS; FLY LUTZOMYIA-LONGIPALPIS; BLACK FLIES DIPTERA; AEDES-AEGYPTI; BINDING-PROTEIN; ANTICOAGULANT ACTIVITY; TRIATOMA-INFESTANS AB Background: Little is known about the composition and function of the saliva in black flies such as Simulium guianense, the main vector of river blindness disease in Brazil. The complex salivary potion of hematophagous arthropods counteracts their host's hemostasis, inflammation, and immunity. Results: Transcriptome analysis revealed ubiquitous salivary protein families-such as the Antigen-5, Yellow, Kunitz domain, and serine proteases-in the S. guianense sialotranscriptome. Insect-specific families were also found. About 63.4% of all secreted products revealed protein families found only in Simulium. Additionally, we found a novel peptide similar to kunitoxin with a structure distantly related to serine protease inhibitors. This study revealed a relative increase of transcripts of the SVEP protein family when compared with Simulium vittatum and S. nigrimanum sialotranscriptomes. We were able to extract coding sequences from 164 proteins associated with blood and sugar feeding, the majority of which were confirmed by proteome analysis. Conclusions: Our results contribute to understanding the role of Simulium saliva in transmission of Onchocerca volvulus and evolution of salivary proteins in black flies. It also consists of a platform for mining novel anti-hemostatic compounds, vaccine candidates against filariasis, and immuno-epidemiologic markers of vector exposure. C1 [Chagas, Andrezza C.; Calvo, Eric; Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Chagas, Andrezza C.; Pimenta, Paulo F. P.] Ctr Pesquisa Rene Rachou, Entomol Lab, Belo Horizonte, MG, Brazil. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Bethesda, MD 20892 USA. EM jribeiro@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Fundacao de Amparo a Pesquisa do Estado do Amazonas (FAPEAM) [N. 019/2006-CAPES/FAPEAM] FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We are grateful to Fundacao de Amparo a Pesquisa do Estado do Amazonas (FAPEAM) for a Fellowship to ACC under the Edital N. 019/2006-CAPES/FAPEAM-Programa de Apoio a Formacao de Recursos Humanos Pos-Graduados do Estado do Amazonas-RH-POSGRAD. We are grateful for the support of the Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Hamilton, Montana), for DNA sequencing, and of the Research Technologies Section at Twinbrook for the proteomic work. We thank NIAID intramural editor Brenda Rae Marshall for assistance. NR 137 TC 10 Z9 12 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 19 PY 2011 VL 12 AR 612 DI 10.1186/1471-2164-12-612 PG 25 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 898IG UT WOS:000300735000001 PM 22182526 ER PT J AU Alcoser, SY Kimmel, DJ Borgel, SD Carter, JP Dougherty, KM Hollingshead, MG AF Alcoser, Sergio Y. Kimmel, David J. Borgel, Suzanne D. Carter, John P. Dougherty, Kelly M. Hollingshead, Melinda G. TI Real-time PCR-based assay to quantify the relative amount of human and mouse tissue present in tumor xenografts SO BMC BIOTECHNOLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; NUDE-MICE; DEVELOPMENTAL VALIDATION; MALIGNANT TRANSFORMATION; SPECIES IDENTIFICATION; HOST-CELLS; DNA; INDUCTION AB Background: Xenograft samples used to test anti-cancer drug efficacies and toxicities in vivo contain an unknown mix of mouse and human cells. Evaluation of drug activity can be confounded by samples containing large amounts of contaminating mouse tissue. We have developed a real-time quantitative polymerase chain reaction (qPCR) assay using TaqMan technology to quantify the amount of mouse tissue that is incorporated into human xenograft samples. Results: The forward and reverse primers bind to the same DNA sequence in the human and the mouse genome. Using a set of specially designed fluorescent probes provides species specificity. The linearity and sensitivity of the assay is evaluated using serial dilutions of single species and heterogeneous DNA mixtures. We examined many xenograft samples at various in vivo passages, finding a wide variety of human: mouse DNA ratios. This variation may be influenced by tumor type, number of serial passages in vivo, and even which part of the tumor was collected and used in the assay. Conclusions: This novel assay provides an accurate quantitative assessment of human and mouse content in xenograft tumors. This assay can be performed on aberrantly behaving human xenografts, samples used in bioinformatics studies, and periodically for tumor tissue frequently grown by serial passage in vivo. C1 [Alcoser, Sergio Y.; Hollingshead, Melinda G.] NCI, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. [Kimmel, David J.; Borgel, Suzanne D.; Carter, John P.; Dougherty, Kelly M.] NCI Frederick, Biol Testing Branch, Dev Therapeut Program, SAIC Frederick Inc, Frederick, MD USA. RP Alcoser, SY (reprint author), NCI, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. EM alcosers@mail.nih.gov RI Alcoser, Sergio/G-9074-2012 OI Alcoser, Sergio/0000-0002-6896-2551 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX The authors thank Andrea De Biase of Life Technologies for discussions involving TaqMan probes, quenchers, and general qPCR optimization. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. All animals used in this research project were cared for and used humanely according to the following policies: The U.S. Public Health Service Policy on Human Care and Use of Animals (1996); the Guide for the Care and Use Of Laboratory Animals (NIH publication No. 86-23, 1985); and the U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (1985). NR 24 TC 13 Z9 13 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD DEC 16 PY 2011 VL 11 AR 124 DI 10.1186/1472-6750-11-124 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 894LL UT WOS:000300428100001 PM 22176647 ER PT J AU Damaraju, VL Mowles, D Smith, KM Yao, SYM Young, JD Marquez, VE Cass, CE AF Damaraju, Vijaya L. Mowles, Delores Smith, Kyla M. Yao, Sylvia Y. M. Young, James D. Marquez, Victor E. Cass, Carol E. TI Influence of Sugar Ring Conformation on the Transportability of Nucleosides by Human Nucleoside Transporters SO CHEMBIOCHEM LA English DT Article DE conformation; hENTs and hCNTs; nucleosides; transport ID FUNCTIONAL-CHARACTERIZATION; MOLECULAR-CLONING; SACCHAROMYCES-CEREVISIAE; CARBOCYCLIC NUCLEOSIDES; RECOMBINANT HUMAN; ADENOSINE; PROTEINS; URIDINE; ANALOGS; PURINE AB The conformational preference of human nucleoside transporters (hNTs) with respect to sugar ring was examined using conformationally fixed purine and pyrimidine nucleosides built on a bicyclo[3.1.0]hexane template. These fixed-conformation nucleosides, methanocarba-deoxyadenosine or methanocarba-deoxycytidine in North (C3'-endo, N-MCdA and N-MCdC) or South (C2'-endo, S-MCdA and S-MCdC) conformations, were used to study inhibition of equilibrative (hENT14) and concentrative (hCNT13) nucleoside transport by individual recombinant hNTs produced in Saccharomyces cerevisiae cells or Xenopus laevis oocytes. Our results indicated that nucleosides in the North conformation were potent inhibitors of transport mediated by hCNTs whereas South nucleosides were inhibitors of hENTs, thus showing differences in the interaction with the hNTs. In summary, hCNTs exhibited strong preferences for North nucleosides whereas hENTs exhibited slight preferences for South nucleosides, demonstrating for the first time different conformational preferences among members of the two families of hNTs. C1 [Damaraju, Vijaya L.; Mowles, Delores; Cass, Carol E.] Univ Alberta, Cross Canc Inst, Dept Oncol, Edmonton, AB T6G 1Z2, Canada. [Smith, Kyla M.; Yao, Sylvia Y. M.; Young, James D.] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2H7, Canada. [Smith, Kyla M.; Yao, Sylvia Y. M.; Young, James D.] Univ Alberta, Membrane Prot Dis Res Grp, Edmonton, AB T6G 2H7, Canada. [Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Cass, CE (reprint author), Univ Alberta, Cross Canc Inst, Dept Oncol, 11560 Univ Ave NW, Edmonton, AB T6G 1Z2, Canada. EM carol.cass@albertahealthservices.ca FU Canadian Institutes of Health Research; Alberta Cancer Foundation; Canadian Cancer Society Research Institute; Center for Cancer Research, National Cancer Institute FX This work was supported by grants from the Canadian Institutes of Health Research (C.E.C., J.D.Y.), the Alberta Cancer Foundation (C.E.C., J.D.Y.) and the Canadian Cancer Society Research Institute (C.E.C.). This work was also funded in part by the Center for Cancer Research, National Cancer Institute. J.D.Y. is an Alberta Heritage Foundation for Medical Research Senior Investigator. NR 34 TC 7 Z9 7 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD DEC 16 PY 2011 VL 12 IS 18 BP 2774 EP 2778 DI 10.1002/cbic.201100567 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 860MB UT WOS:000297951300012 PM 22052809 ER PT J AU Lee, CW Eu, YJ Min, HJ Cho, EM Lee, JH Kim, HH Nah, SY Swartz, KJ Kim, JI AF Lee, Chul Won Eu, Young-Jae Min, Hye Jung Cho, Eun-Mi Lee, Jun-Ho Kim, Ha Hyung Nah, Seung-Yeol Swartz, Kenton J. Kim, Jae Il TI Expression and characterization of recombinant kurtoxin, an inhibitor of T-type voltage-gated calcium channels SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Kurtoxin; Scorpion toxin; T-type calcium channel; Disulfide bond ID DEPENDENT K+ CHANNEL; PROTEIN SECONDARY STRUCTURE; CIRCULAR-DICHROISM SPECTRA; GATING MODIFIER TOXINS; ALPHA-LIKE TOXIN; OMEGA-AGA-IVA; SCORPION TOXINS; CA2+ CHANNELS; N-TYPE; DIVERSITY AB Kurtoxin, a 63-amino acid peptide stabilized by four disulfide bonds, is the first reported peptide inhibitor of T-type voltage-gated calcium channels. Although T-type calcium channels have been implicated in a number of disease states, including epilepsy, chronic pain, hypertension and cancer, the lack of selective inhibitors has slowed progress in understanding their precise roles. Kurtoxin is a potentially valuable tool with which to study T-type calcium channels. However, because of the limited availability of the native protein, little is known about the structure and molecular mechanism of kurtoxin. Here we report the expression of kurtoxin in Escherichia coli and the structural and functional characterization of the recombinant protein. The disulfide bond pairings and secondary structure of recombinant kurtoxin were characterized through enzymatic cleavage, mass analysis and CD spectroscopy. Recombinant kurtoxin almost completely inhibited the T-type calcium channel in a manner identical to the native toxin. The availability of recombinant kurtoxin that is identical to the native toxin should help in the study of T-type calcium channels and enable development of new strategies for producing even more-selective T-type calcium channel inhibitors and for investigating the molecular basis of the toxin-channel interactions. (C) 2011 Elsevier Inc. All rights reserved. C1 [Lee, Chul Won; Eu, Young-Jae; Min, Hye Jung; Cho, Eun-Mi; Kim, Jae Il] GIST, Dept Life Sci, Kwangju 500712, South Korea. [Lee, Chul Won] Chonnam Natl Univ, Dept Chem, Kwangju 500757, South Korea. [Lee, Jun-Ho; Nah, Seung-Yeol] Konkuk Univ, Dept Physiol, Coll Vet Med, Seoul 143701, South Korea. [Kim, Ha Hyung] Chung Ang Univ, Coll Pharm, Seoul 156756, South Korea. [Swartz, Kenton J.] Natl Inst Neurol Disorders & Stroke, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Kim, JI (reprint author), GIST, Dept Life Sci, Kwangju 500712, South Korea. EM jikim@gist.ac.kr FU Next-Generation BioGreen 21 Program [PJ008158]; Rural Development Administration, Republic of Korea; National Research Foundation of Korea; Korean Government (MEST) [NRF-C1ABA001-2011-0018559]; Brain Research Center [M103KV010005-06K2201-00610]; BioImaging Research Center at the Gwangju Institute of Science and Technology; Gwangju Institute of Science and Technology FX This research was supported by Grants from the Next-Generation BioGreen 21 Program (No. PJ008158), Rural Development Administration, Republic of Korea, the National Research Foundation of Korea Grant funded by the Korean Government (MEST) (NRF-C1ABA001-2011-0018559), the Brain Research Center of the 21st Century Frontier Research Program (M103KV010005-06K2201-00610), the BioImaging Research Center at the Gwangju Institute of Science and Technology, and Basic Research Projects in High-tech Industrial Technology funded by Gwangju Institute of Science and Technology in 2011. NR 40 TC 3 Z9 3 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 16 PY 2011 VL 416 IS 3-4 BP 277 EP 282 DI 10.1016/j.bbrc.2011.11.003 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 872RU UT WOS:000298827800009 PM 22093820 ER PT J AU Manalo, DJ Baek, JH Buehler, PW Struble, E Abraham, B Alayash, AI AF Manalo, Dominador J. Baek, Jin Hyen Buehler, Paul W. Struble, Evi Abraham, Bindu Alayash, Abdu I. TI Inactivation of prolyl hydroxylase domain (PHD) protein by epigallocatechin (EGCG) stabilizes hypoxia-inducible factor (HIF-1 alpha) and induces hepcidin (Hamp) in rat kidney SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE EGCG; Hypoxia; PHD2; HIP-1 alpha a; Iron homeostasis; Hepcidin ID REGULATORY PEPTIDE HEPCIDIN; TEA POLYPHENOLS; IRON OVERLOAD; DEGRADATION; ERYTHROPOIESIS; INFLAMMATION; ANTIOXIDANT; PROTECTION; TRANSPORT; BINDING AB HIF-1 alpha plays a key role in iron uptake and transport in the liver, whose activity is tightly linked to the repression of hepcidin (Hamp). Hump prevents intestinal iron uptake and cellular efflux by negatively modulating ferroportin. Hump is also expressed in the kidneys, where transcriptional control by HIF-1 alpha remains poorly understood. We show that the administration of epigallocatechin gallate (EGCG) results in a considerable Hump expression in rat kidneys. We also provide evidence to show that EGCG inhibited prolyl hydroxylase (PHD) activity, essential for HIF-1 alpha degradation in vivo and in vitro. Rats that were dosed with EGCG (60 mg/kg, intraperitoneal) over a 7 day time course stabilized HIF-1 alpha protein in kidney tissues. Interestingly. Hump gene expression was induced, even after subjecting rats to a 4 h hypoxia treatment (8% oxygen). Using Hep3B cells, we determined that EGCG conferred its inhibitory action by complexing with PHD, altering its catalytic iron center and thus preventing HIF-1 alpha hydroxylation. These data demonstrate EGCG's therapeutic potential in modulating hepcidin expression in diseases associated with altered iron metabolism. Published by Elsevier Inc. C1 [Manalo, Dominador J.; Baek, Jin Hyen; Buehler, Paul W.; Struble, Evi; Abraham, Bindu; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Research, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, CBER, NIH Bldg 29,Rm 112,8800 Rockville Pike, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov FU DARPA (Defense Advanced Research Project Agency) FX This work was supported by Grants from DARPA (Defense Advanced Research Project Agency). NR 33 TC 7 Z9 7 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 16 PY 2011 VL 416 IS 3-4 BP 421 EP 426 DI 10.1016/j.bbrc.2011.11.085 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 872RU UT WOS:000298827800033 PM 22138393 ER PT J AU Shchedrina, VA Everley, RA Zhang, Y Gygi, SP Hatfield, DL Gladyshev, VN AF Shchedrina, Valentina A. Everley, Robert A. Zhang, Yan Gygi, Steven P. Hatfield, Dolph L. Gladyshev, Vadim N. TI Selenoprotein K Binds Multiprotein Complexes and Is Involved in the Regulation of Endoplasmic Reticulum Homeostasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UNFOLDED PROTEIN RESPONSE; MEMBRANE-PROTEIN; QUALITY-CONTROL; RETRO-TRANSLOCATION; MISFOLDED PROTEINS; ER PROTEIN; HUMAN HRD1; STRESS; RETROTRANSLOCATION; DEGRADATION AB Background: Selenoprotein K (SelK) is an endoplasmic reticulum (ER) protein of unknown function. Results: SelK associates with proteins involved in elimination of misfolded proteins from the ER. Conclusion: SelK is a functional component of ER homeostasis. Significance: This study defines a new family of selenoproteins and links it to an ER-associated degradation. C1 [Shchedrina, Valentina A.; Zhang, Yan; Gladyshev, Vadim N.] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. [Everley, Robert A.; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Brigham & Womens Hosp, Div Genet, Dept Med, New Res Bldg,77 Ave Louis Pasteur,Rm 435, Boston, MA 02115 USA. EM vgladyshev@rics.bwh.harvard.edu RI Gladyshev, Vadim/A-9894-2013 FU National Institutes of Health [GM061603]; Center for Cancer Research, NCI, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grant GM061603 (to V. N. G.). This work was also supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health (to D. L. H.). NR 54 TC 41 Z9 59 U1 1 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 16 PY 2011 VL 286 IS 50 BP 42937 EP 42948 DI 10.1074/jbc.M111.310920 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866AF UT WOS:000298351300015 PM 22016385 ER PT J AU Nomme, J Fanning, AS Caffrey, M Lye, MF Anderson, JM Lavie, A AF Nomme, Julian Fanning, Alan S. Caffrey, Michael Lye, Ming F. Anderson, James M. Lavie, Arnon TI The Src Homology 3 Domain Is Required for Junctional Adhesion Molecule Binding to the Third PDZ Domain of the Scaffolding Protein ZO-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GUANYLATE KINASE DOMAINS; TIGHT-JUNCTION; INTRAMOLECULAR INTERACTION; LIGAND-BINDING; CELL POLARITY; LOCALIZATION; MEMBRANE; PSD-95; SITES; DIMERIZATION AB Tight junctions are cell-cell contacts that regulate the paracellular flux of solutes and prevent pathogen entry across cell layers. The assembly and permeability of this barrier are dependent on the zonula occludens (ZO) membrane-associated guanylate kinase (MAGUK) proteins ZO-1, -2, and -3. MAGUK proteins are characterized by a core motif of protein-binding domains that include a PDZ domain, a Src homology 3 (SH3) domain, and a region of homology to guanylate kinase (GUK); the structure of this core motif has never been determined for any MAGUK. To better understand how ZO proteins organize the assembly of protein complexes we have crystallized the entire PDZ3-SH3-GUK core motif of ZO-1. We have also crystallized this core motif in complex with the cytoplasmic tail of the ZO-1 PDZ3 ligand, junctional adhesion molecule A (JAM-A) to determine how the activity of different domains is coordinated. Our study shows a new feature for PDZ class II ligand binding that implicates the two highly conserved Phe(-2) and Ser(-3) residues of JAM. Our x-ray structures and NMR experiments also show for the first time a role for adjacent domains in the binding of ligands to PDZ domains in the MAGUK proteins family. C1 [Nomme, Julian; Caffrey, Michael; Lye, Ming F.; Lavie, Arnon] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Fanning, Alan S.] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Anderson, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Lavie, A (reprint author), Univ Illinois, Dept Biochem & Mol Genet, 900 S Ashland Ave,Mol Biol Res Bldg,Rm 1108, Chicago, IL 60607 USA. EM lavie@uic.edu RI Lavie, Arnon/H-4927-2012 FU National Institutes of Health [DK61397]; University of North Carolina; University of Illinois; National Institutes of Health Division of Intramural Research FX This research was supported, in whole or in part, by National Institutes of Health Grant DK61397 (to A. S. F. and A. L.). This work was also supported by the National Institutes of Health Division of Intramural Research and the Universities of North Carolina and Illinois. NR 36 TC 30 Z9 33 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 16 PY 2011 VL 286 IS 50 BP 43352 EP 43360 DI 10.1074/jbc.M111.304089 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866AF UT WOS:000298351300055 PM 22030391 ER PT J AU Li, L Xiao, XS Li, SQ Jiao, XD Hejtmancik, JF Zhang, QJ AF Li, Lin Xiao, Xueshan Li, Shiqiang Jiao, Xiaodong Hejtmancik, J. Fielding Zhang, Qingjiong TI Lack of phenotypic effect of triallelic variation in SPATA7 in a family with Leber congenital amaurosis resulting from CRB1 mutations SO MOLECULAR VISION LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; BARDET-BIEDL-SYNDROME; GENOTYPING MICROARRAY; RETINAL DYSTROPHY; GENE; ALLELES; PERIPHERIN/RDS; PROTEIN; LOCI AB Purpose: To identify the causative gene for autosomal recessive Leber congenital amaurosis (LCA) in a Chinese family. Methods: One Chinese LCA family was identified and an ophthalmologic examination was performed. The genetic defects were analyzed simultaneously by a genome-wide linkage scan with 382 polymorphic microsatellite markers, as well as by comprehensive mutational screening of 15 genes known to associate with LCA on the genomic DNA of this family. Results: Suggestive linkages were found in 13 chromosomal regions, of which only one harbored a known causative gene, crumbs homolog 1 (CRB1), on chromosome 1. Sanger sequencing of CRB1 identified two novel heterozygous mutations, c.3221T>C (p.L1074S) and c.2677-2A>C. In addition, a novel missense heterozygous mutation, c.938C>A (p.A313D), in spermatogenesis associated 7 (SPATA7), was detected in the proband after screening of the other 14 LCA causative genes. All three affected individuals of the family had compound heterozygous CRB1 mutations, and one of the three (the proband) had an additional mutation in SPATA7. The unaffected mother had the heterozygous c.3221T>C mutation in CRB1 and the heterozygous c.938C>A mutation in SPATA7. The unaffected father could not be tested, but presumably had the heterozygous c.2677-2A>C mutation in CRB1. The proband, with triallelic mutations in CRB1 and SPATA7, had a phenotype similar to other two affected brothers, suggesting the additional mutant allele in SPATA7 might not contribute to the disease. Similarly, the mother, with digenic mutations in CRB1 and SPATA7, had normal vision and fundi, suggesting the digenic mutations in these two genes might not cause disease. Conclusions: Digenic and triallelic mutations of CRB1 and SPATA7 were detected in a family with LCA. Our results imply that CRB1 and SPATA7 may not interact with each other directly. This emphasizes that care should be taken in invoking a mutation-disease association for digenic and triallelic mutations. C1 [Li, Lin; Xiao, Xueshan; Li, Shiqiang; Zhang, Qingjiong] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [Li, Lin; Jiao, Xiaodong; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, QJ (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, 54 Xianlie Rd, Guangzhou 510060, Guangdong, Peoples R China. EM zhangqji@mail.sysu.edu.cn FU National Science Fund for Distinguished Young Scholars [30725044]; National 973 Plan of China [2010CB529904] FX We thank all patients and controls for their participation. This study was supported by National Science Fund for Distinguished Young Scholars (30725044 to Q.Z.) and National 973 Plan of China (2010CB529904 to Q.Z.). NR 32 TC 3 Z9 3 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD DEC 16 PY 2011 VL 17 IS 358 BP 3326 EP 3332 PG 7 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 871KX UT WOS:000298738100001 PM 22219627 ER PT J AU Lee, Y Chen, YH Tarasova, NI Gaponenko, V AF Lee, Youngshim Chen, Yuhong Tarasova, Nadya I. Gaponenko, Vadim TI The structure of monomeric components of self-assembling CXCR4 antagonists determines the architecture of resulting nanostructures SO NANOTECHNOLOGY LA English DT Article ID PEPTIDE NANOTUBES; NANOPARTICLES; POLYPEPTIDES; INHIBITION AB Self-assembling peptides play increasingly important roles in the development of novel materials and drug delivery vehicles. Understanding mechanisms governing the assembly of nanoarchitectures is essential for the generation of peptide-based nanodevices. We find that a cone-shaped derivative of the second transmembrane domain of CXCR4 receptor, x4-2-6 self-assembles into nanospheres, while a related cylindrical peptide, x4-2-9 forms fibrils. Stronger intermolecular interactions in nanospheres than in fibrils result in slow rates of particle disassembly and protection against proteolytic degradation. C1 [Lee, Youngshim; Gaponenko, Vadim] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Chen, Yuhong; Tarasova, Nadya I.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Gaponenko, V (reprint author), Univ Illinois, Dept Biochem & Mol Genet, 900 S Ashland Ave, Chicago, IL 60607 USA. EM vadimg@uic.edu FU National Cancer Institute [1R01CA135341-01A1]; Prostate Cancer Research Award [PC08116]; Congressionally Directed Medical Research Program FX We are grateful for a National Cancer Institute grant 1R01CA135341-01A1 to VG and a Prostate Cancer Research Award PC08116, Congressionally Directed Medical Research Program, to NIT. NR 33 TC 1 Z9 1 U1 0 U2 8 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 J9 NANOTECHNOLOGY JI Nanotechnology PD DEC 16 PY 2011 VL 22 IS 50 AR 505101 DI 10.1088/0957-4484/22/50/505101 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 863HU UT WOS:000298154200001 PM 22107755 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI The 2011 Retrovirology Prize winner Masao Matsuoka: forward looking and antisense SO RETROVIROLOGY LA English DT Editorial Material ID HBZ GENE; INFECTION AB Masao Matsuoka wins the 2011 Retrovirology Prize. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 9 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 15 PY 2011 VL 8 AR 102 DI 10.1186/1742-4690-8-102 PG 3 WC Virology SC Virology GA 895KB UT WOS:000300494000001 ER PT J AU Hale, CM Chen, WC Khatau, SB Daniels, BR Lee, JSH Wirtz, D AF Hale, Christopher M. Chen, Wei-Chiang Khatau, Shyam B. Daniels, Brian R. Lee, Jerry S. H. Wirtz, Denis TI SMRT analysis of MTOC and nuclear positioning reveals the role of EB1 and LIC1 in single-cell polarization SO JOURNAL OF CELL SCIENCE LA English DT Article DE MTOC positioning; Nucleus positioning; Cell migration; Cell polarization; Cell biophysics; Cell shape ID MICROTUBULE-ORGANIZING CENTER; NEURONAL MIGRATION; MOTILE FIBROBLASTS; ENDOTHELIAL-CELLS; GOLGI-APPARATUS; SHEAR-STRESS; CENTROSOME; POLARITY; DYNEIN; ACTIN AB In several migratory cells, the microtubule-organizing center (MTOC) is repositioned between the leading edge and nucleus, creating a polarized morphology. Although our understanding of polarization has progressed as a result of various scratch-wound and cell migration studies, variations in culture conditions required for such assays have prevented a unified understanding of the intricacies of MTOC and nucleus positioning that result in cell polarization. Here, we employ a new SMRT (for sparse, monolayer, round, triangular) analysis that uses a universal coordinate system based on cell centroid to examine the pathways regulating MTOC and nuclear positions in cells plated in a variety of conditions. We find that MTOC and nucleus positioning are crucially and independently affected by cell shape and confluence; MTOC off-centering correlates with the polarization of single cells; acto-myosin contractility and microtubule dynamics are required for single-cell polarization; and end binding protein 1 and light intermediate chain 1, but not Par3 and light intermediate chain 2, are required for single-cell polarization and directional cell motility. Using various cellular geometries and conditions, we implement a systematic and reproducible approach to identify regulators of MTOC and nucleus positioning that depend on extracellular guidance cues. C1 [Hale, Christopher M.; Chen, Wei-Chiang; Khatau, Shyam B.; Daniels, Brian R.; Lee, Jerry S. H.; Wirtz, Denis] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Hale, Christopher M.; Chen, Wei-Chiang; Khatau, Shyam B.; Wirtz, Denis] Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD 21218 USA. [Lee, Jerry S. H.] NCI, Ctr Strateg Sci Initiat, Off Director, NIH, Bethesda, MD 20892 USA. RP Wirtz, D (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, 3400 N Charles St, Baltimore, MD 21218 USA. EM wirtz@jhu.edu RI Lee, Jerry/A-3189-2008; Khatau, Shyam/D-6985-2011; Lee, Jerry/K-4553-2014; Hale, Christopher/A-6633-2009 OI Lee, Jerry/0000-0003-1515-0952; Hale, Christopher/0000-0002-2360-7759 FU National Institutes of Health [U54CA143868, R01 GM084204] FX This research was supported in part by the National Institutes of Health [grant numbers U54CA143868, R01 GM084204]. Deposited in PMC for release after 12 months. NR 65 TC 16 Z9 16 U1 0 U2 12 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD DEC 15 PY 2011 VL 124 IS 24 BP 4267 EP 4285 DI 10.1242/jcs.091231 PG 19 WC Cell Biology SC Cell Biology GA 879FD UT WOS:000299314200017 PM 22193958 ER PT J AU Horkay, F Cho, SH Tathireddy, P Rieth, L Solzbacher, F Magda, J AF Horkay, F. Cho, S. H. Tathireddy, P. Rieth, L. Solzbacher, F. Magda, J. TI Thermodynamic analysis of the selectivity enhancement obtained by using smart hydrogels that are zwitterionic when detecting glucose with boronic acid moieties SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Glucose sensor; Smart hydrogel; Boronic acid; Monosaccharides; SANS ID DIRECT ELECTRICAL COMMUNICATION; PHYSIOLOGICAL SALT-SOLUTIONS; CHEMICALLY-MODIFIED ENZYMES; PHENYLBORONIC ACID; SWELLING PRESSURE; METAL-ELECTRODES; PHOTONIC CRYSTAL; RESPONSIVE GEL; IN-VIVO; SENSORS AB Because the botanic acid moiety reversibly binds to sugar molecules and has low cytotoxicity, boronic acid-containing hydrogels are being used in a variety of implantable glucose sensors under development, including sensors based on optical, fluorescence, and swelling pressure measurements. However, some method of glucose selectivity enhancement is often necessary, because isolated boronic acid molecules have a binding constant with glucose that is some 40 times smaller than their binding constant with fructose, the second most abundant sugar in the human body. In many cases, glucose selectivity enhancement is obtained by incorporating pendant tertiary amines into the hydrogel network, thereby giving rise to a hydrogel that is zwitterionic at physiological pH. However, the mechanism by which incorporation of tertiary amines confers selectivity enhancement is poorly understood. In order to clarify this mechanism, we use the osmotic deswelling technique to compare the thermodynamic interactions of glucose and fructose with a zwitterionic smart hydrogel containing boronic acid moieties. We also investigate the change in the structure of the hydrogel that occurs when it binds to glucose or to fructose using the technique of small angle neutron scattering. (C) 2011 Elsevier B.V. All rights reserved. C1 [Horkay, F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Cho, S. H.; Magda, J.] Univ Utah, Dept Chem Engn, Salt Lake City, UT 84112 USA. [Tathireddy, P.; Rieth, L.; Solzbacher, F.] Univ Utah, Dept Elect & Comp Engn, Salt Lake City, UT 84112 USA. [Solzbacher, F.; Magda, J.] Univ Utah, Dept Mat Sci & Engn, Salt Lake City, UT 84112 USA. [Solzbacher, F.] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. RP Horkay, F (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov; jj.magda@utah.edu OI Magda, Jules/0000-0002-1063-6526 FU NICHD, NIH; National Institute of Standards and Technology, U.S. Department of Commerce; National Science Foundation [DMR-0944772]; National Institutes of Health NHLBI/NIBIB [5R21EB008571-02] FX This research was supported by the Intramural Research Program of the NICHD, NIH. We also acknowledge the support of the National Institute of Standards and Technology, U.S. Department of Commerce, in providing the neutron research facilities used in this work. This work utilized facilities supported in part by the National Science Foundation under Agreement No. DMR-0944772. This project was supported by the National Institutes of Health NHLBI/NIBIB Grant no. 5R21EB008571-02. NR 52 TC 14 Z9 14 U1 6 U2 49 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD DEC 15 PY 2011 VL 160 IS 1 BP 1363 EP 1371 DI 10.1016/j.snb.2011.09.079 PG 9 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA 871WJ UT WOS:000298768100189 PM 22190765 ER PT J AU Horwich, TB Broderick, S Chen, L McCullough, PA Strzelczyk, T Kitzman, DW Fletcher, G Safford, RE Ewald, G Fine, LJ Ellis, SJ Fonarow, GC AF Horwich, Tamara B. Broderick, Samuel Chen, Leway McCullough, Peter A. Strzelczyk, Theresa Kitzman, Dalane W. Fletcher, Gerald Safford, Robert E. Ewald, Gregory Fine, Lawrence J. Ellis, Stephen J. Fonarow, Gregg C. TI Relation Among Body Mass Index, Exercise Training, and Outcomes in Chronic Systolic Heart Failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HF-ACTION; MORTALITY; OBESITY; STATEMENT AB Exercise training (ET) in patients with heart failure (HF), as demonstrated in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION), was associated with improved exercise tolerance and health status and a trend toward reduced mortality or hospitalization. The present analysis of the HF-ACTION cohort examined the effect of ET in overweight and obese subjects compared to normal weight subjects with HF. Of 2,331 subjects with systolic HF randomized to aerobic ET versus usual care in the HF-ACTION, 2,314 were analyzed to determine the effect of ET on all-cause mortality, hospitalizations, exercise parameters, quality of life, and body weight changes by subgroups of body mass index (BMI). The strata included normal weight (BMI 18.5 to 24.9 kg/m(2)), overweight (BMI 25.0 to 29.9 kg/m(2)), obese I (BMI 30 to 34.9 kg/m(2)), obese II (BMI 35 to 39.9 kg/m(2)), and obese III (BMI >= 40 kg/m(2)). At enrollment, 19.4% of subjects were normal weight, 31.3% were overweight, and 49.4% were obese. A greater BMI was associated with a nonsignificant increase in all-cause mortality or hospitalization. ET was associated with nonsignificant reductions in all-cause mortality and hospitalization in each weight category (hazard ratio 0.98, 0.95, 0.92, 0.89, and 0.86 in the normal weight, overweight, obese I, obese II, and obese III categories, respectively; all p > 0.05). Modeled improvement in exercise capacity (peak oxygen consumption) and quality of life in the ET group was seen in all BMI categories. In conclusion, aerobic ET in subjects with HF was associated with a nonsignificant trend toward decreased mortality and hospitalization and a significant improvement in quality of life across the range of BMI categories. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1754-1759) C1 [Horwich, Tamara B.; Fonarow, Gregg C.] Ahmanson Univ Calif, Cardiomyopathy Ctr, Los Angeles, CA USA. [Broderick, Samuel; Ellis, Stephen J.] Duke Clin Res Inst, Durham, NC USA. [Chen, Leway] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [McCullough, Peter A.] St John Providence Hlth Syst, Novi, MI USA. [Strzelczyk, Theresa] NW Mem Hosp, Chicago, IL 60611 USA. [Kitzman, Dalane W.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Fletcher, Gerald; Safford, Robert E.] Mayo Clin, Jacksonville, FL 32224 USA. [Ewald, Gregory] Washington Univ, Sch Med, St Louis, MO USA. [Fine, Lawrence J.] NHLBI, Bethesda, MD 20892 USA. RP Fonarow, GC (reprint author), Ahmanson Univ Calif, Cardiomyopathy Ctr, Los Angeles, CA USA. EM gfonarow@mednet.ucla.edu FU National Heart, Lung, and Blood Institute (Bethesda, Maryland) [5U01-HL063747, 5U01-HL066461, HL068973, HL066501, HL066482, HL064250, HL066494, HL064257, HL066497, HL068980, HL064265, HL066491, HL064264] FX HF-ACTION was funded by grants 5U01-HL063747, 5U01-HL066461, HL068973, HL068973, HL066501, HL066482, HL064250, HL066494, HL064257, HL066497, HL068980, HL064265, HL066491, HL064264 from the National Heart, Lung, and Blood Institute (Bethesda, Maryland). NR 14 TC 10 Z9 10 U1 0 U2 6 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 15 PY 2011 VL 108 IS 12 BP 1754 EP 1759 DI 10.1016/j.amjcard.2011.07.051 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 865LM UT WOS:000298312400011 PM 21907317 ER PT J AU Shizukuda, Y Tripodi, DJ Sachdev, V Brenneman, CL Sidenko, S Peter, MS Bolan, CD Yau, YY Leitman, SF Waclawiw, MA Rosing, DR AF Shizukuda, Yukitaka Tripodi, Dorothy J. Sachdev, Vandana Brenneman, Cynthia L. Sidenko, Stanislav Peter, Marilyn St. Bolan, Charles D. Yau, Yu Ying Leitman, Susan F. Waclawiw, Myron A. Rosing, Douglas R. TI Changes in Left Ventricular Diastolic Function of Asymptomatic Hereditary Hemochromatosis Subjects During Five Years of Follow-Up SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ATRIAL SYSTOLIC FUNCTION; CARDIOMYOPATHY; POPULATION; MANAGEMENT; STRESS AB We have previously reported that left ventricular (LV) diastolic function in those with cardiac asymptomatic hereditary hemochromatosis (HH) is similar to that of volunteer control (VC) subjects, despite a presence of augmented left atrial contractile function. However, concern still exists that those with HH might gradually develop LV diastolic dysfunction despite receiving conventional phlebotomy treatment. To address this concern, we prospectively monitored the LV diastolic function of those with HH and VCs during a 5-year period. A total of 14 subjects with newly diagnosed HH (age 51 +/- 12 years, 4 women, group A), 20 with chronic HH (age 51 +/- 9 years, 7 women, group B), and 18 VCs (age 50 +/- 8 years, 6 women, group C) successfully completed both the baseline evaluation of LV diastolic function, including tissue Doppler imaging, strain rate analysis with color-coded tissue Doppler, and the same studies repeated at 5 years of follow-up. All those with HH were New York Heart Association functional class I, were positive for the C282Y homozygote, and received conventional phlebotomy therapy. No VC had HH genetic mutations. The measures of LV diastolic function were comparable among the groups at 5 years of follow-up by analysis of variance. The echocardiographic measures of active left atrial contraction tended to decrease in the HH groups at 5 years of follow-up from baseline. In conclusion, LV diastolic function does not significantly deteriorate statistically during a 5-year period in subjects with cardiac asymptomatic HH after conventional phlebotomy treatment, regardless of their treatment history. (C) 2011 Published by Elsevier Inc. (Am J Cardiol 2011;108:1796-1800) C1 [Shizukuda, Yukitaka; Tripodi, Dorothy J.; Sachdev, Vandana; Brenneman, Cynthia L.; Sidenko, Stanislav; Peter, Marilyn St.; Rosing, Douglas R.] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Bolan, Charles D.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Waclawiw, Myron A.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Shizukuda, Yukitaka] Univ Cincinnati, Div Cardiovasc Dis, Cincinnati, OH USA. [Shizukuda, Yukitaka] Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. [Yau, Yu Ying; Leitman, Susan F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Shizukuda, Y (reprint author), NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. EM shizukya@uc.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland FX This study was supported by Intramural Research Funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. NR 18 TC 1 Z9 1 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 15 PY 2011 VL 108 IS 12 BP 1796 EP 1800 DI 10.1016/j.amjcard.2011.07.054 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 865LM UT WOS:000298312400018 PM 21925635 ER PT J AU Wilcox, AJ Baird, DD AF Wilcox, Allen J. Baird, Donna D. TI Invited Commentary: Natural Versus Unnatural Sex Ratios-A Quandary of Modern Times SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE abortion; sex ratio ID HUMANS; COHORT; CUBA AB The typical dilemma with sex-ratio findings is that when they are real, they aren't interesting, and when they are interesting, they aren't real. In this issue of the Journal, Fernandez et al. (Am J Epidemiol. 2011;174(12):1327-1331) describe a deviation of the sex ratio that is apparently both large and real. There was a temporary but distinct spike in the proportion of boys born in Cuba around the time of the collapse of the national economy during the 1990s. Although an excess of boys does not fit the prevailing biologic theory regarding maternal stress and the sex ratio, the data are consistent with results from the Dutch famine (where population-level deprivation was even more extreme). A new quandary arises in the modern era with interpretation of the sex ratio: If the decision to abort a pregnancy is influenced by the sex of the fetus, a change in the behavior of even a small proportion of women could influence the sex ratio at birth. The possible role of sex selection in the Cuban context is discussed. C1 [Wilcox, Allen J.; Baird, Donna D.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Durham, NC 27709 USA. RP Wilcox, AJ (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, MD A3-05,POB 12233, Durham, NC 27709 USA. EM wilcox@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS NR 13 TC 9 Z9 9 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2011 VL 174 IS 12 BP 1332 EP 1334 DI 10.1093/aje/kwr360 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 863TL UT WOS:000298190800002 PM 22038103 ER PT J AU Sweeney, DA Hicks, CW Cui, XZ Li, Y Eichacker, PQ AF Sweeney, Daniel A. Hicks, Caitlin W. Cui, Xizhong Li, Yan Eichacker, Peter Q. TI Anthrax Infection SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE Bacillus anthracis; diagnosis; pathogenesis; treatment ID BACILLUS-ANTHRACIS; INHALATIONAL ANTHRAX; LETHAL TOXIN; UNITED-STATES; EDEMA TOXINS; GASTROINTESTINAL ANTHRAX; INJECTIONAL ANTHRAX; CLINICAL-FEATURES; CUTANEOUS ANTHRAX; IN-VIVO AB Bacillus anthracis infection is rare in developed countries. However, recent outbreaks in the United States and Europe and the potential use of the bacteria for bioterrorism have focused interest on it. Furthermore, although anthrax was known to typically occur as one of three syndromes related to entry site of (i.e., cutaneous, gastrointestinal, or inhalational), a fourth syndrome including severe soft tissue infection in injectional drug users is emerging. Although shock has been described with cutaneous anthrax, it appears much more common with gastrointestinal, inhalational (5 of 11 patients in the 2001 outbreak in the United States), and injectional anthrax. Based in part on case series, the estimated mortalities of cutaneous, gastrointestinal, inhalational, and injectional anthrax are 1%, 25 to 60%, 46%, and 33%, respectively. Nonspecific early symptomatology makes initial identification of anthrax cases difficult. Clues to anthrax infection include history of exposure to herbivore animal products, heroin use, or clustering of patients with similar respiratory symptoms concerning for a bioterrorist event. Once anthrax is suspected, the diagnosis can usually be made with Gram stain and culture from blood or surgical specimens followed by confirmatory testing (e. g., PCR or immunohistochemistry). Although antibiotic therapy (largely quinolone-based) is the mainstay of anthrax treatment, the use of adjunctive therapies such as anthrax toxin antagonists is a consideration. C1 [Cui, Xizhong; Li, Yan; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Sweeney, Daniel A.] Washington Hosp, Med Intensivist Program, Fremont, CA USA. [Hicks, Caitlin W.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM peichacker@cc.nih.gov RI Hicks, Caitlin/E-8849-2012 FU NIH, Clinical Center, Critical Care Medicine Department FX Supported by the Intramural Program of the NIH, Clinical Center, Critical Care Medicine Department. NR 84 TC 57 Z9 59 U1 7 U2 53 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 15 PY 2011 VL 184 IS 12 BP 1333 EP 1341 DI 10.1164/rccm.201102-0209CI PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 863AF UT WOS:000298134500009 PM 21852539 ER PT J AU Kim, H White, CD Li, ZG Sacks, DB AF Kim, Hugh White, Colin D. Li, Zhigang Sacks, David B. TI Salmonella enterica serotype Typhimurium usurps the scaffold protein IQGAP1 to manipulate Rac1 and MAPK signalling SO BIOCHEMICAL JOURNAL LA English DT Article DE IQ motif-containing GTPase-activating protein 1 (IQGAP1); microbial pathogenesis; protein scaffold; Salmonella ID EPITHELIAL-CELLS; COLLAGEN PHAGOCYTOSIS; NUCLEAR RESPONSES; RHO-GTPASES; HOST-CELL; HUMAN FIBROBLASTS; KINASE PATHWAYS; CDC42; ACTIN; CYTOSKELETAL AB Salmonella enterica serotype Typhimurium invades eukaryotic cells by re-arranging the host-cell cytoskeleton. However, the precise mechanisms by which Salmonella induces cytoskeletal changes remain undefined. IQGAP1 (IQ motif-containing GTPase-activating protein 1) is a scaffold protein that binds multiple proteins including actin, the Rho GTPases Rac1 and Cdc42 (cell division cycle 42), and components of the MAPK (mitogen-activated protein kinase) pathway. We have shown previously that optimal invasion of Salmonella into HeLa cells requires IQGAP1. In the present paper, we use IQGAP1-null MEFs (mouse embryonic fibroblasts) and selected well-characterized IQGAP1 mutant constructs to dissect the molecular determinants of Salmonella invasion. Knockout of IQGAP1 expression reduced Salmonella invasion into MEFs by 75%. Reconstituting IQGAP1-null MEFs with wild-type IQGAP1 completely rescued invasion. By contrast, reconstituting IQGAP1-null cells with mutant C1 [Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Kim, Hugh] Brigham & Womens Hosp, Dept Translat Med, Boston, MA 02115 USA. [Kim, Hugh; White, Colin D.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [White, Colin D.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. EM david.sacks2@nih.gov OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health (NIH) [AI075104]; Canadian Institutes of Health Research (CIHR) FX This work was supported, in part, by the National Institutes of Health (NIH) [grant number AI075104 (to D.B.S.)] and a Canadian Institutes of Health Research (CIHR) Clinician-Scientist Award (to H.K.). NR 50 TC 6 Z9 6 U1 1 U2 5 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 15 PY 2011 VL 440 BP 309 EP 318 DI 10.1042/BJ20110419 PN 3 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 867FM UT WOS:000298440300002 PM 21851337 ER PT J AU Marti, GE AF Marti, Gerald E. TI MBL: mostly benign lymphocytes, but ... SO BLOOD LA English DT Editorial Material ID B-CELL LYMPHOCYTOSIS; NUMBERS C1 NHLBI, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), NHLBI, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 2 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 15 PY 2011 VL 118 IS 25 BP 6480 EP 6481 PG 3 WC Hematology SC Hematology GA 863JC UT WOS:000298157600006 PM 22174306 ER PT J AU Kean, LS Sen, S Onabajo, O Singh, K Robertson, J Stempora, L Bonifacino, AC Metzger, ME Promislow, DEL Mattapallil, JJ Donahue, RE AF Kean, Leslie S. Sen, Sharon Onabajo, Olusegun Singh, Karnail Robertson, Jennifer Stempora, Linda Bonifacino, Aylin C. Metzger, Mark E. Promislow, Daniel E. L. Mattapallil, Joseph J. Donahue, Robert E. TI Significant mobilization of both conventional and regulatory T cells with AMD3100 SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; VERSUS-HOST-DISEASE; BONE-MARROW; HEMATOPOIETIC STEM; CXCR4 ANTAGONIST; PROGENITOR CELLS; RHESUS MACAQUES; HEMATOLOGIC MALIGNANCIES; COSTIMULATION BLOCKADE; NONHUMAN-PRIMATES AB In this study, we used the rhesus macaque model to determine the impact that AMD3100 has on lymphocyte mobilization, both alone and in combination with G-CSF. Our results indicate that, unlike G-CSF, AMD3100 substantially mobilizes both B and T lymphocytes into the peripheral blood. This led to significant increases in the peripheral blood content of both effector and regulatory T-cell populations, which translated into greater accumulation of these cells in the resulting leukapheresis products. Notably, CD4(+)/CD25(high)/CD127(low)/FoxP3(+) Tregs were efficiently mobilized with AMD3100-containing regimens, with as much as a 4.0-fold enrichment in the leukapheresis product compared with G-CSF alone. CD8(+) T cells were mobilized to a greater extent than CD4(+) T cells, with accumulation of 3.7 +/- 0.4-fold more total CD8+ T cells and 6.2 +/- 0.4-fold more CD8(+) effector memory T cells in the leukapheresis product compared with G-CSF alone. Given that effector memory T-cell sub-populations may mediate less GVHD compared with other effector T-cell populations and that Tregs are protective against GVHD, our results indicate that AMD3100 may mobilize a GVHD-protective T-cell repertoire, which would be of benefit in allogeneic hematopoietic stem cell transplantation. (Blood. 2011;118(25):6580-6590) C1 [Kean, Leslie S.; Sen, Sharon] Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA 30322 USA. [Kean, Leslie S.; Singh, Karnail; Robertson, Jennifer; Stempora, Linda] Emory Univ, Sch Med, Emory Transplant Ctr, Dept Surg, Atlanta, GA 30322 USA. [Onabajo, Olusegun; Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Bonifacino, Aylin C.; Metzger, Mark E.; Donahue, Robert E.] NHLBI, Hematol Branch, NIH, Rockville, MD USA. [Promislow, Daniel E. L.] Univ Georgia, Dept Genet, Athens, GA 30602 USA. RP Kean, LS (reprint author), Childrens Healthcare Atlanta, Dept Pediat, 5203 WMB,101 Woodruff Circle NE, Atlanta, GA 30322 USA. EM Leslie.kean@oz.ped.emory.edu FU National Heart, Lung, and Blood Institute; Yerkes National Primate Research Center [RR00165]; Burroughs Wellcome Fund (Career Award in the Biomedical Sciences); National Institute of Dental and Craniofacial Research [DE018339, DE019397]; [2U19 AI051731]; [1 R01 HL095791]; [2U24 RR018109] FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute and the Yerkes National Primate Research Center (Base Grant RR00165). L. S. K. was supported by (grants 2U19 AI051731, 1 R01 HL095791, and 2U24 RR018109) and Burroughs Wellcome Fund (Career Award in the Biomedical Sciences). R. E. D., A. C. B., and M. E. M. were supported by the intramural research program of the National Heart, Lung, and Blood Institute. J.J.M. was supported by the National Institute of Dental and Craniofacial Research (DE018339 and DE019397). NR 52 TC 28 Z9 29 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 15 PY 2011 VL 118 IS 25 BP 6580 EP 6590 DI 10.1182/blood-2011-06-359331 PG 11 WC Hematology SC Hematology GA 863JC UT WOS:000298157600021 PM 21989987 ER PT J AU Hooten, NN Evans, MK AF Hooten, Nicole Noren Evans, Michele K. TI The ultimate transformers Mesenchymal stem cells SO CELL CYCLE LA English DT Editorial Material ID GENE-EXPRESSION; OSTEOARTHRITIS; DISEASES C1 [Hooten, Nicole Noren; Evans, Michele K.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Hooten, NN (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM norenhootenn@mail.nih.gov OI Noren Hooten, Nicole/0000-0002-1683-3838 NR 11 TC 3 Z9 3 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD DEC 15 PY 2011 VL 10 IS 24 BP 4189 EP 4190 DI 10.4161/cc.10.24.18490 PG 2 WC Cell Biology SC Cell Biology GA 866TP UT WOS:000298407200009 ER PT J AU Yoshida, S Koga, F Tatokoro, M Kawakami, S Fujii, Y Kumagai, J Neckers, L Kihara, K AF Yoshida, Soichiro Koga, Fumitaka Tatokoro, Manabu Kawakami, Satoru Fujii, Yasuhisa Kumagai, Jiro Neckers, Len Kihara, Kazunori TI Low-dose Hsp 90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy SO CELL CYCLE LA English DT Article DE urinary bladder neoplasms; HSP90 heat-shock proteins; radiotherapy; combined modality therapy; 17-(allylamino)-17-demethoxygeldanamycin; 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin ID HEAT-SHOCK-PROTEIN; PHASE-I TRIAL; ORGAN PRESERVATION; BREAST-CANCER; GROWTH-FACTOR; MOLECULAR CHAPERONE; RADICAL CYSTECTOMY; ADULT PATIENTS; RADIATION; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN AB Although radical cystectomy with urinary diversion is the standard treatment for muscle-invasive bladder cancer (MIBC), loss of native bladder frequently impairs patient's quality of life (QOL). Bladder-sparing approach incorporating chemoradiotherapy (CRT) improves QOL while not compromising survival outcomes in MIBC patients. In this approach, complete response to induction CRT is a prerequisite for bladder preservation and favorable oncological outcomes. We investigated a strategy to potentiate CRT response of bladder cancer cells by using Hsp90 inhibitors in preclinical models. Hsp90 inhibitors at low concentrations, which did not exert cytocidal effects but inactivated key anti-apoptotic proteins including erbB2, Akt and NF kappa B, efficiently sensitized bladder cancer cells (T24, 5637 and UM-UC-3 cells) to in vitro CRT by enhancing apoptosis. Importantly, the sensitizing effects were not observed in primarily cultured normal human urothelial cells. We also showed that CRT induces accumulation of nuclear phospho-Akt, which antagonizes apoptosis, and that Hsp90 inhibitors block the cellular process. Hsp90 inhibition sensitized bladder cancer cells to in vitro CRT more effectively than sole or combined inhibition of erbB2 and Akt. In mice UM-UC-3 tumor xenografts model, Hsp90 inhibitors successfully potentiated anti-tumor activity of CRT. These results encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance in patients with MIBC. C1 [Yoshida, Soichiro; Koga, Fumitaka; Tatokoro, Manabu; Kawakami, Satoru; Fujii, Yasuhisa; Kihara, Kazunori] Tokyo Med & Dent Univ, Grad Sch, Dept Urol, Bunkyo Ku, Tokyo, Japan. [Neckers, Len] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Koga, F (reprint author), Tokyo Med & Dent Univ, Grad Sch, Dept Urol, Bunkyo Ku, Tokyo, Japan. EM f-koga.uro@tmd.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [19791102, 19791103] FX 17-DMAG and 17-AAG were provided by National Cancer Institute and Kosan Biosciences. This work was supported, in part, by grants-in-aids for Scientific research (19791102, 19791103), from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The ethical committee of Tokyo Medical and Dental University approved the study protocol. Written informed consent was obtained from all patients whose surgically resected specimens were used for primary cell culture. NR 46 TC 17 Z9 17 U1 0 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD DEC 15 PY 2011 VL 10 IS 24 BP 4291 EP 4299 DI 10.4161/cc.10.24.18616 PG 9 WC Cell Biology SC Cell Biology GA 866TP UT WOS:000298407200030 PM 22134243 ER PT J AU Dunleavy, K Wilson, WH AF Dunleavy, Kieron Wilson, Wyndham H. TI Differential Role of BCL2 in Molecular Subtypes of Diffuse Large B-cell Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID NON-HODGKINS-LYMPHOMA; DOSE-ADJUSTED EPOCH; PROTEIN EXPRESSION; GERMINAL CENTER; RITUXIMAB; CHEMOTHERAPY; APOPTOSIS; SURVIVAL AB Gene expression profiling has been used to divide diffuse large B-cell lymphoma into distinct molecular subtypes with different outcomes following immunochemotherapy. Recently, researchers have shown much interest in investigating the role of biomarkers, such as BCL2, in predicting outcome in diffuse large B-cell lymphoma, particularly in the context of these molecular subtypes. Clin Cancer Res; 17(24); 7505-7. (C)2011 AACR. C1 [Dunleavy, Kieron] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Metab Branch, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov FU Intramural NIH HHS [ZIA BC010716-05] NR 13 TC 5 Z9 5 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2011 VL 17 IS 24 BP 7505 EP 7507 DI 10.1158/1078-0432.CCR-11-2372 PG 3 WC Oncology SC Oncology GA 866UL UT WOS:000298410300001 PM 22184285 ER PT J AU Liu, G Jeraj, R Vanderhoek, M Perlman, S Kolesar, J Harrison, M Simoncic, U Eickhoff, J Carmichael, L Chao, B Marnocha, R Ivy, P Wilding, G AF Liu, Glenn Jeraj, Robert Vanderhoek, Matt Perlman, Scott Kolesar, Jill Harrison, Michael Simoncic, Urban Eickhoff, Jens Carmichael, Lakeesha Chao, Bo Marnocha, Rebecca Ivy, Percy Wilding, George TI Pharmacodynamic Study Using FLT PET/CT in Patients with Renal Cell Cancer and Other Solid Malignancies Treated with Sunitinib Malate SO CLINICAL CANCER RESEARCH LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; METASTATIC COLORECTAL-CANCER; ENDOTHELIAL GROWTH-FACTOR; PHASE-I TRIAL; LUNG-CANCER; THYMIDINE KINASE-1; TUMOR VASCULATURE; INTERFERON-ALPHA; CARCINOMA; BEVACIZUMAB AB Purpose: To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3'-deoxy-3'-[(18)F] fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging. Patients and Methods: Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points. Results: Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV(mean)) increased +15% (range: -14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: -5.3% to 200%; P 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal. Conclusions: The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early "angiogenic escape." Clin Cancer Res; 17(24); 7634-44. (C)2011 AACR. C1 [Liu, Glenn] Univ Wisconsin, Carbone Canc Ctr, Wisconsin Inst Med Res, Madison, WI 53705 USA. [Liu, Glenn; Jeraj, Robert; Perlman, Scott; Harrison, Michael] Univ Wisconsin, Translat Imaging Res Grp, Madison, WI 53705 USA. [Liu, Glenn; Harrison, Michael; Chao, Bo; Wilding, George] Univ Wisconsin, Dept Med, Div Hematol Oncol, Madison, WI 53705 USA. [Jeraj, Robert; Vanderhoek, Matt; Simoncic, Urban] Univ Wisconsin, Dept Med Phys, Madison, WI 53705 USA. [Jeraj, Robert; Perlman, Scott] Univ Wisconsin, Dept Radiol, Madison, WI 53705 USA. [Eickhoff, Jens; Carmichael, Lakeesha] Univ Wisconsin, Dept Biostat, Madison, WI 53705 USA. [Kolesar, Jill; Marnocha, Rebecca] Univ Wisconsin, Sch Pharm, Madison, WI 53705 USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Liu, G (reprint author), Univ Wisconsin, Carbone Canc Ctr, Wisconsin Inst Med Res, Room 7051,1111 Highland Ave, Madison, WI 53705 USA. EM gxl@medicine.wisc.edu OI Simoncic, Urban/0000-0002-5835-072X FU Pfizer [GA6180ST]; National Cancer Institute [UO1 CA062491]; NIH/NCI [P30 CA014520, K12 CA087718, T32 CA009614-20, T32 CA009206] FX Funding for imaging correlatives was provided by a Pfizer Investigator Initiated Research Grant. No financial compensation was received from Pfizer.; The clinical conduct of this study was supported by National Cancer Institute UO1 CA062491 (Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis) and NIH/NCI P30 CA014520 (UW Comprehensive Cancer Center Support). FLT PET/CT costs were funded through a Pfizer Oncology Investigator-Initiated Research grant (GA6180ST). Drs. Harrison, Chao, and Vanderhoek were supported by NIH/NCI grants K12 CA087718, T32 CA009614-20, and T32 CA009206, respectively. NR 45 TC 28 Z9 28 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2011 VL 17 IS 24 BP 7634 EP 7644 DI 10.1158/1078-0432.CCR-11-1677 PG 11 WC Oncology SC Oncology GA 866UL UT WOS:000298410300015 PM 22038997 ER PT J AU Iqbal, J Meyer, PN Smith, LM Johnson, NA Vose, JM Greiner, TC Connors, JM Staudt, LM Rimsza, L Jaffe, E Rosenwald, A Ott, G Delabie, J Campo, E Braziel, RM Cook, JR Tubbs, RR Gascoyne, RD Armitage, JO Weisenburger, DD Chan, WC AF Iqbal, Javeed Meyer, Paul N. Smith, Lynette M. Johnson, Nathalie A. Vose, Julie M. Greiner, Timothy C. Connors, Joseph M. Staudt, Louis M. Rimsza, Lisa Jaffe, Elaine Rosenwald, Andreas Ott, German Delabie, Jan Campo, Elias Braziel, Rita M. Cook, James R. Tubbs, Raymond R. Gascoyne, Randy D. Armitage, James O. Weisenburger, Dennis D. Chan, Wing C. TI BCL2 Predicts Survival in Germinal Center B-cell-like Diffuse Large B-cell Lymphoma Treated with CHOP-like Therapy and Rituximab SO CLINICAL CANCER RESEARCH LA English DT Article ID NON-HODGKINS-LYMPHOMA; R-CHOP; PROGNOSTIC-SIGNIFICANCE; PROTEIN EXPRESSION; ELDERLY-PATIENTS; IMMUNOHISTOCHEMICAL BIOMARKERS; BCL-2-ASSOCIATED RESISTANCE; CLINICAL-SIGNIFICANCE; MYC REARRANGEMENTS; MOLECULAR SUBTYPES AB Purpose: We have previously shown the prognostic significance of BCL2 expression in the activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) patients treated with cyclophosphamide-Adriamycin-vincristine- prednisone (CHOP) or CHOP-like therapy. However, after the inclusion of rituximab (R) in the CHOP regimen, several conflicting observations about the prognostic value of BCL2 expression have been reported. Experimental Design: We evaluated the R-CHOP cohort of 221 DLBCL cases with gene expression profiling data. BCL2 protein (n = 169), mRNA(n = 221) expression, and t(14; 18) (n = 144) were correlated with clinical outcome. The CHOP cohort (n = 181) was used for comparative analysis. Results: BCL2 protein expression has significant impact on overall survival (OS) and event-free survival (EFS) in DLBCL (OS, P = 0.009; EFS, P = 0.001) and GCB-DLBCL (OS, P = 0.03; EFS, P = 0.002) but not in ABC-DLBCL in the R-CHOP cohort. The survival differences for EFS in GCB-DLBCL were still observed in multivariate analysis. At the mRNA level, this correlation was observed in EFS in DLBCL (P = 0.006), but only a trend was observed in GCB-DLBCL (P = 0.09). The t(14; 18) was detected in 34% of GCB-DLBCL but was not associated with significant differences in survival. Gene enrichment analysis identified significant enrichment of the DLBCL "stromal-1" signatures and hypoxia-inducible factor 1 (HIF1-alpha) signature in BCL2 (-)GCB-DLBCL, whereas T(FH) cell signatures were enriched in BCL2(+) GCB-DLBCL. Conclusion: The prognostic significance of BCL2 has changed after inclusion of rituximab in the treatment protocol and is observed in the GCB-DLBCL rather than the ABC-DLBCL. Although rituximab has benefited patients in both DLBCL subgroups, the BCL2(+) GCB-DLBCL seems to receive less benefit from this treatment and may require other novel therapeutic intervention. Clin Cancer Res; 17(24); 7785-95. (C) 2011 AACR. C1 [Iqbal, Javeed; Meyer, Paul N.; Greiner, Timothy C.; Weisenburger, Dennis D.; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Vose, Julie M.; Armitage, James O.] Univ Nebraska Med Ctr, Dept Hematol Oncol, Omaha, NE USA. [Smith, Lynette M.] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Biostat, Omaha, NE USA. [Johnson, Nathalie A.; Connors, Joseph M.; Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jaffe, Elaine] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rimsza, Lisa] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Baden Wurttembe, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Baden Wurttembe, Germany. [Delabie, Jan] Univ Oslo, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. [Campo, Elias] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Braziel, Rita M.] Oregon Hlth, Clin Pathol, Portland, OR USA. [Cook, James R.; Tubbs, Raymond R.] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44106 USA. RP Chan, WC (reprint author), Ctr Res Lymphoma & Leukemia, 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM jchan@unmc.edu OI Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU NCI [5U01/CA114778] FX This work was supported in part by NCI grant5U01/CA114778. This study is part of Lymphoma/Leukemia Molecular profiling project (LLMPP). NR 56 TC 69 Z9 75 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2011 VL 17 IS 24 BP 7785 EP 7795 DI 10.1158/1078-0432.CCR-11-0267 PG 11 WC Oncology SC Oncology GA 866UL UT WOS:000298410300030 PM 21933893 ER PT J AU Hilton, TF AF Hilton, Thomas F. TI The promise of PROMIS (R) for addiction SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Measurement burden; Item Response Theory; Computerized adaptive testing; Classic test theory; Recovery monitoring ID SUBSTANCE-ABUSE TREATMENT; ITEM RESPONSE THEORY; QUALITY-OF-LIFE; COGNITIVE IMPAIRMENT; FOLLOW-UP; RECOVERY; ADULTS; ADOLESCENTS; RETENTION; CARE AB The field of addiction treatment has a measurement problem that pervades efforts to help patients achieve self-sustainable recovery. The impact of using older measurement technology has increased the measurement burden on both service providers and patients, while at the same time limiting the scope and frequency of measurement. The resulting burden can affect provider performance, patient access, and addiction recovery. This paper underscores the need for applying modern measurement theory techniques to reduce the measurement burden currently affecting most if not all major aspects of treatment and recovery. It is currently possible to obtain information more precisely, over a broad spectrum of recovery-oriented domains, faster and at lower cost than current measurement practices allow. However, a persistent research effort will be necessary to achieve that goal. C1 NIDA, NIH, Bethesda, MD 20892 USA. RP Hilton, TF (reprint author), NIDA, NIH, 6001 Execut Blvd,Rm 5197, Bethesda, MD 20892 USA. EM tom.hilton@nih.gov NR 68 TC 11 Z9 11 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD DEC 15 PY 2011 VL 119 IS 3 BP 229 EP 234 DI 10.1016/j.drugalcdep.2011.09.031 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 868OE UT WOS:000298531800011 PM 22238781 ER PT J AU Liu, J Cao, L Finkel, T AF Liu, Jie Cao, Liu Finkel, Toren TI Oxidants, metabolism, and stem cell biology SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE stem cell; redox; mitochondria; aging ID OXIDATIVE STRESS; LIFE-SPAN; SELF-RENEWAL; BONE-MARROW; C-ELEGANS; LKB1; MAINTENANCE; HOMEOSTASIS; AUTOPHAGY; HYPOXIA AB Adult stem cells persist throughout the lifetime of the organism and may therefore require specific mechanisms to limit the effects of chronic oxidative stress. Recently, several instructive genetic mouse models have demonstrated the unique susceptibility of stem cells to perturbations in metabolic or redox homeostasis. These results have implications not only for stem cell biology but also suggest a mechanistic link between intracellular oxidants and the decline in regenerative function that occurs as a normal consequence of aging. Published by Elsevier Inc. C1 [Liu, Jie; Cao, Liu; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10,CRC 5-3330, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU Intramural NIH HHS [ZIA HL006037-03] NR 49 TC 17 Z9 18 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD DEC 15 PY 2011 VL 51 IS 12 BP 2158 EP 2162 DI 10.1016/j.freeradbiomed.2011.10.434 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 860PK UT WOS:000297960000003 PM 22041454 ER PT J AU Yang, Y Gu, DY Aisa, HA Ito, Y AF Yang, Yi Gu, Dongyu Aisa, Haji Akber Ito, Yoichiro TI Evaluation of the performance of protein separation in figure-8 centrifugal counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Centrifugal counter-current chromatography; Figure-8 column; Protein separation; Polymer phase system; Lysozyme; Myoglobin; Hollow fiber membrane dialyzer ID COLUMN; SPEED; DESIGN AB The performance of protein separation using the figure-8 column configuration in centrifugal countercurrent chromatography was investigated under various flow rates and revolution speeds. The separation was performed with a two-phase solvent system composed of polyethylene glycol 1000/potassium phosphate each at 12.5% (w/w) in water and with lysozyme and myoglobin as test samples. In order to improve tracing of the elution curve, a hollow fiber membrane dialyzer was inserted at the inlet of the UV detector. The results showed that the retention of stationary phase (Sf) and resolution (Rs) increased with decreased flow rate and increased revolution speed. The highest Rs of approximately 1 was obtained at a flow rate of 0.01 mL/min under a revolution speed of 1200 rpm with a 3.4 mL capacity column. (C) 2011 Elsevier B.V. All rights reserved. C1 [Yang, Yi; Gu, Dongyu; Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Yang, Yi; Gu, Dongyu; Aisa, Haji Akber] Chinese Acad Sci, Key Lab Chem Plant Resources Arid Reg, Xinjiang Tech Inst Phys & Chem, Urumqi 830011, Peoples R China. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov FU China National Founds for Distinguished Young Scientists [30925045]; CAS/SAFEA; Scientific-Research Plan of the Xinjiang High Technology [200910105] FX This work was funded by the China National Founds for Distinguished Young Scientists (Grant No. 30925045). Research was also supported by the CAS/SAFEA International Partnership Program for Creative Research Teams and the Scientific-Research Plan of the Xinjiang High Technology (No. 200910105). NR 21 TC 5 Z9 5 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD DEC 15 PY 2011 VL 879 IS 32 BP 3802 EP 3805 DI 10.1016/j.jchromb.2011.10.019 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 868NO UT WOS:000298530200004 PM 22100551 ER PT J AU Popovic, ZV Wang, SJ Papatriantafyllou, M Kaya, Z Porubsky, S Meisner, M Bonrouhi, M Burgdorf, S Young, MF Schaefer, L Grone, HJ AF Popovic, Zoran V. Wang, Shijun Papatriantafyllou, Maria Kaya, Ziya Porubsky, Stefan Meisner, Maria Bonrouhi, Mahnaz Burgdorf, Sven Young, Marian F. Schaefer, Liliana Groene, Hermann-Josef TI The Proteoglycan Biglycan Enhances Antigen-Specific T Cell Activation Potentially via MyD88 and TRIF Pathways and Triggers Autoimmune Perimyocarditis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LEUCINE-RICH PROTEOGLYCANS; CARDIAC TROPONIN-I; MYOCARDIAL-INFARCTION; DENDRITIC CELLS; TOLL-LIKE; CROSS-PRESENTATION; HEART-FAILURE; LYMPHOCYTE-RESPONSES; DECORIN DEFICIENCY; INNATE IMMUNITY AB Biglycan is a proteoglycan ubiquitously present in extracellular matrix of a variety of organs, including heart, and it was reported to be overexpressed in myocardial infarction. Myocardial infarction may be complicated by perimyocarditis through unknown mechanisms. Our aim was to investigate the capacity of TLR2/TLR4 ligand biglycan to enhance the presentation of specific Ags released upon cardiomyocyte necrosis. In vitro, OVA-pulsed bone marrow-derived dendritic cells from wild-type (WT; C57BL/6) and TLR2-, TLR4-, MyD88-, or TRIF-deficient mice were cotreated with LPS, biglycan, or vehicle and incubated with OVA-recognizing MHC I- or MHC II-restricted T cells. Biglycan enhanced OVA-specific cross-priming by >80% to MHC I-restricted T cells in both TLR2- and TLR4-pathway-dependent manners. Accordingly, biglycan-induced cross-priming by both MyD88- and TRIF-deficient dendritic cells (DCs) was strongly diminished. OVA-specific activation of MHC II-restricted T cells was predominantly TLR4 dependent. Our first in vivo correlate was a model of experimental autoimmune perimyocarditis triggered by injection of cardiac Ag-pulsed DCs (BALB/c). Biglycan-treated DCs triggered perimyocarditis to a comparable extent and intensity as LPS-treated DCs (mean scores 1.3 +/- 0.3 and 1.5 +/- 0.4, respectively). Substitution with TLR4-deficient DCs abolished this effect. In a second in vivo approach, WT and biglycan-deficient mice were followed 2 wk after induction of myocardial infarction. WT mice demonstrated significantly greater myocardial T lymphocyte infiltration in comparison with biglycandeficient animals. We concluded that the TLR2/4 ligand biglycan, a component of the myocardial matrix, may enhance Ag-specific T cell priming, potentially via MyD88 and TRIF, and stimulate autoimmune perimyocarditis. The Journal of Immunology, 2011, 187: 6217-6226. C1 [Popovic, Zoran V.; Wang, Shijun; Porubsky, Stefan; Meisner, Maria; Bonrouhi, Mahnaz; Groene, Hermann-Josef] German Canc Res Ctr, Dept Cellular & Mol Pathol, D-69120 Heidelberg, Baden Wuerttemb, Germany. [Papatriantafyllou, Maria] German Canc Res Ctr, Dept Mol Immunol, D-69120 Heidelberg, Baden Wuerttemb, Germany. [Kaya, Ziya] Heidelberg Univ, Univ Heidelberg Hosp, Dept Internal Med 3, D-69120 Heidelberg, Germany. [Burgdorf, Sven] Univ Hosp Bonn, Inst Mol Med, D-53115 Bonn, Germany. [Burgdorf, Sven] Univ Hosp Bonn, Inst Expt Immunol, D-53115 Bonn, Germany. [Young, Marian F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Schaefer, Liliana] Goethe Univ Clin, Dept Pharmacol & Toxicol, D-60596 Frankfurt, Germany. RP Grone, HJ (reprint author), German Canc Res Ctr, Dept Cellular & Mol Pathol, Neuenheimer Feld 280, D-69120 Heidelberg, Baden Wuerttemb, Germany. EM Z.Popovic@dkfz.de; H.J.Groene@dkfz.de RI Porubsky, Stefan/J-5738-2015; Popovic, Zoran/J-5933-2015; OI Porubsky, Stefan/0000-0002-7647-7265; Schaefer, Liliana/0000-0002-3318-3005 FU Deutsche Forschungsgemeinschaft [Sonderforschungsbereich 953, SCHA 1082/2-1] FX This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 953 to H.-J.G. and SCHA 1082/2-1 to L. S. and H.-J.G.). NR 94 TC 17 Z9 18 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2011 VL 187 IS 12 BP 6217 EP 6226 DI 10.4049/jimmunol.1003478 PG 10 WC Immunology SC Immunology GA 863MG UT WOS:000298167800011 PM 22095710 ER PT J AU Gonzaga, R Matzinger, P Perez-Diez, A AF Gonzaga, Rosemary Matzinger, Polly Perez-Diez, Ainhoa TI Resident Peritoneal NK Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; TUMOR REJECTION; IFN-GAMMA; MACROPHAGES; MATURATION; SUBSETS; PROLIFERATION; ENDOMETRIOSIS; LYMPHOCYTES; MIGRATION AB In this study, we describe a new population of NK cells that reside in the normal, uninflamed peritoneal cavity. Phenotypically, they share some similarities with the small population of CD49b(-), CD27(+) immature splenic NK cells, as well as liver NK cells, but they differ in their expression of CD62L, TRAIL, and EOMES. Functionally, the peritoneal NK cells resemble the immature splenic NK cells in their production of IFN-gamma, GM-CSF, and TNF-alpha and in the killing of YAC-1 target cells. We also found that the peritoneum induces different behavior in mature and immature splenic NK cells. When transferred i.v. into RAG gamma c knockout mice, both populations undergo homeostatic proliferation in the spleen, but only the immature splenic NK cells are able to reach the peritoneum. When transferred directly into the peritoneum, the mature NK cells survive but do not divide, whereas the immature NK cells proliferate profusely. These data suggest that the peritoneum is not only home to a new subset of tissue-resident NK cells, but that it differentially regulates the migration and homeostatic proliferation of immature versus mature NK cells. The Journal of Immunology, 2011, 187: 6235-6242. C1 [Gonzaga, Rosemary; Matzinger, Polly; Perez-Diez, Ainhoa] NIAID, Ghost Lab, T Cell Memory & Tolerance Sect, Lab Cellular & Mol Immunol,NIH, Bethesda, MD 20892 USA. RP Perez-Diez, A (reprint author), NIAID, Ghost Lab, T Cell Memory & Tolerance Sect, Lab Cellular & Mol Immunol,NIH, 9000 Rockville Pike,Bldg 4,Room 211, Bethesda, MD 20892 USA. EM ainhoa@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institute of Allergy and Infectious Diseases Office of Training and Diversity FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. R. G. was partially funded by the National Institute of Allergy and Infectious Diseases Office of Training and Diversity's program to recruit populations underrepresented in biomedical research. NR 35 TC 8 Z9 9 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2011 VL 187 IS 12 BP 6235 EP 6242 DI 10.4049/jimmunol.1101540 PG 8 WC Immunology SC Immunology GA 863MG UT WOS:000298167800013 PM 22079985 ER PT J AU Wu, Y Gao, F Liu, J Qi, JX Gostick, E Price, DA Gao, GF AF Wu, Yan Gao, Feng Liu, Jun Qi, Jianxun Gostick, Emma Price, David A. Gao, George F. TI Structural Basis of Diverse Peptide Accommodation by the Rhesus Macaque MHC Class I Molecule Mamu-B*17: Insights into Immune Protection from Simian Immunodeficiency Virus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; CYTOTOXIC T-LYMPHOCYTES; CELL-RECEPTOR RECOGNITION; LONG-TERM NONPROGRESSORS; CRYSTAL-STRUCTURES; PERIPHERAL-BLOOD; ESCAPE VARIANTS; VACCINE DESIGN; VIRAL PEPTIDES; SIV INFECTION AB The MHC class I molecule Mamu-B*17 has been associated with elite control of SIV infection in rhesus macaques, akin to the protective effects described for HLA-B*57 in HIV-infected individuals. In this study, we determined the crystal structures of Mamu-B*17 in complex with eight different peptides corresponding to immunodominant SIV(mac)239-derived CD8(+) T cell epitopes: HW8 (HLEVQGYW), GW10 (GSHLEVQGYW), MW9 (MHPAQTSQW), QW9 (QTSQWDDPW), FW9 (FQWMGYELW), MF8 (MRHVLEPF), IW9 (IRYPKTFGW), and IW11 (IRYPKTFGWLW). The structures reveal that not only P2, but also P1 and P3, can be used as N-terminal anchor residues by Mamu-B*17-restricted peptides. Moreover, the N-terminal anchor residues exhibit a broad chemical specificity, encompassing basic (H and R), bulky polar aliphatic (Q), and small (T) residues. In contrast, Mamu-B*17 exhibits a very narrow preference for aromatic residues (W and F) at the C terminus, similar to that displayed by HLA-B*57. Flexibility within the whole peptide-binding groove contributes to the accommodation of these diverse peptides, which adopt distinct conformations. Furthermore, the unusually large pocket D enables compensation from other peptide residues if P3 is occupied by an amino acid with a small side chain. In addition, residues located at likely TCR contact regions present highly flexible conformations, which may impact TCR repertoire profiles. These findings provide novel insights into the structural basis of diverse peptide accommodation by Mamu-B*17 and highlight unique atomic features that might contribute to the protective effect of this MHC I molecule in SIV-infected rhesus macaques. The Journal of Immunology, 2011, 187: 6382-6392. C1 [Wu, Yan; Liu, Jun; Qi, Jianxun; Gao, George F.] Chinese Acad Sci, CAS Key Lab Pathogen Microbiol & Immunol, Inst Microbiol, Beijing 100101, Peoples R China. [Wu, Yan; Qi, Jianxun; Gao, George F.] Chinese Acad Sci, China Japan Joint Lab Mol Immunol & Mol Microbiol, Inst Microbiol, Beijing 100101, Peoples R China. [Gao, Feng] Chinese Acad Sci, Natl Lab Biomacromol, Inst Biophys, Beijing 100101, Peoples R China. [Gao, Feng] Sichuan Univ, Sch Life Sci, Chengdu 610064, Peoples R China. [Liu, Jun; Gao, George F.] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff CF14 4XN, Wales. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gao, George F.] Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China. RP Gao, GF (reprint author), Chinese Acad Sci, CAS Key Lab Pathogen Microbiol & Immunol, Inst Microbiol, Bldg 3,1 Beichen W Rd, Beijing 100101, Peoples R China. EM gaof@im.ac.cn RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU China Ministry of Science and Technology [2011CB504703]; National Natural Science Foundation of China [31030030]; China National Grand Science and Technology Special Project [2009ZX10004-201, 2009ZX10004-305]; National Natural Science Foundation of China Innovative Research Group [81021003] FX This work was supported by the 973 Project of the China Ministry of Science and Technology (2011CB504703), the National Natural Science Foundation of China (31030030), and the China National Grand Science and Technology Special Project (2009ZX10004-201 and 2009ZX10004-305). The funders had no role in study design, data collection, and analysis, the decision to publish, or preparation of the manuscript. D.A.P. is a Medical Research Council (U.K.) Senior Clinical Fellow. G.F.G. is a leading principal investigator of the National Natural Science Foundation of China Innovative Research Group (Grant 81021003). NR 74 TC 10 Z9 11 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2011 VL 187 IS 12 BP 6382 EP 6392 DI 10.4049/jimmunol.1101726 PG 11 WC Immunology SC Immunology GA 863MG UT WOS:000298167800029 PM 22084443 ER PT J AU Rapoport, J Ahn, K AF Rapoport, Judith Ahn, Kwangmi TI Rare Variants and Risk for Schizophrenia: More Support SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID CHILDHOOD-ONSET SCHIZOPHRENIA; ASSOCIATION; POPULATION; DISEASE; AUTISM C1 [Rapoport, Judith; Ahn, Kwangmi] NIMH, Child Psychiat Branch, Bethesda, MD 20814 USA. RP Rapoport, J (reprint author), NIMH, Child Psychiat Branch, 10 Ctr Dr,Room 3N202,MSC 1600, Bethesda, MD 20814 USA. EM rapoporj@mail.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 15 PY 2011 VL 70 IS 12 BP 1102 EP 1103 DI 10.1016/j.biopsych.2011.10.003 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 860WW UT WOS:000297980000001 PM 22115410 ER PT J AU Topczewski, JJ Callahan, MP Kodet, JG Inbarasu, JD Mente, NR Beutler, JA Wiemer, DF AF Topczewski, Joseph J. Callahan, Michael P. Kodet, John G. Inbarasu, Jery D. Mente, Nolan R. Beutler, John A. Wiemer, David F. TI Relevance of the C-5 position to schweinfurthin induced cytotoxicity SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Schweinfurthins; Apoptosis; Cytotoxic; Anti-proliferative; Bioassay ID MACARANGA-SCHWEINFURTHII; ANALOGS; EPOXIDATION; STILBENES; POTENT AB The schweinfurthins are an intriguing group of anti-proliferative agents that display low nanomolar activities against several cell types, including the human-derived glioblastoma cell line SF-295, but have little impact on other cell lines even at micromolar concentrations. This activity has inspired the synthesis of seven of the natural schweinfurthins, all with the correct absolute stereochemistry, and a variety of analogues designed to probe different facets of the pharmacophore. Reported herein is the synthesis of several new schweinfurthin analogues varied at the C-5 position along with data on their biological activity in the NCI 60 cell-line assay. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Topczewski, Joseph J.; Callahan, Michael P.; Kodet, John G.; Inbarasu, Jery D.; Mente, Nolan R.; Wiemer, David F.] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Wiemer, DF (reprint author), Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. EM david-wiemer@uiowa.edu RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU ACS Division of Medicinal Chemistry; University of Iowa Department of Chemistry; UI Graduate College; Iowa Center for Research; NIH, National CancerInstitute, Center for Cancer Research; Roy J. Carver Charitable Trust FX We thank the ACS Division of Medicinal Chemistry for support in the form of a predoctoral fellowship (to J.J.T.), the University of Iowa Department of Chemistry for a Shriner Fellowship (to J.J.T.), the UI Graduate College for a Presidential Fellowship (to J.G.K.), and the Iowa Center for Research by Undergraduates for a summer fellowship (to J.D.I.). This research was supported in part by the Intramural Research Program of NIH, National CancerInstitute, Center for Cancer Research. Financial support from the Roy J. Carver Charitable Trust as a Research Program of Excellence is gratefully acknowledged. NR 31 TC 4 Z9 4 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD DEC 15 PY 2011 VL 19 IS 24 BP 7570 EP 7581 DI 10.1016/j.bmc.2011.10.034 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 859ES UT WOS:000297860100029 PM 22055715 ER PT J AU Ye, XG Wang, GL Altschul, SF AF Ye, Xugang Wang, Guoli Altschul, Stephen F. TI An assessment of substitution scores for protein profile-profile comparison SO BIOINFORMATICS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; DISTANTLY RELATED PROTEINS; STATISTICAL SIGNIFICANCE; FOLD-RECOGNITION; COMPARISON TOOL; HOMOLOGY; DATABASE; INFORMATION; BENCHMARK; WEIGHTS AB Results: A simple symmetrization of mean profile-sequence scores usually performed the best. These were followed closely by several specific scoring systems constructed using a variety of rationales. C1 [Ye, Xugang; Altschul, Stephen F.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Wang, Guoli] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Altschul, SF (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM altschul@ncbi.nlm.nih.gov FU National Library of Medicine; Center for Information Technology at National Institutes of Health FX Intramural Research Programs of the National Library of Medicine and the Center for Information Technology at the National Institutes of Health. NR 70 TC 3 Z9 3 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 15 PY 2011 VL 27 IS 24 BP 3356 EP 3363 DI 10.1093/bioinformatics/btr565 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 859ER UT WOS:000297860000005 PM 21998158 ER PT J AU Dale, RK Pedersen, BS Quinlan, AR AF Dale, Ryan K. Pedersen, Brent S. Quinlan, Aaron R. TI Pybedtools: a flexible Python library for manipulating genomic datasets and annotations SO BIOINFORMATICS LA English DT Article AB pybedtools is a flexible Python software library for manipulating and exploring genomic datasets in many common formats. It provides an intuitive Python interface that extends upon the popular BEDTools genome arithmetic tools. The library is well documented and efficient, and allows researchers to quickly develop simple, yet powerful scripts that enable complex genomic analyses. C1 [Dale, Ryan K.] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Pedersen, Brent S.] Univ Colorado, Dept Med, Aurora, CO 80045 USA. [Quinlan, Aaron R.] Univ Virginia, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. RP Dale, RK (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM dalerr@niddk.nih.gov; arq5x@virginia.edu RI Sincan, Murat /A-3794-2010; OI Dale, Ryan/0000-0003-2664-3744; Quinlan, Aaron/0000-0003-1756-0859 FU National Institute of Diabetes and Digestive and Kidney Diseases FX Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 8 TC 48 Z9 48 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 15 PY 2011 VL 27 IS 24 BP 3423 EP 3424 DI 10.1093/bioinformatics/btr539 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 859ER UT WOS:000297860000014 PM 21949271 ER PT J AU Baris, HN Raas-Rothschild, A Garty, BZ Tor, R Klontz, S Tayebi, N Sidransky, E Cohen, IJ AF Baris, Hagit N. Raas-Rothschild, Annick Garty, Ben-Zion Tor, Ruth Klontz, Sarah Tayebi, Nahid Sidransky, Ellen Cohen, Ian J. TI Gaucher disease type 2-Homozygosity for the mutation F331S in two unrelated consanguineous Muslim Arab patients with Gaucher disease from the Gaza and Jenin regions SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Letter ID GLUCOCEREBROSIDASE GENE; THERAPY C1 [Baris, Hagit N.] Beilinson Med Ctr, Rabin Med Ctr, Raphael Recanati Genet Inst, IL-49100 Petah Tiqwa, Israel. [Raas-Rothschild, Annick] Hadassah Hebrew Univ, Med Ctr, Dept Human Genet & Metab Dis, Jerusalem, Israel. [Garty, Ben-Zion; Cohen, Ian J.] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Garty, Ben-Zion] Schneider Childrens Med Ctr Israel, Dept Pediat C, Petah Tiqwa, Israel. [Tor, Ruth] Beilinson Med Ctr, Rabin Med Ctr, Clin Biochem Lab, IL-49100 Petah Tiqwa, Israel. [Klontz, Sarah; Tayebi, Nahid; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Cohen, Ian J.] Schneider Childrens Med Ctr Israel, Dept Pediat Hematol & Oncol, Petah Tiqwa, Israel. RP Baris, HN (reprint author), Beilinson Med Ctr, Rabin Med Ctr, Raphael Recanati Genet Inst, IL-49100 Petah Tiqwa, Israel. EM barish@clalit.org.il RI Cohen, Ian/H-3358-2013; OI Cohen, Ian Joseph/0000-0002-5364-3275 FU Intramural NIH HHS [ZIA HG200336-06] NR 8 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD DEC 15 PY 2011 VL 47 IS 4 BP 262 EP 263 DI 10.1016/j.bcmd.2011.08.002 PG 2 WC Hematology SC Hematology GA 856BB UT WOS:000297610100010 PM 21889374 ER PT J AU Breen, N Cronin, KA Tiro, JA Meissner, HI McNeel, TS Sabatino, SA Tangka, FK Taplin, SH AF Breen, Nancy Cronin, Kathleen A. Tiro, Jasmin A. Meissner, Helen I. McNeel, Timothy S. Sabatino, Susan A. Tangka, Florence K. Taplin, Stephen H. TI Was the drop in mammography rates in 2005 associated with the drop in hormone therapy use? SO CANCER LA English DT Article DE mammography; hormone therapy; breast cancer; National Health Interview Surveys; women's health; primary care ID BREAST-CANCER INCIDENCE; HEALTH-CARE PROVIDERS; SCREENING MAMMOGRAPHY; UNITED-STATES; INCREASE RECOMMENDATION; COLORECTAL CANCERS; WOMEN; ACCURACY; PROGRAMS; BENEFITS AB BACKGROUND: In 2005, mammography rates in the United States dropped nationally for the first time among age-eligible women. An increased risk of breast cancer related to hormone therapy (HT) use reported in 2002 led to a dramatic drop in its use by 2005. Because current users of HT also tend to have higher mammography rates, the authors examined whether concurrent drops in HT and mammography use were associated. METHODS: Multivariate logistic regression was used to test for an interaction between HT use and survey year, controlling for a range of measurable factors in data from the 2000 and 2005 National Health Interview Surveys (NHIS). RESULTS: Women ages 50 to 64 years were more likely to report a recent mammogram if they also reported more education, a usual source of care, private health insurance, any race except non-Hispanic Asian, talking with an obstetrician/gynecologist or other physician in the past 12 months, or were currently taking HT. Women aged >= 65 years were more likely to report a recent mammogram if they also reported younger age (ages 65-74 years), more education, a usual source of care, having Medicare Part B or other supplemental Medicare insurance, excellent health, any race except non-Hispanic Asian, talking with an obstetrician/gynecologist or other physician in the past 12 months, or were currently taking HT. CONCLUSIONS: The change in HT use was associated with the drop in mammography use for women ages 50 to 64 years but not for women aged >= 65 years. NHIS data explained 70% to 80% of the change in mammography use. Cancer 2011; 117: 5450-60. (C) 2011 American Cancer Society. C1 [Breen, Nancy] Natl Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. [Cronin, Kathleen A.; Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Tiro, Jasmin A.] Univ Texas SW Med Ctr Dallas, Div Behav & Commun Sci, Dallas, TX 75390 USA. [Meissner, Helen I.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Rockville, MD USA. [Sabatino, Susan A.; Tangka, Florence K.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. RP Breen, N (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Execut Plaza N,Room 4005,6130 Executive Blvd,MSC, Rockville, MD 20852 USA. EM breenn@mail.nih.gov OI Tiro, Jasmin/0000-0001-8300-0441 FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 5 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2011 VL 117 IS 24 BP 5450 EP 5460 DI 10.1002/cncr.26218 PG 11 WC Oncology SC Oncology GA 855PB UT WOS:000297575600003 PM 21861265 ER PT J AU Wuthrick, EJ Kamrava, M Curran, WJ Werner-Wasik, M Camphausen, KA Hyslop, T Axelrod, R Andrews, DW Glass, J Machtay, M Dicker, AP AF Wuthrick, Evan J. Kamrava, Mitchell Curran, Walter J., Jr. Werner-Wasik, Maria Camphausen, Kevin A. Hyslop, Terry Axelrod, Rita Andrews, David W. Glass, Jon Machtay, Mitchell Dicker, Adam P. TI A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies SO CANCER LA English DT Article DE sunitinib; radiation therapy; central nervous system; antiangiogenesis; brain metastases ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; RENAL-CELL CARCINOMA; BRAIN METASTASES; TUMOR VASCULATURE; IONIZING-RADIATION; FACTOR RECEPTOR; IN-VIVO; RESPONSE CRITERIA; RANDOMIZED-TRIAL AB BACKGROUND: In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies. METHODS: Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative bio-marker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3. RESULTS: Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade <= 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT. CONCLUSIONS: Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial. Cancer 2011; 117: 5548-59. (C) 2011 American Cancer Society. C1 [Wuthrick, Evan J.; Curran, Walter J., Jr.; Werner-Wasik, Maria; Machtay, Mitchell; Dicker, Adam P.] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Kamrava, Mitchell; Camphausen, Kevin A.] NCI, Radiat Oncol Branch, Sect Imaging & Mol Therapeut, Ctr Canc Res, Bethesda, MD 20892 USA. [Hyslop, Terry] Thomas Jefferson Univ, Div Biostat, Philadelphia, PA 19107 USA. [Axelrod, Rita] Thomas Jefferson Univ, Jefferson Med Coll, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Andrews, David W.; Glass, Jon] Thomas Jefferson Univ, Jefferson Med Coll, Dept Neurol Surg, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. RP Dicker, AP (reprint author), Thomas Jefferson Univ Hosp, Dept Radiat Oncol, 111 S 11th St, Philadelphia, PA 19107 USA. EM adam.dicker@jeffersonhospital.org OI Dicker, Adam/0000-0003-0733-3337 FU Intramural NIH HHS; NCI NIH HHS [P30 CA051008, P30 CA051008-15S3, P30 CA056036, P30 CA056036-08] NR 55 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2011 VL 117 IS 24 BP 5548 EP 5559 DI 10.1002/cncr.26216 PG 12 WC Oncology SC Oncology GA 855PB UT WOS:000297575600014 PM 21647871 ER PT J AU Price, RA Tiro, JA Saraiya, M Meissner, H Breen, N AF Price, Rebecca Anhang Tiro, Jasmin A. Saraiya, Mona Meissner, Helen Breen, Nancy TI Use of human papillomavirus vaccines among young adult women in the United States: An analysis of the 2008 National Health Interview Survey SO CANCER LA English DT Article DE human papillomavirus; vaccines; cervical cancer; disparities ID AGED 13-17 YEARS; AREA VACCINATION COVERAGE; CANCER-SOCIETY GUIDELINE; CERVICAL-CANCER; QUADRIVALENT VACCINE; HPV INFECTION; IMMUNIZATION; DISPARITIES; EFFICACY; CARE AB BACKGROUND: The Centers for Disease Control and Prevention recommends catch-up administration of human papillomavirus (HPV) vaccines to girls and women ages 13 to 26 who have not been vaccinated previously. In response to debate regarding catch-up vaccination of young adult women, this study examined whether 18- to 26-year-old women most likely to benefit from catch-up vaccination were aware of the HPV vaccine, and initiated the vaccine series by the end of 2008. METHODS: We used data from the 2008 National Health Interview Survey to assess HPV vaccine awareness and use, and reasons for not vaccinating, among women aged 18-26 years (n = 1583). Sociodemographic, health care access, and health history factors associated with vaccine initiation were assessed using multivariate logistic regression. RESULTS: Overall, 11.7% of women aged 18-26 years reported receiving at least 1 dose of the HPV vaccine by the end of 2008. In multivariate analyses, younger age, history of previous HPV infection, unmarried status, health insurance, flu shot in the past year, and receipt of 1 or more recommended lifetime vaccines were significantly associated with HPV vaccine initiation. Two-fifths (39.6%) of unvaccinated women were interested in receiving the HPV vaccine (n 1327). Primary reasons for lack of interest in the vaccine were belief that it was not needed, not knowing enough about it, concerns about safety, and not being sexually active. CONCLUSION: HPV vaccine coverage among young adult women was low, and lower among the uninsured than the insured. Public financing and care provision programs have the potential to expand vaccine coverage among uninsured women, who are at increased risk of cervical cancer. Cancer 2011; 117: 5560-8. (C) 2011 American Cancer Society. C1 [Price, Rebecca Anhang] RAND Corp, Arlington, VA 22202 USA. [Tiro, Jasmin A.] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Div Behav & Commun Sci, Dallas, TX 75390 USA. [Saraiya, Mona] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Meissner, Helen] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Breen, Nancy] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Price, RA (reprint author), RAND Corp, 1200 S Hayes St,Room 7139, Arlington, VA 22202 USA. EM ranhangp@rand.org OI Tiro, Jasmin/0000-0001-8300-0441 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Centers for Disease Control and Prevention FX This study was funded in part with federal funds from the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800001E). The Cancer Control Module of the National Health Interview Survey was supported by the Centers for Disease Control and Prevention, and the National Cancer Institute, National Institutes of Health. NR 39 TC 30 Z9 30 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2011 VL 117 IS 24 BP 5560 EP 5568 DI 10.1002/cncr.26244 PG 9 WC Oncology SC Oncology GA 855PB UT WOS:000297575600015 ER PT J AU Koutros, S Silverman, DT Baris, D Zahm, SH Morton, LM Colt, JS Hein, DW Moore, LE Johnson, A Schwenn, M Cherala, S Schned, A Doll, MA Rothman, N Karagas, MR AF Koutros, Stella Silverman, Debra T. Baris, Dalsu Zahm, Shelia Hoar Morton, Lindsay M. Colt, Joanne S. Hein, David W. Moore, Lee E. Johnson, Alison Schwenn, Molly Cherala, Sai Schned, Alan Doll, Mark A. Rothman, Nathaniel Karagas, Margaret R. TI Hair dye use and risk of bladder cancer in the New England bladder cancer study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE hair dyes; bladder; cancer; aromatic amines; genetics ID PERSONAL USE; METAANALYSIS; N-ACETYLTRANSFERASE-2; SMOKING; SUSCEPTIBILITY; CARCINOGENESIS; IDENTIFICATION; POLYMORPHISM; NAT2 AB Aromatic amine components in hair dyes and polymorphisms in genes that encode enzymes responsible for hair dye metabolism may be related to bladder cancer risk. We evaluated the association between hair dye use and bladder cancer risk and effect modification by N-acetyltransferase-1 (NAT1), NAT2, glutathione S-transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) genotypes in a population-based case-control study of 1193 incident cases and 1418 controls from Maine, Vermont and New Hampshire enrolled between 2001 and 2004. Individuals were interviewed in person using a computer-assisted personal interview to assess hair dye use and information on potential confounders and effect modifiers. No overall association between age at first use, year of first use, type of product, color, duration or number of applications of hair dyes and bladder cancer among women or men was apparent, but increased risks were observed in certain subgroups. Women who used permanent dyes and had a college degree, a marker of socioeconomic status, had an increased risk of bladder cancer [odds ratio (OR) = 3.3, 95% confidence interval (CI): 1.2-8.9]. Among these women, we found an increased risk of bladder cancer among exclusive users of permanent hair dyes who had NAT2 slow acetylation phenotype (OR = 7.3, 95% CI: 1.6-32.6) compared to never users of dye with NAT2 rapid/intermediate acetylation phenotype. Although we found no relation between hair dye use and bladder cancer risk in women overall, we detected evidence of associations and gene-environment interaction with permanent hair dye use; however, this was limited to educated women. These results need confirmation with larger numbers, requiring pooling data from multiple studies. C1 [Koutros, Stella; Silverman, Debra T.; Baris, Dalsu; Zahm, Shelia Hoar; Morton, Lindsay M.; Colt, Joanne S.; Moore, Lee E.; Rothman, Nathaniel] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Hein, David W.; Doll, Mark A.] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Cherala, Sai] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. [Schned, Alan] Dartmouth Med Sch, Dept Pathol, Hanover, NH USA. [Karagas, Margaret R.] Dartmouth Med Sch, Dept Community & Family Med, Sect Biostat & Epidemiol, Hanover, NH USA. RP Koutros, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8115,MSC 7240, Rockville, MD 20852 USA. EM koutross@mail.nih.gov RI Hein, David/A-9707-2008; Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Cherala, Sai/0000-0002-3485-574X FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [Z01CP010119] FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Grant number: Z01CP010119 NR 32 TC 20 Z9 20 U1 1 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2011 VL 129 IS 12 BP 2894 EP 2904 DI 10.1002/ijc.26245 PG 11 WC Oncology SC Oncology GA 853WM UT WOS:000297456400014 PM 21678399 ER PT J AU Tobian, AAR Kong, XR Gravitt, PE Eaton, KP Kigozi, G Serwadda, D Oliver, AE Nalugoda, F Makumbi, F Chen, MZ Wawer, MJ Quinn, TC Gray, RH AF Tobian, Aaron A. R. Kong, Xiangrong Gravitt, Patti E. Eaton, Kevin P. Kigozi, Godfrey Serwadda, David Oliver, Amy E. Nalugoda, Fred Makumbi, Frederick Chen, Michael Z. Wawer, Maria J. Quinn, Thomas C. Gray, Ronald H. TI Male circumcision and anatomic sites of penile high-risk human papillomavirus in Rakai, Uganda SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE male circumcision; human papillomavirus (HPV); HIV; Uganda; foreskin; penis; coronal sulcus; penile shaft; cervical cancer; sexually transmitted infections ID RANDOMIZED-TRIAL; CERVICAL-CANCER; HPV INFECTIONS; MEN; PREVALENCE; PREVENTION; HIV; ACQUISITION; FEMALE; METAANALYSIS AB Male circumcision (MC) reduces penile high-risk human papillomavirus (HR-HPV) on the coronal sulcus and urethra. HR-HPV varies by anatomic site, and it is unknown whether MC decreases HR-HPV on the penile shaft. We assessed the efficacy of MC to reduce HR-HPV on the penile shaft and compared it to known efficacy of MC to reduce HR-HPV on the coronal sulcus. HIV-negative men randomized to receive immediate circumcision (intervention) or circumcision delayed for 24 months (control) were evaluated for HR-HPV at 12 months postenrollment using the Roche HPV Linear Array assay. Among swabs with detectable beta-globin or HPV, year 1 HR-HPV prevalence on the coronal sulcus was 21.5% in the intervention arm and 36.3% in the control arm men [ adjusted prevalence risk ratios (PRRs) = 0.57, 95% CI 0.39-0.84, p = 0.005]. On the shaft, year 1 HR-HPV prevalence was 15.5% in the intervention and 23.8% in the control arm (adjusted PRR = 0.66, 95% CI 0.39-1.12, p = 0.12). Efficacy of MC to reduce HR-HPV on the shaft was similar to efficacy on the coronal sulcus (p = 0.52). In a sensitivity analysis in which swabs without detectable b-globin or HPV were included as HPV negative, prevalence of HR-HPV on the shaft was lower in the intervention arm (7.8%) than control arm (13.6%; PRR 0.57, 95% CI 0.33-0.99, p < 0.05). HR-HPV was more frequently detected on the coronal sulcus than penile shaft among uncircumcised men (36.3% vs. 23.8%, respectively, p = 0.02) and circumcised men (21.5% vs. 15.5%, respectively, p = 0.24). MC reduced HR-HPV prevalence on both the coronal sulcus and shaft. C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. [Tobian, Aaron A. R.; Kong, Xiangrong; Chen, Michael Z.; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD 21287 USA. [Kong, Xiangrong] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21287 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Eaton, Kevin P.; Oliver, Amy E.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Kigozi, Godfrey; Serwadda, David; Nalugoda, Fred; Makumbi, Frederick; Wawer, Maria J.] Rakai Hlth Sci Program, Entebbe, Uganda. [Makumbi, Frederick] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Sch Med, Carnegie 667,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Bill and Melinda Gates Foundation [22006.02]; National Institutes of Health [U01AI51171, 3U01-AI075115-03S1]; Fogarty International Center [5D43TW001508, 2D43TW000010-19-AITRPl]; National Institute of Allergy and Infectious Diseases, NIH; Roche Molecular Diagnostics; Johns Hopkins University FX Grant sponsor: Bill and Melinda Gates Foundation; Grant number: 22006.02; Grant sponsor: National Institutes of Health; Grant numbers: U01AI51171 and 3U01-AI075115-03S1; Grant sponsor: Fogarty International Center; Grant numbers: 5D43TW001508, 2D43TW000010-19-AITRPl (training); Grant sponsor: Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; Dr. Gravitt received research funding from Roche Molecular Diagnostics who manufacture the HPV genotyping test used in this study.; A. A. R. T. was supported by the Johns Hopkins University Clinician Scientist Award. We are most grateful to the study participants and the Rakai Community Advisory Board whose commitment and cooperation made this study possible. We wish to thank Dr. Edward M'bidde, Director, Uganda Virus Research Institute, for his ongoing support. NR 24 TC 20 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2011 VL 129 IS 12 BP 2970 EP 2975 DI 10.1002/ijc.25957 PG 6 WC Oncology SC Oncology GA 853WM UT WOS:000297456400022 PM 21462185 ER PT J AU Hassan, SA Steinbach, PJ AF Hassan, Sergio A. Steinbach, Peter J. TI Water-Exclusion and Liquid-Structure Forces in Implicit Solvation SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SOLVENT-INDUCED FORCES; PROTEIN-PROTEIN INTERACTIONS; SCREENED COULOMB POTENTIALS; SIDE-CHAIN INTERACTIONS; CONTINUUM ELECTROSTATICS; AMINO-ACID; DIELECTRIC-PROPERTIES; MOLECULAR-MECHANICS; FOLDING SIMULATIONS; NEUTRON-SCATTERING AB A continuum model of solvation is proposed to describe (i) long-range electrostatic effects of water exclusion resulting from incomplete and anisotropic hydration in crowded environments and (ii) short-range effects of liquid-structure forces on the hydrogen-bond interactions at solute/water interfaces. The model is an extension of the phenomenological screened coulomb potential-based implicit model of solvation. The developments. reported here allow a more realistic representation of highly crowded and spatially heterogeneous environments, such as those in the interior of a living cell. Only the solvent is treated as a continuum medium. It is shown that the electrostatic effects of long-range water-exclusion can strongly affect protein protein binding energies and are then related to the thermodynamics of complex formation. Hydrogen-bond interactions modulated by the liquid structure at interfaces are calibrated based on systematic calculations of potentials of mean force in explicit water. The electrostatic component of the model is parametrized for, monovalent, divalent and trivalent ions. The conceptual and practical aspects of the model are discussed based on simulations of protein complexation and peptide folding. The current implementation is similar to 1.5 times slower than the gas-phase force field and exhibits good parallel performance. C1 [Hassan, Sergio A.; Steinbach, Peter J.] NIH, Ctr Mol Modeling, DCB CIT, US DHHS, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, Ctr Mol Modeling, DCB CIT, US DHHS, Bldg 10, Bethesda, MD 20892 USA. FU NIH, Center for Information Technology FX This study was supported by the Intramural Reserach Program of the NIH, Center for Information Technology, and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (http://biowulf.nih.gov). The authors thank Rick Venable, Aaron Bornstein, and Milan Hodoscek for computational help. NR 92 TC 14 Z9 14 U1 0 U2 7 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 DEC 15 PY 2011 VL 115 IS 49 BP 14668 EP 14682 DI 10.1021/jp208184e PG 15 WC Chemistry, Physical SC Chemistry GA 856AM UT WOS:000297608600038 PM 22007697 ER PT J AU McLellan, JS Pancera, M Carrico, C Gorman, J Julien, JP Khayat, R Louder, R Pejchal, R Sastry, M Dai, KF O'Dell, S Patel, N Shahzad-ul-Hussan, S Yang, YP Zhang, BS Zhou, TQ Zhu, J Boyington, JC Chuang, GY Diwanji, D Georgiev, I Do Kwon, Y Lee, D Louder, MK Moquin, S Schmidt, SD Yang, ZY Bonsignori, M Crump, JA Kapiga, SH Sam, NE Haynes, BF Burton, DR Koff, WC Walker, LM Phogat, S Wyatt, R Orwenyo, J Wang, LX Arthos, J Bewley, CA Mascola, JR Nabel, GJ Schief, WR Ward, AB Wilson, IA Kwong, PD AF McLellan, Jason S. Pancera, Marie Carrico, Chris Gorman, Jason Julien, Jean-Philippe Khayat, Reza Louder, Robert Pejchal, Robert Sastry, Mallika Dai, Kaifan O'Dell, Sijy Patel, Nikita Shahzad-ul-Hussan, Syed Yang, Yongping Zhang, Baoshan Zhou, Tongqing Zhu, Jiang Boyington, Jeffrey C. Chuang, Gwo-Yu Diwanji, Devan Georgiev, Ivelin Do Kwon, Young Lee, Doyung Louder, Mark K. Moquin, Stephanie Schmidt, Stephen D. Yang, Zhi-Yong Bonsignori, Mattia Crump, John A. Kapiga, Saidi H. Sam, Noel E. Haynes, Barton F. Burton, Dennis R. Koff, Wayne C. Walker, Laura M. Phogat, Sanjay Wyatt, Richard Orwenyo, Jared Wang, Lai-Xi Arthos, James Bewley, Carole A. Mascola, John R. Nabel, Gary J. Schief, William R. Ward, Andrew B. Wilson, Ian A. Kwong, Peter D. TI Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9 SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; POTENT NEUTRALIZATION; DEXTRAN SULFATE; T-CELLS; EPITOPE; SOFTWARE; RECEPTOR; BINDING; SYSTEM AB Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded beta-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand. C1 [McLellan, Jason S.; Pancera, Marie; Gorman, Jason; Louder, Robert; Sastry, Mallika; Dai, Kaifan; O'Dell, Sijy; Shahzad-ul-Hussan, Syed; Yang, Yongping; Zhang, Baoshan; Zhou, Tongqing; Zhu, Jiang; Boyington, Jeffrey C.; Chuang, Gwo-Yu; Georgiev, Ivelin; Do Kwon, Young; Lee, Doyung; Louder, Mark K.; Moquin, Stephanie; Schmidt, Stephen D.; Yang, Zhi-Yong; Mascola, John R.; Nabel, Gary J.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Carrico, Chris; Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Julien, Jean-Philippe; Khayat, Reza; Pejchal, Robert; Diwanji, Devan; Ward, Andrew B.; Wilson, Ian A.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Julien, Jean-Philippe; Khayat, Reza; Pejchal, Robert; Diwanji, Devan; Ward, Andrew B.; Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Patel, Nikita; Arthos, James] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Shahzad-ul-Hussan, Syed; Bewley, Carole A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Crump, John A.] Duke Univ, Med Ctr, Dept Med, Div Infect Dis & Int Hlth, Durham, NC 27710 USA. [Crump, John A.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Crump, John A.; Sam, Noel E.] Tumaini Univ, Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Crump, John A.; Sam, Noel E.] Tumaini Univ, Kilimanjaro Christian Med Coll, Moshi, Tanzania. [Kapiga, Saidi H.; Sam, Noel E.] Kilimanjaro Reprod Hlth Programme, Moshi, Tanzania. [Wyatt, Richard] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, TSRI, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02129 USA. [Koff, Wayne C.; Phogat, Sanjay] IAVI, New York, NY 10004 USA. [Orwenyo, Jared; Wang, Lai-Xi] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Orwenyo, Jared; Wang, Lai-Xi] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Schmidt, Stephen/B-5398-2012; Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010; Louder, Robert/F-4713-2014; Ward, Andrew/F-9203-2014; OI Zhou, Tongqing/0000-0002-3935-4637; Louder, Robert/0000-0002-6944-9346; Ward, Andrew/0000-0001-7153-3769; Carrico, Chris/0000-0003-0939-9006 FU National Institutes of Health (NIH); International AIDS Vaccine Initiative; Ragon Institute; Canadian Institute of Health Research; NIH through the National Center for Research Resources [RR017573]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank A. Changela and X. Wu for assistance with mapping the PG16 paratope, J. Sodroski for discussions, J. Stuckey for assistance with figures, and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript. Support for this work was provided by the Intramural Research Program of the National Institutes of Health (NIH), by the International AIDS Vaccine Initiative, by the Ragon Institute, by the Canadian Institute of Health Research and by grants from the NIH. The three-dimensional reconstructions were conducted at the National Resource for Automated Molecular Microscopy (NRAMM), which is supported by the NIH through the National Center for Research Resources' P41 program(RR017573). Use of sector 22 (Southeast Regional Collaborative Access Team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 69 TC 403 Z9 405 U1 5 U2 80 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 15 PY 2011 VL 480 IS 7377 BP 336 EP U86 DI 10.1038/nature10696 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861PZ UT WOS:000298033000044 PM 22113616 ER PT J AU Poulikakos, PI Persaud, Y Janakiraman, M Kong, XJ Ng, C Moriceau, G Shi, HB Atefi, M Titz, B Gabay, MT Salton, M Dahlman, KB Tadi, M Wargo, JA Flaherty, KT Kelley, MC Misteli, T Chapman, PB Sosman, JA Graeber, TG Ribas, A Lo, RS Rosen, N Solit, DB AF Poulikakos, Poulikos I. Persaud, Yogindra Janakiraman, Manickam Kong, Xiangju Ng, Charles Moriceau, Gatien Shi, Hubing Atefi, Mohammad Titz, Bjoern Gabay, May Tal Salton, Maayan Dahlman, Kimberly B. Tadi, Madhavi Wargo, Jennifer A. Flaherty, Keith T. Kelley, Mark C. Misteli, Tom Chapman, Paul B. Sosman, Jeffrey A. Graeber, Thomas G. Ribas, Antoni Lo, Roger S. Rosen, Neal Solit, David B. TI RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) SO NATURE LA English DT Article ID BRAF; KINASE; HETERODIMERIZATION; MELANOMA; PATHWAY; CRAF; MEK AB Activated RAS promotes dimerization of members of the RAF kinase family(1-3). ATP-competitive RAF inhibitors activate ERK signalling(4-7) by transactivating RAF dimers(4). In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E)(8). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner. C1 [Persaud, Yogindra; Janakiraman, Manickam; Solit, David B.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Poulikakos, Poulikos I.; Gabay, May Tal; Tadi, Madhavi; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10065 USA. [Kong, Xiangju; Moriceau, Gatien; Shi, Hubing; Lo, Roger S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Div Dermatol, Los Angeles, CA 90095 USA. [Ng, Charles; Atefi, Mohammad; Ribas, Antoni] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Titz, Bjoern; Graeber, Thomas G.; Ribas, Antoni; Lo, Roger S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Salton, Maayan; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Dahlman, Kimberly B.; Sosman, Jeffrey A.] Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37232 USA. [Wargo, Jennifer A.] Massachusetts Gen Hosp, Ctr Canc, Dept Surg, Boston, MA 02114 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Kelley, Mark C.] Vanderbilt Ingram Canc Ctr, Dept Surg, Nashville, TN 37232 USA. [Chapman, Paul B.; Rosen, Neal; Solit, David B.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. RP Solit, DB (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. EM solitd@mskcc.org RI Titz, Bjorn/B-9516-2008; Shi, Hubing/B-8445-2014; OI Janakiraman, Manickam/0000-0003-4423-6237; Titz, Bjoern/0000-0003-4414-4105; Graeber, Thomas/0000-0001-8574-9181; Shi, Hubing/0000-0002-2926-3440 FU Vanderbilt-Ingram Cancer Center; T. J. Martell Foundation; National Institutes of Health (NIH); Beene Foundation; Melanoma Research Alliance; STARR Foundation; Burroughs Wellcome Fund; American Skin Association; Joint Center for Translational Medicine; Sidney Kimmel Foundation; Stand Up to Cancer; NIH, NCI, Center for Cancer Research; Danny Federici Melanoma Fund; [T32 CACA062948-15] FX We are grateful to M. Baccarini and C. Pritchard for the RAF knockout mouse embryonic fibroblasts. We would like to thank K. Shokat, C. Zhang, S. Chandarlapaty, C. Pratilas and K. Robzyk for useful discussions, C. Liu for her technical expertise and T. J. Riley. We also thank D. Hucks for technical assistance, P. L. Lyle for scoring the tumour sections, and T. Chodon for assistance with tumour procurement. The ITR is supported by the Vanderbilt-Ingram Cancer Center and the T. J. Martell Foundation. This work has been funded by the National Institutes of Health (NIH; R. S. L., N.R., D. B. S.), the Beene Foundation (D. B. S.), the Melanoma Research Alliance (K. T. F., J. A. S. P. B. C., R. S. L., N.R., D. B. S.) and the STARR Foundation (N.R., D. B. S.). R. S. L. was supported by the Burroughs Wellcome Fund, American Skin Association, Joint Center for Translational Medicine, Sidney Kimmel Foundation, and Stand Up to Cancer. T. M. was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research and P. B. C. was supported in part by the Danny Federici Melanoma Fund. P. I. P. was supported by T32 CACA062948-15. NR 22 TC 572 Z9 581 U1 5 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 DEC 15 PY 2011 VL 480 IS 7377 BP 387 EP U144 DI 10.1038/nature10662 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861PZ UT WOS:000298033000056 PM 22113612 ER PT J AU Boden, WE Probstfield, JL Anderson, T Chaitman, BR Desvignes-Nickens, P Koprowicz, K McBride, R Teo, K Weintraub, W AF Boden, William E. Probstfield, Jeffrey L. Anderson, Todd Chaitman, Bernard R. Desvignes-Nickens, Patrice Koprowicz, Kent McBride, Ruth Teo, Koon Weintraub, William CA AIM-HIGH Investigators TI Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; EXTENDED-RELEASE NIACIN; CARDIOVASCULAR EVENTS; SECONDARY PREVENTION; ARTERIAL BIOLOGY; LDL CHOLESTEROL; ATHEROSCLEROSIS; COMBINATION; IMPACT AB BACKGROUND In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk. METHODS We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. RESULTS A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P = 0.79 by the log-rank test). CONCLUSIONS Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; AIM-HIGH ClinicalTrials.gov number, NCT00120289.) C1 [Koprowicz, Kent; McBride, Ruth] Axio Res, Seattle, WA 98121 USA. [Boden, William E.] SUNY Buffalo, Buffalo, NY 14260 USA. [Probstfield, Jeffrey L.] Univ Washington, Seattle, WA 98195 USA. [Anderson, Todd] Univ Calgary, Calgary, AB, Canada. [Anderson, Todd] Libin Cardiovasc Inst, Calgary, AB, Canada. [Chaitman, Bernard R.] St Louis Univ, St Louis, MO 63103 USA. [Desvignes-Nickens, Patrice] NHLBI, NIH, Bethesda, MD 20892 USA. [Teo, Koon] McMaster Univ, Hamilton, ON, Canada. [Weintraub, William] Christiana Care Hlth Syst, Wilmington, DE USA. RP McBride, R (reprint author), Axio Res, 2601 4th Ave,Suite 200, Seattle, WA 98121 USA. EM ruthm@axioresearch.com OI Guyton, John/0000-0003-0224-7923 FU National Heart, Lung, and Blood Institute; Abbott; Amylin; Genentech; Sanofi-Aventis; Eli Lilly; Merck; Oryx Pharmaceuticals; Pfizer; Roche; Novartis FX Supported by the National Heart, Lung, and Blood Institute and by an unrestricted grant from Abbott Laboratories. Abbott Laboratories donated the extended-release niacin, the matching placebo, and the ezetimibe; Merck donated the simvastatin. Neither of these companies had any role in the oversight or design of the study or in the analysis or interpretation of the data.; Dr. Boden reports receiving consulting fees from Abbott; Dr. Probstfield, receiving consulting fees from Amylin, Genentech, and Sanofi-Aventis and grant support through his institution from Abbott, Eli Lilly, and Sanofi-Aventis; Dr. Anderson, receiving consulting fees from Merck, lecture fees from Merck and Oryx Pharmaceuticals, and support through his institution from Merck for rounds speakers; Dr. Chaitman, receiving consulting fees from Merck, Pfizer, and Roche; Mr. Koprowicz, being employed by Axio Research; Ms. McBride, being employed by Axio Research; and Dr. Teo, receiving grant support through his institution from Novartis. No other potential conflict of interest relevant to this article was reported. NR 24 TC 976 Z9 994 U1 41 U2 88 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 DEC 15 PY 2011 VL 365 IS 24 BP 2255 EP 2267 DI 10.1056/NEJMoa1107579 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 861PN UT WOS:000298031800006 ER PT J AU Kitagaki, J Ueda, Y Chi, X Sharma, N Elder, CM Truffer, E Costantini, F Lewandoski, M Perantoni, AO AF Kitagaki, Jirouta Ueda, Yutaka Chi, Xuan Sharma, Nirmala Elder, Cynthia M. Truffer, Erika Costantini, Frank Lewandoski, Mark Perantoni, Alan O. TI FGF8 is essential for formation of the ductal system in the male reproductive tract SO DEVELOPMENT LA English DT Article DE FGF8; T-Cre; Mesonephric tubules; Wolffian duct; Mullerian duct; Efferent ductules; Epididymis; Mouse ID URETERAL BUD MORPHOGENESIS; FIBROBLAST-GROWTH-FACTOR; HOMEOBOX GENE LIM1; KIDNEY DEVELOPMENT; WOLFFIAN DUCT; UROGENITAL DEVELOPMENT; INTERMEDIATE MESODERM; TRANSGENIC MICE; RENAL AGENESIS; MOUSE EMBRYO AB During development of the urogenital tract, fibroblast growth factor 8 (Fgf8) is expressed in mesonephric tubules, but its role in this tissue remains undefined. An evaluation of previously generated T-Cre-mediated Fgf8-deficient mice (T-Cre; Fgf8(flox/Delta 2,3) mice), which lack Fgf8 expression in the mesoderm, revealed that the cranial region of the Wolffian duct degenerated prematurely and the cranial mesonephric tubules were missing. As a result, the epididymis, vas deferens and efferent ductules were largely absent in mutant mice. Rarb2-Cre was used to eliminate FGF8 from the mesonephric tubules but to allow expression in the adjacent somites. These mutants retained the cranial end of the Wolffian duct and formed the epididymis and vas deferens, but failed to elaborate the efferent ductules, indicating that Fgf8 expression by the mesonephric tubules is required specifically for the formation of the ductules. Ret knockout mice do not form the ureteric bud, a caudal outgrowth of the Wolffian duct and progenitor for the collecting duct network in the kidney, but they do develop the cranial end normally. This indicates that Fgf8, but not Ret, expression is essential to the outgrowth of the cranial mesonephric tubules from the Wolffian duct and to the development of major portions of the sex accessory tissues in the male reproductive tract. Mechanistically, FGF8 functions upstream of Lhx1 expression in forming the nephron, and analysis of Fgf8 mutants similarly shows deficient Lhx1 expression in the mesonephric tubules. These results demonstrate a multifocal requirement for FGF8 in establishing the male reproductive tract ducts and implicate Lhx1 signaling in tubule elongation. C1 [Kitagaki, Jirouta; Ueda, Yutaka; Sharma, Nirmala; Elder, Cynthia M.; Truffer, Erika; Lewandoski, Mark; Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. [Chi, Xuan; Costantini, Frank] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA. RP Lewandoski, M (reprint author), NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. EM lewandom@mail.nih.gov; perantoa@mail.nih.gov FU National Institutes of Health, National Cancer Institute and Center for Cancer Research; Japan Society for the Promotion of the Science FX This work was supported by the National Institutes of Health, National Cancer Institute and Center for Cancer Research. J.K. and Y.U. were supported in part by the Japan Society for the Promotion of the Science. Deposited in PMC for release after 12 months. NR 59 TC 12 Z9 12 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD DEC 15 PY 2011 VL 138 IS 24 BP 5369 EP 5378 DI 10.1242/dev.051888 PG 10 WC Developmental Biology SC Developmental Biology GA 852DW UT WOS:000297329900009 PM 22110055 ER PT J AU Andreopoulou, E Chen, AP Zujewski, JA Kalinsky, K Vahdat, L Raptis, G Hershman, D Novic, Y Muggia, F Sparano, J AF Andreopoulou, E. Chen, A. P. Zujewski, J. A. Kalinsky, K. Vahdat, L. Raptis, G. Hershman, D. Novic, Y. Muggia, F. Sparano, J. TI Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Low-Dose Metronomic Cyclophosphamide Alone or in Combination with Veliparib (ABT-888) in Chemotherapy-Resistant ER and/or PR-Positive, HER2/neu-Negative Metastatic Breast Cancer: New York Cancer Consortium Trial P8853. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Andreopoulou, E.; Chen, A. P.; Zujewski, J. A.; Kalinsky, K.; Vahdat, L.; Raptis, G.; Hershman, D.; Novic, Y.; Muggia, F.; Sparano, J.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. NCI, Bethesda, MD 20892 USA. Columbia Univ, Med Ctr, New York, NY USA. Weill Cornell Med Coll, New York, NY USA. Mt Sinai Sch Med, New York, NY USA. NYU, Langone Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA OT3-01-17 DI 10.1158/0008-5472.SABCS11-OT3-01-17 PG 2 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800044 ER PT J AU Bode, AM Li, J Zhu, F Normanno, NE Ericson, ME Lubet, RA AF Bode, A. M. Li, J. Zhu, F. Normanno, N. E. Ericson, M. E. Lubet, R. A. TI Quercetin-3-Methyl Ether Inhibits Lapatinib-Sensitive and Lapatinib-Resistant Breast Cancer Cell Growth by Inducing G2/M Arrest and Apoptosis. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Bode, A. M.; Li, J.; Zhu, F.; Normanno, N. E.; Ericson, M. E.; Lubet, R. A.] Univ Minnesota, Austin, MN USA. INT Fdn Pascale, Naples, Italy. Univ Minnesota, Minneapolis, MN USA. NCI, Rockville, MD USA. RI ericson, marna/C-9591-2017 OI ericson, marna/0000-0003-1862-4957 NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P5-06-11 DI 10.1158/0008-5472.SABCS11-P5-06-11 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699802206 ER PT J AU Cekanova, M Fernando, R Wimalasena, J AF Cekanova, M. Fernando, R. Wimalasena, J. TI The BCL2 Antagonist of Death, BAD Is Down-Regulated in Breast Cancer and Inhibits Cancer Cell Invasion SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Cekanova, M.; Fernando, R.; Wimalasena, J.] Univ Tennessee, Knoxville, TN USA. NCI, NIH, Bethesda, MD 20892 USA. OI Cekanova, Maria/0000-0002-9651-1619 NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P1-02-11 DI 10.1158/0008-5472.SABCS11-P1-02-11 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800330 ER PT J AU Connolly, RM Jankowitz, RC Andreopoulou, E Allred, JB Jeter, SC Adam, BM Espinoza-Delgado, I Baylin, SB Zahnow, CA Ahuja, N Davidson, NE Stearns, V AF Connolly, R. M. Jankowitz, R. C. Andreopoulou, E. Allred, J. B. Jeter, S. C. Adam, B. M. Espinoza-Delgado, I. Baylin, S. B. Zahnow, C. A. Ahuja, N. Davidson, N. E. Stearns, V. TI A Phase 2 Study Investigating the Safety, Efficacy and Surrogate Biomarkers of Response of 5-Azacitidine (5-AZA) and Entinostat (MS-275) in Patients with Advanced Breast Cancer. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Connolly, R. M.; Jankowitz, R. C.; Andreopoulou, E.; Allred, J. B.; Jeter, S. C.; Adam, B. M.; Espinoza-Delgado, I.; Baylin, S. B.; Zahnow, C. A.; Ahuja, N.; Davidson, N. E.; Stearns, V.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Montefiore Med Ctr, Albert Einstein Coll Med, New York, NY USA. Mayo Clin, Rochester, MN USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA OT3-01-06 DI 10.1158/0008-5472.SABCS11-OT3-01-06 PG 2 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800034 ER PT J AU Dunlap, SM Chiao, LJ Nogueria, L Usary, J Perou, CM Varticovski, L Hursting, SD AF Dunlap, S. M. Chiao, L. J. Nogueria, L. Usary, J. Perou, C. M. Varticovski, L. Hursting, S. D. TI S6-5: Obesity Drives Epithelial-to-Mesenchymal Transition and Tumor Progression in a Novel Claudin-Low Mammary Cancer Model SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Dunlap, S. M.; Chiao, L. J.; Nogueria, L.; Usary, J.; Perou, C. M.; Varticovski, L.; Hursting, S. D.] Univ Texas Austin, Austin, TX 78712 USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Smithville, TX USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA S6-5 DI 10.1158/0008-5472.SABCS11-56-5 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800347 ER PT J AU Ford, NA Nunez, NP Perkins, SN Hursting, SD AF Ford, N. A. Nunez, N. P. Perkins, S. N. Hursting, S. D. TI Genetic Reduction of Circulating Insulin-Like Growth Factor (IGF)-1 Differentially Impacts the Effects of Diet-Induced Obesity and Calorie Restriction on Mammary Tumor Progression. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Ford, N. A.; Nunez, N. P.; Perkins, S. N.; Hursting, S. D.] Univ Texas Austin, Austin, TX 78712 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P2-03-01 DI 10.1158/0008-5472.SABCS11-P2-03-01 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699802231 ER PT J AU Gatti, M Venzon, D Zujewski, J Korde, L Isaacs, C Cohen, P Warren, R Gallagher, A Eng-Wong, J AF Gatti, M. Venzon, D. Zujewski, J. Korde, L. Isaacs, C. Cohen, P. Warren, R. Gallagher, A. Eng-Wong, J. TI Effects of Exemestane Therapy on the Lipid Profile of Postmenopausal Women with an Elevated Risk of Developing Invasive Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Gatti, M.; Venzon, D.; Zujewski, J.; Korde, L.; Isaacs, C.; Cohen, P.; Warren, R.; Gallagher, A.; Eng-Wong, J.] Georgetown Univ Hosp, Washington, DC 20007 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P3-11-01 DI 10.1158/0008-5472.SABCS11-P3-11-01 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801103 ER PT J AU Harvie, M Wright, C Pegington, M Mitchell, E Evans, DG Jebb, S Clarke, R Goodacre, R Dunn, W Mattson, M Howell, A AF Harvie, M. Wright, C. Pegington, M. Mitchell, E. Evans, D. G. Jebb, S. Clarke, R. Goodacre, R. Dunn, W. Mattson, M. Howell, A. TI Intermittent Dietary Carbohydrate Restriction Enables Weight Loss and Reduces Breast Cancer Risk Biomarkers. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Harvie, M.; Wright, C.; Pegington, M.; Mitchell, E.; Evans, D. G.; Jebb, S.; Clarke, R.; Goodacre, R.; Dunn, W.; Mattson, M.; Howell, A.] Univ S Manchester Hosp, Manchester M20 8LR, Lancs, England. MRC, Human Nutr Res Grp, Cambridge, England. Univ Manchester, Manchester, Lancs, England. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P3-09-02 DI 10.1158/0008-5472.SABCS11-P3-09-02 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801111 ER PT J AU Heckman-Stoddard, B Lubet, RA Bode, AM Grubbs, CJ AF Heckman-Stoddard, B. Lubet, R. A. Bode, A. M. Grubbs, C. J. TI Mammary Gland Biopsy To Examine Surrogate Endpoint Biomarkers of Preventive Agent Efficacy. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Heckman-Stoddard, B.; Lubet, R. A.; Bode, A. M.; Grubbs, C. J.] NCI, Bethesda, MD 20892 USA. Univ Minnesota, Austin, MN USA. Univ AL Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P3-11-07 DI 10.1158/0008-5472.SABCS11-P3-11-07 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801109 ER PT J AU Hershman, DL Unger, JM Crew, KD Moinpour, CM Minasian, LM Hansen, L Lew, DL Kaberle, K Wade, JL Meyskens, FL AF Hershman, D. L. Unger, J. M. Crew, K. D. Moinpour, C. M. Minasian, L. M. Hansen, L. Lew, D. L. Kaberle, K. Wade, J. L. Meyskens, F. L. TI A Randomized Double Blind Placebo-Controlled Trial of Omega-3-Fatty Acid for the Control of Aromatase Inhibitor (Al)-Induced Musculoskeletal Pain in Women with Early Stage Breast Cancer. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Hershman, D. L.; Unger, J. M.; Crew, K. D.; Moinpour, C. M.; Minasian, L. M.; Hansen, L.; Lew, D. L.; Kaberle, K.; Wade, J. L.; Meyskens, F. L.] Columbia Univ, New York, NY USA. SWOG, Seattle, WA USA. NCI, Bethesda, MD 20892 USA. Legacy Good Samaritan Hosp & MC, Portland, OR USA. SWOG, San Antonio, TX USA. Canc Care Specialists Illinois, Decatur, IL USA. Univ Calif Irvine, Orange, CA USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA SWOG S0927 DI 10.1158/0008-5472.SABCS11-OT2-07-02 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800028 ER PT J AU Jolles, PJ Kostakoglu, L Bear, HD Idowu, MO Kurdziel, K Shankar, L Mankoff, DA Duan, F L'Heureux, DZ AF Jolles, P. J. Kostakoglu, L. Bear, H. D. Idowu, M. O. Kurdziel, K. Shankar, L. Mankoff, D. A. Duan, F. L'Heureux, D. Z. TI ACRIN 6688 Phase II Study of Fluorine-18 3 '-Deoxy-3 ' Fluorothymidine (FLT) in Invasive Breast Cancer. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Jolles, P. J.; Kostakoglu, L.; Bear, H. D.; Idowu, M. O.; Kurdziel, K.; Shankar, L.; Mankoff, D. A.; Duan, F.; L'Heureux, D. Z.] Virginia Commonwealth Univ, Richmond, VA USA. Mt Sinai Sch Med, New York, NY USA. NCI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Brown Univ, Providence, RI 02912 USA. Amer Coll Radiol Imaging Network, Philadelphia, PA USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA OT2-05-03 DI 10.1158/0008-5472.SABCS11-OT2-05-03 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800017 ER PT J AU Julian, TB Vicini, FA Costantino, JP Arthur, DW Kidwell, KM Land, SR Mamounas, EP Wolmark, N AF Julian, T. B. Vicini, F. A. Costantino, J. P. Arthur, D. W. Kidwell, K. M. Land, S. R. Mamounas, E. P. Wolmark, N. TI Boost Radiation Therapy Not of Value in Reducing IBTR of Invasive or Noninvasive Breast Cancers for Patients with DCIS: Results from the NSABP B-24 Trial. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Julian, T. B.; Vicini, F. A.; Costantino, J. P.; Arthur, D. W.; Kidwell, K. M.; Land, S. R.; Mamounas, E. P.; Wolmark, N.] Natl Surg Adjuvant Breast Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Beaumont Hlth Syst, Royal Oak, MI USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Aultman Hlth Fdn, Canton, OH USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P3-13-01 DI 10.1158/0008-5472.SABCS11-P3-13-01 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801127 ER PT J AU Julian, TB Anderson, SJ Cobleigh, MA Siziopikou, KP Arthur, DW Zheng, P Mamounas, EP Pajon, ER Behrens, RJ Chu, L Leasure, NC Atkins, JN Polikoff, J Seay, TE McCaskill-Stevens, W Rabinovitch, R Wolmark, N AF Julian, T. B. Anderson, S. J. Cobleigh, M. A. Siziopikou, K. P. Arthur, D. W. Zheng, P. Mamounas, E. P. Pajon, E. R. Behrens, R. J. Chu, L. Leasure, N. C. Atkins, J. N. Polikoff, J. Seay, T. E. McCaskill-Stevens, W. Rabinovitch, R. Wolmark, N. TI A Phase III Clinical Trial Comparing Trastuzumab Given Concurrently with Radiation Therapy to Radiation Therapy (RT) Alone for Women with HER2-Positive DCIS Resected by Lumpectomy: NSABP B-43. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Julian, T. B.; Anderson, S. J.; Cobleigh, M. A.; Siziopikou, K. P.; Arthur, D. W.; Zheng, P.; Mamounas, E. P.; Pajon, E. R.; Behrens, R. J.; Chu, L.; Leasure, N. C.; Atkins, J. N.; Polikoff, J.; Seay, T. E.; McCaskill-Stevens, W.; Rabinovitch, R.; Wolmark, N.] Natl Surg Breast & Bowel Project NSABP, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Virginia Commonwealth Univ, Richmond, VA USA. Aultman Hlth Fdn, Canton, OH USA. Colorado Canc Res Program, Denver, CO USA. Iowa Oncol Res Assoc, Des Moines, IA USA. Florida Canc Specialists, Sarasota, FL USA. Reading Reg Canc Ctr, W Reading, PA USA. SCCC CCOP, Goldsboro, NC USA. Kaiser Permanente So Calif, San Diego, CA USA. Atlanta Reg Community Clin Oncol Program, Atlanta, GA USA. NCI, Rockville, MD USA. Univ Colorado, Aurora, CO USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA OT1-02-05 DI 10.1158/0008-5472.SABCS11-OT1-02-05 PG 2 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801010 ER PT J AU Kesarwala, AH Pfalzer, LA O'Meara, WP Stout, NL AF Kesarwala, A. H. Pfalzer, L. A. O'Meara, W. P. Stout, N. L. TI The Effect of Breast Conservation Therapy vs Mastectomy on Symptoms, Physical Impairments, and Function SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Kesarwala, A. H.; Pfalzer, L. A.; O'Meara, W. P.; Stout, N. L.] NCI, Bethesda, MD 20892 USA. Univ Michigan, Flint, MI 48503 USA. Natl Naval Med Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA PD02-03 DI 10.1158/0008-5472.SABCS11-PD02-03 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800064 ER PT J AU Lin, S Yang, J Elkahloun, AG Bandyopadhyay, A Wang, L Cornell, JE Yeh, IT Agyin, JK Sun, LZ AF Lin, S. Yang, J. Elkahloun, A. G. Bandyopadhyay, A. Wang, L. Cornell, J. E. Yeh, I-T Agyin, J. K. Sun, L-Z TI Attenuation of TGF-beta Signaling Suppresses Premature Senescence in a p21-Dependent Manner and Promotes Oncogenic ras-Mediated Metastatic Transformation in hTERT-Immortalized Basal-Like Human Mammary Epithelial Cells. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Lin, S.; Yang, J.; Elkahloun, A. G.; Bandyopadhyay, A.; Wang, L.; Cornell, J. E.; Yeh, I-T; Agyin, J. K.; Sun, L-Z] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P2-03-05 DI 10.1158/0008-5472.SABCS11-P2-03-05 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699802236 ER PT J AU Lubet, RA Townsend, R Vedell, P Steele, VE Grubbs, CJ AF Lubet, R. A. Townsend, R. Vedell, P. Steele, V. E. Grubbs, C. J. TI Bardoxolone (5MeCDDO) Inhibits Cancer Initiation but Promotes Progression in Rodent Models of Breast Cancer. What Does It Mean for the Antioxidant Response Element (ARE) as a Primary Prevention Target? SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Lubet, R. A.; Townsend, R.; Vedell, P.; Steele, V. E.; Grubbs, C. J.] NCI, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P3-10-03 DI 10.1156/0006-5472.SABCS11-P3-10-03 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801119 ER PT J AU Lubet, RA Grubbs, CJ Bode, A You, M Lu, Y AF Lubet, R. A. Grubbs, C. J. Bode, A. You, M. Lu, Y. TI Gene Expression Changes in Methylnitrosourea (MNU)-Induced ER plus Mammary Cancers Following Short-Term Treatment of Rats with the Aromatase Inhibitor Vorozole. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Lubet, R. A.; Grubbs, C. J.; Bode, A.; You, M.; Lu, Y.] NCI, Bethesda, MD 20892 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P3-10-02 DI 10.1158/0008-5472.SABCS11-P3-10-02 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801118 ER PT J AU Lubet, RA Bode, AM Szabo, E Grubbs, CJ AF Lubet, R. A. Bode, A. M. Szabo, E. Grubbs, C. J. TI Alternative Dosing Regimens with the EGFr Inhibitors (Gefitinib and Lapatinib) in Mammary Cancer Models: Prevention and Therapeutic Efficacy. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Lubet, R. A.; Bode, A. M.; Szabo, E.; Grubbs, C. J.] NCI, Bethesda, MD 20892 USA. Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P3-10-01 DI 10.1158/0008-5472.SABCS11-P3-10-01 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801117 ER PT J AU Mukhopadhyay, KD Elkahloun, AG Yoon, K Cornell, JE Yu, L Liu, Z Sun, LZ AF Mukhopadhyay, K. D. Elkahloun, A. G. Yoon, K. Cornell, J. E. Yu, L. Liu, Z. Sun, L-Z TI Determining the Molecular Signature That Drives Breast Cancer-Induced Brain Metastasis in a Mouse Xenograft Model. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Mukhopadhyay, K. D.; Elkahloun, A. G.; Yoon, K.; Cornell, J. E.; Yu, L.; Liu, Z.; Sun, L-Z] UT Hlth Sci Ctr, San Antonio, TX USA. NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P2-01-12 DI 10.1158/0008-5472.SABCS11-P2-01-12 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801030 ER PT J AU Nyante, SJ Dallal, CM Gierach, GL Sherman, ME Park, Y Hollenbeck, AR Brinton, LA AF Nyante, S. J. Dallal, C. M. Gierach, G. L. Sherman, M. E. Park, Y. Hollenbeck, A. R. Brinton, L. A. TI Association between BMI, Physical Activity and Breast Cancer Histologic Types. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Nyante, S. J.; Dallal, C. M.; Gierach, G. L.; Sherman, M. E.; Park, Y.; Hollenbeck, A. R.; Brinton, L. A.] NCI, Rockville, MD USA. AARP, Washington, DC USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P4-10-03 DI 10.1158/0008-5472.SABCS11-P4-10-03 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801327 ER PT J AU Shen, K Tang, G Kim, C Pogue-Geile, K Anderson, SJ Constantino, JP Bear, HD Song, N Tian, C Gabrin, MJ Zhang, Y Geyer, CE Wolmark, N AF Shen, K. Tang, G. Kim, C. Pogue-Geile, K. Anderson, S. J. Constantino, J. P. Bear, H. D. Song, N. Tian, C. Gabrin, M. J. Zhang, Y. Geyer, C. E., Jr. Wolmark, N. TI A Genomic Predictor Developed from Breast Cancer Cell Lines Predicts Both Disease-Free Survival and Overall Survival in Breast Cancer Patients Treated with Doxorubicin and Cyclophosphamide: A Collaborative Project of the NSABP and Precision Therapeutics SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Shen, K.; Tang, G.; Kim, C.; Pogue-Geile, K.; Anderson, S. J.; Constantino, J. P.; Bear, H. D.; Song, N.; Tian, C.; Gabrin, M. J.; Zhang, Y.; Geyer, C. E., Jr.; Wolmark, N.] Precis Therapeut Inc, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Virginia Commonwealth Univ, Richmond, VA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P1-06-15 DI 10.1158/0008-5472.SABCS11-P1-06-15 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699800220 ER PT J AU Stout, NL Pfalzer, L Levy, E McGarvey, C Gerber, L Springer, B Bohaile, P AF Stout, N. L. Pfalzer, L. Levy, E. McGarvey, C. Gerber, L. Springer, B. Bohaile, P. TI Five Year Preliminary Outcomes of a Prospective Surveillance Model To Reduce Upper Extremity Morbidity Related to Breast Cancer Treatment. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Stout, N. L.; Pfalzer, L.; Levy, E.; McGarvey, C.; Gerber, L.; Springer, B.; Bohaile, P.] Natl Naval Med Ctr, New York, NY USA. Univ Michigan Flint, Flint, MI USA. NIH, Baton Rouge, LA USA. George Mason Univ, Fairfax, VA 22030 USA. Off Surg Gen, New York, NY USA. Naval Hosp San Diego, San Diego, CA USA. NR 0 TC 1 Z9 1 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P4-12-08 DI 10.1158/0008-5472.SABCS11-P4-12-08 PG 1 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801393 ER PT J AU Villanueva, H Visbal, AP Birnbaumer, L Plummer, NW Lewis, MT AF Villanueva, H. Visbal, A. P. Birnbaumer, L. Plummer, N. W. Lewis, M. T. TI Smoothened Function as a G-Protein Coupled Receptor in Mammary Epithelial Cells. SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Villanueva, H.; Visbal, A. P.; Birnbaumer, L.; Plummer, N. W.; Lewis, M. T.] Baylor Coll Med, Houston, TX 77030 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2011 VL 71 SU 24 MA P4-04-02 DI 10.1158/0008-5472.SABCS11-P4-04-02 PG 2 WC Oncology SC Oncology GA V43RZ UT WOS:000209699801488 ER PT J AU Messina, A Ferraris, N Wray, S Cagnoni, G Donohue, DE Casoni, F Kramer, PR Derijck, AA Adolfs, Y Fasolo, A Pasterkamp, RJ Giacobini, P AF Messina, Andrea Ferraris, Nicoletta Wray, Susan Cagnoni, Gabriella Donohue, Duncan E. Casoni, Filippo Kramer, Phillip R. Derijck, Alwin A. Adolfs, Youri Fasolo, Aldo Pasterkamp, Ronald J. Giacobini, Paolo TI Dysregulation of Semaphorin7A/beta 1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility SO HUMAN MOLECULAR GENETICS LA English DT Article ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; HORMONE LHRH NEURONS; SEMAPHORIN 7A; KALLMANN-SYNDROME; OLFACTORY-BULB; EXPLANT CULTURES; AXON GUIDANCE; PLEXIN C1; MICE; RECEPTOR AB Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropin-releasing hormone-1 (GnRH-1). These neurons originate prenatally in the nasal placode and migrate into the forebrain along the olfactory-vomeronasal nerves. Alterations in this migratory process lead to defective GnRH-1 secretion, resulting in heterogeneous genetic disorders such as idiopathic hypogonadotropic hypogonadism (IHH), and other reproductive diseases characterized by the reduction or failure of sexual competence. Combining mouse genetics with in vitro models, we demonstrate that Semaphorin 7A (Sema7A) is essential for the development of the GnRH-1 neuronal system. Loss of Sema7A signaling alters the migration of GnRH-1 neurons, resulting in significantly reduced numbers of these neurons in the adult brain as well as in reduced gonadal size and subfertility. We also show that GnRH-1 cells differentially express the Sema7 receptors beta 1-integrin and Plexin C1 as a function of their migratory stage, whereas the ligand is robustly expressed along developing olfactory/vomeronasal fibers. Disruption of Sema7A function in vitro inhibits beta 1-integrin-mediated migration. Analysis of Plexin C1(-/-) mice did not reveal any difference in the migratory process of GnRH-1 neurons, indicating that Sema7A mainly signals through b1-integrin to regulate GnRH-1 cell motility. In conclusion, we have identified Sema7A as a gene implicated in the normal development of the GnRH-1 system in mice and as a genetic marker for the elucidation of some forms of GnRH-1 deficiency in humans. C1 [Messina, Andrea; Ferraris, Nicoletta; Cagnoni, Gabriella; Fasolo, Aldo; Giacobini, Paolo] Univ Turin, Dept Human & Anim Biol, I-10123 Turin, Italy. [Wray, Susan; Donohue, Duncan E.; Casoni, Filippo; Kramer, Phillip R.; Giacobini, Paolo] NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Derijck, Alwin A.; Adolfs, Youri; Pasterkamp, Ronald J.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurosci & Pharmacol, NL-3584 CG Utrecht, Netherlands. [Messina, Andrea; Casoni, Filippo; Giacobini, Paolo] INSERM, Jean Pierre Aubert Res Ctr, U837, F-59045 Lille, France. RP Giacobini, P (reprint author), Univ Turin, Dept Human & Anim Biol, I-10123 Turin, Italy. EM paolo.giacobini@inserm.fr RI Giacobini, Paolo/P-5451-2015 OI Giacobini, Paolo/0000-0002-3075-1441 FU Compagnia di San Paolo, Turin, Italy [2008.1224]; Regione Piemonte Ricerca Sanitaria Finalizzata, Italy; Fondazione CRT ('Progetto Alfieri' and 'Progetto Lagrange'), Turin, Italy; Institut National de la Sante et de la Recherche Medicale, Inserm, France [U837]; Agence Nationale de la Recherche, ANR, France [ANR-2010-JCJC-1404-01]; NINDS, NIH, Bethesda, MD, USA; Netherlands Organization for Health Research and Development (ZonMW-VIDI/TOP); Human Frontier Science Program (HFSP-CDA); ABC Genomics Center Utrecht; European Union [222999] FX This work was supported by Compagnia di San Paolo (grant number 2008.1224 to P. G.), Turin, Italy; Regione Piemonte Ricerca Sanitaria Finalizzata, Italy; Fondazione CRT ('Progetto Alfieri' and 'Progetto Lagrange'), Turin, Italy; the Institut National de la Sante et de la Recherche Medicale, Inserm, France (grant number U837); Agence Nationale de la Recherche, ANR, France (grant number ANR-2010-JCJC-1404-01 to P. G.); the intramural research program of the NINDS, NIH, Bethesda, MD, USA; the Netherlands Organization for Health Research and Development (ZonMW-VIDI/TOP to J.R.P.), the Human Frontier Science Program (HFSP-CDA to J.R.P.) and the ABC Genomics Center Utrecht and the European Union mdDANeurodev, FP7/2007-2011 (grant number 222999 to J.R.P.). NR 56 TC 28 Z9 30 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 DEC 15 PY 2011 VL 20 IS 24 BP 4759 EP 4774 DI 10.1093/hmg/ddr403 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 851BA UT WOS:000297242100001 PM 21903667 ER PT J AU Amos, CI Wang, LE Lee, JE Gershenwald, JE Chen, WV Fang, SY Kosoy, R Zhang, MF Qureshi, AA Vattathil, S Schacherer, CW Gardner, JM Wang, YL Bishop, DT Barrett, JH MacGregor, S Hayward, NK Martin, NG Duffy, DL Mann, GJ Cust, A Hopper, J Brown, KM Grimm, EA Xu, YJ Han, YH Jing, KY McHugh, C Laurie, CC Doheny, KF Pugh, EW Seldin, MF Han, JL Wei, QY AF Amos, Christopher I. Wang, Li-E Lee, Jeffrey E. Gershenwald, Jeffrey E. Chen, Wei V. Fang, Shenying Kosoy, Roman Zhang, Mingfeng Qureshi, Abrar A. Vattathil, Selina Schacherer, Christopher W. Gardner, Julie M. Wang, Yuling Bishop, D. Tim Barrett, Jennifer H. MacGregor, Stuart Hayward, Nicholas K. Martin, Nicholas G. Duffy, David L. Mann, Graham J. Cust, Anne Hopper, John Brown, Kevin M. Grimm, Elizabeth A. Xu, Yaji Han, Younghun Jing, Kaiyan McHugh, Caitlin Laurie, Cathy C. Doheny, Kim F. Pugh, Elizabeth W. Seldin, Michael F. Han, Jiali Wei, Qingyi CA GenoMEL Investigators Q-Mega Investigators AMFS Investigators TI Genome-wide association study identifies novel loci predisposing to cutaneous melanoma SO HUMAN MOLECULAR GENETICS LA English DT Article ID POPULATION; RISK; GENE; PIGMENTATION; SUSCEPTIBILITY; CARCINOMA; VARIANTS; ANCESTRY; CANCER; EYE AB We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 x 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma. C1 [Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Unit 1340, Houston, TX 77030 USA. [Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Schacherer, Christopher W.; Gardner, Julie M.; Wang, Yuling] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Grimm, Elizabeth A.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Kosoy, Roman; Seldin, Michael F.] Univ Calif Davis, Rowe Program Genet, Davis, CA 95616 USA. [Zhang, Mingfeng; Qureshi, Abrar A.; Han, Jiali] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Qureshi, Abrar A.; Han, Jiali] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, Boston, MA 02115 USA. [Bishop, D. Tim; Barrett, Jennifer H.] Univ Leeds, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds, W Yorkshire, England. [MacGregor, Stuart; Hayward, Nicholas K.; Martin, Nicholas G.; Duffy, David L.] Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Westmead, NSW 2145, Australia. [Mann, Graham J.] Melanoma Inst Australia, Westmead, NSW 2145, Australia. [Cust, Anne] Univ Sydney, Sydney Sch Publ Hlth, CESR, Sydney, NSW 2006, Australia. [Hopper, John] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt MEGA Epidemiol, Melbourne, Vic, Australia. [Brown, Kevin M.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [McHugh, Caitlin; Laurie, Cathy C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Doheny, Kim F.; Pugh, Elizabeth W.] Johns Hopkins Univ, Sch Med, Ctr Inherited Dis Res, Baltimore, MD USA. [Han, Jiali] Harvard Univ, Channing Lab, Dept Epidemiol, Boston, MA 02115 USA. RP Amos, CI (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Unit 1340, 1155 Pressler Blvd, Houston, TX 77030 USA. EM camos@mdanderson.org; qwei@mdanderson.org RI Duffy, David/B-7392-2013; Marti, Rosa/A-2256-2010; Whiteman, David/P-2728-2014; Bruno, William/N-7477-2013; Andreotti, Virginia/K-4506-2016; Akslen, Lars /C-1202-2017; bertazzi, pietro alberto/D-5039-2017; Bakker, Egbert/D-3525-2009; Macgregor, Stuart/C-6442-2009; Mann, Graham/G-4758-2014; hayward, nicholas/C-1367-2015; Xu, Yaji/M-4985-2015; Martin, Ludovic/K-2674-2015; Jenkins, Mark/P-7803-2015; OI Duffy, David/0000-0001-7227-632X; Marti, Rosa/0000-0001-6866-6114; Whiteman, David/0000-0003-2563-9559; Bruno, William/0000-0002-0337-0168; Andreotti, Virginia/0000-0002-2569-0832; Akslen, Lars /0000-0003-2710-9543; bertazzi, pietro alberto/0000-0003-3475-2449; Bakker, Egbert/0000-0002-2843-7357; Macgregor, Stuart/0000-0001-6731-8142; Mann, Graham/0000-0003-1301-405X; hayward, nicholas/0000-0003-4760-1033; Giles, Graham/0000-0003-4946-9099; CARRERA, CRISTINA/0000-0003-1608-8820; Martin, Nicholas/0000-0003-4069-8020; Gruis, Nelleke/0000-0002-5210-9150; Jenkins, Mark/0000-0002-8964-6160; Badenas, Celia/0000-0002-0621-0477; Barrett, Jenny/0000-0002-1720-7724; Mila, Montserrat/0000-0002-7906-0916; Puig, Susana/0000-0003-1337-9745 FU NIH [R01CA100264, 2P50CA093459, P30CA016672, R01CA133996, HG004446]; Marit Peterson Fund for Melanoma Research; Australian National Health and Medical Research Council (NHMRC) [2004-2009, 241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 566946, 107359, 211172, 402761]; Melanoma Research Alliance; Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC); Cerylid Biosciences (Melbourne); Neville and Shirley Hawkins; NHMRC [496674, 613705, 520018]; Cancer Council New South Wales [77/00, 06/10]; Cancer Council Victoria; Cancer Council Queensland [371]; US National Institutes of Health [CA-83115-01A2, R01 CA83115]; National Cancer Institute [10/ECF/2-06, RO1 CA5558]; University of Sydney Medical Foundation; European Commission [LSHC-CT-2006-018702]; Cancer Research UK [C588/A4994, C588/A10589, C8216/A6129]; DCEG; Swedish Cancer Society; Swedish Research Council; Region Skane funds; Kamprad Foundation; Comprehensive Cancer Center, Oslo University Hospital; University of Bergen; Institut National du Cancer [INCa-PL016]; Ligue Nationale Contre Le Cancer [PRE05/FD, PRE 09/FD]; Programme Hospitalier de Recherche Clinique (PHRC) [2007/AOM-07-195]; Marie-Francoise Avril and Florence Demenais; Institut National du Cancer (Melanoma Network) [13]; Association pour la Recherche sur le Cancer (ARC) [A09/5/5003]; Societe Francaise de Dermatologie [SFD2009]; INSERM; [HHSN268200782096C] FX Research at MD Anderson Cancer Center was partially supported by NIH grants R01CA100264, 2P50CA093459, P30CA016672, R01CA133996 and by the Marit Peterson Fund for Melanoma Research.; The Center for Inherited Disease Research is supported by contract HHSN268200782096C. Geneva is supported by NIH grant HG004446.; The Australian Twin Registry is supported by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant (2004-2009).; The QIMR Study was supported by grants from the Melanoma Research Alliance, the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927,389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne), and donations from Neville and Shirley Hawkins.; S.M. is supported by NHMRC Career Development Awards (496674, 613705). G. W. M. is supported by the NHMRC Fellowships Scheme.; The AMFS study is funded by the National Health and Medical Research Council of Australia (NHMRC) (project grants 566946, 107359, 211172 and program grant number 402761 to G.J.M. and R. F. K.); the Cancer Council New South Wales (project grant 77/00, 06/10), the Cancer Council Victoria and the Cancer Council Queensland (project grant 371); and the US National Institutes of Health (via RO1 grant CA-83115-01A2 to the international Melanoma Genetics Consortium - GenoMEL). A. E. C. is the recipient of an NHMRC public health postdoctoral fellowship (520018) and a National Cancer Institute NSW Early Career Development Fellowship (10/ECF/2-06). B.K.A.'s research is supported by a University of Sydney Medical Foundation Program Grant, and J.L.H. is an Australia Fellow of the NHMRC.; The GenoMEL study was funded by the European Commission under the 6th Framework Programme, contract no: LSHC-CT-2006-018702; by Cancer Research UK Programme Awards, C588/A4994, and C588/A10589, and Cancer Research UK Project Grant C8216/A6129; and by US National Institutes of Health R01 CA83115. This research was also supported by the Intramural Research Program of the NIH, NCI and DCEG.; Emilia-Romagna: National Cancer Institute grants RO1 CA5558 to Maria Teresa Landi.; Genoa: IRCSS 2007 Italian Ministry of Health DGRST.4/4235-P1.9.A.B, Fondazione CARIGE, PRIN 2008 to G.B.-S.; Leeds: Cancer Research UK Programme grants Genetic Epidemiology of Cancer C588/A10589, C588/A4994 and Cancer Research UK Project grant C8216/A6129.; Lund: Swedish Cancer Society, Swedish Research Council, Region Skane funds, Kamprad Foundation.; Norway: Grants from the Comprehensive Cancer Center, Oslo University Hospital and the University of Bergen.; Paris: Grants from Institut National du Cancer (INCa-PL016) and Ligue Nationale Contre Le Cancer (PRE05/FD and PRE 09/FD) to Florence Demenais, Programme Hospitalier de Recherche Clinique (PHRC 2007/AOM-07-195) to Marie-Francoise Avril and Florence Demenais, Institut National du Cancer (Melanoma Network RS Number 13), Association pour la Recherche sur le Cancer (ARC No. A09/5/5003), and Societe Francaise de Dermatologie (SFD2009) to Brigitte Bressac-de Paillerets. Brigitte Bressac-de Paillerets has been awarded an INSERM Research Fellowship for hospital-based scientists. NR 27 TC 79 Z9 80 U1 1 U2 30 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 15 PY 2011 VL 20 IS 24 BP 5012 EP 5023 DI 10.1093/hmg/ddr415 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 851BA UT WOS:000297242100020 PM 21926416 ER PT J AU Petralia, RS Schwartz, CM Wang, YX Mattson, MP Yao, PJ AF Petralia, Ronald S. Schwartz, Catherine M. Wang, Ya-Xian Mattson, Mark P. Yao, Pamela J. TI Subcellular localization of patched and smoothened, the receptors for sonic hedgehog signaling, in the hippocampal neuron SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE Sonic hedgehog; Patched; Smoothened; hippocampal neuron; synapse; synaptic spinule; autophagosome; primary cilium ID HINDBRAIN CHOROID-PLEXUS; PRIMARY CILIUM; MONOCLONAL-ANTIBODIES; ADENYLYL-CYCLASE; DENDRITIC SPINE; RAT HIPPOCAMPUS; PROTEINS AP180; AXON GROWTH; CEREBELLUM; BRAIN AB Cumulative evidence suggests that, aside from patterning the embryonic neural tube, Sonic hedgehog (Shh) signaling plays important roles in the mature nervous system. In this study, we investigate the expression and localization of the Shh signaling receptors, Patched (Ptch) and Smoothened (Smo), in the hippocampal neurons of young and mature rats. Reverse transcriptase-polymerase chain reaction and immunoblotting analyses show that the expression of Ptch and Smo remains at a moderate level in young postnatal and adult brains. By using immunofluorescence light microscopy and immunoelectron microscopy, we examine the spatial distribution of Ptch and Smo within the hippocampal neurons. In young developing neurons, Ptch and Smo are present in the processes and are clustered at their growth cones. In mature neurons, Ptch and Smo are concentrated in dendrites, spines, and postsynaptic sites. Synaptic Ptch and Smo often co-exist with unusual structuressynaptic spinules and autophagosomes. Our results reveal the anatomical organization of the Shh receptors within both the young and the mature hippocampal neurons. J. Comp. Neurol. 519:3684-3699, 2011. (c) 2011 Wiley-Liss, Inc. C1 [Yao, Pamela J.] NIA, Neurosci Lab, NIH, Biomed Res Ctr,Intramural Res Program, Baltimore, MD 21224 USA. [Petralia, Ronald S.; Wang, Ya-Xian] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, NIH, Biomed Res Ctr,Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging; National Institute on Deafness and Other Communication Disorders, National Institutes of Health FX Grant sponsor: Intramural Research Programs of the National Institute on Aging and the National Institute on Deafness and Other Communication Disorders, National Institutes of Health. NR 64 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 15 PY 2011 VL 519 IS 18 BP 3684 EP 3699 DI 10.1002/cne.22681 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 847YD UT WOS:000297010700005 PM 21618238 ER PT J AU Shebl, FM Pfeiffer, RM Buckett, D Muchmore, B Chen, S Dotrang, M Prokunina-Olsson, L Edlin, BR O'Brien, TR AF Shebl, Fatma M. Pfeiffer, Ruth M. Buckett, Dianna Muchmore, Brian Chen, Sabrina Dotrang, Myhanh Prokunina-Olsson, Ludmila Edlin, Brian R. O'Brien, Thomas R. TI IL28B rs12979860 Genotype and Spontaneous Clearance of Hepatitis C Virus in a Multi-Ethnic Cohort of Injection Drug Users: Evidence for a Supra-Additive Association SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID POLYMORPHISM; INFECTION AB Among 1369 Urban Health Study participants, we evaluated genetic models for the association of IL28B genotype (rs12979860 and rs8099917) with hepatitis C virus (HCV) clearance. For rs12979860, adjusted odds ratios for spontaneous HCV clearance were as follows: IL28B-CC, 3.88 (P < .001); IL28B-CT, 1.48 (P = .08). On the basis of Akaike information criteria values and chi(2) tests, a supra-additive (quadratic) model fit these data best. Models based on rs8099917 provided poorer fit. Evidence that a supra-additive rs12979860-based model best fits the association of IL28B-genotype with HCV clearance may improve clinical prediction models and foster a better understanding of functional mechanisms underlying this association. C1 [Shebl, Fatma M.; Buckett, Dianna; O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Buckett, Dianna; Muchmore, Brian; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Chen, Sabrina] Informat Management Serv Inc, Silver Spring, MD USA. [Dotrang, Myhanh] CSC, Rockville, MD USA. [Edlin, Brian R.] SUNY Downstate Coll Med, Brooklyn, NY USA. [Edlin, Brian R.] Cornell Univ, Ctr Study Hepatitis C, Weill Med Coll, New York, NY 10021 USA. [Edlin, Brian R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP O'Brien, TR (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Room 6111, Rockville, MD 20852 USA. EM obrient@mail.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Edlin, Brian/0000-0001-8172-8797 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Institute on Drug Abuse [R01-DA09532, R01-DA12109, R01-DA13245]; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Substance Abuse and Mental Health Services Administration [H79-TI12103]; San Francisco Department of Public Health FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. This research was also supported by federal funds from the National Institute on Drug Abuse (R01-DA09532, R01-DA12109, R01-DA13245); the National Cancer Institute, National Institutes of Health (N01-CO-12400); the Substance Abuse and Mental Health Services Administration (H79-TI12103); and the San Francisco Department of Public Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 14 TC 12 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2011 VL 204 IS 12 BP 1843 EP 1847 DI 10.1093/infdis/jir647 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 848QU UT WOS:000297069100006 PM 22013224 ER PT J AU Dyall, J Johnson, RF Chen, DY Huzella, L Ragland, DR Mollura, DJ Byrum, R Reba, RC Jennings, G Jahrling, PB Blaney, JE Paragas, J AF Dyall, Julie Johnson, Reed F. Chen, Dar-Yeong Huzella, Louis Ragland, Dan R. Mollura, Daniel J. Byrum, Russell Reba, Richard C. Jennings, Gerald Jahrling, Peter B. Blaney, Joseph E. Paragas, Jason TI Evaluation of Monkeypox Disease Progression by Molecular Imaging SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; CHEST RADIOGRAPHIC FINDINGS; MODIFIED VACCINIA VIRUS; INFLUENZA-A H1N1; IMMUNODEFICIENCY VIRUS; INHALATIONAL ANTHRAX; RHESUS MACAQUES; RISK-FACTORS; INFECTION; ORTHOPOXVIRUS AB Infection of nonhuman primates (NHPs) with monkeypox virus (MPXV) is currently being developed as an animal model of variola infection in humans. We used positron emission tomography and computed tomography (PET/CT) to identify inflammatory patterns as predictors for the outcome of MPXV disease in NHPs. Two NHPs were sublethally inoculated by the intravenous (IV) or intrabronchial (IB) routes and imaged sequentially using fluorine-18 fluorodeoxyglucose ((18)FDG) uptake as a nonspecific marker of inflammation/immune activation. Inflammation was observed in the lungs of IB-infected NHPs, and bilobular involvement was associated with morbidity. Lymphadenopathy and immune activation in the axillary lymph nodes were evident in IV- and IB-infected NHPs. Interestingly, the surviving NHPs had significant (18)FDG uptake in the axillary lymph nodes at the time of MPXV challenge with no clinical signs of illness, suggesting an association between preexisting immune activation and survival. Molecular imaging identified patterns of inflammation/immune activation that may allow risk assessment of monkeypox disease. C1 [Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Johnson, Reed F.; Jahrling, Peter B.; Blaney, Joseph E.] NIAID, Emerging Viral Pathogens Sect, Frederick, MD 21702 USA. [Mollura, Daniel J.; Reba, Richard C.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Jahrling, PB (reprint author), NIAID, Integrated Res Facil, NIH, 8200 Res Plaza, Frederick, MD 21702 USA. EM jahrlingp@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility (NIAID, Division of Clinical Research); Battelle Memorial Institute's with NIAID [HHSN272200200016I] FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility (NIAID, Division of Clinical Research); and Battelle Memorial Institute's prime contract with NIAID (HHSN272200200016I). NR 46 TC 11 Z9 11 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2011 VL 204 IS 12 BP 1902 EP 1911 DI 10.1093/infdis/jir663 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 848QU UT WOS:000297069100013 PM 22013221 ER PT J AU Eshleman, SH Hudelson, SE Redd, AD Wang, L Debes, R Chen, YQ Martens, CA Ricklefs, SM Selig, EJ Porcella, SF Munshaw, S Ray, SC Piwowar-Manning, E McCauley, M Hosseinipour, MC Kumwenda, J Hakim, JG Chariyalertsak, S de Bruyn, G Grinsztejn, B Kumarasamy, N Makhema, J Mayer, KH Pilotto, J Santos, BR Quinn, TC Cohen, MS Hughes, JP AF Eshleman, Susan H. Hudelson, Sarah E. Redd, Andrew D. Wang, Lei Debes, Rachel Chen, Ying Q. Martens, Craig A. Ricklefs, Stacy M. Selig, Ethan J. Porcella, Stephen F. Munshaw, Supriya Ray, Stuart C. Piwowar-Manning, Estelle McCauley, Marybeth Hosseinipour, Mina C. Kumwenda, Johnstone Hakim, James G. Chariyalertsak, Suwat de Bruyn, Guy Grinsztejn, Beatriz Kumarasamy, Nagalingeswaran Makhema, Joseph Mayer, Kenneth H. Pilotto, Jose Santos, Breno R. Quinn, Thomas C. Cohen, Myron S. Hughes, James P. TI Analysis of Genetic Linkage of HIV From Couples Enrolled in the HIV Prevention Trials Network 052 Trial SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MOLECULAR EPIDEMIOLOGY; INFECTION; IDENTIFICATION; EVOLUTIONARY; TRANSMISSION AB Methods. Linkage was assessed using phylogenetic analysis of HIV pol sequences and Bayesian analysis of genetic distances between pol sequences from index-partner pairs and controls. Selected samples were also analyzed using next-generation sequencing (env region). Results. In 29 of the 38 (76.3%) cases analyzed, the index was the likely source of the partner's HIV infection (linked). In 7 cases (18.4%), the partner was most likely infected from a source other than the index participant (unlinked). In 2 cases (5.3%), linkage status could not be definitively established. Conclusions. Nearly one-fifth of the seroconversion events in HPTN 052 were unlinked. The association of early ART and reduced HIV transmission was stronger when the analysis included only linked events. This underscores the importance of assessing the genetic linkage of HIV seroconversion events in HIV prevention studies involving serodiscordant couples. C1 [Eshleman, Susan H.; Hudelson, Sarah E.; Piwowar-Manning, Estelle] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Redd, Andrew D.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. [Wang, Lei; Chen, Ying Q.; Hughes, James P.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Debes, Rachel; Hughes, James P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Martens, Craig A.; Ricklefs, Stacy M.; Selig, Ethan J.; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,Div Intramural Res,NIH, Hamilton, MT USA. [Munshaw, Supriya; Ray, Stuart C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [McCauley, Marybeth] FHI 360, Hlth & Dev Sci Div, Arlington, VA USA. [Hosseinipour, Mina C.] Kamuzu Cent Hosp, UNC Project, Lilongwe, Malawi. [Kumwenda, Johnstone] Coll Med, Blantyre, Malawi. [Hakim, James G.] Univ Zimbabwe, Dept Med, Harare, Zimbabwe. [Chariyalertsak, Suwat] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai, Thailand. [de Bruyn, Guy] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Grinsztejn, Beatriz] Inst Pesquisa Clin Evandro Chagas Fiocruz, Lab Pesquisa Clin DST AIDS, Rio De Janeiro, Brazil. [Kumarasamy, Nagalingeswaran] YRG CARE Med Ctr, Madras, Tamil Nadu, India. [Makhema, Joseph] Botswana Harvard Sch Publ Hlth AIDS Initiat Partn, Gaborone, Botswana. [Mayer, Kenneth H.] Fenway Hlth, Boston, MA USA. [Pilotto, Jose] Hosp Geral Nova Iguacu, Rio De Janeiro, Brazil. [Pilotto, Jose] Lab AIDS & Imunol Mol IOC Fiocruz, Rio De Janeiro, Brazil. [Cohen, Myron S.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Santos, Breno R.] Hosp Nossa Senhora da Conceicao, Porto Alegre, RS, Brazil. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Room 646,720 Rutland Ave, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu RI Ray, Stuart/B-7527-2008 OI Ray, Stuart/0000-0002-1051-7260 FU HIV Prevention Trials Network (HPTN); National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research, of NIH; Department of Health and Human Services [U01AI068613/UM1AI068613, U01AI068617, U01AI068619]; Division of Intramural Research, NIAID, NIH; NIAID, NIH [R01AI029168]; NIDA, NIH [R01DA024565]; Abbott Diagnostics FX This work was supported by the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research, of NIH, Department of Health and Human Services (U01AI068613/UM1AI068613 to HPTN Network Laboratory; U01AI068617 to HPTN Statistical and Data Management Center; and U01AI068619 to HPTN Core and Operations Center); the Division of Intramural Research, NIAID, NIH; NIAID, NIH(R01AI029168); and NIDA, NIH(R01DA024565).; S. H. E. has given presentations at meetings sponsored by Abbott Diagnostics (distributor of the ViroSeq HIV Genotyping System) and has collaborated with Celera (manufacturer of the ViroSeq HIV Genotyping System) and Abbott Diagnostics on evaluation of HIV-related assays. All other authors report no potential conflicts. NR 17 TC 56 Z9 58 U1 0 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2011 VL 204 IS 12 BP 1918 EP 1926 DI 10.1093/infdis/jir651 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 848QU UT WOS:000297069100015 PM 21990420 ER PT J AU Dadwal, M Kang, CS Song, HA Sun, X Dai, AZ Baidoo, KE Brechbiel, MW Chong, HS AF Dadwal, Mamta Kang, Chi Soo Song, Hyun A. Sun, Xiang Dai, Anzhi Baidoo, Kwamena E. Brechbiel, Martin W. Chong, Hyun-Soon TI Synthesis and evaluation of a bifunctional chelate for development of Bi(III)-labeled radioimmunoconjugates SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Radioimmunotherapy; Bifunctional ligand; (212)Bi; (213)Bi; Trastuzumab ID MYELOID-LEUKEMIA; RADIOIMMUNOTHERAPY; TRASTUZUMAB; ANTIBODIES; ANTI-CD33; THERAPY; BI-213 AB A new bifunctional ligand C-DEPA was designed and synthesized as a component for antibody-targeted radiation therapy (radioimmunotherapy, RIT) of cancer. C-DEPA was conjugated to a tumor targeting antibody, trastuzumab, and the corresponding C-DEPA-trastuzumab conjugate was evaluated for radiolabeling kinetics with (205/6)Bi. C-DEPA-trastuzumab conjugate rapidly bound (205/6)Bi, and (205/6)Bi-C-DEPA-trastuzumab conjugate was stable in human serum for 72 h. The in vitro radiolabeling kinetics and serum stability data suggest that C-DEPA is a potential chelate for preclinical RIT applications using (212)Bi and (213)Bi. (C) 2011 Published by Elsevier Ltd. C1 [Dadwal, Mamta; Kang, Chi Soo; Song, Hyun A.; Sun, Xiang; Dai, Anzhi; Chong, Hyun-Soon] IIT, Biol Chem & Phys Sci Dept, Div Chem, Chicago, IL 60616 USA. [Baidoo, Kwamena E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Chong, HS (reprint author), IIT, Biol Chem & Phys Sci Dept, Div Chem, 3101 S Dearborn St,LS 182, Chicago, IL 60616 USA. EM Chong@iit.edu FU National Institutes of Health [K22CA102637, R01CA112503]; NIH, National Cancer Institute, Center for Cancer Research FX We appreciate the financial support from the National Institutes of Health (K22CA102637 and R01CA112503). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 17 TC 5 Z9 5 U1 2 U2 13 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 DEC 15 PY 2011 VL 21 IS 24 BP 7513 EP 7515 DI 10.1016/j.bmcl.2011.06.107 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 849UK UT WOS:000297150600055 PM 22047687 ER PT J AU Shah, SK Dawson, L Dixon, DO Lie, RK AF Shah, Seema K. Dawson, Liza Dixon, Dennis O. Lie, Reidar K. TI Should Sponsors and DSMBs Share Interim Results Across Trials? SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material ID MONITORING CLINICAL-TRIALS; CONFIDENTIALITY; ISSUES C1 [Shah, Seema K.] NIAID, Ctr Clin, Dept Bioeth, NIH Clin Ctr,NIH, Bethesda, MD 20892 USA. [Dawson, Liza] NIAID, Res Eth Team, Basic Sci Program, Div Aids,NIH, Bethesda, MD 20892 USA. [Dixon, Dennis O.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Shah, SK (reprint author), NIAID, Ctr Clin, Dept Bioeth, NIH Clin Ctr,NIH, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 22 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2011 VL 58 IS 5 BP 433 EP 435 DI 10.1097/QAI.0b013e318236eca3 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 846RT UT WOS:000296921600006 PM 21937922 ER PT J AU Zhu, AP Romero, R Petty, HR AF Zhu, Aiping Romero, Roberto Petty, Howard R. TI An enzymatic colorimetric assay for glucose-6-phosphate SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE WST-1; Glucose-6-phosphate; Colorimetric assay; Glucose-6-phosphate dehydrogenase ID ELECTROSPRAY-IONIZATION; MASS-SPECTROMETRY; SACCHAROMYCES-CEREVISIAE; TETRAZOLIUM SALT; CHROMATOGRAPHY; METABOLITES; GLUCOSE; QUANTIFICATION; VALIDATION; PHOSPHATES AB A specific colorimetric assay for the determination of glucose-6-phosphate (G6P) was developed. This assay is based on the oxidation of G6P in the presence of glucose-6-phosphate dehydrogenase (G6PD) and nicotinamide adenine dinucleotide phosphate (NADP(+)); the NADPH thereby generated reduces the tetrazolium salt WST-1 [2-(4-indophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium, monosodium salt] to water-soluble yellow-colored formazan with 1-methoxy-5-methylphenazium methylsulfate (1-mPMS) as an electron carrier. The assay is optimized for reaction buffer pH, enzyme/dye concentration, and reaction time course. The limit of detection of the assay is 0.15 mu M (15 pmol/well). The usefulness of the assay is demonstrated by the accurate measurement of the G6P concentration in fetal bovine serum (FBS). (C) 2011 Elsevier Inc. All rights reserved. C1 [Zhu, Aiping; Petty, Howard R.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Div Intramural Res, NIH, Bethesda, MD USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Div Intramural Res, NIH, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Romero, Roberto] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI 48201 USA. [Petty, Howard R.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48105 USA. RP Petty, HR (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. EM hpetty@umich.edu FU Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [N01-HD-2-3342, WSU04055] FX This work was supported, in part, by the Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (contract N01-HD-2-3342 and subcontract WSU04055). NR 26 TC 5 Z9 5 U1 2 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 15 PY 2011 VL 419 IS 2 BP 266 EP 270 DI 10.1016/j.ab.2011.08.037 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 836NW UT WOS:000296119400028 PM 21925475 ER PT J AU Pineda, I Vazquez, MV Berezhkovskii, AM Dagdug, L AF Pineda, Inti Vazquez, Marco-Vinicio Berezhkovskii, Alexander M. Dagdug, Leonardo TI Diffusion in periodic two-dimensional channels formed by overlapping circles: Comparison of analytical and numerical results SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article AB We study two-dimensional diffusion in a channel formed by periodic overlapping circles. Periodic variation of the channel width leads to the slowdown of diffusion along the channel axis. There are several approximate approaches, which allow one to analyze the slowdown. We use these approaches to derive five expressions for the effective diffusion coefficient of a point Brownian particle in the channel. To check the accuracy of the expressions we compare their predictions with the effective diffusion coefficient obtained from Brownian dynamics simulations. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3664179] C1 [Berezhkovskii, Alexander M.; Dagdug, Leonardo] NCI, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Pineda, Inti; Vazquez, Marco-Vinicio] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Distrito Fed 09340, Mexico. RP Dagdug, L (reprint author), NCI, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. EM dagdug@mail.nih.gov FU CONACyT; National Institutes of Health (NIH), Center for Information Technology FX I.P. thanks CONACyT for partial support. We are grateful to Super Computer Division of Universidad Autonoma Metropolitana-Iztapalapa for the use of their computational facilities. This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology. NR 16 TC 19 Z9 19 U1 0 U2 6 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD DEC 14 PY 2011 VL 135 IS 22 AR 224101 DI 10.1063/1.3664179 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 864OX UT WOS:000298250600002 PM 22168674 ER PT J AU Noberini, R Mitra, S Salvucci, O Valencia, F Duggineni, S Prigozhina, N Wei, K Tosato, G Huang, ZW Pasquale, EB AF Noberini, Roberta Mitra, Sayantan Salvucci, Ombretta Valencia, Fatima Duggineni, Srinivas Prigozhina, Natalie Wei, Ke Tosato, Giovanna Huang, Ziwei Pasquale, Elena B. TI PEGylation Potentiates the Effectiveness of an Antagonistic Peptide That Targets the EphB4 Receptor with Nanomolar Affinity SO PLOS ONE LA English DT Article ID COLORECTAL-CANCER PROGRESSION; GROWTH-FACTOR WITHDRAWAL; TUMOR-GROWTH; TYROSINE KINASE; MELANOMA-CELLS; BLOOD-VESSELS; IN-VIVO; VASCULAR MORPHOGENESIS; DRUG-DELIVERY; ANGIOGENESIS AB The EphB4 receptor tyrosine kinase together with its preferred ligand, ephrin-B2, regulates a variety of physiological and pathological processes, including tumor progression, pathological forms of angiogenesis, cardiomyocyte differentiation and bone remodeling. We previously reported the identification of TNYL-RAW, a 15 amino acid-long peptide that binds to the ephrin-binding pocked of EphB4 with low nanomolar affinity and inhibits ephrin-B2 binding. Although ephrin-B2 interacts promiscuously with all the EphB receptors, the TNYL-RAW peptide is remarkably selective and only binds to EphB4. Therefore, this peptide is a useful tool for studying the biological functions of EphB4 and for imaging EphB4-expressing tumors. Furthermore, TNYL-RAW could be useful for treating pathologies involving EphB4-ephrin-B2 interaction. However, the peptide has a very short half-life in cell culture and in the mouse blood circulation due to proteolytic degradation and clearance by the kidneys and reticuloendothelial system. To overcome these limitations, we have modified TNYL-RAW by fusion with the Fc portion of human IgG1, complexation with streptavidin or covalent coupling to a 40 KDa branched polyethylene glycol (PEG) polymer. These modified forms of TNYL-RAW all have greatly increased stability in cell culture, while retaining high binding affinity for EphB4. Furthermore, PEGylation most effectively increases peptide half-life in vivo. Consistent with increased stability, submicromolar concentrations of PEGylated TNYL-RAW effectively impair EphB4 activation by ephrin-B2 in cultured B16 melanoma cells as well as capillary-like tube formation and capillary sprouting in co-cultures of endothelial and epicardial mesothelial cells. Therefore, PEGylated TNYL-RAW may be useful for inhibiting pathological forms of angiogenesis through a novel mechanism involving disruption of EphB4-ephrin-B2 interactions between endothelial cells and supporting perivascular mesenchymal cells. Furthermore, the PEGylated peptide is suitable for other cell culture and in vivo applications requiring prolonged EphB4 receptor targeting. C1 [Noberini, Roberta; Mitra, Sayantan; Valencia, Fatima; Prigozhina, Natalie; Wei, Ke; Pasquale, Elena B.] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [Salvucci, Ombretta; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Duggineni, Srinivas; Huang, Ziwei] SUNY Syracuse, Dept Pharmacol, State Univ New York Upstate Canc Res Inst, Syracuse, NY USA. [Prigozhina, Natalie] Univ San Diego, Dept Biol, San Diego, CA 92110 USA. [Pasquale, Elena B.] Univ San Diego, Dept Pathol, San Diego, CA 92110 USA. RP Noberini, R (reprint author), Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. EM elenap@sanfordburnham.org RI duggineni, srinivas/J-3691-2012; OI Noberini, Roberta/0000-0002-7267-1079 FU National Institutes of Health [CA116099, CA138390]; Department of Defense [W81XWH-07-1-0462]; MedImmune/AstraZeneca FX Funding provided by the National Institutes of Health grants CA116099 and CA138390 (EP) and Department of Defense grant W81XWH-07-1-0462 (ZH and EP). Funding was also received from a commercial source: MedImmune/AstraZeneca (EP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 21 Z9 21 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 14 PY 2011 VL 6 IS 12 AR e28611 DI 10.1371/journal.pone.0028611 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866GS UT WOS:000298369100062 PM 22194865 ER PT J AU Zhang, J Tan, KL Wu, XF Chen, GF Sun, JJ Reck-Peterson, SL Hammer, JA Xiang, X AF Zhang, Jun Tan, Kaeling Wu, Xufeng Chen, Guifang Sun, Jinjin Reck-Peterson, Samara L. Hammer, John A., III Xiang, Xin TI Aspergillus Myosin-V Supports Polarized Growth in the Absence of Microtubule-Based Transport SO PLOS ONE LA English DT Article ID FUNGUS USTILAGO-MAYDIS; HYPHAL TIP GROWTH; MOTOR-LIKE DOMAIN; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; PLUS-ENDS; NIDULANS; KINESIN; PROTEIN AB In the filamentous fungus Aspergillus nidulans, both microtubules and actin filaments are important for polarized growth at the hyphal tip. Less clear is how different microtubule-based and actin-based motors work together to support this growth. Here we examined the role of myosin-V (MYOV) in hyphal growth. MYOV-depleted cells form elongated hyphae, but the rate of hyphal elongation is significantly reduced. In addition, although wild type cells without microtubules still undergo polarized growth, microtubule disassembly abolishes polarized growth in MYOV-depleted cells. Thus, MYOV is essential for polarized growth in the absence of microtubules. Moreover, while a triple kinesin null mutant lacking kinesin-1 (KINA) and two kinesin-3s (UNCA and UNCB) undergoes hyphal elongation and forms a colony, depleting MYOV in this triple mutant results in lethality due to a severe defect in polarized growth. These results argue that MYOV, through its ability to transport secretory cargo, can support a significant amount of polarized hyphal tip growth in the absence of any microtubule-based transport. Finally, our genetic analyses also indicate that KINA (kinesin-1) rather than UNCA (kinesin-3) is the major kinesin motor that supports polarized growth in the absence of MYOV. C1 [Zhang, Jun; Chen, Guifang; Xiang, Xin] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Tan, Kaeling; Reck-Peterson, Samara L.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Wu, Xufeng; Sun, Jinjin; Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Sun, Jinjin] River Hill High Sch, Clarksville, MD USA. RP Zhang, J (reprint author), Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. EM hammerj@nhlbi.nih.gov; xxiang@usuhs.mil FU National Institutes of the Health [5RO1GM069527, 1RO1GM097580-01, 1 DP2 OD004268-01]; Uniformed Services University of the Health Sciences [R071JD] FX This work was supported by National Institutes of the Health grants (5RO1GM069527 and 1RO1GM097580-01 to X. X. and 1 DP2 OD004268-01 to S. R. -P.) and a Uniformed Services University of the Health Sciences intramural grant (R071JD to X. X.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 16 Z9 20 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 14 PY 2011 VL 6 IS 12 AR e28575 DI 10.1371/journal.pone.0028575 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866GS UT WOS:000298369100054 PM 22194856 ER PT J AU Khan, AM Kaminski, KL Sanchez-Watts, G Ponzio, TA Kuzmiski, JB Bains, JS Watts, AG AF Khan, Arshad M. Kaminski, Kimberly L. Sanchez-Watts, Graciela Ponzio, Todd A. Kuzmiski, J. Brent Bains, Jaideep S. Watts, Alan G. TI MAP Kinases Couple Hindbrain-Derived Catecholamine Signals to Hypothalamic Adrenocortical Control Mechanisms during Glycemia-Related Challenges SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; MITOGEN-ACTIVATED PROTEIN; PITUITARY-ADRENAL AXIS; INSULIN-INDUCED HYPOGLYCEMIA; PARAVENTRICULAR NUCLEUS; PARVOCELLULAR NEURONS; GENE-EXPRESSION; IN-VITRO; SYNTHESIZING NEURONS; RAT HYPOTHALAMUS AB Physiological responses to hypoglycemia, hyperinsulinemia, and hyperglycemia include a critical adrenocortical component that is initiated by hypothalamic control of the anterior pituitary and adrenal cortex. These adrenocortical responses ensure appropriate long-term glucocorticoid-mediated modifications to metabolism. Despite the importance of these mechanisms to disease processes, how hypothalamic afferent pathways engage the intracellular mechanisms that initiate adrenocortical responses to glycemia-related challenges are unknown. This study explores these mechanisms using network-and cellular-level interventions in in vivo and ex vivo rat preparations. Results show that a hindbrain-originating catecholamine afferent system selectively engages a MAP kinase pathway in rat paraventricular hypothalamic CRH (corticotropin-releasing hormone) neuroendocrine neurons shortly after vascular insulin and 2-deoxyglucose challenges. In turn, this MAP kinase pathway can control both neuroendocrine neuronal firing rate and the state of CREB phosphorylation in a reduced ex vivo paraventricular hypothalamic preparation, making this signaling pathway an ideal candidate for coordinating CRH synthesis and release. These results establish the first clear structural and functional relationships linking neurons in known nutrient-sensing regions with intracellular mechanisms in hypothalamic CRH neuroendocrine neurons that initiate the adrenocortical response to various glycemia-related challenges. C1 [Khan, Arshad M.; Sanchez-Watts, Graciela; Watts, Alan G.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Kaminski, Kimberly L.; Watts, Alan G.] Univ So Calif, Grad Program Neurosci, Los Angeles, CA 90089 USA. [Khan, Arshad M.] Univ Texas El Paso, Border Biomed Res Ctr, Neurosci & Metab Disorders Unit, El Paso, TX 79968 USA. [Khan, Arshad M.] Univ Texas El Paso, Dept Biol Sci, El Paso, TX 79968 USA. [Ponzio, Todd A.] NINDS, NIH, Bethesda, MD 20892 USA. [Kuzmiski, J. Brent; Bains, Jaideep S.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada. RP Watts, AG (reprint author), Univ So Calif, Dept Biol Sci, Hedco Neurosci Bldg,MC 2520,3641 Watt Way, Los Angeles, CA 90089 USA. EM amkhan2@utep.edu; watts@usc.edu RI Khan, Arshad/L-1705-2013; OI Khan, Arshad/0000-0003-0254-3546; Kuzmiski, Brent/0000-0002-9240-4867 FU NIH [NS029728, MH071108, DK081937]; Juvenile Diabetes Research Foundation [1-2008-710]; Canadian Institutes for Health Research FX This work was supported by NIH Grants NS029728 (A. G. W.), and MH071108 and DK081937 (A. M. K.), a research grant from the Juvenile Diabetes Research Foundation to A. G. W. (1-2008-710), and an operating grant from the Canadian Institutes for Health Research (J.S.B.). We are grateful for the guidance and support of Dr. Glenn I. Hatton, who died before the final stages of this project were completed. We thank Dr. MaryAnn Bohland, Dr. Christina Boyle, and Tracey Nichols for technical assistance; Dr. Marc Montminy for providing the polyclonal pCREB antibody; and Dr. Richard H. Thompson for stimulating discussion. We also thank Dr. Harold Gainer for providing access to some facilities in his laboratory. NR 50 TC 17 Z9 18 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 14 PY 2011 VL 31 IS 50 BP 18479 EP 18491 DI 10.1523/JNEUROSCI.4785-11.2011 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 861YA UT WOS:000298055600025 PM 22171049 ER PT J AU Bukowski, R Carpenter, M Conway, D Coustan, D Dudley, DJ Goldenberg, RL Hogue, CJR Koch, MA Parker, CB Pinar, H Reddy, UM Saade, GR Silver, RM Stoll, BJ Varner, MW Willinger, M AF Bukowski, Radek Carpenter, Marshall Conway, Deborah Coustan, Donald Dudley, Donald J. Goldenberg, Robert L. Hogue, Carol J. Rowland Koch, Matthew A. Parker, Corette B. Pinar, Halit Reddy, Uma M. Saade, George R. Silver, Robert M. Stoll, Barbara J. Varner, Michael W. Willinger, Marian CA Stillbirth Collaborative Res Netwo TI Causes of Death Among Stillbirths SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PERINATAL-MORTALITY; RACIAL DISPARITY; PRENATAL-CARE; UNITED-STATES; FETAL-DEATH; WORK-UP; RATES; RISK; CLASSIFICATION; CRITERIA AB Context Stillbirth affects 1 in 160 pregnancies in the United States, equal to the number of infant deaths each year. Rates are higher than those of other developed countries and have stagnated over the past decade. There is significant racial disparity in the rate of stillbirth that is unexplained. Objective To ascertain the causes of stillbirth in a population that is diverse by race/ethnicity and geography. Design, Setting, and Participants A population-based study from March 2006 to September 2008 with surveillance for all stillbirths at 20 weeks or later in 59 tertiary care and community hospitals in 5 catchment areas defined by state and county boundaries to ensure access to at least 90% of all deliveries. Termination of a live fetus was excluded. Standardized evaluations were performed at delivery. Main Outcome Measures Medical history, fetal postmortem and placental pathology, karyotype, other laboratory tests, systematic assignment of causes of death. Results Of 663 women with stillbirth enrolled, 500 women consented to complete postmortem examinations of 512 neonates. A probable cause of death was found in 312 stillbirths (60.9%; 95% CI, 56.5%-65.2%) and possible or probable cause in 390 (76.2%; 95% CI, 72.2%-79.8%). The most common causes were obstetric conditions (150 [29.3%; 95% CI, 25.4%-33.5%]), placental abnormalities (121 [23.6%; 95% CI, 20.1%-27.6%]), fetal genetic/structural abnormalities (70 [13.7%; 95% CI, 10.9%-17.0%]), infection (66 [12.9%; 95% CI, 10.2%-16.2%]), umbilical cord abnormalities (53 [10.4%; 95% CI, 7.9%-13.4%]), hypertensive disorders (47 [9.2%; 95% CI, 6.9%-12.1%]), and other maternal medical conditions (40 [7.8%; 95% CI, 5.7%-10.6%]). A higher proportion of stillbirths in non-Hispanic black women compared with non-Hispanic white and Hispanic ones was associated with obstetric complications (43.5% [50] vs 23.7% [85]; difference, 19.8%; 95% CI, 9.7%-29.9%; P < .001) and infections (25.2% [29] vs 7.8% [28]; difference, 17.4%; 95% CI, 9.0%-25.8%; P < .001). Stillbirths occurring intrapartum and early in gestation were more common in non-Hispanic black women. Sources most likely to provide positive information regarding cause of death were placental histology (268 [52.3%; 95% CI, 47.9%-56.7%]), perinatal postmortem examination (161 [31.4%; 95% CI, 27.5%-35.7%]), and karyotype (32 of 357 with definitive results [9%; 95% CI, 6.3%-12.5%]). Conclusions A systematic evaluation led to a probable or possible cause in the majority of stillbirths. Obstetric conditions and placental abnormalities were the most common causes of stillbirth, although the distribution differed by race/ethnicity. JAMA. 2011;306(22):2459-2468 C1 [Silver, Robert M.; Varner, Michael W.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT 84132 USA. [Silver, Robert M.; Varner, Michael W.] Intermt Healthcare, Maternal Fetal Med, Salt Lake City, UT USA. [Bukowski, Radek; Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX USA. [Carpenter, Marshall; Coustan, Donald] Brown Univ, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Providence, RI 02912 USA. [Conway, Deborah; Dudley, Donald J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, Div Maternal Fetal Med, San Antonio, TX 78229 USA. [Goldenberg, Robert L.] Drexel Univ, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Hogue, Carol J. Rowland] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Hogue, Carol J. Rowland] Emory Univ, Womens & Childrens Ctr, Atlanta, GA 30322 USA. [Koch, Matthew A.; Parker, Corette B.] RTI Int, Div Hlth Sci, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Pinar, Halit] Brown Univ, Sch Med, Dept Pathol & Lab Med, Div Perinatal & Pediat Pathol, Providence, RI 02912 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA USA. RP Silver, RM (reprint author), Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, 30 N 1900 E,Room 2B200, Salt Lake City, UT 84132 USA. EM bsilver@hsc.utah.edu RI Bukowski, Radek/B-6976-2013; Hogue, Carol/H-5442-2012; Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10-HD045953, U10-HD045925, U10-HD045952, U10-HDO45955, U10-HD045944, U01-HD045954] FX This research was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10-HD045953 Brown University; U10-HD045925 Emory University; U10-HD045952 University of Texas Medical Branch at Galveston; U10-HDO45955 University of Texas Health Sciences Center at San Antonio; U10-HD045944 University of Utah Health Sciences Center; and U01-HD045954 RTI International, RTP. NR 32 TC 113 Z9 113 U1 0 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 14 PY 2011 VL 306 IS 22 BP 2459 EP 2468 DI 10.1001/jama.2011.1823 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 860YB UT WOS:000297983300019 ER PT J AU Bukowski, R Carpenter, M Conway, D Coustan, D Dudley, DJ Goldenberg, RL Hogue, CJR Koch, MA Parker, CB Pinar, H Reddy, UM Saade, GR Silver, RM Stoll, BJ Varner, MW Willinger, M AF Bukowski, Radek Carpenter, Marshall Conway, Deborah Coustan, Donald Dudley, Donald J. Goldenberg, Robert L. Hogue, Carol J. Rowland Koch, Matthew A. Parker, Corette B. Pinar, Halit Reddy, Uma M. Saade, George R. Silver, Robert M. Stoll, Barbara J. Varner, Michael W. Willinger, Marian CA Stillbirth Collaborative Res Netwo TI Association Between Stillbirth and Risk Factors Known at Pregnancy Confirmation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ABO(H) BLOOD-GROUPS; UNITED-STATES; METAANALYSIS; PREVALENCE; DISPARITY; DELIVERY; OBESITY; TRENDS; BIRTHS AB Context Stillbirths account for almost half of US deaths from 20 weeks' gestation to 1 year of life. Most large studies of risk factors for stillbirth use vital statistics with limited data. Objective To determine the relation between stillbirths and risk factors that could be ascertained at the start of pregnancy, particularly the contribution of these factors to racial disparities. Design, Setting, and Participants Multisite population-based case-control study conducted between March 2006 and September 2008. Fifty-nine US tertiary care and community hospitals, with access to at least 90% of deliveries within 5 catchment areas defined by state and county lines, enrolled residents with deliveries of 1 or more stillborn fetuses and a representative sample of deliveries of only live-born infants, over-sampled for those at less than 32 weeks' gestation and those of African descent. Main Outcome Measure Stillbirth. Results Analysis included 614 case and 1816 control deliveries. In multivariate analyses, the following factors were independently associated with stillbirth: non-Hispanic black race/ethnicity (23.1% stillbirths, 11.2% live births) (vs non-Hispanic whites; adjusted odds ratio [AOR], 2.12 [95% CI, 1.41-3.20]); previous stillbirth (6.7% stillbirths, 1.4% live births); nulliparity with (10.5% stillbirths, 5.2% live births) and without (34.0% stillbirths, 29.7% live births) previous losses at fewer than 20 weeks' gestation (vs multiparity without stillbirth or previous losses; AOR, 5.91 [95% CI, 3.18-11.00]; AOR, 3.13 [95% CI, 2.06-4.75]; and AOR, 1.98 [95% CI, 1.51-2.60], respectively); diabetes (5.6% stillbirths, 1.6% live births) (vs no diabetes; AOR, 2.50 [95% CI, 1.39-4.48]); maternal age 40 years or older (4.5% stillbirths, 2.1% live births) (vs age 20-34 years; AOR, 2.41 [95% CI, 1.24-4.70]); maternal AB blood type (4.9% stillbirths, 3.0% live births) (vs type O; AOR, 1.96 [95% CI, 1.16-3.30]); history of drug addiction (4.5% stillbirths, 2.1% live births) (vs never use; AOR, 2.08 [95% CI, 1.12-3.88]); smoking during the 3 months prior to pregnancy (<10 cigarettes/d, 10.0% stillbirths, 6.5% live births) (vs none; AOR, 1.55 [95% CI, 1.02-2.35]); obesity/overweight (15.5% stillbirths, 12.4% live births) (vs normal weight; AOR, 1.72 [95% CI, 1.22-2.43]); not living with a partner (25.4% stillbirths, 15.3% live births) (vs married; AOR, 1.62 [95% CI, 1.15-2.27]); and plurality (6.4% stillbirths, 1.9% live births) (vs singleton; AOR, 4.59 [95% CI, 2.63-8.00]). The generalized R-2 was 0.19, explaining little of the variance. Conclusion Multiple risk factors that would have been known at the time of pregnancy confirmation were associated with stillbirth but accounted for only a small amount of the variance in this outcome. JAMA. 2011;306(22):2469-2479 C1 [Saade, George R.] Univ Texas Med Branch Galveston, Dept Obstet & Gynecol, Div Maternal Fetal Med, Galveston, TX 77555 USA. [Carpenter, Marshall; Coustan, Donald] Brown Univ, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Providence, RI 02912 USA. [Conway, Deborah; Dudley, Donald J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, Div Maternal Fetal Med, San Antonio, TX 78229 USA. [Goldenberg, Robert L.] Drexel Univ, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Hogue, Carol J. Rowland] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Hogue, Carol J. Rowland] Emory Univ, Womens & Childrens Ctr, Atlanta, GA 30322 USA. [Koch, Matthew A.; Parker, Corette B.] RTI Int, Div Hlth Sci, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Pinar, Halit] Brown Univ, Sch Med, Dept Pathol & Lab Med, Div Perinatal & Pediat Pathol, Providence, RI 02912 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Silver, Robert M.; Varner, Michael W.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT 84132 USA. [Silver, Robert M.; Varner, Michael W.] Intermt Healthcare, Maternal Fetal Med, Salt Lake City, UT USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA USA. RP Saade, GR (reprint author), Univ Texas Med Branch Galveston, Dept Obstet & Gynecol, Div Maternal Fetal Med, 301 Univ Blvd, Galveston, TX 77555 USA. EM gsaade@utmb.edu RI Bukowski, Radek/B-6976-2013; Hogue, Carol/H-5442-2012; Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [U10-HD045953, U10-HD045925, U10-HD045952, U10-HDO45955, U10-HD045944, U01-HD045954] FX This study was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health: U10-HD045953 (Brown University, Rhode Island); U10-HD045925 (Emory University, Georgia); U10-HD045952 (University of Texas Medical Branch at Galveston); U10-HDO45955 (University of Texas Health Sciences Center at San Antonio); U10-HD045944 (University of Utah Health Sciences Center); and U01-HD045954 (RTI International, North Carolina). NR 32 TC 61 Z9 61 U1 1 U2 29 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 14 PY 2011 VL 306 IS 22 BP 2469 EP 2479 DI 10.1001/jama.2011.1798 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 860YB UT WOS:000297983300020 ER PT J AU Gadalla, SM Lund, M Pfeiffer, RM Gortz, S Mueller, CM Moxley, RT Kristinsson, SY Bjorkholm, M Shebl, FM Hilbert, JE Landgren, O Wohlfahrt, J Melbye, M Greene, MH AF Gadalla, Shahinaz M. Lund, Marie Pfeiffer, Ruth M. Gortz, Sanne Mueller, Christine M. Moxley, Richard T., III Kristinsson, Sigurdur Y. Bjoerkholm, Magnus Shebl, Fatma M. Hilbert, James E. Landgren, Ola Wohlfahrt, Jan Melbye, Mads Greene, Mark H. TI Cancer Risk Among Patients With Myotonic Muscular Dystrophy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID TRIPLET REPEAT EXPANSION; BASAL-CELL CARCINOMA; HUNTINGTON-DISEASE; TRUE ASSOCIATION; MISMATCH-REPAIR; CTG REPEAT; TYPE-2; GENE; RNA; INSTABILITY AB Context Myotonic muscular dystrophy (MMD) is an autosomal-dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks that have never been quantified. Objective To quantitatively evaluate cancer risk in patients with MMD, overall and by sex and age. Design, Setting, and Participants We identified 1658 patients with an MMD discharge diagnosis in the Swedish Hospital Discharge Register or Danish National Patient Registry between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed up from date of first MMD-related inpatient or outpatient contact to first cancer diagnosis, death, emigration, or completion of cancer registration. Main Outcome Measures Risks of all cancers combined and by anatomic site, stratified by sex and age. Results One hundred four patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during postdischarge follow-up. This corresponds to an observed cancer rate of 73.4 per 10 000 person-years in MMD vs an expected rate of 36.9 per 10 000 person-years in the general Swedish and Danish populations combined (standardized incidence ratio [SIR], 2.0; 95% CI, 1.6-2.4). Specifically, we observed significant excess risks of cancers of the endometrium (n=11; observed rate, 16.1/10 000 person-years; SIR, 7.6; 95% CI, 4.0-13.2), brain (n=7; observed rate, 4.9/10 000 person-years; SIR, 5.3; 95% CI, 2.3-10.4), ovary (n=7; observed rate, 10.3/10 000 person-years; SIR, 5.2; 95% CI, 2.3-10.2), and colon (n=10; observed rate, 7.1/10 000 person-years; SIR, 2.9; 95% CI, 1.5-5.1). Cancer risks were similar in women and men after excluding genital organ tumors (SIR, 1.9; 95% CI, 1.4-2.5, vs SIR, 1.8; 95% CI, 1.3-2.5, respectively; P=.81 for heterogeneity; observed rates, 64.5 and 47.7 per 10 000 person-years in women and men, respectively). The same pattern of cancer excess was observed first in the Swedish and then in the Danish cohorts, which were studied sequentially and initially analyzed independently. Conclusion Patients with MMD identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites. JAMA. 2011;306(22):2480-2486 C1 [Gadalla, Shahinaz M.; Mueller, Christine M.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Shebl, Fatma M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Gadalla, Shahinaz M.] NCI, Ctr Canc Res, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [Lund, Marie; Gortz, Sanne; Wohlfahrt, Jan; Melbye, Mads] Statens Serum Inst, Div Epidemiol, Dept Epidemiol Res, Copenhagen, Denmark. [Moxley, Richard T., III; Hilbert, James E.] Univ Rochester, Med Ctr, Dept Neurol, Neuromuscular Dis Ctr, Rochester, NY 14642 USA. [Kristinsson, Sigurdur Y.; Bjoerkholm, Magnus] Karolinska Univ Hosp Solna, Dept Med, Div Hematol, Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjoerkholm, Magnus] Karolinska Inst, Stockholm, Sweden. RP Greene, MH (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7023, Bethesda, MD 20892 USA. EM greenem@mail.nih.gov RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; Danish Medical Research Council; US National Cancer Institute [N02CP31003-3]; University of Rochester Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center [NIH/U54/NS048843]; National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members [NIH/N01-AR-50-227450]; Clinical and Translational Science Institute and Clinical Research Center (National Center for Research Resources) [NIH UL1 RR024160] FX This research was supported by grants from the Swedish Cancer Society, Stockholm County Council, Karolinska Institutet Foundations, Danish Medical Research Council, Intramural Research Program of the US National Cancer Institute (including contract N02CP31003-3 to Westat), University of Rochester Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (NIH/U54/NS048843), National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members (NIH/N01-AR-50-227450), and Clinical and Translational Science Institute and Clinical Research Center (NIH UL1 RR024160; National Center for Research Resources). NR 41 TC 30 Z9 30 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 14 PY 2011 VL 306 IS 22 BP 2480 EP 2486 DI 10.1001/jama.2011.1796 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 860YB UT WOS:000297983300021 PM 22166607 ER PT J AU Mutuku, FM King, CH Mungai, P Mbogo, C Mwangangi, J Muchiri, EM Walker, ED Kitron, U AF Mutuku, Francis M. King, Charles H. Mungai, Peter Mbogo, Charles Mwangangi, Joseph Muchiri, Eric M. Walker, Edward D. Kitron, Uriel TI Impact of insecticide-treated bed nets on malaria transmission indices on the south coast of Kenya SO MALARIA JOURNAL LA English DT Article ID PAPUA-NEW-GUINEA; PERMETHRIN-IMPREGNATED BEDNETS; HOUSEHOLD RISK-FACTORS; WESTERN KENYA; PLASMODIUM-FALCIPARUM; ANOPHELES-GAMBIAE; SPATIAL-DISTRIBUTION; CHILD-MORTALITY; ENDEMIC AREA; MOSQUITOS AB Background: Besides significantly reducing malaria vector densities, prolonged usage of bed nets has been linked to decline of Anopheles gambiae s.s. relative to Anopheles arabiensis, changes in host feeding preference of malaria vectors, and behavioural shifts to exophagy (outdoor biting) for the two important malaria vectors in Africa, An. gambiae s.l. and Anopheles funestus. In southern coastal Kenya, bed net use was negligible in 1997-1998 when Anopheles funestus and An. gambiae s.s. were the primary malaria vectors, with An. arabiensis and Anopheles merus playing a secondary role. Since 2001, bed net use has increased progressively and reached high levels by 20092010 with corresponding decline in malaria transmission. Methods: To evaluate the impact of the substantial increase in household bed net use within this area on vector density, vector composition, and human-vector contact, indoor and outdoor resting mosquitoes were collected in the same region during 2009-2010 using pyrethrum spray catches and clay pots for indoor and outdoor collections respectively. Information on bed net use per sleeping spaces and factors influencing mosquito density were determined in the same houses using Poisson regression analysis. Species distribution was determined, and number of mosquitoes per house, human-biting rates (HBR), and entomological inoculation rate (EIR) were compared to those reported for the same area during 1997-1998, when bed net coverage had been minimal. Results: Compared to 1997-1998, a significant decline in the relative proportion of An. gambiae s.s. among collected mosquitoes was noted, coupled with a proportionate increase of An. arabiensis. Following > 5 years of 60-86% coverage with bed nets, the density, human biting rate and EIR of indoor resting mosquitoes were reduced by more than 92% for An. funestus and by 75% for An. gambiae s.l. In addition, the host feeding choice of both vectors shifted more toward non-human vertebrates. Besides bed net use, malaria vector abundance was also influenced by type of house construction and according to whether one sleeps on a bed or a mat (both of these are associated with household wealth). Mosquito density was positively associated with presence of domestic animals. Conclusions: These entomological indices indicate a much reduced human biting rate and a diminishing role of An. gambiae s. s. in malaria transmission following high bed net coverage. While increasing bed net coverage beyond the current levels may not significantly reduce the transmission potential of An. arabiensis, it is anticipated that increasing or at least sustaining high bed net coverage will result in a diminished role for An. funestus in malaria transmission. C1 [Mutuku, Francis M.; Kitron, Uriel] Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. [King, Charles H.; Mungai, Peter] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Mbogo, Charles; Mwangangi, Joseph] Kenya Govt Med Res Ctr, Ctr Geog Med Res Coast, Kilifi, Kenya. [Muchiri, Eric M.] Minist Publ Hlth & Sanitat, DVBNTD, Nairobi, Kenya. [Walker, Edward D.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. [Kitron, Uriel] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Mutuku, FM (reprint author), Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. EM fmutuku73@gmail.com OI King, Charles/0000-0001-8349-9270 FU National Institutes of Health/National Science Foundation [R01 TW008067]; Fogarty International Center FX The authors thank communities of all the eight study villages for their continued support. We thank the staff at the DVBNTD especially Robin Bundi, Charles Nganga, Elton Mzungu, Alex Osore and Jackson Muinde for technical assistance in conducting entomological surveys, All community health workers who assisted also during entomological surveys, Shirley Onyango and Garret Berry for assistance with molecular analysis. This work was funded by a program award R01 TW008067 from the National Institutes of Health/National Science Foundation Ecology of Infectious Disease program award funded by the Fogarty International Center to UK and CHK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 50 Z9 51 U1 2 U2 30 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD DEC 13 PY 2011 VL 10 AR 356 DI 10.1186/1475-2875-10-356 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 909VE UT WOS:000301592800001 PM 22165904 ER PT J AU Ene, CI Fine, HA AF Ene, Chibawanye I. Fine, Howard A. TI Many Tumors in One: A Daunting Therapeutic Prospect SO CANCER CELL LA English DT Editorial Material ID STEM-CELLS; GLIOBLASTOMA; CANCER; EVOLUTION AB In this issue of Cancer Cell, Snuderl and coworkers demonstrate intratumoral genetic heterogeneity in glioblastoma based on in situ amplification of distinct genomic loci within individual cells in a mutually exclusive pattern. These findings may herald trouble for current targeted therapies but provide insights for future treatment strategies. C1 [Ene, Chibawanye I.; Fine, Howard A.] NCI, Neurooncol Branch, Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NCI, Neurooncol Branch, Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov NR 10 TC 19 Z9 19 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD DEC 13 PY 2011 VL 20 IS 6 BP 695 EP 697 DI 10.1016/j.ccr.2011.11.018 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 864VV UT WOS:000298269500004 PM 22172718 ER PT J AU Beauvais, G Atwell, K Jayanthi, S Ladenheim, B Cadet, JL AF Beauvais, Genevieve Atwell, Kenisha Jayanthi, Subramaniam Ladenheim, Bruce Cadet, Jean Lud TI Involvement of Dopamine Receptors in Binge Methamphetamine-Induced Activation of Endoplasmic Reticulum and Mitochondrial Stress Pathways SO PLOS ONE LA English DT Article ID UNFOLDED-PROTEIN RESPONSE; INDUCED NEURONAL APOPTOSIS; HEAT-SHOCK-PROTEIN; INDUCED NEUROTOXICITY; RAT-BRAIN; INDUCED HYPERTHERMIA; MESSENGER-RNA; CELL-DEATH; HYBRIDIZATION HISTOCHEMISTRY; TRANSGENIC MICE AB Single large doses of methamphetamine ( METH) cause endoplasmic reticulum ( ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D(1) receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D(1) and D(2) receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D(1) or D(2) receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58(IPK), in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins ( HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D(2)-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors. C1 [Beauvais, Genevieve; Atwell, Kenisha; Jayanthi, Subramaniam; Ladenheim, Bruce; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, Baltimore, MD USA. [Beauvais, Genevieve] Univ Paris 05, Fac Pharm, Paris, France. RP Beauvais, G (reprint author), NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, Baltimore, MD USA. EM jcadet@intra.nida.nih.gov FU National Institutes of Health/National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute on Drug Abuse. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 28 Z9 29 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 13 PY 2011 VL 6 IS 12 AR e28946 DI 10.1371/journal.pone.0028946 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866GA UT WOS:000298367300035 PM 22174933 ER PT J AU Jin, SH Lin, P Hallett, M AF Jin, Seung-Hyun Lin, Peter Hallett, Mark TI Abnormal Reorganization of Functional Cortical Small-World Networks in Focal Hand Dystonia SO PLOS ONE LA English DT Article ID GRAPH-THEORETICAL ANALYSIS; TRANSCRANIAL MAGNETIC STIMULATION; SCIENTIFIC HYPOTHESIS GENERATION; MUTUAL INFORMATION ANALYSIS; PACED FINGER MOVEMENTS; HIGH-RESOLUTION EEG; MOTOR AREAS; SENSORIMOTOR INTEGRATION; OSCILLATORY SYNCHRONY; ALZHEIMERS-DISEASE AB We investigated the large-scale functional cortical connectivity network in focal hand dystonia (FHD) patients using graph theoretic measures to assess efficiency. High-resolution EEGs were recorded in 15 FHD patients and 15 healthy volunteers at rest and during a simple sequential finger tapping task. Mutual information (MI) values of wavelet coefficients were estimated to create an association matrix between EEG electrodes, and to produce a series of adjacency matrices or graphs, G, by thresholding with network cost. Efficiency measures of small-world networks were assessed. As a result, we found that FHD patients have economical small-world properties in their brain functional networks in the alpha and beta bands. During a motor task, in the beta band network, FHD patients have decreased efficiency of small-world networks, whereas healthy volunteers increase efficiency. Reduced efficient beta band network in FHD patients during the task was consistently observed in global efficiency, cost-efficiency, and maximum cost-efficiency. This suggests that the beta band functional cortical network of FHD patients is reorganized even during a task that does not induce dystonic symptoms, representing a loss of long-range communication and abnormal functional integration in large-scale brain functional cortical networks. Moreover, negative correlations between efficiency measures and duration of disease were found, indicating that the longer duration of disease, the less efficient the beta band network in FHD patients. In regional efficiency analysis, FHD patients at rest have high regional efficiency at supplementary motor cortex (SMA) compared with healthy volunteers; however, it is diminished during the motor task, possibly reflecting abnormal inhibition in FHD patients. The present study provides the first evidence with graph theory for abnormal reconfiguration of brain functional networks in FHD during motor task. C1 [Jin, Seung-Hyun; Lin, Peter; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Jin, Seung-Hyun] Seoul Natl Univ Hosp, Dept Neurosurg, Seoul 110744, South Korea. RP Jin, SH (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM hallettm@mail.nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) FX This research was supported by the Intramural Research program of the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 66 TC 13 Z9 13 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 13 PY 2011 VL 6 IS 12 AR e28682 DI 10.1371/journal.pone.0028682 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866GA UT WOS:000298367300021 PM 22174867 ER PT J AU McGlinchey, RP Gruschus, JM Nagy, A Lee, JC AF McGlinchey, Ryan P. Gruschus, James M. Nagy, Attila Lee, Jennifer C. TI Probing Fibril Dissolution of the Repeat Domain of a Functional Amyloid, Pmel17, on the Microscopic and Residue Level SO BIOCHEMISTRY LA English DT Article ID ATOMIC-FORCE MICROSCOPY; ALPHA-SYNUCLEIN; PROTEIN; POLYMORPHISM; AGGREGATION; MELANOSOMES; OLIGOMERS; DISEASE; FIBRILLIZATION; PATHWAYS AB Pmel17 is a human amyloid involved in melanin synthesis. A fragment of Pmel17, the repeat domain (RPT) rich in glutamic acids, forms amyloid only at mildly acidic pH. Unlike pathological amyloids, these fibrils dissolve at neutral pH, supporting a reversible aggregation disaggregation process. Here, we study RPT dissolution using atomic force microscopy and solution-state nuclear magnetic resonance spectroscopy. Our results reveal asymmetric fibril disassembly proceeding in the absence of intermediates. We suggest that fibril unfolding involves multiple deprotonation events resulting in electrostatic charge repulsion and filament dissolution. C1 [McGlinchey, Ryan P.; Gruschus, James M.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Nagy, Attila] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU NIH, NHLBI FX This work was supported by the Intramural Research Program of the NIH, NHLBI. NR 39 TC 12 Z9 12 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 13 PY 2011 VL 50 IS 49 BP 10567 EP 10569 DI 10.1021/bi201578h PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 855XE UT WOS:000297598800001 PM 22092386 ER PT J AU Avella, MA Dean, J AF Avella, Matteo A. Dean, Jurrien TI Fertilization with acrosome-reacted mouse sperm: Implications for the site of exocytosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID GUINEA-PIG SPERMATOZOA; ZONA-PELLUCIDA; IN-VITRO; HAMSTER; INVITRO; BINDING; INTACT; EGGS; PENETRATION; INDUCTION C1 [Avella, Matteo A.; Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM jurrien@helix.nih.gov FU Intramural NIH HHS NR 20 TC 7 Z9 7 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2011 VL 108 IS 50 BP 19843 EP 19844 DI 10.1073/pnas.1118234109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861QR UT WOS:000298034800009 PM 22143800 ER PT J AU Kim, JH Kononenko, A Erliandri, I Kim, TA Nakano, M Iida, Y Barrett, JC Oshimura, M Masumoto, H Earnshaw, WC Larionov, V Kouprina, N AF Kim, Jung-Hyun Kononenko, Artem Erliandri, Indri Kim, Tae-Aug Nakano, Megumi Iida, Yuichi Barrett, J. Carl Oshimura, Mitsuo Masumoto, Hiroshi Earnshaw, William C. Larionov, Vladimir Kouprina, Natalay TI Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene delivery vector; gene therapy; transformation-associated recombination cloning ID NIJMEGEN BREAKAGE SYNDROME; ENGINEERED CHROMOSOMES; HUMAN MINICHROMOSOMES; STEM-CELLS; CONSTRUCTION; EXPRESSION; DELIVERY; DNA; THERAPY; MOUSE AB Human artificial chromosome (HAC)-based vectors offer a promising system for delivery and expression of full-length human genes of any size. HACs avoid the limited cloning capacity, lack of copy number control, and insertional mutagenesis caused by integration into host chromosomes that plague viral vectors. We previously described a synthetic HAC that can be easily eliminated from cell populations by inactivation of its conditional kinetochore. Here, we demonstrate the utility of this HAC, which has a unique gene acceptor site, for delivery of full-length genes and correction of genetic deficiencies in human cells. A battery of functional tests was performed to demonstrate expression of NBS1 and VHL genes from the HAC at physiological levels. We also show that phenotypes arising from stable gene expression can be reversed when cells are "cured" of the HAC by inactivating its kinetochore in proliferating cell populations, a feature that provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This generation of human artificial chromosomes should be suitable for studies of gene function and therapeutic applications. C1 [Kim, Jung-Hyun; Kononenko, Artem; Erliandri, Indri; Larionov, Vladimir; Kouprina, Natalay] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Kim, Tae-Aug] NCI, Lab Tumor & Stem Cell Biol, Bethesda, MD 20892 USA. [Nakano, Megumi; Masumoto, Hiroshi] Kazusa DNA Res Inst, Kisarazu, Chiba 2920818, Japan. [Iida, Yuichi; Oshimura, Mitsuo] Tottori Univ, Inst Regenerat Med & Biofunct, Tottori 6838503, Japan. [Barrett, J. Carl] AstraZeneca, Boston, MA 02451 USA. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH14 4AS, Midlothian, Scotland. RP Kouprina, N (reprint author), NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM kouprinn@mail.nih.gov FU NIH NCI Center for Cancer Research; Ministry of Education, Science, Sports and Culture of Japan; Ministry of Education, Culture, Sports, Science and Technology of Japan; Wellcome Trust FX We thank Hee-Sheung Lee for technical advice and help with microcell-mediated chromosome transfer experiments. We also thank Olga Aprelikova and Bill Bonner [National Cancer Institute (NCI), National Institutes of Health (NIH)] for helpful discussion. This study was supported by the Intramural Research Program of the NIH NCI Center for Cancer Research (V. L.); grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (H. M.); and the 21st Century Center of Excellence program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.O.). Work in the laboratory of W. C. E. is funded by the Wellcome Trust, of which W. C. E. is a principal research fellow. NR 47 TC 30 Z9 31 U1 2 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2011 VL 108 IS 50 BP 20048 EP 20053 DI 10.1073/pnas.1114483108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861QR UT WOS:000298034800046 PM 22123967 ER PT J AU Regard, JB Cherman, N Palmer, D Kuznetsov, SA Celi, FS Guettier, JM Chen, M Bhattacharyya, N Wess, J Coughlin, SR Weinstein, LS Collins, MT Robey, PG Yang, YZ AF Regard, Jean B. Cherman, Natasha Palmer, Daniel Kuznetsov, Sergei A. Celi, Francesco S. Guettier, Jean-Marc Chen, Min Bhattacharyya, Nisan Wess, Jurgen Coughlin, Shaun R. Weinstein, Lee S. Collins, Michael T. Robey, Pamela G. Yang, Yingzi TI Wnt/beta-catenin signaling is differentially regulated by G alpha proteins and contributes to fibrous dysplasia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUPPRESSES OSTEOGENIC DIFFERENTIATION; MCCUNE-ALBRIGHT-SYNDROME; MESENCHYMAL STEM-CELLS; HIGH-BONE-MASS; BETA-CATENIN; PROMOTES PROLIFERATION; INTESTINAL POLYPOSIS; SKELETAL PROGENITORS; PARATHYROID-HORMONE; WNT AB Skeletal dysplasias are common disabling disorders characterized by aberrant growth of bone and cartilage leading to abnormal skeletal structures and functions, often attributable to defects in skeletal progenitor cells. The underlying molecular and cellular mechanisms of most skeletal dysplasias remain elusive. Although the Wnt/beta-catenin signaling pathway is required for skeletal progenitor cells to differentiate along the osteoblastic lineage, inappropriately elevated levels of signaling can also inhibit bone formation by suppressing osteoblast maturation. Here, we investigate interactions of the four major G alpha protein families (G alpha(s), G alpha(i/o), G alpha(q/11), and G alpha(12/13)) with the Wnt/beta-catenin signaling pathway and identify a causative role of Wnt/beta-catenin signaling in fibrous dysplasia (FD) of bone, a disease that exhibits abnormal differentiation of skeletal progenitor cells. The activating G alpha(s) mutations that cause FD potentiated Wnt/beta-catenin signaling, and removal of G alpha(s) led to reduced Wnt/beta-catenin signaling and decreased bone formation. We further show that activation of Wnt/beta-catenin signaling in osteoblast progenitors results in an FD-like phenotype and reduction of beta-catenin levels rescued differentiation defects of FD patient-derived stromal cells. Ga proteins may act at the level of beta-catenin destruction complex assembly by binding Axin. Our results indicate that activated G alpha proteins differentially regulate Wnt/beta-catenin signaling but, importantly, are not required core components of Wnt/beta-catenin signaling. Our data suggest that activated Ga proteins are playing physiologically significant roles during both skeletal development and disease by modulating Wnt/beta-catenin signaling strength. C1 [Regard, Jean B.; Yang, Yingzi] NHGRI, Bethesda, MD 20892 USA. [Cherman, Natasha; Kuznetsov, Sergei A.; Bhattacharyya, Nisan; Collins, Michael T.; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Celi, Francesco S.; Guettier, Jean-Marc; Chen, Min; Wess, Jurgen; Weinstein, Lee S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Palmer, Daniel; Coughlin, Shaun R.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. RP Regard, JB (reprint author), NHGRI, Bethesda, MD 20892 USA. EM regardj@mail.nih.gov; yingzi@mail.nih.gov RI Robey, Pamela/H-1429-2011; Palmer, Daniel/Q-7595-2016 OI Robey, Pamela/0000-0002-5316-5576; FU National Institutes of Health, Department of Health and Human Services FX We thank Dr. J. Silvio Gutkind for generously sharing reagents and for thoughtful discussions, Helen Wimer and Li Li for plastic sections and staining, and Drs. Regis O'Keefe and Lea Gunnell for immunostaining protocols. This study was supported by the Division of Intramural Research of the National Institutes of Health, Department of Health and Human Services. NR 52 TC 27 Z9 33 U1 6 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2011 VL 108 IS 50 BP 20101 EP 20106 DI 10.1073/pnas.1114656108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861QR UT WOS:000298034800055 PM 22106277 ER PT J AU Walker, LM Sok, D Nishimura, Y Donau, O Sadjadpour, R Gautam, R Shingai, M Pejchal, R Ramos, A Simek, MD Geng, Y Wilson, IA Poignard, P Martin, MA Burton, DR AF Walker, Laura M. Sok, Devin Nishimura, Yoshiaki Donau, Olivia Sadjadpour, Reza Gautam, Rajeev Shingai, Masashi Pejchal, Robert Ramos, Alejandra Simek, Melissa D. Geng, Yu Wilson, Ian A. Poignard, Pascal Martin, Malcolm A. Burton, Dennis R. TI Rapid development of glycan-specific, broad, and potent anti-HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MONOCLONAL-ANTIBODIES; IN-VITRO; IMMUNODEFICIENCY; PROTECTION; GLYCOPROTEIN; BINDING; SITE; VIVO; 2G12 AB It is widely believed that the induction of a broadly neutralizing antibody (bNAb) response will be a critical component of a successful vaccine against HIV. A significant fraction of HIV-infected individuals mount bNAb responses, providing support for the notion that such responses could be elicited through vaccination. Infection of macaques with simian immunodeficiency virus (SIV) or SIV/HIV chimeric virus (SHIV) has been widely used to model aspects of HIV infection, but to date, only limited bNAb responses have been described. Here, we screened plasma from 14 R5-tropic SHIV-infected macaques for broadly neutralizing activity and identified a macaque with highly potent cross-clade plasma NAb response. Longitudinal studies showed that the development of broad and autologous NAb responses occurred coincidentally in this animal. Serum-mapping studies, using pseudovirus point mutants and antigen adsorption assays, indicated that the plasma bNAbs are specific for epitopes that include carbohydrates and are critically dependent on the glycan at position 332 of Env gp120. The results described herein provide insight into the development and evolution of a broad response, suggest that certain bNAb specificities may be more rapidly induced by immunization than others, and provide a potential model for the facile study of the development of bNAb responses. C1 [Nishimura, Yoshiaki; Donau, Olivia; Sadjadpour, Reza; Gautam, Rajeev; Shingai, Masashi; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Walker, Laura M.; Sok, Devin; Ramos, Alejandra; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Walker, Laura M.; Sok, Devin; Ramos, Alejandra; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Pejchal, Robert; Wilson, Ian A.] Scripps Res Inst, Dept Mol Biol, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Pejchal, Robert; Wilson, Ian A.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Ramos, Alejandra; Simek, Melissa D.; Poignard, Pascal] Int AIDS Vaccine Initiat, New York, NY 10038 USA. [Geng, Yu] ProSci Inc, Poway, CA 92064 USA. [Burton, Dennis R.] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02142 USA. [Burton, Dennis R.] Harvard Univ, Boston, MA 02142 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM mmartin@niaid.nih.gov; burton@scripps.edu RI poignard, pascal/N-6678-2013 FU International AIDS Vaccine Initiative through Neutralizing Antibody Consortium; National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI33292, AI084817]; Ragon Institute of Massachusetts General Hospital; Massachusetts Institute of Technology; Harvard University FX We thank C. Corbaci, C. Williams, and S. M. Eagol for figure preparation. This study was funded by the International AIDS Vaccine Initiative through Neutralizing Antibody Consortium, National Institute of Allergy and Infectious Diseases, National Institutes of Health Grants AI33292 (to D.R.B.) and AI084817 (to I.A.W.); the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 25 TC 51 Z9 52 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2011 VL 108 IS 50 BP 20125 EP 20129 DI 10.1073/pnas.1117531108 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861QR UT WOS:000298034800059 PM 22123961 ER PT J AU Liu, L Cimbro, R Lusso, P Berger, EA AF Liu, Li Cimbro, Raffaello Lusso, Paolo Berger, Edward A. TI Intraprotomer masking of third variable loop (V3) epitopes by the first and second variable loops (V1V2) within the native HIV-1 envelope glycoprotein trimer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE envelope glycoprotein trimer; functional complementation; Env trimer structure; cis versus trans ID HUMAN-IMMUNODEFICIENCY-VIRUS; COOPERATIVE SUBUNIT INTERACTIONS; HUMAN MONOCLONAL-ANTIBODY; NEUTRALIZING ANTIBODIES; CLADE-A; TYPE-1; GP120; PARTICLES; ENV; COMPLEMENTATION AB Within the trimeric HIV-1 envelope (Env) spike, the first and second variable loops (V1V2 region) and the third variable loop (V3) of the gp120 subunit play dual roles in antibody recognition, because they contain neutralization epitopes and also participate in epitope masking. The spatial relationships between V1V2 and V3 and the associated mechanisms of epitope masking remain unclear. Here we investigated interactions between these domains using two monoclonal antibodies recognizing distinct conserved linear epitopes that are subject to masking in the functional trimer, which limits their neutralizing activities. Using Env pseudotype virus infection assays, we found that deleting the V1V2 region greatly enhanced neutralization by both antibodies, leading us to consider two alternative models: V1V2 on one gp120 protomer masks V3 on the same protomer (intraprotomer or cis masking) versus on an adjacent protomer (interprotomer or trans masking). Our experimental approach exploited a previously described complementation system wherein two variant Envs harboring different inactivating mutations (one in gp120, the other in gp41) are coexpressed in the same cell; functional Env results only from cooperative interactions within mixed trimers, thereby enabling selective examination of mixed trimer activity. We introduced additional mutations that either promoted (V1V2 deletion, i.e., unmasking) or prevented (GPGR to GPGQ mutation, i.e., epitope destruction) interaction with the antibodies. The observed neutralization sensitivities of mixed trimers produced from various combinations of constructs support the intraprotomer (cis) model of V1V2 masking of V3 epitopes. C1 [Liu, Li; Berger, Edward A.] NIAID, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. [Cimbro, Raffaello; Lusso, Paolo] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, Lab Viral Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM edward_berger@nih.gov RI Liu, Li/B-3545-2012; OI Cimbro, Raffaello/0000-0002-6251-5160 FU National Institutes of Health National Institute of Allergy and Infectious Diseases FX We thank Virgilio Bundoc for excellent technical assistance; Sriram Subramaniam for critical commentary on the manuscript; and John Mascola, Robert Doms, Susan Zolla-Pazner, Carol Weiss, Bernard Moss, Dennis Burton, and Shirley Leow for generous donation of reagents. This research was funded in part by the National Institutes of Health National Institute of Allergy and Infectious Diseases Intramural Program. NR 51 TC 37 Z9 38 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2011 VL 108 IS 50 BP 20148 EP 20153 DI 10.1073/pnas.1104840108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861QR UT WOS:000298034800063 PM 22128330 ER PT J AU Bosmans, F Milescu, M Swartz, KJ AF Bosmans, Frank Milescu, Mirela Swartz, Kenton J. TI Palmitoylation influences the function and pharmacology of sodium channels SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cholesterol; lipid microdomains; sphingomyelin ID DEPENDENT K+ CHANNEL; PERFORMANCE LIQUID-CHROMATOGRAPHY; VOLTAGE-SENSOR; TARANTULA TOXINS; PROTEIN PALMITOYLATION; GATING MODIFIER; LIPID-MEMBRANE; SCORPION TOXIN; ALPHA-SUBUNIT; ION CHANNELS AB Palmitoylation is a common lipid modification known to regulate the functional properties of various proteins and is a vital step in the biosynthesis of voltage-activated sodium (Nav) channels. We discovered a mutation in an intracellular loop of rNav1.2a (G1079C), which results in a higher apparent affinity for externally applied PaurTx3 and ProTx-II, two voltage sensor toxins isolated from tarantula venom. To explore whether palmitoylation of the introduced cysteine underlies this observation, we compared channel susceptibility to a range of animal toxins in the absence and presence of 2-Br-palmitate, a palmitate analog that prevents palmitate incorporation into proteins, and found that palmitoylation contributes to the increased affinity of PaurTx3 and ProTx-II for G1079C. Further investigations with 2-Br-palmitate revealed that palmitoylation can regulate the gating and pharmacology of wild-type (wt) rNav1.2a. To identify rNav1.2a palmitoylation sites contributing to these phenomena, we substituted three endogenous cysteines predicted to be palmitoylated and found that the gating behavior of this triple cysteine mutant is similar to wt rNav1.2a treated with 2-Br-palmitate. As with chemically depalmitoylated rNav1.2a channels, this mutant also exhibits an increased susceptibility for PaurTx3. Additional mutagenesis experiments showed that palmitoylation of one cysteine in particular (C1182) primarily influences PaurTx3 sensitivity and may enhance the inactivation process of wt rNav1.2a. Overall, our results demonstrate that lipid modifications are capable of altering the gating and pharmacological properties of rNav1.2a. C1 [Bosmans, Frank; Milescu, Mirela; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bosmans, F (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM bosmansf@ninds.nih.gov; swartzk@ninds.nih.gov RI Bosmans, Frank/A-9660-2013 OI Bosmans, Frank/0000-0002-6476-235X NR 72 TC 17 Z9 17 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2011 VL 108 IS 50 BP 20213 EP 20218 DI 10.1073/pnas.1108497108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861QR UT WOS:000298034800074 PM 22123950 ER PT J AU Bellizzi, KM Breslau, ES Burness, A Waldron, W AF Bellizzi, Keith M. Breslau, Erica S. Burness, Allison Waldron, William TI Prevalence of Cancer Screening in Older, Racially Diverse Adults Still Screening After All These Years SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID UNITED-STATES; TRENDS; OPPORTUNITIES; BREAST; RISK; MEN AB Background: While a great deal is known about cancer screening behaviors and trends in young and middle-aged adults, little is known about screening behaviors in older adults from different racial backgrounds. Our goal was to establish prevalence estimates and correlates of cancer screening, including physician recommendation in older (>75 years), racially diverse adults. Methods: Data were analyzed from the National Health Interview Survey-an annual, in-person, nationwide survey used to track health trends in US civilians. The analytic sample included 49 575 individuals, of whom 1697 were 75 to 79 years old and 2376 were 80 years or older. Screening behaviors were examined according to the US Preventive Services Task Force recommendations for breast, cervical, colorectal, and prostate cancer screening. Results: Among adults aged 75 to 79 years, the percentage screened for cancer was as follows: colorectal, 57%; breast, 62%; cervical, 53%; and prostate, 56%. Among those 80 years or older, rates of screening ranged from a low of 38% for cervical cancer to a high of 50% for breast cancer. Although unadjusted screening prevalence rates differed by race/ethnicity, these differences were accounted for by low education attainment in the multivariate logistic regression model. Physician recommendation for a specific test was the largest predictor of screening. Over 50% of men and women older than 75 years report that their physicians continue to recommend screening. Conclusion: A high percentage of older adults continue to be screened in the face of ambiguity of recommendations for this group. C1 [Bellizzi, Keith M.] Univ Connecticut, Dept Human Dev & Family Studies, Storrs, CT 06269 USA. [Breslau, Erica S.; Burness, Allison] NCI, Appl Canc Screening Res Branch, Bethesda, MD 20892 USA. [Waldron, William] Informat Management Serv Inc IMS, Silver Spring, MD USA. RP Bellizzi, KM (reprint author), Univ Connecticut, Dept Human Dev & Family Studies, 348 Mansfield Rd,Unit 2058, Storrs, CT 06269 USA. EM keith.m.bellizzi@uconn.edu FU National Cancer Institute FX Dr Bellizzi received compensation from the National Cancer Institute for this work. NR 24 TC 31 Z9 31 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD DEC 12 PY 2011 VL 171 IS 22 BP 2031 EP 2037 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 860VD UT WOS:000297975100011 PM 22158573 ER PT J AU Chatterjee, SS Chen, L Joo, HS Cheung, GYC Kreiswirth, BN Otto, M AF Chatterjee, Som S. Chen, Liang Joo, Hwang-Soo Cheung, Gordon Y. C. Kreiswirth, Barry N. Otto, Michael TI Distribution and Regulation of the Mobile Genetic Element-Encoded Phenol-Soluble Modulin PSM-mec in Methicillin-Resistant Staphylococcus aureus SO PLOS ONE LA English DT Article ID VIRULENCE; AGR; IDENTIFICATION; EVOLUTION; PEPTIDES AB The phenol-soluble modulin PSM-mec is the only known staphylococcal toxin that is encoded on a mobile antibiotic resistance determinant, namely the staphylococcal cassette chromosome (SCC) element mec encoding resistance to methicillin. Here we show that the psm-mec gene is found frequently among methicillin-resistant Staphylococcus aureus (MRSA) strains of SCCmec types II, III, and VIII, and is a conserved part of the class A mec gene complex. Controlled expression of AgrA versus RNAIII in agr mutants of all 3 psm-mec-positive SCCmec types demonstrated that expression of psm-mec, which is highly variable, is controlled by AgrA in an RNAIII-independent manner. Furthermore, psm-mec isogenic deletion mutants showed only minor changes in PSM alpha peptide production and unchanged (or, as previously described, diminished) virulence compared to the corresponding wild-type strains in a mouse model of skin infection. This indicates that the recently reported regulatory impact of the psm-mec locus on MRSA virulence, which is opposite to that of the PSM-mec peptide and likely mediated by a regulatory RNA, is minor when analyzed in the original strain background. Our study gives new insight in the distribution, regulation, and role in virulence of the PSM-mec peptide and the psm-mec gene locus. C1 [Chatterjee, Som S.; Joo, Hwang-Soo; Cheung, Gordon Y. C.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Chen, Liang; Kreiswirth, Barry N.] Univ Med & Dent New Jersey, Publ Hlth Res Inst, TB Ctr, Newark, NJ 07103 USA. RP Chatterjee, SS (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov RI Cheung, Yiu Chong /K-3565-2012; Chen, Liang/D-3583-2009; OI JOO, HWANG-SOO/0000-0003-4668-3225; Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), The National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 28 Z9 34 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 12 PY 2011 VL 6 IS 12 AR e28781 DI 10.1371/journal.pone.0028781 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866FT UT WOS:000298366600038 PM 22174895 ER PT J AU Guo, W Wu, SH Wang, L Wei, XL Liu, XY Wang, J Lu, ZM Hollingshead, M Fang, BL AF Guo, Wei Wu, Shuhong Wang, Li Wei, Xiaoli Liu, Xiaoying Wang, Ji Lu, Zhimin Hollingshead, Melinda Fang, Bingliang TI Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition SO PLOS ONE LA English DT Article ID RNA-POLYMERASE-II; HUMAN CANCER-CELLS; INDUCED APOPTOSIS; SELICICLIB CYC202; MULTIPLE-MYELOMA; DOWN-REGULATION; SMALL-MOLECULE; R-ROSCOVITINE; P-TEFB; FLAVOPIRIDOL AB Background: To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1. Methodology and Principal Findings: In vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI(50)) for eight of the most sensitive cell lines was <= 10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity. Conclusions: NSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors. C1 [Guo, Wei; Wu, Shuhong; Wang, Li; Wei, Xiaoli; Liu, Xiaoying; Wang, Ji; Fang, Bingliang] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA. [Lu, Zhimin] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Hollingshead, Melinda] NCI, Biol Testing Branch, Frederick, MD 21701 USA. RP Guo, W (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA. EM Bfang@mdanderson.org FU National Institutes of Health (NIH) [R01 CA 092481, R01 CA 124951]; Rapid Access to Interventional Development (RAID) Program; Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), NIH; University of Texas MD Anderson Cancer Center [CA-016672]; National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This work was supported in part by the National Institutes of Health (NIH) through R01 CA 092481 and R01 CA 124951 to B. Fang, the Rapid Access to Interventional Development (RAID) Program, the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), NIH, The University of Texas MD Anderson Cancer Center Support Grant CA-016672, Lung Program, Nuclear Magnetic Resonance, DNA Analysis and Flow Cytometry, and Cellular Imaging Core Facility. Additional support was provided with federal funds from the National Cancer Institute, National Institutes of Health, under contract NO1-CO-12400. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 14 Z9 15 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 12 PY 2011 VL 6 IS 12 AR e28487 DI 10.1371/journal.pone.0028487 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866FT UT WOS:000298366600021 PM 22174819 ER PT J AU Paukner, A Ferrari, PF Suomi, SJ AF Paukner, Annika Ferrari, Pier F. Suomi, Stephen J. TI Delayed Imitation of Lipsmacking Gestures by Infant Rhesus Macaques (Macaca mulatta) SO PLOS ONE LA English DT Article ID NEONATAL IMITATION; TONGUE PROTRUSION; FACIAL GESTURES; MANUAL GESTURES; NEURONS AB Human infants are capable of accurately matching facial gestures of an experimenter within a few hours after birth, a phenomenon called neonatal imitation. Recent studies have suggested that rather than being a simple reflexive-like behavior, infants exert active control over imitative responses and 'provoke' previously imitated gestures even after a delay of up to 24 h. Delayed imitation is regarded as the hallmark of a sophisticated capacity to control and flexibly engage in affective communication and has been described as an indicator of innate protoconversational readiness. However, we are not the only primates to exhibit neonatal imitation, and delayed imitation abilities may not be uniquely human. Here we report that 1-week-old infant rhesus macaques (Macaca mulatta) who show immediate imitation of a lipsmacking gesture also show delayed imitation of lipsmacking, facilitated by a tendency to refrain from lipsmacking toward a still face during baseline measurements. Individual differences in delayed imitation suggest that differentially matured cortical mechanisms may be involved, allowing some newborns macaques to actively participate in communicative exchanges from birth. Macaque infants are endowed with basic social competencies of intersubjective communication that indicate cognitive and emotional commonality between humans and macaques, which may have evolved to nurture an affective mother-infant relationship in primates. C1 [Paukner, Annika; Suomi, Stephen J.] NIH, Comparat Ethol Lab, Anim Ctr, Poolesville, MD USA. [Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Ferrari, Pier F.] Univ Parma, Dipartimento Biol Evolut & Funz, I-43100 Parma, Italy. RP Paukner, A (reprint author), NIH, Comparat Ethol Lab, Anim Ctr, Poolesville, MD USA. EM pauknera@mail.nih.gov FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01 HD064653] FX This research was supported by the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development. PFF was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development P01 HD064653. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 16 Z9 16 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 12 PY 2011 VL 6 IS 12 AR e28848 DI 10.1371/journal.pone.0028848 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866FT UT WOS:000298366600044 PM 22174913 ER PT J AU Simoes, T Charro, N Blonder, J Faria, D Couto, FM Chan, KC Waybright, T Isaaq, HJ Veenstra, TD Penque, D AF Simoes, Tania Charro, Nuno Blonder, Josip Faria, Daniel Couto, Francisco M. Chan, King C. Waybright, Timothy Isaaq, Haleem J. Veenstra, Timothy D. Penque, Deborah TI Molecular profiling of the human nasal epithelium: A proteomics approach SO JOURNAL OF PROTEOMICS LA English DT Article DE Nasal epithelium; Upper and lower airways; Cellular fractionation; Two-dimensional liquid chromatography; Multidimensional chromatographic separations; Tandem mass spectrometry; Functional analysis ID FIBROSIS LUNG-DISEASE; CYSTIC-FIBROSIS; MEMBRANE-PROTEINS; MASS-SPECTROMETRY; ION-TRANSPORT; SIGNALING PATHWAY; OXIDATIVE STRESS; AIRWAY CELLS; IN-VIVO; ASTHMA AB A comprehensive proteomic profiling of nasal epithelium (NE) is described. This study relies on simple subcellular fractionation used to obtain soluble- and membrane-enriched fractions followed by 2-dimensional liquid chromatography (2D-LC) separation and tandem mass spectrometry (MS/MS). The cells were collected using a brushing technique applied on NE of clinically evaluated volunteers. Subsequently, the soluble- and the membrane-protein enriched fractions were prepared and analyzed in parallel using 2D-LC-MS/MS. In a set of 1482 identified proteins, 947 (63.9%) proteins were found to be associated to membrane fraction. Grand average hydropathy value index (GRAVY) analysis, the transmembrane protein mapping and annotations of primary location deposited in the Human Protein Reference Database (HPRD) confirmed an enrichment of hydrophobic proteins on this dataset. Ingenuity Pathway Analysis (IPA) of soluble fraction revealed an enrichment of molecular and cellular functions associated with cell death, protein folding and drug metabolism while in membrane fraction showed an enrichment of functions associated with molecular transport, protein trafficking and cell-to-cell signaling and interaction. The IPA showed similar enrichment of functions associated with cellular growth and proliferation in both soluble and membrane subproteomes. This finding was in agreement with protein content analysis using exponentially modified protein abundance index (emPAI). A comparison of our data with previously published studies focusing on respiratory tract epithelium revealed similarities related to identification of proteins associated with physical barrier function and immunological defence. In summary, we extended the NE molecular profile by identifying and characterizing proteins associated to pivotal functions of a respiratory epithelium, including the control of fluid volume and ionic composition at the airways' surface, physical barrier maintenance, detoxification and immunological defence. The extent of similarities supports the applicability of a less invasive analysis of NE to assess prognosis and treatment response of lung diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. (C) 2011 Elsevier B.V. All rights reserved. C1 [Simoes, Tania; Charro, Nuno; Penque, Deborah] INSA, Inst Nacl Saude Dr Ricardo Jorge, Dept Genet, Lab Prote,IP, P-1649016 Lisbon, Portugal. [Blonder, Josip; Chan, King C.; Waybright, Timothy; Isaaq, Haleem J.; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Frederick, MD 21701 USA. [Faria, Daniel; Couto, Francisco M.] Univ Lisbon, Fac Ciencias, Dept Informat, Lisbon, Portugal. RP Penque, D (reprint author), INSA, Inst Nacl Saude Dr Ricardo Jorge, Dept Genet, Lab Prote,IP, Edificio INSA 2,Ave Padre Cruz, P-1649016 Lisbon, Portugal. EM deborah.penque@insa.min-saude.pt RI Simoes, Tania/A-8584-2013; Penque, Deborah/F-4830-2013; Couto, Francisco/A-4066-2010; OI Penque, Deborah/0000-0002-4527-7148; Couto, Francisco/0000-0003-0627-1496; Faria, Daniel/0000-0003-1511-277X FU Fundacao para Ciencia e Tecnologia (FCT) [POCI/SAU-MMO/56163/2004]; FCT-Poly Annual Funding; FEDER-Saude XXI FX Tania Simoes and Nuno Charro were supported by Fundacao para Ciencia e Tecnologia (FCT) fellowships. The present study was partially financed by FCT (research grant POCI/SAU-MMO/56163/2004), FCT-Poly Annual Funding and FEDER-Saude XXI. Authors would like to acknowledge all volunteers and donors of nasal epithelium specimens and doctors for their valuable cooperation in this study. NR 82 TC 7 Z9 7 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD DEC 10 PY 2011 VL 75 IS 1 SI SI BP 56 EP 69 DI 10.1016/j.jprot.2011.05.012 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 871AQ UT WOS:000298710400007 PM 21621024 ER PT J AU Korn, EL Freidlin, B Abrams, JS AF Korn, Edward L. Freidlin, Boris Abrams, Jeffrey S. TI Survival Is Not a Good Outcome for Randomized Trials With Effective Subsequent Therapies Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Korn, Edward L.; Freidlin, Boris; Abrams, Jeffrey S.] NCI, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2011 VL 29 IS 35 BP 4720 EP 4721 DI 10.1200/JCO.2011.38.5195 PG 3 WC Oncology SC Oncology GA 863CZ UT WOS:000298141700031 ER PT J AU Parra, M Derrick, SC Yang, A Tian, JH Kolibab, K Oakley, M Perera, LP Jacobs, WR Kumar, S Morris, SL AF Parra, Marcela Derrick, Steven C. Yang, Amy Tian, JinHua Kolibab, Kristopher Oakley, Miranda Perera, Liyanage P. Jacobs, William R. Kumar, Sanjai Morris, Sheldon L. TI Malaria Infections Do Not Compromise Vaccine-Induced Immunity against Tuberculosis in Mice SO PLOS ONE LA English DT Article ID CALMETTE-GUERIN VACCINE; MYCOBACTERIUM-TUBERCULOSIS; PROTECTIVE IMMUNITY; BOVIS BCG; ENVIRONMENTAL MYCOBACTERIA; PUBLISHED LITERATURE; PLASMODIUM-YOELII; TGF-BETA; IN-VITRO; T-CELLS AB Background: Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis. Principal Findings: Here we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naive mice. Multi-parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-gamma, TNF-alpha, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL. Conclusions: Our data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the deployment of new TB vaccines in malaria endemic areas. C1 [Parra, Marcela; Derrick, Steven C.; Yang, Amy; Tian, JinHua; Kolibab, Kristopher; Oakley, Miranda; Morris, Sheldon L.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Review, Bethesda, MD 20014 USA. [Perera, Liyanage P.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jacobs, William R.] Yeshiva Univ Albert Einstein Coll Med, Howard Hughes Med Inst, Bronx, NY 10461 USA. [Jacobs, William R.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Kumar, Sanjai] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Review, Bethesda, MD 20014 USA. RP Parra, M (reprint author), US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Review, Bethesda, MD 20014 USA. EM steven.derrick@fda.hhs.gov FU FDA FX Annual lab budget allocation from the FDA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 3 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 9 PY 2011 VL 6 IS 12 AR e28164 DI 10.1371/journal.pone.0028164 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 870JO UT WOS:000298665600004 PM 22205939 ER PT J AU Paul, WE AF Paul, William E. TI Bridging Innate and Adaptive Immunity SO CELL LA English DT Editorial Material ID PERIPHERAL LYMPHOID ORGANS; DENDRITIC CELLS; IN-VIVO; MICE; UNRESPONSIVENESS; IDENTIFICATION; GENE C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov NR 15 TC 11 Z9 11 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 9 PY 2011 VL 147 IS 6 BP 1212 EP 1215 DI 10.1016/j.cell.2011.11.036 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 863FL UT WOS:000298148100007 PM 22153065 ER PT J AU Hu, JJ Prinz, WA Rapoport, TA AF Hu, Junjie Prinz, William A. Rapoport, Tom A. TI Weaving the Web of ER Tubules SO CELL LA English DT Review ID HEREDITARY SPASTIC PARAPLEGIA; ENDOPLASMIC-RETICULUM; MITOCHONDRIAL FUSION; MEMBRANE-PROTEINS; HOMOTYPIC FUSION; GOLGI-APPARATUS; ATLASTIN; MICROTUBULES; MECHANISMS; REVEALS C1 [Hu, Junjie] Nankai Univ, Dept Genet & Cell Biol, Coll Life Sci, Tianjin 300071, Peoples R China. [Hu, Junjie] Nankai Univ, Tianjin Key Lab Prot Sci, Tianjin 300071, Peoples R China. [Prinz, William A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Rapoport, Tom A.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Cell Biol, Boston, MA 02115 USA. RP Hu, JJ (reprint author), Nankai Univ, Dept Genet & Cell Biol, Coll Life Sci, Tianjin 300071, Peoples R China. EM huj@nankai.edu.cn; tom_rapoport@hms.harvard.edu RI Hu, Junjie/F-9713-2013 FU National Basic Research Program of China (973 Program) [2010CB833702]; National Institute of Diabetes and Digestive and Kidney Diseases FX J.H. is supported by the National Basic Research Program of China (973 Program, Grant 2010CB833702). W.A.P. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. T.A.R. is a Howard Hughes Medical Institute Investigator. NR 31 TC 62 Z9 62 U1 3 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 9 PY 2011 VL 147 IS 6 BP 1226 EP 1231 DI 10.1016/j.cell.2011.11.022 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 863FL UT WOS:000298148100013 PM 22153070 ER PT J AU Chen, Y Zhang, Y Liu, YQ Matkovich, SJ Murphy, E Dorn, GW AF Chen, Yun Zhang, Yan Liu, Yingqiu Matkovich, Scot J. Murphy, Elizabeth Dorn, Gerald W., II TI A Parkin-Mitofusin Interaction Directs Cardiac Mitochondria! Culling Independent of Mitochondrial Fusion SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT American-Heart-Association Scientific Sessions on Resuscitation Science Symposium CY NOV 12-16, 2011 CL Orlando, FL SP Amer Heart Assoc DE Cardiovascular development; Mitochondrial energetics, heart failure, arrhythmias C1 [Chen, Yun; Zhang, Yan; Liu, Yingqiu; Matkovich, Scot J.; Dorn, Gerald W., II] Washington Univ, St Louis, MO USA. [Murphy, Elizabeth] NHLBI, Syst Biol Cntr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 9 PY 2011 VL 109 IS 12 BP E57 EP E57 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 863MD UT WOS:000298167400006 ER PT J AU DeRouchey, JE Rau, DC AF DeRouchey, Jason E. Rau, Donald C. TI Role of Amino Acid Insertions on Intermolecular Forces between Arginine Peptide Condensed DNA Helices IMPLICATIONS FOR PROTAMINE-DNA PACKAGING IN SPERM SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID X-RAY-DIFFRACTION; NUCLEOPROTAMINE STRUCTURE; HYDRATION FORCES; COMPLEXES; FRAGMENTATION; AGGREGATION; SPERMATOZOA; POLYAMINES; MOLECULES; CHROMATIN AB In spermatogenesis, chromatin histones are replaced by arginine-rich protamines to densely compact DNA in sperm heads. Tight packaging is considered necessary to protect the DNA from damage. To better understand the nature of the forces condensing protamine-DNA assemblies and their dependence on amino acid content, the effect of neutral and negatively charged amino acids on DNA-DNA intermolecular forces was studied using model peptides containing six arginines. We have previously observed that the neutral amino acids in salmon protamine decrease the net attraction between protamine-DNA helices compared with the equivalent homo-arginine peptide. Using osmotic stress coupled with x-ray scattering, we have investigated the component attractive and repulsive forces that determine the net attraction and equilibrium interhelical distance as a function of the chemistry, position, and number of the amino acid inserted. Neutral amino acids inserted into hexa-arginine increase the short range repulsion while only slightly affecting longer range attraction. The amino acid content alone of salmon protamine is enough to rationalize the forces that package DNA in sperm heads. Inserting a negatively charged amino acid into hexa-arginine dramatically weakens the net attraction. Both of these observations have biological implications for protamine-DNA packaging in sperm heads. C1 [DeRouchey, Jason E.] Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. [Rau, Donald C.] NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP DeRouchey, JE (reprint author), Univ Kentucky, Dept Chem, 125 Chem Phys Bldg, Lexington, KY 40506 USA. EM derouchey@uky.edu RI DeRouchey, Jason/C-5907-2011 OI DeRouchey, Jason/0000-0002-3624-4432 FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Eunice Kennedy Shriver Intramural Research Program. NR 42 TC 10 Z9 11 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 DEC 9 PY 2011 VL 286 IS 49 BP 41985 EP 41992 DI 10.1074/jbc.M111.295808 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863QI UT WOS:000298180900009 PM 21994948 ER PT J AU Abuhatzira, L Shamir, A Schones, DE Schaffer, AA Bustin, M AF Abuhatzira, Liron Shamir, Alon Schones, Dustin E. Schaeffer, Alejandro A. Bustin, Michael TI The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; AUTISM SPECTRUM DISORDERS; DOWN-SYNDROME PHENOTYPES; RETT-SYNDROME; CHROMOSOMAL-PROTEINS; NEUROLOGICAL DISEASE; HISTONE DEACETYLASE; NEURONAL MECP2; MOUSE; TRANSCRIPTION AB High mobility group N1 protein (HMGN1), a nucleosomal-binding protein that affects the structure and function of chromatin, is encoded by a gene located on chromosome 21 and is overexpressed in Down syndrome, one of the most prevalent genomic disorders. Misexpression of HMGN1 affects the cellular transcription profile; however, the biological function of this protein is still not fully understood. We report that HMGN1 modulates the expression of methyl CpG-binding protein 2 (MeCP2), a DNA-binding protein known to affect neurological functions including autism spectrum disorders, and whose alterations in HMGN1 levels affect the behavior of mice. Quantitative PCR and Western analyses of cell lines and brain tissues from mice that either overexpress or lack HMGN1 indicate that HMGN1 is a negative regulator of MeCP2 expression. Alterations in HMGN1 levels lead to changes in chromatin structure and histone modifications in the MeCP2 promoter. Behavior analyses by open field test, elevated plus maze, Reciprocal Social Interaction, and automated sociability test link changes in HMGN1 levels to abnormalities in activity and anxiety and to social deficits in mice. Targeted analysis of the Autism Genetic Resource Exchange genotype collection reveals a non-random distribution of genotypes within 500 kbp of HMGN1 in a region affecting its expression in families predisposed to autism spectrum disorders. Our results reveal that HMGN1 affects the behavior of mice and suggest that epigenetic changes resulting from altered HMGN1 levels could play a role in the etiology of neurodevelopmental disorders. C1 [Abuhatzira, Liron; Bustin, Michael] NCI, Prot Sect, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Shamir, Alon] NICHD, Bethesda, MD 20892 USA. [Schones, Dustin E.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. RP Bustin, M (reprint author), Bldg 37,Rm 3122, Bethesda, MD 20892 USA. EM Bustin@helix.nih.gov RI Schaffer, Alejandro/F-2902-2012; Bustin, Michael/G-6155-2015 FU National Institutes of Health Center for Cancer Research; NCI; National Library of Medicine; NIMH, National Institutes of Health [1U24MH081810] FX This work was supported, in whole or in part, by National Institutes of Health Center for Cancer Research, the intramural program of the NCI, and by the Intramural Research Program of the National Library of Medicine.; Human brain tissue was obtained from the NICHD, National Institutes of Health Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. We acknowledge the resources provided by the AGRE Consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by NIMH, National Institutes of Health Grant 1U24MH081810 (to Dr. Clara M. Lajonchere). We thank Dr. Vlad Kustanovich at AGRE for answering numerous questions, Dr. Stefan Wuchty for extracting the FHS data from dbGa-Pand, and Dr. Mu Yang, NIMH, National Institutes of Health for critical review of the mouse behavior test results. NR 68 TC 22 Z9 22 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 9 PY 2011 VL 286 IS 49 BP 42051 EP 42062 DI 10.1074/jbc.M111.300541 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863QI UT WOS:000298180900015 PM 22009741 ER PT J AU Jayaraman, T Tejero, J Chen, BB Blood, AB Frizzell, S Shapiro, C Tiso, M Hood, BL Wang, XD Zhao, XJ Conrads, TP Mallampalli, RK Gladwin, MT AF Jayaraman, Thottala Tejero, Jesus Chen, Bill B. Blood, Arlin B. Frizzell, Sheila Shapiro, Calli Tiso, Mauro Hood, Brian L. Wang, Xunde Zhao, Xuejun Conrads, Thomas P. Mallampalli, Rama K. Gladwin, Mark T. TI 14-3-3 Binding and Phosphorylation of Neuroglobin during Hypoxia Modulate Six-to-Five Heme Pocket Coordination and Rate of Nitrite Reduction to Nitric Oxide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; INDUCIBLE FACTOR-1-ALPHA; OXIDATIVE STRESS; GLOBIN FAMILY; PROTEIN; BRAIN; CYTOGLOBIN; ACTIVATION; CELLS; MECHANISMS AB Neuroglobin protects neurons from hypoxia in vitro and in vivo; however, the underlying mechanisms for this effect remain poorly understood. Most of the neuroglobin is present in a hexacoordinate state with proximal and distal histidines in the heme pocket directly bound to the heme iron. At equilibrium, the concentration of the five-coordinate neuroglobin remains very low (0.1-5%). Recent studies have shown that post-translational redox regulation of neuroglobin surface thiol disulfide formation increases the open probability of the heme pocket and allows nitrite binding and reaction to form NO. We hypothesized that the equilibrium between the six-and five-coordinate states and secondary reactions with nitrite to form NO could be regulated by other hypoxia-dependent post-translational modification(s). Protein sequence models identified candidate sites for both 14-3-3 binding and phosphorylation. In both in vitro experiments and human SH-SY5Y neuronal cells exposed to hypoxia and glucose deprivation, we observed that 1) neuroglobin phosphorylation and protein-protein interactions with 14-3-3 increase during hypoxic and metabolic stress; 2) neuroglobin binding to 14-3-3 stabilizes and increases the half-life of phosphorylation; and 3) phosphorylation increases the open probability of the heme pocket, which increases ligand binding (CO and nitrite) and accelerates the rate of anaerobic nitrite reduction to form NO. These data reveal a series of hypoxia-dependent post-translational modifications to neuroglobin that regulate the six-to-five heme pocket equilibrium and heme access to ligands. Hypoxia-regulated reactions of nitrite and neuroglobin may contribute to the cellular adaptation to hypoxia. C1 [Hood, Brian L.; Conrads, Thomas P.; Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15261 USA. [Jayaraman, Thottala; Tejero, Jesus; Frizzell, Sheila; Shapiro, Calli; Tiso, Mauro; Zhao, Xuejun; Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Jayaraman, Thottala; Chen, Bill B.; Mallampalli, Rama K.; Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Dept Med, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. [Wang, Xunde] NHLBI, NIH, Bethesda, MD 20892 USA. [Blood, Arlin B.] Loma Linda Univ, Sch Med, Dept Pediat, Div Neonatol, Loma Linda, CA 92354 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15261 USA. EM gladwinmt@upmc.edu OI Tejero, Jesus/0000-0003-3245-9978 FU National Institutes of Health [R01 HL098032, R01 HL096973, P01 HL103455, R01 HL096376, R01 HL097376, R01 HL098174]; Institute for Transfusion Medicine; Hemophilia Center of Western Pennsylvania FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 HL098032, R01 HL096973, and P01 HL103455 (to M. T. G.) and R01 HL096376, R01 HL097376, and R01 HL098174 (to R. K. M.). This work was also supported by the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania (to M. T. G.). M. Tiso and M. T. Gladwin are listed as co-inventors on a patent application entitled "Neuroglobin as a Six-to-Five Coordinate-regulated Nitrite Reductase." NR 48 TC 29 Z9 31 U1 2 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 9 PY 2011 VL 286 IS 49 BP 42679 EP 42689 DI 10.1074/jbc.M111.271973 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863QI UT WOS:000298180900075 PM 21965683 ER PT J AU Bisanzio, D Giacobini, M Bertolotti, L Mosca, A Balbo, L Kitron, U Vazquez-Prokopec, GM AF Bisanzio, Donal Giacobini, Mario Bertolotti, Luigi Mosca, Andrea Balbo, Luca Kitron, Uriel Vazquez-Prokopec, Gonzalo M. TI Spatio-temporal patterns of distribution of West Nile virus vectors in eastern Piedmont Region, Italy SO PARASITES & VECTORS LA English DT Article ID APPROXIMATE BAYESIAN-INFERENCE; NESTED LAPLACE APPROXIMATIONS; SOUTHERN FRANCE; MOSQUITO VECTORS; CULEX; CULICIDAE; ABUNDANCE; CAMARGUE; DIPTERA; DIFFERENTIATION AB Background: West Nile Virus (WNV) transmission in Italy was first reported in 1998 as an equine outbreak near the swamps of Padule di Fucecchio, Tuscany. No other cases were identified during the following decade until 2008, when horse and human outbreaks were reported in Emilia Romagna, North Italy. Since then, WNV outbreaks have occurred annually, spreading from their initial northern foci throughout the country. Following the outbreak in 1998 the Italian public health authority defined a surveillance plan to detect WNV circulation in birds, horses and mosquitoes. By applying spatial statistical analysis (spatial point pattern analysis) and models (Bayesian GLMM models) to a longitudinal dataset on the abundance of the three putative WNV vectors [Ochlerotatus caspius (Pallas 1771), Culex pipiens (Linnaeus 1758) and Culex modestus (Ficalbi 1890)] in eastern Piedmont, we quantified their abundance and distribution in space and time and generated prediction maps outlining the areas with the highest vector productivity and potential for WNV introduction and amplification. Results: The highest abundance and significant spatial clusters of Oc. caspius and Cx. modestus were in proximity to rice fields, and for Cx. pipiens, in proximity to highly populated urban areas. The GLMM model showed the importance of weather conditions and environmental factors in predicting mosquito abundance. Distance from the preferential breeding sites and elevation were negatively associated with the number of collected mosquitoes. The Normalized Difference Vegetation Index (NDVI) was positively correlated with mosquito abundance in rice fields (Oc. caspius and Cx. modestus). Based on the best models, we developed prediction maps for the year 2010 outlining the areas where high abundance of vectors could favour the introduction and amplification of WNV. Conclusions: Our findings provide useful information for surveillance activities aiming to identify locations where the potential for WNV introduction and local transmission are highest. Such information can be used by vector control offices to stratify control interventions in areas prone to the invasion of WNV and other mosquito-transmitted pathogens. C1 [Bisanzio, Donal; Giacobini, Mario; Bertolotti, Luigi] Univ Turin, Fac Vet Med, Dept Anim Prod Epidemiol & Ecol, I-10124 Turin, Italy. [Bisanzio, Donal; Giacobini, Mario; Bertolotti, Luigi] Univ Turin, MBC, I-10124 Turin, Italy. [Bisanzio, Donal; Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] Emory Univ, Atlanta, GA 30322 USA. [Mosca, Andrea; Balbo, Luca] Reg Govt Owned Corp Reg Piemonte, IPLA, Turin, Italy. [Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bisanzio, D (reprint author), Univ Turin, Fac Vet Med, Dept Anim Prod Epidemiol & Ecol, I-10124 Turin, Italy. EM dbisanz@emory.edu RI Bertolotti, Luigi/F-9236-2013; OI Bertolotti, Luigi/0000-0001-7931-4528; Giacobini, Mario/0000-0002-7647-5649; Bisanzio, Donal/0000-0002-7832-2291 FU ISI (Institute for Scientific Interchange) Foundation of Torino, Italy; Ministero dell'Universita e della Ricerca Scientifica e Tecnologica; Emory University (UK, Department of Environmental Studies); Ricerca Sanitaria Finalizzata; Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This research was supported by the ISI (Institute for Scientific Interchange) Foundation of Torino, Italy (Lagrange Fellowship awarded to DB), the Ministero dell'Universita e della Ricerca Scientifica e Tecnologica (award to MG), and Emory University (UK, Department of Environmental Studies). This work was partially funded by Ricerca Sanitaria Finalizzata 2008 - Regione Piemonte (award LBertolotti). Mosquito surveillance and control have been possible by the contribution of Regione Piemonte, Provincia di Alessandria, and the municipalities of the Casale Monferrato Agreement for Mosquito Control. Special thanks to the field technicians that collected, counted, and identified more than one million of mosquitoes. Thanks also to Prof. Alessandro Mannelli, Dr. Stefano Guazzetti e Dr. Luis Fernando Chavez for comments and suggestions on earlier versions of this manuscript. UK and GVP acknowledge the support of the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 56 TC 18 Z9 18 U1 2 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD DEC 9 PY 2011 VL 4 AR 230 DI 10.1186/1756-3305-4-230 PG 11 WC Parasitology SC Parasitology GA 874KO UT WOS:000298956200001 PM 22152822 ER PT J AU Brinkley, TE Jerosch-Herold, M Folsom, AR Carr, JJ Hundley, WG Allison, MA Bluemke, DA Burke, GL Szklo, M Ding, JZ AF Brinkley, Tina E. Jerosch-Herold, Michael Folsom, Aaron R. Carr, J. Jeffrey Hundley, W. Gregory Allison, Matthew A. Bluemke, David A. Burke, Gregory L. Szklo, Moyses Ding, Jingzhong TI Pericardial Fat and Myocardial Perfusion in Asymptomatic Adults from the Multi-Ethnic Study of Atherosclerosis SO PLOS ONE LA English DT Article ID PERIVASCULAR ADIPOSE-TISSUE; NORMAL CORONARY-ARTERIES; BLOOD-FLOW; COMPUTED-TOMOGRAPHY; VASCULAR FUNCTION; RISK-FACTORS; RESERVE; HEART; CALCIUM; DISEASE AB Background: Pericardial fat has adverse effects on the surrounding vasculature. Previous studies suggest that pericardial fat may contribute to myocardial ischemia in symptomatic individuals. However, it is unknown if pericardial fat has similar effects in asymptomatic individuals. Methods: We determined the association between pericardial fat and myocardial blood flow (MBF) in 214 adults with no prior history of cardiovascular disease from the Minnesota field center of the Multi-Ethnic Study of Atherosclerosis (43% female, 56% Caucasian, 44% Hispanic). Pericardial fat volume was measured by computed tomography. MBF was measured by MRI at rest and during adenosine-induced hyperemia. Myocardial perfusion reserve (PR) was calculated as the ratio of hyperemic to resting MBF. Results: Gender-stratified analyses revealed significant differences between men and women including less pericardial fat (71.9 +/- 31.3 vs. 105.2 +/- 57.5 cm(3), p<0.0001) and higher resting MBF (1.12 +/- 0.23 vs. 0.93 +/- 0.19 ml/min/g, p<0.0001), hyperemic MBF (3.49 +/- 0.76 vs. 2.65 +/- 0.72 ml/min/g, p<0.0001), and PR (3.19 +/- 0.78 vs. 2.93 +/- 0.89, p = 0.03) in women. Correlations between pericardial fat and clinical and hemodynamic variables were stronger in women. In women only (p = 0.01 for gender interaction) higher pericardial fat was associated with higher resting MBF (p = 0.008). However, this association was attenuated after accounting for body mass index or rate-pressure product. There were no significant associations between pericardial fat and hyperemic MBF or PR after multivariate adjustment in either gender. In logistic regression analyses there was also no association between impaired coronary vasoreactivity, defined as having a PR <2.5, and pericardial fat in men (OR, 1.18; 95% CI, 0.82-1.70) or women (OR, 1.11; 95% CI, 0.68-1.82). Conclusions: Our data fail to support an independent association between pericardial fat and myocardial perfusion in adults without symptomatic cardiovascular disease. Nevertheless, these findings highlight potentially important differences between asymptomatic and symptomatic individuals with respect to the underlying subclinical disease burden. C1 [Brinkley, Tina E.; Hundley, W. Gregory; Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Jerosch-Herold, Michael] Univ Minnesota, Sch Med, Dept Radiol, Minneapolis, MN 55455 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Carr, J. Jeffrey] Wake Forest Sch Med, Dept Radiol, Winston Salem, NC USA. [Allison, Matthew A.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Burke, Gregory L.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Szklo, Moyses] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Brinkley, TE (reprint author), Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. EM tbrinkle@wakehealth.edu RI Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Bluemke, David/0000-0002-8323-8086; Allison, Matthew/0000-0003-0777-8272 FU Oristano Foundation; National Heart, Lung, and Blood Institute, National Institutes of Health [N01-HC-95159, N01-HC-95169]; [R01-HL-085323]; [R01-HL-65580]; [K01-AG-033652] FX This research was supported by the Oristano Foundation, as well as grants R01-HL-085323, R01-HL-65580, and K01-AG-033652, and contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 9 PY 2011 VL 6 IS 12 AR e28410 DI 10.1371/journal.pone.0028410 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866FK UT WOS:000298365700031 PM 22174800 ER PT J AU Taher, L Collette, NM Murugesh, D Maxwell, E Ovcharenko, I Loots, GG AF Taher, Leila Collette, Nicole M. Murugesh, Deepa Maxwell, Evan Ovcharenko, Ivan Loots, Gabriela G. TI Global Gene Expression Analysis of Murine Limb Development SO PLOS ONE LA English DT Article ID NAIL-PATELLA SYNDROME; VERTEBRATE LIMB; T-BOX; HINDLIMB IDENTITY; TBX4; SPECIFICATION; BIOCONDUCTOR; OUTGROWTH; MODELS; LMX1B AB Detailed information about stage-specific changes in gene expression is crucial for understanding the gene regulatory networks underlying development and the various signal transduction pathways contributing to morphogenesis. Here we describe the global gene expression dynamics during early murine limb development, when cartilage, tendons, muscle, joints, vasculature and nerves are specified and the musculoskeletal system of limbs is established. We used whole-genome microarrays to identify genes with differential expression at 5 stages of limb development E9.5 to 13.5), during fore- and hind-limb patterning. We found that the onset of limb formation is characterized by an up-regulation of transcription factors, which is followed by a massive activation of genes during E10.5 and E11.5 which levels off at later time points. Among the 3520 genes identified as significantly up-regulated in the limb, we find similar to 30% to be novel, dramatically expanding the repertoire of candidate genes likely to function in the limb. Hierarchical and stage-specific clustering identified expression profiles that are likely to correlate with functional programs during limb development and further characterization of these transcripts will provide new insights into specific tissue patterning processes. Here, we provide for the first time a comprehensive analysis of developmentally regulated genes during murine limb development, and provide some novel insights into the expression dynamics governing limb morphogenesis. C1 [Taher, Leila; Ovcharenko, Ivan] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. [Collette, Nicole M.; Murugesh, Deepa; Loots, Gabriela G.] Lawrence Livermore Natl Lab, Biol & Biotechnol Div, Livermore, CA USA. [Loots, Gabriela G.] Univ Calif Merced, Sch Nat Sci, Merced, CA USA. [Maxwell, Evan] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. RP Taher, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. EM loots1@llnl.gov FU National Institutes of Health [DK075730, HG003963]; National Institutes of Health, National Library of Medicine; U.S. Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344] FX GGL, NMC and DM were supported by National Institutes of Health grants DK075730 and HG003963. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We would like to thank Carsten Jacobi and Michaela Kneissel from the Bone and Cartilage Group at Novartis Pharma and Shalini Mabery at LLNL for assistance with generating the microarray data. Special thanks to Jim Kent for giving us permission to use in situ images from Visigene; Nick Fischer for graphic design of Figure 1 and all members of the Loots group who have helped with animal husbandry, embryo isolation and engaged in insightful manuscript discussions. This work performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. NR 36 TC 30 Z9 30 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 9 PY 2011 VL 6 IS 12 AR e28358 DI 10.1371/journal.pone.0028358 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 866FK UT WOS:000298365700028 PM 22174793 ER PT J AU Sui, YJ Gagnon, S Dzutsev, A Zhu, Q Yu, HF Hogg, A Wang, YC Xia, Z Belyakov, IM Venzon, D Klinman, D Strober, W Kelsall, B Franchini, G Berzofsky, JA AF Sui, Yongjun Gagnon, Susan Dzutsev, Amiran Zhu, Qing Yu, Huifeng Hogg, Alison Wang, Yichuan Xia, Zheng Belyakov, Igor M. Venzon, David Klinman, Dennis Strober, Warren Kelsall, Brian Franchini, Genoveffa Berzofsky, Jay A. TI TLR agonists and/or IL-15 adjuvanted mucosal Sly vaccine reduced gut CD4(+) memory T cell loss in SIVmac251-challenged rhesus macaques SO VACCINE LA English DT Article DE HIV/SIV vaccine; IL-15; TLR agonist; APOBEG3G; Viral-specific tetramer ID SIMIAN IMMUNODEFICIENCY VIRUS; GASTROINTESTINAL-TRACT; IMMUNE-RESPONSES; HIV-1 INFECTION; HOMEOSTATIC PROLIFERATION; SIVMAC251 INFECTION; VIRAL REPLICATION; CD8-T-CELL MEMORY; TYPE-1 INFECTION; CD4-T-CELL HELP AB Adjuvant plays an important role in increasing and directing vaccine-induced immune responses. In a previous study, we found that a mucosal SIV vaccine using a combination of IL-15 and TLR agonists as adjuvant mediated partial protection against SIVmac251 rectal challenge, whereas neither IL-15 nor TLR agonists alone as an adjuvant impacted the plasma viral loads. In this study, dissociation of CD4(+) T cell preservation with viral loads was observed in the animals vaccinated with adjuvants. Significantly higher levels of memory CD4(+) T cell numbers were preserved after SIVmac251 infection in the colons of the animals vaccinated with vaccine containing any of these adjuvants compared to no adjuvant. When we measured the viral-specific CD8(+) tetramer responses in the colon lamina propria, we found significantly higher levels of gag, tat, and pol epitope tetramer(+) T cell responses in these animals compared to ones without adjuvant, even if some of the animals had similarly high viral loads. Furthermore, this CD4(+) T preservation was positively correlated with increased levels of gag and Tat, but not pol tetramer. T cell responses, and inversely correlated with beta-chemokine expression. The pre-challenged APOBEC3G expression level, which has previously been shown inversely associated with viral loads, was further found positively correlated with CD4(+) T cell number preservation. Overall, these data highlight one unrecognized role of adjuvant in HIV vaccine development, and show that vaccines can produce a surprising discordance between CD4(+) T cell levels and SIV viral load. Published by Elsevier Ltd. C1 [Sui, Yongjun; Gagnon, Susan; Dzutsev, Amiran; Zhu, Qing; Yu, Huifeng; Hogg, Alison; Wang, Yichuan; Xia, Zheng; Belyakov, Igor M.; Franchini, Genoveffa; Berzofsky, Jay A.] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Klinman, Dennis] NCI, Expt Immunol Lab, NIH, Bethesda, MD 20892 USA. [Strober, Warren] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Kelsall, Brian] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Sui, YJ (reprint author), NCI, Vaccine Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM suiy@mail.nih.gov; berzofsj@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; NIH FX This work was supported in part by the Intramural Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the NIH Intramural AIDS Targeted Antiretroviral Program. We thank the NIAID tetramer core facility for providing the tetramers. NR 66 TC 11 Z9 11 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 DEC 9 PY 2011 VL 30 IS 1 BP 59 EP 68 DI 10.1016/j.vaccine.2011.10.043 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 868NA UT WOS:000298528800010 PM 22041305 ER PT J AU Bialuk, I Whitney, S Andresen, V Florese, RH Nacsa, J Cecchinato, V Valeri, VW Heraud, JM Gordon, S Parks, RW Montefiori, DC Venzon, D Demberg, T Robert-Guroff, M Landucci, G Forthal, DN Franchini, G AF Bialuk, Izabela Whitney, Stephen Andresen, Vibeke Florese, Ruth H. Nacsa, Janos Cecchinato, Valentina Valeri, Valerio W. Heraud, Jean-Michel Gordon, Shari Parks, Robyn Washington Montefiori, David C. Venzon, David Demberg, Thorsten Robert-Guroff, Marjorie Landucci, Gary Forthal, Donald N. Franchini, Genoveffa TI Vaccine induced antibodies to the first variable loop of human immunodeficiency virus type 1 gp120, mediate antibody-dependent virus inhibition in macaques SO VACCINE LA English DT Article DE ADCC; ADCVI; V1, Vaccine ID N-LINKED GLYCOSYLATION; EXTRACELLULAR ENVELOPE GLYCOPROTEIN; HUMAN MONOCLONAL-ANTIBODIES; RHESUS MACAQUES; NEUTRALIZING ANTIBODIES; CELLULAR CYTOTOXICITY; SIVMAC251 CHALLENGE; INFECTED MACAQUES; REPLICATION-COMPETENT; LYMPHOCYTE DEPLETION AB The role of antibodies directed against the hyper variable envelope region V1 of human immunodeficiency virus type 1 (HIV-1), has not been thoroughly studied. We show that a vaccine able to elicit strain-specific non-neutralizing antibodies to this region of gp120 is associated with control of highly pathogenic chimeric SHIV(89.6p) replication in rhesus macaques. The vaccinated animal that had the highest titers of antibodies to the amino terminus portion of VI, prior to challenge, had secondary antibody responses that mediated cell killing by antibody-dependent cellular cytotoxicity (ADCC), as early as 2 weeks after infection and inhibited viral replication by antibody-dependent cell-mediated virus inhibition (ADCVI), by 4 weeks after infection. There was a significant inverse correlation between virus level and binding antibody titers to the envelope protein, (R = -0.83,p = 0.015), and ADCVI (R= -0.84 p = 0.044). Genotyping of plasma virus demonstrated in vivo selection of three SHIV(89.6p) variants with changes in potential N-linked glycosylation sites in Vi. We found a significant inverse correlation between virus levels and titers of antibodies that mediated ADCVI against all the identified V1 virus variants. A significant inverse correlation was also found between neutralizing antibody titers to SHIV(89.6) and virus levels (R = -0.72 p = 0.0050). However, passive inoculation of purified immunoglobulin from animal M316, the macaque that best controlled virus, to a naive macaque, resulted in a low serum neutralizing antibodies and low ADCVI activity that failed to protect from SHIV(89.6p) challenge. Collectively, while our data suggest that anti-envelope antibodies with neutralizing and non-neutralizing Fc(R-dependent activities may be important in the control of SHIV replication, they also demonstrate that low levels of these antibodies alone are not sufficient to protect from infection. Published by Elsevier Ltd. C1 [Bialuk, Izabela; Andresen, Vibeke; Nacsa, Janos; Cecchinato, Valentina; Valeri, Valerio W.; Heraud, Jean-Michel; Gordon, Shari; Parks, Robyn Washington; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. [Bialuk, Izabela] Med Univ Bialystok, Dept Gen & Expt Pathol, PL-15222 Bialystok, Poland. [Florese, Ruth H.; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Whitney, Stephen] Adv BioSci Labs, Kensington, MD 20895 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. [Landucci, Gary; Forthal, Donald N.] Univ Calif Irvine, Div Infect Dis, Dept Med, Sch Med, Irvine, CA 92697 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccine Sect MD, NIH, 9000 Rockville Pike,Bldg 41,Room D-804, Bethesda, MD 20892 USA. EM genoveffa.franchini@nih.hhs.gov RI HERAUD, Jean-Michel/O-1464-2013 OI HERAUD, Jean-Michel/0000-0003-1107-0859 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Teresa Habina for editorial assistance; Norman L. Letvin for providing the virus challenge stock; Maria Grazia Ferrari, Vaniambadi S., Kalyanaraman, and Ranajit Pal for help with antibody analysis, George Pavlakis and Barbara Felber for helpful discussions; Phillip D. Markham, Jim Treece, Deborah Weiss, and Sharon Orndorff for the coordination of the animal studies. NR 73 TC 12 Z9 12 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 9 PY 2011 VL 30 IS 1 BP 78 EP 94 DI 10.1016/j.vaccine.2011.10.040 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 868NA UT WOS:000298528800012 PM 22037204 ER PT J AU Sanghvi, M Moaddel, R Wainer, IW AF Sanghvi, Mitesh Moaddel, Ruin Wainer, Irving W. TI The development and characterization of protein-based stationary phases for studying drug-protein and protein-protein interactions SO JOURNAL OF CHROMATOGRAPHY A LA English DT Review DE Hsp90; ERR; HSA; Protein fishing; Frontal affinity chromatography ID FRONTAL AFFINITY-CHROMATOGRAPHY; 2ND VIRIAL-COEFFICIENTS; COATED MAGNETIC BEADS; RECEPTOR-GAMMA; EXCLUSION CHROMATOGRAPHY; QUANTITATIVE-ANALYSIS; GLUCOSE-TRANSPORTER; MASS-SPECTROMETRY; ATPASE ACTIVITY; CYTOCHALASIN-B AB Protein-based liquid chromatography stationary phases are used in bioaffinity chromatography for studying drug-protein interactions, the determination of binding affinities, competitive and allosteric interactions, as well as for studying protein-protein interactions. This review addresses the development and characterization of protein-based stationary phase, and the application of these phases using frontal and zonal chromatography techniques. The approach will be illustrated using immobilized heat shock protein 90 alpha and the immobilized estrogen related receptor stationary phases. In addition, the review discusses the use of the protein-coated magnetic beads for ligand and protein fishing as well as for the identification of unknown ligands from cellular or botanical extracts. Published by Elsevier B.V. C1 [Moaddel, Ruin] NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Moaddel, R (reprint author), NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM moaddelru@grc.nia.nih.gov RI Sanghvi, Mitesh/C-6740-2013 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. There are no financial conflicts. NR 75 TC 14 Z9 15 U1 0 U2 53 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD DEC 9 PY 2011 VL 1218 IS 49 SI SI BP 8791 EP 8798 DI 10.1016/j.chroma.2011.05.067 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 858DT UT WOS:000297776800007 PM 21704318 ER PT J AU Bharti, N Tatem, AJ Ferrari, MJ Grais, RF Djibo, A Grenfell, BT AF Bharti, N. Tatem, A. J. Ferrari, M. J. Grais, R. F. Djibo, A. Grenfell, B. T. TI Explaining Seasonal Fluctuations of Measles in Niger Using Nighttime Lights Imagery SO SCIENCE LA English DT Article ID TRANSMISSION; DYNAMICS; RISK; EPIDEMIC AB Measles epidemics in West Africa cause a significant proportion of vaccine-preventable childhood mortality. Epidemics are strongly seasonal, but the drivers of these fluctuations are poorly understood, which limits the predictability of outbreaks and the dynamic response to immunization. We show that measles seasonality can be explained by spatiotemporal changes in population density, which we measure by quantifying anthropogenic light from satellite imagery. We find that measles transmission and population density are highly correlated for three cities in Niger. With dynamic epidemic models, we demonstrate that measures of population density are essential for predicting epidemic progression at the city level and improving intervention strategies. In addition to epidemiological applications, the ability to measure fine-scale changes in population density has implications for public health, crisis management, and economic development. C1 [Bharti, N.; Grenfell, B. T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Bharti, N.; Grenfell, B. T.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Ctr Hlth & Wellbeing, Princeton, NJ 08544 USA. [Tatem, A. J.] Univ Florida, Dept Geog, Gainesville, FL 32610 USA. [Tatem, A. J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Ferrari, M. J.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Ferrari, M. J.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Grais, R. F.] Epictr, F-75011 Paris, France. [Grais, R. F.] Harvard Humanitarian Initiat, Cambridge, MA 02138 USA. [Djibo, A.] Minist Sante, DGSP, Niamey, Niger. [Tatem, A. J.; Grenfell, B. T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bharti, N (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM nbharti@princeton.edu FU Bill and Melinda Gates Foundation [49446]; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, NIH FX This study was supported by the Bill and Melinda Gates Foundation. A.J.T. is supported by a grant from the Bill and Melinda Gates Foundation (49446). A.J.T., M.J.F., and B. T. G. are also supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, NIH. All DMSP OLS imagery is available from the Space Physics Interactive Data Resource (http://spidr.ngdc.noaa.gov/spidr/). NR 27 TC 65 Z9 67 U1 5 U2 42 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 9 PY 2011 VL 334 IS 6061 BP 1424 EP 1427 DI 10.1126/science.1210554 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 858HW UT WOS:000297787700059 PM 22158822 ER PT J AU Pan, J Sun, LC Tao, YF Zhou, ZA Du, XL Peng, L Feng, X Wang, J Li, YP Liu, L Wu, SY Zhang, YL Hu, SY Zhao, WL Zhu, XM Lou, GL Ni, J AF Pan, Jian Sun, Li-Chao Tao, Yan-Fang Zhou, Zhuan Du, Xiao-Li Peng, Liang Feng, Xing Wang, Jian Li, Yi-Ping Liu, Ling Wu, Shui-Yan Zhang, Yan-Lan Hu, Shao-Yan Zhao, Wen-Li Zhu, Xue-Ming Lou, Guo-Liang Ni, Jian TI ATP synthase ecto-alpha-subunit: a novel therapeutic target for breast cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Two-dimensional liquid phase chromatographic fractionation; ATP synthase alpha-subunit; Tissue microarray; breast cancer; monoclonal antibody ID CELL-SURFACE; BETA-SUBUNIT; MONOCLONAL-ANTIBODY; TUMOR-CELLS; ANGIOSTATIN; ASSOCIATION; EXPRESSION AB Background: Treatment failure for breast cancer is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion-and metastasis-related genes in breast cancer cells in vitro and in vivo. Identification of new targets will facilitate the developmental pace of new techniques in screening and early diagnosis. Improved abilities to predict progression and metastasis, therapeutic response and toxicity will help to increase survival of breast cancer patients. Methods: Differential protein expression in two breast cancer cell lines, one with high and the other with low metastatic potential, was analyzed using two-dimensional liquid phase chromatographic fractionation (Proteome Lab PF 2D system) followed by matrix-assisted laser desorption/time-of-flight mass spectrometry (MALDI-TOF/MS). Results: Up regulation of a-subunit of ATP synthase was identified in high metastatic cells compared with low metastatic cells. Immunohistochemical analysis of 168 human breast cancer specimens on tissue microarrays revealed a high frequency of ATP synthase a-subunit expression in breast cancer (94.6%) compared to normal (21.2%) and atypical hyperplasia (23%) breast tissues. Levels of ATP synthase expression levels strongly correlated with large tumor size, poor tumor differentiation and advanced tumor stages (P < 0.05). ATP synthase a-subunit over-expression was detected on the surface of a highly invasive breast cancer cell line. An antibody against the ATP synthase a-subunit inhibited proliferation, migration and invasion in these breast cancer cells but not that of a non-tumor derived breast cell line. Conclusions: Over-expression of ATP synthase a-subunit may be involved in the progression and metastasis of breast cancer, perhaps representing a potential biomarker for diagnosis, prognosis and a therapeutic target for breast cancer. This finding of this study will help us to better understand the molecular mechanism of tumor metastasis and to improve the screening, diagnosis, as well as prognosis and/or prediction of responses to therapy for breast cancer. C1 [Pan, Jian; Tao, Yan-Fang; Feng, Xing; Wang, Jian; Li, Yi-Ping; Liu, Ling; Wu, Shui-Yan; Zhang, Yan-Lan; Hu, Shao-Yan; Zhao, Wen-Li; Zhu, Xue-Ming; Lou, Guo-Liang] Soochow Univ, Childrens Hosp, Dept Hematol & Oncol, Suzhou 215003, Peoples R China. [Pan, Jian; Sun, Li-Chao; Zhou, Zhuan; Du, Xiao-Li; Peng, Liang] Chinese Acad Med Sci, Peking Union Med Coll, State Key Lab Mol Oncol, Canc Inst Hosp, Beijing 100021, Peoples R China. [Zhou, Zhuan] Univ Pittsburgh, Dept Pathol, Hillman Canc Ctr Lab, Pittsburgh, PA 15206 USA. [Du, Xiao-Li] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Peng, Liang] China Japan Friendship Hosp, Inst Clin Med Sci, Beijing, Peoples R China. [Lou, Guo-Liang] Second Mil Med Univ, Chang Hai Hosp, Translat Res Ctr, Shanghai, Peoples R China. [Ni, Jian] Nanjing Med Univ, Clin Sch 2, Hosp 2, Translat Res Ctr, Nanjing, Peoples R China. RP Lou, GL (reprint author), Soochow Univ, Childrens Hosp, Dept Hematol & Oncol, Suzhou 215003, Peoples R China. EM lou115@sohu.com; ni_jian2008@163.com FU National Key Basic Research Program [2010CB933902]; National Natural Science Foundation [81100371]; Natural Science Foundation of Jiangsu Province [BK2011308]; Universities Natural Science Foundation of Jiangsu Province [11KJB320014]; Talent's subsidy project in science and education of department of public health of Suzhou City [SWKQ1020]; Medical innovation team and leading talent of jiangsu Province [LJ201126] FX This work was supported by grants from the National Key Basic Research Program No. 2010CB933902, National Natural Science Foundation for youth No. 81100371, Natural Science Foundation of Jiangsu Province No. BK2011308, Universities Natural Science Foundation of Jiangsu Province No. 11KJB320014 and Talent's subsidy project in science and education of department of public health of Suzhou City No. SWKQ1020. Medical innovation team and leading talent of jiangsu Province. No. LJ201126. NR 38 TC 15 Z9 15 U1 0 U2 12 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 DEC 8 PY 2011 VL 9 AR 211 DI 10.1186/1479-5876-9-211 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 874HY UT WOS:000298947400001 PM 22152132 ER PT J AU Gough, SM Slape, CI Aplan, PD AF Gough, Sheryl M. Slape, Christopher I. Aplan, Peter D. TI NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights SO BLOOD LA English DT Review ID ACUTE MYELOID-LEUKEMIA; BONE-MARROW-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; RNA EXPORT FACTOR; CHROMOSOME-TRANSLOCATION T(7/11)(P15,P15); ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE LYMPHOCYTIC-LEUKEMIA; NUCLEAR-PORE COMPLEX; POLYCOMB-GROUP GENES AB Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodomain proteins, and at least 5 NUP98 fusions involve known histone-modifying genes. Several of the NUP98 fusions, including NUP98-homeobox (HOX)A9, NUP98-HOXD13, and NUP98-JARID1A, have been used to generate animal models of both lymphoid and myeloid malignancy; these models typically up-regulate HOXA cluster genes, including HOXA5, HOXA7, HOXA9, and HOXA10. In addition, several of the NUP98 fusion proteins have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of hematopoietic stem or progenitor cells, providing a potential mechanism for malignant transformation. (Blood. 2011;118(24):6247-6257) C1 [Aplan, Peter D.] NCI, Leukemia Biol Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Slape, Christopher I.] Monash Univ, Australian Ctr Blood Dis Cent Clin Sch, Div Blood Canc, Melbourne, Vic 3004, Australia. RP Aplan, PD (reprint author), NCI, Leukemia Biol Sect, Genet Branch, Ctr Canc Res,NIH, 41 Ctr Dr, Bethesda, MD 20892 USA. EM aplanp@mail.nih.gov RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016 OI Slape, Christopher/0000-0002-8407-3092; FU National Cancer Institute, National Institutes of Health; Cancer Council of Victoria; National Health and Medical Research Council of Australia [628367] FX This research was supported by the Intramural Research Program, National Cancer Institute, National Institutes of Health; the Cancer Council of Victoria; and the National Health and Medical Research Council of Australia (grant 628367). NR 152 TC 81 Z9 88 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 8 PY 2011 VL 118 IS 24 BP 6247 EP 6257 DI 10.1182/blood-2011-07-328880 PG 11 WC Hematology SC Hematology GA 861SS UT WOS:000298040100007 PM 21948299 ER PT J AU Lindqvist, EK Goldin, LR Landgren, O Blimark, C Mellqvist, UH Turesson, I Wahlin, A Bjorkholm, M Kristinsson, SY AF Lindqvist, Ebba K. Goldin, Lynn R. Landgren, Ola Blimark, Cecilie Mellqvist, Ulf-Henrik Turesson, Ingemar Wahlin, Anders Bjorkholm, Magnus Kristinsson, Sigurdur Y. TI Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study SO BLOOD LA English DT Article ID UNDETERMINED SIGNIFICANCE MGUS; PRECEDES MULTIPLE-MYELOMA; MONOCLONAL GAMMOPATHY; RHEUMATOID-ARTHRITIS; 1ST-DEGREE RELATIVES; UNITED-STATES; MALIGNANCIES; AUTOIMMUNE; SWEDEN; SCANDINAVIA AB The associations between immune-related conditions and multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) have previously been investigated with inconsistent results. In a large population-based study, we identified 19 112 patients with MM, 5403 patients with MGUS, 96 617 matched control subjects, and 262 931 first-degree relatives. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MM and MGUS with immune-related conditions by use of logistic regression. A personal history of all infections combined was associated with a significantly increased risk of MM (OR = 1.2; 95% CI, 1.1-1.3), and a personal history of all conditions in the categories infections (OR = 1.6; 95% CI, 1.5-1.7), inflammatory conditions (OR = 1.4; 95% CI, 1.2-1.5), and autoimmune diseases (OR = 2.1; 95% CI, 1.9-2.4) was associated with a significantly increased risk of MGUS. Several specific immune-related conditions elevated the risk of MM and/or MGUS. A family history of autoimmune disease was associated with a significantly increased risk of MGUS (OR = 1.1; 95% CI, 1.00-1.2), but not MM. Our findings suggest that immune-related conditions and/or their treatment are of importance in the etiology of MGUS and possibly MM. The association of both personal and family history of autoimmune disease with MGUS indicates the potential for shared susceptibility for these conditions. (Blood. 2011; 118(24): 6284-6291) C1 [Lindqvist, Ebba K.; Landgren, Ola; Bjorkholm, Magnus; Kristinsson, Sigurdur Y.] Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. [Lindqvist, Ebba K.; Landgren, Ola; Bjorkholm, Magnus; Kristinsson, Sigurdur Y.] Karolinska Inst, Stockholm, Sweden. [Goldin, Lynn R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Blimark, Cecilie; Mellqvist, Ulf-Henrik] Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Med, Gothenburg, Sweden. [Turesson, Ingemar] Skane Univ Hosp, Dept Hematol, Malmo, Sweden. [Wahlin, Anders] Umea Univ Hosp, Sect Hematol, Ctr Canc, S-90185 Umea, Sweden. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Wahlin, Anders/F-6043-2013; Kristinsson, Sigurdur /M-2910-2015; OI Wahlin, Anders/0000-0001-6402-0463; Kristinsson, Sigurdur /0000-0002-4964-7476; Lindqvist, Ebba K/0000-0001-7662-1338 FU Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; National Institutes of Health, National Cancer Institute; Roche Diagnostics FX This work was supported by the Swedish Cancer Society, the Stockholm County Council, the Karolinska Institutet Foundations, the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Roche Diagnostics (unrestricted grant). NR 34 TC 24 Z9 26 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 8 PY 2011 VL 118 IS 24 BP 6284 EP 6291 DI 10.1182/blood-2011-04-347559 PG 8 WC Hematology SC Hematology GA 861SS UT WOS:000298040100011 PM 21998210 ER PT J AU Sohn, HW Krueger, PD Davis, RS Pierce, SK AF Sohn, Hae Won Krueger, Peter D. Davis, Randall S. Pierce, Susan K. TI FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling SO BLOOD LA English DT Article ID B-CELL-RECEPTOR; ANTIGEN RECEPTOR; TYROSINE KINASE; ACTIVATION; MEMBRANE; PROTEIN; EXHAUSTION; EXPRESSION; SYK; INDIVIDUALS AB Fc receptor-like 4 (FcRL4) is expressed on the surface of a subset of memory B cells (MBCs) located at sites of invading pathogens in mucosal lymphoid tissues in healthy individuals. Recently, FcRL4(+) MBCs were shown to be greatly increased in number in the peripheral blood of HIV-infected viremic individuals, in whom they are associated with B-cell exhaustion, and in individuals chronically reinfected with malaria. In the present study, we provide evidence that the expression of FcRL4 in human B-cell lines disrupts immune synapse formation and blocks antigen-induced BCR signaling at the point of Syk phosphorylation, blocking downstream activation of PLC-gamma 2 and Vav and the induction of calcium responses and CD69 expression. FcRL4 functions by ligation-independent mechanisms that require the 3 tyrosine residues in its cytoplasmic domain and involves its phosphorylation and association with the tyrosine phosphatases SHP-1 and SHP-2. Remarkably, FcRL4 is concentrated in endosomes after treatment with the TLR9 agonist CpG and enhances signaling through TLR9, as measured by increased expression of CD23. These findings suggest that FcRL4 may act as a molecular switch in B cells to dampen adaptive immune signaling and enhance innate signaling in response to chronic antigenic stimulation. (Blood. 2011;118(24):6332-6341) C1 [Sohn, Hae Won; Krueger, Peter D.; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Davis, Randall S.] Univ Alabama, Dept Med Microbiol Mol Genet & Biochem, Birmingham, AL USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr,Rm 200B,MSC 8180, Rockville, MD 20852 USA. EM spierce@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [AI067467, CA131656] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. R. S. D was supported by grants from National Institutes of Health (AI067467 and CA131656). NR 36 TC 34 Z9 35 U1 0 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 8 PY 2011 VL 118 IS 24 BP 6332 EP 6341 DI 10.1182/blood-2011-05-353102 PG 10 WC Hematology SC Hematology GA 861SS UT WOS:000298040100017 PM 21908428 ER PT J AU Raznahan, A Lerch, JP Lee, N Greenstein, D Wallace, GL Stockman, M Clasen, L Shaw, PW Giedd, JN AF Raznahan, Armin Lerch, Jason P. Lee, Nancy Greenstein, Dede Wallace, Gregory L. Stockman, Michael Clasen, Liv Shaw, Phillip W. Giedd, Jay N. TI Patterns of Coordinated Anatomical Change in Human Cortical Development: A Longitudinal Neuroimaging Study of Maturational Coupling SO NEURON LA English DT Article ID BRAINS DEFAULT NETWORK; INTRINSIC FUNCTIONAL ARCHITECTURE; AUTOMATED 3-D EXTRACTION; RESTING-STATE NETWORKS; MODE NETWORK; STRUCTURAL CONNECTIVITY; CEREBRAL-CORTEX; PREFRONTAL CORTEX; COGNITIVE CONTROL; THICKNESS AB Understanding of human structural brain development has rapidly advanced in recent years, but remains fundamentally "localizational" in nature. Here, we use 376 longitudinally acquired structural brain scans from 108 typically developing adolescents to conduct the first study of coordinated anatomical change within the developing cortex. Correlation in rates of anatomical change was regionally heterogeneous, with fronto-temporal association cortices showing the strongest and most widespread maturational coupling with other cortical areas, and lower-order sensory cortices showing the least. Canonical cortical systems with rich structural and functional interconnectivity showed significantly elevated maturational coupling. Evidence for sexually dimorphic maturational coupling was found within a frontopolar-centered prefrontal system involved in complex decision-making. By providing the first link between cortical connectivity and the coordination of cortical development, we reveal a hitherto unseen property of healthy brain maturation, which may represent a target for neurodeveloprnental disease processes, and a substrate for sexually dimorphic behavior in adolescence. C1 [Raznahan, Armin; Lee, Nancy; Greenstein, Dede; Wallace, Gregory L.; Stockman, Michael; Clasen, Liv; Shaw, Phillip W.; Giedd, Jay N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Lerch, Jason P.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Lerch, Jason P.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/A-3080-2008; Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; Lee, Nancy/M-7492-2016; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Lee, Nancy/0000-0002-6663-0713; Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS [Z99 MH999999] NR 76 TC 97 Z9 97 U1 3 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 8 PY 2011 VL 72 IS 5 BP 873 EP 884 DI 10.1016/j.neuron.2011.09.028 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 860TR UT WOS:000297971100019 PM 22153381 ER PT J AU Gieger, C Radhakrishnan, A Cvejic, A Tang, WH Porcu, E Pistis, G Serbanovic-Canic, J Elling, U Goodall, AH Labrune, Y Lopez, LM Magi, R Meacham, S Okada, Y Pirastu, N Sorice, R Teumer, A Voss, K Zhang, WH Ramirez-Solis, R Bis, JC Ellinghaus, D Gogele, M Hottenga, JJ Langenberg, C Kovacs, P O'Reilly, PF Shin, SY Esko, T Hartiala, J Kanoni, S Murgia, F Parsa, A Stephens, J van der Harst, P van der Schoot, CE Allayee, H Attwood, A Balkau, B Bastardot, F Basu, S Baumeister, SE Biino, G Bomba, L Bonnefond, A Cambien, F Chambers, JC Cucca, F D'Adamo, P Davies, G de Boer, RA de Geus, EJC Doring, A Elliott, P Erdmann, J Evans, DM Falchi, M Feng, W Folsom, AR Frazer, IH Gibson, QD Glazer, NL Hammond, C Hartikainen, AL Heckbert, SR Hengstenberg, C Hersch, M Illig, T Loos, RJF Jolley, J Khaw, KT Kuhnel, B Kyrtsonis, MC Lagou, V Lloyd-Jones, H Lumley, T Mangino, M Maschio, A Leach, IM McKnight, B Memari, Y Mitchell, BD Montgomery, GW Nakamura, Y Nauck, M Navis, G Nothlings, U Nolte, IM Porteous, DJ Pouta, A Pramstaller, PP Pullat, J Ring, SM Rotter, JI Ruggiero, D Ruokonen, A Sala, C Samani, NJ Sambrook, J Schlessinger, D Schreiber, S Schunkert, H Scott, J Smith, NL Snieder, H Starr, JM Stumvoll, M Takahashi, A Tang, WHW Taylor, K Tenesa, A Thein, SL Tonjes, A Uda, M Ulivi, S van Veldhuisen, DJ Visscher, PM Volker, U Wichmann, HE Wiggins, KL Willemsen, G Yang, TP Zhao, JH Zitting, P Bradley, JR Dedoussis, GV Gasparini, P Hazen, SL Metspalu, A Pirastu, M Shuldiner, AR van Pelt, LJ Zwaginga, JJ Boomsma, DI Deary, IJ Franke, A Froguel, P Ganesh, SK Jarvelin, MR Martin, NG Meisinger, C Psaty, BM Spector, TD Wareham, NJ Akkerman, JWN Ciullo, M Deloukas, P Greinacher, A Jupe, S Kamatani, N Khadake, J Kooner, JS Penninger, J Prokopenko, I Stemple, D Toniolo, D Wernisch, L Sanna, S Hicks, AA Rendon, A Ferreira, MA Ouwehand, WH Soranzo, N AF Gieger, Christian Radhakrishnan, Aparna Cvejic, Ana Tang, Weihong Porcu, Eleonora Pistis, Giorgio Serbanovic-Canic, Jovana Elling, Ulrich Goodall, Alison H. Labrune, Yann Lopez, Lorna M. Maegi, Reedik Meacham, Stuart Okada, Yukinori Pirastu, Nicola Sorice, Rossella Teumer, Alexander Voss, Katrin Zhang, Weihua Ramirez-Solis, Ramiro Bis, Joshua C. Ellinghaus, David Goegele, Martin Hottenga, Jouke-Jan Langenberg, Claudia Kovacs, Peter O'Reilly, Paul F. Shin, So-Youn Esko, Toenu Hartiala, Jaana Kanoni, Stavroula Murgia, Federico Parsa, Afshin Stephens, Jonathan van der Harst, Pim van der Schoot, C. Ellen Allayee, Hooman Attwood, Antony Balkau, Beverley Bastardot, Francois Basu, Saonli Baumeister, Sebastian E. Biino, Ginevra Bomba, Lorenzo Bonnefond, Amelie Cambien, Francois Chambers, John C. Cucca, Francesco D'Adamo, Pio Davies, Gail de Boer, Rudolf A. de Geus, Eco J. C. Doering, Angela Elliott, Paul Erdmann, Jeanette Evans, David M. Falchi, Mario Feng, Wei Folsom, Aaron R. Frazer, Ian H. Gibson, Quince D. Glazer, Nicole L. Hammond, Chris Hartikainen, Anna-Liisa Heckbert, Susan R. Hengstenberg, Christian Hersch, Micha Illig, Thomas Loos, Ruth J. F. Jolley, Jennifer Khaw, Kay Tee Kuehnel, Brigitte Kyrtsonis, Marie-Christine Lagou, Vasiliki Lloyd-Jones, Heather Lumley, Thomas Mangino, Massimo Maschio, Andrea Leach, Irene Mateo McKnight, Barbara Memari, Yasin Mitchell, Braxton D. Montgomery, Grant W. Nakamura, Yusuke Nauck, Matthias Navis, Gerjan Noethlings, Ute Nolte, Ilja M. Porteous, David J. Pouta, Anneli Pramstaller, Peter P. Pullat, Janne Ring, Susan M. Rotter, Jerome I. Ruggiero, Daniela Ruokonen, Aimo Sala, Cinzia Samani, Nilesh J. Sambrook, Jennifer Schlessinger, David Schreiber, Stefan Schunkert, Heribert Scott, James Smith, Nicholas L. Snieder, Harold Starr, John M. Stumvoll, Michael Takahashi, Atsushi Tang, W. H. Wilson Taylor, Kent Tenesa, Albert Thein, Swee Lay Toenjes, Anke Uda, Manuela Ulivi, Sheila van Veldhuisen, Dirk J. Visscher, Peter M. Voelker, Uwe Wichmann, H-Erich Wiggins, Kerri L. Willemsen, Gonneke Yang, Tsun-Po Zhao, Jing Hua Zitting, Paavo Bradley, John R. Dedoussis, George V. Gasparini, Paolo Hazen, Stanley L. Metspalu, Andres Pirastu, Mario Shuldiner, Alan R. van Pelt, L. Joost Zwaginga, Jaap-Jan Boomsma, Dorret I. Deary, Ian J. Franke, Andre Froguel, Philippe Ganesh, Santhi K. Jarvelin, Marjo-Riitta Martin, Nicholas G. Meisinger, Christa Psaty, Bruce M. Spector, Timothy D. Wareham, Nicholas J. Akkerman, Jan-Willem N. Ciullo, Marina Deloukas, Panos Greinacher, Andreas Jupe, Steve Kamatani, Naoyuki Khadake, Jyoti Kooner, Jaspal S. Penninger, Josef Prokopenko, Inga Stemple, Derek Toniolo, Daniela Wernisch, Lorenz Sanna, Serena Hicks, Andrew A. Rendon, Augusto Ferreira, Manuel A. Ouwehand, Willem H. Soranzo, Nicole TI New gene functions in megakaryopoiesis and platelet formation SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; LOCI; HEMATOPOIESIS; POPULATION; DROSOPHILA; BLOOD AB Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. C1 [Gieger, Christian; Kuehnel, Brigitte] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Radhakrishnan, Aparna; Cvejic, Ana; Serbanovic-Canic, Jovana; Meacham, Stuart; Voss, Katrin; Stephens, Jonathan; Attwood, Antony; Jolley, Jennifer; Lloyd-Jones, Heather; Sambrook, Jennifer; Rendon, Augusto; Ouwehand, Willem H.] Univ Cambridge & NHS Blood & Transplant, Dept Haematol, Cambridge CB2 0PT, England. [Radhakrishnan, Aparna; Cvejic, Ana; Serbanovic-Canic, Jovana; Meacham, Stuart; Ramirez-Solis, Ramiro; Shin, So-Youn; Kanoni, Stavroula; Attwood, Antony; Memari, Yasin; Yang, Tsun-Po; Deloukas, Panos; Stemple, Derek; Ouwehand, Willem H.; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Radhakrishnan, Aparna; Cvejic, Ana; Serbanovic-Canic, Jovana; Meacham, Stuart; Ramirez-Solis, Ramiro; Shin, So-Youn; Kanoni, Stavroula; Attwood, Antony; Memari, Yasin; Yang, Tsun-Po; Deloukas, Panos; Stemple, Derek; Ouwehand, Willem H.; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Tang, Weihong; Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Porcu, Eleonora; Cucca, Francesco; Uda, Manuela; Sanna, Serena] Cittadella Univ Monserrato, CNR, Ist Ric Genet & Biomed, I-09042 Cagliari, Italy. [Pistis, Giorgio; Sala, Cinzia; Toniolo, Daniela] Ist Sci San Raffaele, I-20132 Milan, Italy. [Elling, Ulrich; Penninger, Josef] Austrian Acad Sci, Inst Mol Biotechnol, IMBA, A-1030 Vienna, Austria. [Goodall, Alison H.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Goodall, Alison H.; Samani, Nilesh J.] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England. [Labrune, Yann; Bonnefond, Amelie; Froguel, Philippe] Inst Biol Lille, CNRS, UMR 8199, F-59019 Lille, France. [Lopez, Lorna M.; Porteous, David J.; Starr, John M.; Visscher, Peter M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Lopez, Lorna M.; Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Maegi, Reedik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Okada, Yukinori; Takahashi, Atsushi; Kamatani, Naoyuki] RIKEN Ctr Genom Med, Inst Phys & Chem Res, Lab Stat Anal, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Okada, Yukinori] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Bunkyo Ku, Tokyo 1138654, Japan. [Pirastu, Nicola; D'Adamo, Pio; Ulivi, Sheila; Gasparini, Paolo] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, I-34137 Trieste, Italy. [Sorice, Rossella; Ruggiero, Daniela; Ciullo, Marina] CNR, Inst Genet & Biophys A Buzzati Traverso, I-8031 Naples, Italy. [Teumer, Alexander; Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany. [Zhang, Weihua; Chambers, John C.; Elliott, Paul] Fac Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Bis, Joshua C.; Wiggins, Kerri L.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Ellinghaus, David; Schreiber, Stefan; Franke, Andre] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Goegele, Martin; Pramstaller, Peter P.; Hicks, Andrew A.] European Acad Bozen Bolzano, Ctr Biomed, I-39100 Bolzano, Italy. [Hottenga, Jouke-Jan; de Geus, Eco J. C.; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Langenberg, Claudia; Loos, Ruth J. F.; Zhao, Jing Hua; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, D-04103 Leipzig, Germany. [O'Reilly, Paul F.; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [Shin, So-Youn; Hammond, Chris; Mangino, Massimo; Memari, Yasin; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Maegi, Reedik; Esko, Toenu; Pullat, Janne; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50410 Tartu, Estonia. [Esko, Toenu; Metspalu, Andres] Estonian Bioctr, EE-51010 Tartu, Estonia. [Esko, Toenu; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50410 Tartu, Estonia. [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90089 USA. [Kanoni, Stavroula; Dedoussis, George V.] Harokopio Univ, Dept Nutr Dietet, Athens 17671, Greece. [Murgia, Federico; Biino, Ginevra; Pirastu, Mario] CNR, Inst Populat Genet, I-07100 Sassari, Italy. [Parsa, Afshin; Gibson, Quince D.; Maschio, Andrea; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [van der Harst, Pim; de Boer, Rudolf A.; Leach, Irene Mateo; van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands. [van der Schoot, C. Ellen] Sanquin Res, Dept Expt Immunohaematol, NL-1066 CX Amsterdam, Netherlands. [van der Schoot, C. Ellen] Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands. [Balkau, Beverley] INSERM, U1018, CESP Ctr Res Epidemiol & Populat Hlth, F-94807 Villejuif, France. [Balkau, Beverley] Univ Paris 11, UMRS 1018, F-94807 Villejuif, France. [Bastardot, Francois] CHUV, Serv Med Interne, CH-1011 Lausanne, Switzerland. [Basu, Saonli; Feng, Wei] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Baumeister, Sebastian E.] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Biino, Ginevra; Pirastu, Mario] Shardna Life Sci, Loc Piscinamanna, I-09010 Pula, CA, Italy. [Biino, Ginevra; Toniolo, Daniela] CNR, Inst Mol Genet, I-27100 Pavia, Italy. [Bomba, Lorenzo] Univ Cattolica Sacro Cuore Sede Piacenza, Ist Zootecnia, I-29122 Piacenza, Italy. [Cambien, Francois] Univ Paris 06, INSERM, UMRS 937, F-75013 Paris, France. [Cambien, Francois] Sch Med, F-75013 Paris, France. [Doering, Angela; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Doering, Angela; Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London W2 1PG, England. [Erdmann, Jeanette; Schunkert, Heribert] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Evans, David M.; Ring, Susan M.] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol BS8 2BN, Avon, England. [Falchi, Mario; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England. [Frazer, Ian H.] Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. [Glazer, Nicole L.] Boston Univ, Dept Med, Boston, MA 02118 USA. [Hartikainen, Anna-Liisa; Pouta, Anneli] Univ Oulu, Dept Clin Sci Obstet & Gynecol, SF-90220 Oulu, Finland. [Heckbert, Susan R.; Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Hengstenberg, Christian] Univ Klinikum Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany. [Hersch, Micha] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Hersch, Micha] Swiss Inst Bioinformat, Lausanne, Switzerland. [Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Khaw, Kay Tee] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Khaw, Kay Tee] Addenbrookes Hosp, Clin Gerontol Unit, Cambridge CB2 2QQ, England. [Kyrtsonis, Marie-Christine] Univ Athens, Sch Med, Laikon Gen Hosp, Dept Propedeut Internal Med 1, Athens 11727, Greece. [Kyrtsonis, Marie-Christine] Univ Athens, Sch Med, Laikon Gen Hosp, Dept Hematol, Athens 11727, Greece. [Lagou, Vasiliki; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Lumley, Thomas; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Montgomery, Grant W.; Visscher, Peter M.; Martin, Nicholas G.; Ferreira, Manuel A.] Queensland Inst Med Res, Bancroft Ctr, Herston, Qld 4006, Australia. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo 1088639, Japan. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9713 GZ Groningen, Netherlands. [Noethlings, Ute] Univ Kiel, Inst Expt Med, Epidemiol Sect, D-24105 Kiel, Germany. [Noethlings, Ute] Univ Clin Schleswig Holstein, D-24105 Kiel, Germany. [Nolte, Ilja M.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, NL-9713 GZ Groningen, Netherlands. [Porteous, David J.] Univ Edinburgh, Western Gen Hosp, Mol Med Ctr, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland. [Pouta, Anneli] Natl Inst Hlth & Welf, Oulu 90220, Finland. [Rotter, Jerome I.; Taylor, Kent] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Ruokonen, Aimo] Univ Oulu, Inst Diagnost, Oulu 90014, Finland. [Sambrook, Jennifer; Bradley, John R.; Ouwehand, Willem H.] NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, Fac Med, London W12 0HS, England. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA 98108 USA. [Starr, John M.] Univ Edinburgh, Geriatr Med Unit, Edinburgh EH4 2DN, Midlothian, Scotland. [Stumvoll, Michael; Toenjes, Anke] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Tang, W. H. Wilson; Hazen, Stanley L.] Cleveland Clin, Dept Cell Biol & Cardiovasc Med, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH 44195 USA. [Tang, W. H. Wilson] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44195 USA. [Tenesa, Albert] MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Tenesa, Albert] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland. [Thein, Swee Lay] Kings Coll London, Dept Mol Haematol, London SE5 9NU, England. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Wichmann, H-Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Zitting, Paavo] Lapland Cent Hosp, Dept Physiatr, Rovaniemi 96101, Finland. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21208 USA. [van Pelt, L. Joost] Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, NL-9713 GZ Groningen, Netherlands. [Zwaginga, Jaap-Jan] Sanquin Res Leiden, Jon J van Rood Ctr Clin Transfus Res, NL-2333 Leiden, Netherlands. [Zwaginga, Jaap-Jan] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 Leiden, Netherlands. [Ganesh, Santhi K.] Univ Michigan Hlth Syst, Div Cardiovasc Med, Ann Arbor, MI USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, SF-90220 Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Natl Inst Hlth & Welf, SF-90220 Oulu, Finland. [Psaty, Bruce M.] Univ Washington, Dept Med Epidemiol & Hlth Serv, Seattle, WA 98101 USA. [Akkerman, Jan-Willem N.] Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, NL-3584 CX Utrecht, Netherlands. [Greinacher, Andreas] Ernst Moritz Arndt Univ Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany. [Jupe, Steve; Khadake, Jyoti] EMBL European Bioinformat Inst, Prote Serv, Cambridge CB10 1SD, England. [Wernisch, Lorenz; Rendon, Augusto] Univ Forvie Site, Inst Publ Hlth, MRC, Biostat Unit, Cambridge CB2 0SR, England. [Erdmann, Jeanette; Schunkert, Heribert] Nord Ctr Cardiovasc Res, Lubeck, Germany. [Pirastu, Nicola; D'Adamo, Pio; Gasparini, Paolo] Univ Trieste, I-34127 Trieste, Italy. RP Gieger, C (reprint author), German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. EM christian.gieger@helmholtz-muenchen.de; who1000@cam.ac.uk; ns6@sanger.ac.uk RI Erdmann, Jeanette/P-7513-2014; Franke, Andre/B-2151-2010; Hicks, Andrew/E-9518-2017; d'Adamo, Adamo Pio/G-4064-2011; Meisinger, Christine/B-5358-2014; Schreiber, Stefan/B-6748-2008; van Veldhuisen, Dirk Jan/E-8967-2014; Pramstaller, Peter/C-2357-2008; Ferreira, Manuel/D-3609-2013; Biino, Ginevra/B-5334-2013; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Prokopenko, Inga/H-3241-2014; ruggiero, daniela/K-5638-2016; mangino, massimo/F-5134-2011; Erdmann, Jeanette/A-4417-2009; Nothlings, Ute/B-2713-2010; Deary, Ian/C-6297-2009; Lopez, Lorna/F-7265-2010; Ellinghaus, David/G-4467-2012; Deloukas, Panos/B-2922-2013; Pirastu, Nicola/G-4358-2011; Porteous, David/C-7289-2013; Falchi, Mario/F-5956-2013; Lagou, Vasiliki/N-8451-2013; Ulivi, Sheila/H-3700-2013; Evans, David/H-6325-2013; Tang, Wai Hong/I-1238-2013; Penninger, Josef/I-6860-2013 OI Visscher, Peter/0000-0002-2143-8760; Hammond, Christopher/0000-0002-3227-2620; Evans, David/0000-0003-0663-4621; Mitchell, Braxton/0000-0003-4920-4744; Cvejic, Ana/0000-0003-3204-9311; Ouwehand, Willem/0000-0002-7744-1790; Martin, Nicholas/0000-0003-4069-8020; Memari, Yasin/0000-0002-1747-542X; Erdmann, Jeanette/0000-0002-4486-6231; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Frazer, Ian/0000-0002-8002-4680; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Bradley, John/0000-0002-7774-8805; Franke, Andre/0000-0003-1530-5811; Hicks, Andrew/0000-0001-6320-0411; Radhakrishnan, Aparna/0000-0002-8153-9037; Jupe, Steven/0000-0001-5807-0069; bomba, lorenzo/0000-0002-6290-8984; Pirastu, Nicola/0000-0002-5363-3886; Yang, Tsun-Po/0000-0002-9077-4434; Esko, Tonu/0000-0003-1982-6569; Meisinger, Christa/0000-0002-9026-6544; Rendon, Augusto/0000-0001-8994-0039; Magi, Reedik/0000-0002-2964-6011; sanna, serena/0000-0002-3768-1749; d'Adamo, Adamo Pio/0000-0001-9367-4909; Schreiber, Stefan/0000-0003-2254-7771; Biino, Ginevra/0000-0002-9936-946X; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Prokopenko, Inga/0000-0003-1624-7457; ruggiero, daniela/0000-0003-3898-7827; mangino, massimo/0000-0002-2167-7470; Deloukas, Panos/0000-0001-9251-070X; Porteous, David/0000-0003-1249-6106; Ulivi, Sheila/0000-0003-3606-835X; Penninger, Josef/0000-0002-8194-3777 FU US National Institutes of Health [P41 HG003751]; EU [LSHG-CT-2005-518254 'ENFIN', 215820]; EBI Industry Programme; Wellcome Trust [WT 082597/Z/07/Z, WT 077037/Z/05/Z, WT 077047/Z/05/Z, 098051]; National Institute for Health Research, UK; British Heart Foundation [RG/09/012/28096]; ERC; EC under SLING [226073, FP7-HEALTH-2007-223411]; European Community; ENGAGE Consortium [HEALTH-F4-2007-201413] FX Reactome is supported by grants from the US National Institutes of Health (P41 HG003751), EU grant LSHG-CT-2005-518254 'ENFIN', and the EBI Industry Programme. A. C. and D. L. S. are supported by the Wellcome Trust grants WT 082597/Z/07/Z and WT 077037/Z/05/Z and WT 077047/Z/05/Z, respectively. J.S.C. and K. V. are supported by the European Union NetSim training fellowship scheme (number 215820). A. Radhakrishnan, A. A., H.L.J., J.J., J.S. and W.H.O. are funded by the National Institute for Health Research, UK. Augusto Rendon is funded by programme grant RG/09/012/28096 from the British Heart Foundation. J.M.P. is supported by an Advanced ERC grant. IntAct is funded by the EC under SLING, grant agreement no. 226073 (Integrating Activity) within Research Infrastructures of the FP7, under PSIMEX, contract no. FP7-HEALTH-2007-223411. C. G. received support by the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. N.S. is supported by the Wellcome Trust (Grant Number 098051). Acknowledgements by individual participating studies are provided in Supplementary Information. NR 25 TC 170 Z9 171 U1 4 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 8 PY 2011 VL 480 IS 7376 BP 201 EP 208 DI 10.1038/nature10659 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 857TR UT WOS:000297744200043 PM 22139419 ER PT J AU Fawzi, NL Ying, JF Ghirlando, R Torchia, DA Clore, GM AF Fawzi, Nicolas L. Ying, Jinfa Ghirlando, Rodolfo Torchia, Dennis A. Clore, G. Marius TI Atomic-resolution dynamics on the surface of amyloid-beta protofibrils probed by solution NMR SO NATURE LA English DT Article ID ALZHEIMERS-DISEASE; EXPERIMENTAL CONSTRAINTS; CHEMICAL-EXCHANGE; FIBRIL FORMATION; PROTEIN; OLIGOMERS; MECHANISM; STATE; A-BETA(1-40); AGGREGATION AB Exchange dynamics between molecules free in solution and bound to the surface of a large supramolecular structure, a polymer, a membrane or solid support are important in many phenomena in biology and materials science. Here we present a novel and generally applicable solution NMR technique, known as dark-state exchange saturation transfer (DEST), to probe such exchange phenomena with atomic resolution. This is illustrated by the exchange reaction between amyloid-beta (A beta) monomers and polydisperse, NMR-invisible ('dark') protofibrils, a process of significant interest because the accumulation of toxic, aggregated forms of A beta, from small oligomers to very large assemblies, has been implicated in the aetiology of Alzheimer's disease(1-6). The (15)N-DEST experiment imprints with single-residue-resolution dynamic information on the protofibril-bound species in the form of (15)N transverse relaxation rates ((15)N-R(2)) and exchange kinetics between monomers and protofibrils onto the easily observed two-dimensional (1)H-(15)N correlation spectrum of the monomer. The exchanging species on the protofibril surface comprise an ensemble of sparsely populated states where each residue is either tethered to (through other residues) or in direct contact with the surface. The first eight residues exist predominantly in a mobile tethered state, whereas the largely hydrophobic central region and part of the carboxy (C)-terminal hydrophobic region are in direct contact with the protofibril surface for a significant proportion of the time. The C-terminal residues of both A beta 40 and A beta 42 display lower affinity for the protofibril surface, indicating that they are likely to be surface exposed rather than buried as in structures of A beta fibrils(7-10), and might therefore comprise the critical nucleus for fibril formation(11,12). The (15)N-R(2)(tethered) values, however, are significantly larger for the C-terminal residues of A beta 42 than A beta 40, which might explain the former's higher propensity for rapid aggregation and fibril formation(13,14). C1 [Fawzi, Nicolas L.; Ying, Jinfa; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Torchia, Dennis A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Fawzi, Nicolas/E-2555-2013; Clore, G. Marius/A-3511-2008 OI Fawzi, Nicolas/0000-0001-5483-0577; Clore, G. Marius/0000-0003-3809-1027 FU National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health; Office of the Director of the National Institutes of Health FX We thank R. Tycko for discussions, D. Baber, D. Garrett and M. Cai for NMR technical assistance, F. Shewmaker for performing dot blots, and W. Qiang, B. Chen and K. Thurber for assistance with atomic force microscopy and electron microscopy imaging. This work was supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health and the AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health (to G.M.C.). NR 32 TC 124 Z9 124 U1 2 U2 130 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 8 PY 2011 VL 480 IS 7376 BP 268 EP U161 DI 10.1038/nature10577 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 857TR UT WOS:000297744200057 PM 22037310 ER PT J AU Landgren, O Thomas, A Mailankody, S AF Landgren, Ola Thomas, Anish Mailankody, Sham TI Myeloma and Second Primary Cancers SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID DISEASE; RISK C1 [Landgren, Ola; Thomas, Anish; Mailankody, Sham] NCI, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov OI Thomas, Anish/0000-0003-3293-3115 FU Intramural NIH HHS NR 5 TC 27 Z9 28 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 DEC 8 PY 2011 VL 365 IS 23 BP 2241 EP 2242 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 857PQ UT WOS:000297731400030 PM 22150057 ER PT J AU Nguyen, AT Feasley, CL Jackson, KW Nitz, TJ Salzwedel, K Air, GM Sakalian, M AF Nguyen, Albert T. Feasley, Christa L. Jackson, Ken W. Nitz, Theodore J. Salzwedel, Karl Air, Gillian M. Sakalian, Michael TI The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MAJOR HOMOLOGY REGION; ANTI-AIDS AGENTS; BETULINIC ACID; HELICAL STRUCTURE; PROCESSING SITES; SPACER PEPTIDE-1; VIRAL PROTEASE; CAPSID PROTEIN; P2 DOMAIN AB Background: Bevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, bevirimat specifically inhibits a single cleavage event, the final processing step for the Gag precursor where p25 (CA-SP1) is cleaved to p24 (CA) and SP1. Results: In this study, photoaffinity analogs of bevirimat and mass spectrometry were employed to map the binding site of bevirimat to Gag within immature virus-like particles. Bevirimat analogs were found to crosslink to sequences overlapping, or proximal to, the CA-SP1 cleavage site, consistent with previous biochemical data on the effect of bevirimat on Gag processing and with genetic data from resistance mutations, in a region predicted by NMR and mutational studies to have alpha-helical character. Unexpectedly, a second region of interaction was found within the Major Homology Region (MHR). Extensive prior genetic evidence suggests that the MHR is critical for virus assembly. Conclusions: This is the first demonstration of a direct interaction between the maturation inhibitor, bevirimat, and its target, Gag. Information gained from this study sheds light on the mechanisms by which the virus develops resistance to this class of drug and may aid in the design of next-generation maturation inhibitors. C1 [Nguyen, Albert T.; Feasley, Christa L.; Air, Gillian M.] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73104 USA. [Nguyen, Albert T.; Sakalian, Michael] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. [Jackson, Ken W.] Univ Oklahoma, Hlth Sci Ctr, Warren Med Res Inst, Oklahoma City, OK 73104 USA. [Nitz, Theodore J.; Salzwedel, Karl; Sakalian, Michael] Panacos Pharmaceut, Watertown, MA 02472 USA. [Sakalian, Michael] NIGMS, Div Cell Biol & Biophys, NIH, Bethesda, MD 20892 USA. RP Air, GM (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73104 USA. EM gillian-air@ouhsc.edu; sakalianm@nigms.nih.gov FU Oklahoma Center for the Advancement of Science and Technology (OCAST) FX We would like to acknowledge excellent assistance from the Oklahoma Center for Medical Glycobiology and from the University of Oklahoma Health Sciences Center Molecular Biology-Proteomics Facility. This work was funded in part by a grant from the Oklahoma Center for the Advancement of Science and Technology (OCAST) to Michael Sakalian. NR 53 TC 30 Z9 31 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 7 PY 2011 VL 8 AR 101 DI 10.1186/1742-4690-8-101 PG 13 WC Virology SC Virology GA 895JZ UT WOS:000300493800001 PM 22151792 ER PT J AU Suto, N Wise, RA AF Suto, Nobuyoshi Wise, Roy A. TI Satiating Effects of Cocaine Are Controlled by Dopamine Actions in the Nucleus Accumbens Core SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INTRACRANIAL SELF-STIMULATION; D-AMPHETAMINE; INTRAVENOUS COCAINE; SATIETY THRESHOLD; NEURAL SYSTEMS; RATS; REINFORCEMENT; REWARD; BRAIN; RECEPTORS AB Intravenous cocaine intake in laboratory animals is characterized by periods of apparent drug satiety between regularly spaced earned injections. The reinforcing properties of cocaine are linked primarily to dopaminergic neurotransmission in the shell and not the core of nucleus accumbens. To determine whether the satiating effects of cocaine are similarly mediated, we perfused dopamine receptor agonists into the core or the shell during intravenous cocaine self-administrations by rats. Neither D1-type (SKF38393) nor D2-type (quinpirole) agonist was effective when given alone. However, a combination of the two agonists perfused into the core but not the shell significantly increased the time between cocaine self-injections, decreasing the amount of earned intake. Together with previous findings, the current data suggest that the satiating and reinforcing effects of cocaine are mediated by different ventral striatal output neurons. C1 [Suto, Nobuyoshi; Wise, Roy A.] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH DHHS, Baltimore, MD 21224 USA. [Suto, Nobuyoshi] Univ Maryland Baltimore Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21228 USA. RP Suto, N (reprint author), Scripps Res Inst, MIND, 10550 N Torrey Pines Rd,Maildrop SP30-2120, La Jolla, CA 92037 USA. EM nsuto@scripps.edu FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; NIDA Residual Research Services [N01DA-5-9909] FX This work was supported by funding from the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, as well as NIDA Residual Research Services (N01DA-5-9909). We thank Dr. Greg Elmer for the help on the statistical analyses. NR 49 TC 18 Z9 18 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 7 PY 2011 VL 31 IS 49 BP 17917 EP 17922 DI 10.1523/JNEUROSCI.1903-11.2011 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 861QX UT WOS:000298035400016 PM 22159106 ER PT J AU Okano, T Xuan, SH Kelley, MW AF Okano, Takayuki Xuan, Shouhong Kelley, Matthew W. TI Insulin-Like Growth Factor Signaling Regulates the Timing of Sensory Cell Differentiation in the Mouse Cochlea SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MAMMALIAN INNER-EAR; SENSORINEURAL HEARING-LOSS; CENTRAL-NERVOUS-SYSTEM; TYPE-1 IGF RECEPTOR; FACTOR-I RECEPTOR; TRANSCRIPTION FACTOR; POSTNATAL-GROWTH; BINDING-PROTEINS; HAIR-CELLS; ORGAN AB The mammalian auditory sensory epithelium, the organ of Corti, is a highly ordered cellular structure that comprises two types of auditory hair cells and several types of nonsensory supporting cells. During embryogenesis, a stereotyped sequence of cellular and molecular events is required for its development. These processes are assumed to be regulated by multiple growth and transcription factors. However, the majority of these factors have not been identified. One potential regulator of cochlear development is the insulin-like growth factor (IGF) signaling family. To examine the roles of the IGF pathway in inner ear formation, cochleae from Igf1r mutant mice were analyzed. Deletion of Igf1r leads to several changes in inner ear development including a shortened cochlear duct, a decrease in the total number of cochlear hair cells, and defects in the formation of the semicircular canals. In addition, maturation of the cochlear sensory epithelium was delayed at the transition point between cellular proliferation and differentiation. To determine the molecular basis for these defects, inhibition of IGF signaling was replicated pharmacologically in vitro. Results indicated that IGF signaling regulates cochlear length and hair cell number as well as Atoh1 expression through the phosphatidylinositol 3-kinase/Akt signaling pathway. These results demonstrate novel roles for IGF signaling in inner ear development including regulation of vestibular formation, length of the cochlear duct, and the number of cochlear hair cells. The results also provide new insights regarding the pathological processes that underlie auditory defects in the absence of IGF signaling in both humans and mice. C1 [Okano, Takayuki; Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Xuan, Shouhong] Columbia Univ, Med Ctr, Dept Genet & Dev, Naomi Berrie Diabet Ctr, New York, NY 10032 USA. RP Kelley, MW (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Porter Neurosci Res Ctr, 35 Convent Dr,2A-100, Bethesda, MD 20892 USA. EM kelleymt@nidcd.nih.gov FU NIH; Japan Society for the Promotion of Science at NIH FX This work was supported by funds from the NIH Intramural program (M. W. K.) and by a grant from the Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH (T.O.). We thank Drs. Doris Wu and Lisa Cunningham for helpful comments on this manuscript. We are also grateful to Dr. Weise Chang for his excellent technical assistance. We thank Dr. Helen May-Simera for assistance with scanning electron microscopy and Dr. Junko Okano for critical discussion. NR 66 TC 18 Z9 21 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 7 PY 2011 VL 31 IS 49 BP 18104 EP 18118 DI 10.1523/JNEUROSCI.3619-11.2011 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 861QX UT WOS:000298035400032 PM 22159122 ER PT J AU Dimitrov, EL Kim, YY Usdin, TB AF Dimitrov, Eugene L. Kim, Yoon Yi Usdin, Ted B. TI Regulation of Hypothalamic Signaling by Tuberoinfundibular Peptide of 39 Residues Is Critical for the Response to Cold: A Novel Peptidergic Mechanism of Thermoregulation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BROWN ADIPOSE-TISSUE; CENTRAL-NERVOUS-SYSTEM; EXPRESSING PREOPTIC NEURONS; HORMONE 2 RECEPTOR; NONSHIVERING THERMOGENESIS; DORSOMEDIAL HYPOTHALAMUS; BODY-TEMPERATURE; PARATHYROID-HORMONE-2 RECEPTOR; AMBIENT-TEMPERATURE; ANESTHETIZED RATS AB Euthermia is critical for mammalian homeostasis. Circuits within the preoptic hypothalamus regulate temperature, with fine control exerted via descending GABAergic inhibition of presympathetic motor neurons that control brown adipose tissue (BAT) thermogenesis and cutaneous vascular tone. The thermoregulatory role of hypothalamic excitatory neurons is less clear. Here we report peptidergic regulation of preoptic glutamatergic neurons that contributes to temperature regulation. Tuberoinfundibular peptide of 39 residues (TIP39) is a ligand for the parathyroid hormone 2 receptor (PTH2R). Both peptide and receptor are abundant in the preoptic hypothalamus. Based on PTH2R and vesicular glutamate transporter 2 (VGlut2) immunolabeling in animals with retrograde tracer injection, PTH2R-containing glutamatergic fibers are presynaptic to neurons projecting from the median preoptic nucleus (MnPO) to the dorsomedial hypothalamus. Transneuronal retrograde pathway tracing with pseudorabies virus revealed connectivity between MnPO VGlut2 and PTH2R neurons and BAT. MnPO injection of TIP39 increased body temperature by 2 degrees C for several hours. Mice lacking TIP39 signaling, either because of PTH2R-null mutation or brain delivery of a PTH2R antagonist had impaired heat production upon cold exposure, but no change in basal temperature and no impairment in response to a hot environment. Thus, TIP39 appears to act on PTH2Rs present on MnPO glutamatergic terminals to regulate their activation of projection neurons and subsequent sympathetic BAT activation. This excitatory mechanism of heat production appears to be activated on demand, during cold exposure, and parallels the tonic inhibitory GABAergic control of body temperature. C1 [Dimitrov, Eugene L.; Kim, Yoon Yi; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, NIH, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, NIH, Bldg 35,Room 1B-215,35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov FU National Institute of Mental Health, NIH FX This work was supported by the Intramural Program of the National Institute of Mental Health, NIH. We appreciate the help and support provided by Milan Rusnak and Jonathan Kuo. Viruses were obtained through the Center for Neuroanatomy with Neurotropic Viruses. NR 63 TC 7 Z9 8 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 7 PY 2011 VL 31 IS 49 BP 18166 EP 18179 DI 10.1523/JNEUROSCI.2619-11.2011 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 861QX UT WOS:000298035400038 PM 22159128 ER PT J AU Holleboom, AG Karlsson, H Lin, RS Beres, TM Sierts, JA Herman, DS Stroes, ESG Aerts, JM Kastelein, JJP Motazacker, MM Dallinga-Thie, GM Levels, JHM Zwinderman, AH Seidman, JG Seidman, CE Ljunggren, S Lefeber, DJ Morava, E Wevers, RA Fritz, TA Tabak, LA Lindahl, M Hovingh, GK Kuivenhoven, JA AF Holleboom, Adriaan G. Karlsson, Helen Lin, Ruei-Shiuan Beres, Thomas M. Sierts, Jeroen A. Herman, Daniel S. Stroes, Erik S. G. Aerts, Johannes M. Kastelein, John J. P. Motazacker, Mohammad M. Dallinga-Thie, Geesje M. Levels, Johannes H. M. Zwinderman, Aeilko H. Seidman, Jonathan G. Seidman, Christine E. Ljunggren, Stefan Lefeber, Dirk J. Morava, Eva Wevers, Ron A. Fritz, Timothy A. Tabak, Lawrence A. Lindahl, Mats Hovingh, G. Kees Kuivenhoven, Jan Albert TI Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man SO CELL METABOLISM LA English DT Article ID APOLIPOPROTEIN-C-III; 2-DIMENSIONAL GEL-ELECTROPHORESIS; ANGIOPOIETIN-LIKE PROTEIN-3; LIPOPROTEIN-LIPASE S447X; RICH LIPOPROTEINS; MASS-SPECTROMETRY; HEPATIC-UPTAKE; GLYCOSYLATION; METABOLISM; APOPROTEINS AB Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGal-NAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGaINAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGaINAc-T2 can affect lipid metabolism through apoC-III glyco-sylation, thereby establishing GALNT2 as a lipid-modifying gene. C1 [Holleboom, Adriaan G.; Stroes, Erik S. G.; Kastelein, John J. P.; Dallinga-Thie, Geesje M.; Hovingh, G. Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Sierts, Jeroen A.; Motazacker, Mohammad M.; Dallinga-Thie, Geesje M.; Levels, Johannes H. M.; Kuivenhoven, Jan Albert] Univ Amsterdam, Acad Med Ctr, Dept Expt Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Aerts, Johannes M.] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, NL-1105 AZ Amsterdam, Netherlands. [Zwinderman, Aeilko H.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands. [Karlsson, Helen] Cty Council Ostergotland, Ctr Occupat & Environm Med, S-58185 Linkoping, Sweden. [Lin, Ruei-Shiuan; Beres, Thomas M.; Tabak, Lawrence A.] Natl Inst Dent & Craniofacial Res, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. [Herman, Daniel S.; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Karlsson, Helen; Ljunggren, Stefan; Lindahl, Mats] Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden. [Lefeber, Dirk J.] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6525 GA Nijmegen, Netherlands. [Lefeber, Dirk J.; Wevers, Ron A.] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, NL-6525 GA Nijmegen, Netherlands. [Lefeber, Dirk J.; Morava, Eva; Wevers, Ron A.] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, NL-6525 GA Nijmegen, Netherlands. [Morava, Eva] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, NL-6525 GA Nijmegen, Netherlands. [Fritz, Timothy A.] US FDA, Rockville, MD 20852 USA. [Kuivenhoven, Jan Albert] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, NL-9713 AV Groningen, Netherlands. RP Hovingh, GK (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM g.k.hovingh@amc.uva.nl; j.a.kuivenhoven@umcg.nl RI lefeber, dirk/G-5063-2012; Lefeber, Dirk/A-2146-2014; Wevers, Ron/H-8116-2014; Morava, E./L-4529-2015; Aerts, Johannes/A-1028-2009; OI Wevers, Ron/0000-0003-2278-9746; Karlsson, Helen/0000-0002-1620-6180; Ljunggren, Stefan/0000-0003-3984-3964 FU European Union [FP6-2005-LIFESCIHEALTH-6, 037631]; Fondation Leducq Transatlantic Networks of Excellence; NWO [40-00506-98-9001]; National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health; Netherlands Organisation for Scientific Research [021.001.035]; Netherlands Heart Foundation [2010T082] FX We are indebted to the study participants and thank C.A. Koch, A.W. Schimmel, J. Coelho Amado de Azevedo, J. Peter, J. Legemate, A. van der Made, and B. van den Bogaard for their help facilitating this family study. We thank the Sanquin Blood Bank for providing control DNA samples, M. Nieuwdorp for his help designing the desialylation experiments, and Xenon Genetics for financing the collection of DNA. This study was supported by the European Union (FP6-2005-LIFESCIHEALTH-6; STREP contract number 037631), Fondation Leducq Transatlantic Networks of Excellence (2010), NWO Medium Investment Grant (40-00506-98-9001 to D.J.L.), and the Intramural Research Program of the National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health. A.G.H. is supported by the Netherlands Organisation for Scientific Research (021.001.035). J.J.P.K. received the Lifetime Achievement Award of the Netherlands Heart Foundation (2010T082). NR 38 TC 43 Z9 43 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD DEC 7 PY 2011 VL 14 IS 6 BP 811 EP 818 DI 10.1016/j.cmet.2011.11.005 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 862VO UT WOS:000298122400014 PM 22152306 ER PT J AU Wang, MH Ma, WX Zhao, L Fariss, RN Wong, WT AF Wang, Minhua Ma, Wenxin Zhao, Lian Fariss, Robert N. Wong, Wai T. TI Adaptive Muller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE M?u?ller cell; microglia; retina; cytokine; cellular interaction; gliosis; migration; adhesion; inflammation; neuroprotection ID LEUKEMIA INHIBITORY FACTOR; CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; GLIAL-CELLS; MOUSE RETINA; IN-VIVO; PHOTORECEPTOR DEGENERATION; CONFOCAL MICROSCOPY; CROSS-TALK; ASTROCYTES AB Purpose: Microglia and Muller cells are prominent participants in retinal responses to injury and disease that shape eventual tissue adaptation or damage. This investigation examined how microglia and Muller cells interact with each other following initial microglial activation. Methods: Mouse Muller cells were cultured alone, or co-cultured with activated or unactivated retinal microglia, and their morphological, molecular, and functional responses were evaluated. Muller cell-feedback signaling to microglia was studied using Muller cell-conditioned media. Corroborative in vivo analyses of retinal microglia-Muller cell interactions in the mouse retina were also performed. Results: Our results demonstrate that Muller cells exposed to activated microglia, relative to those cultured alone or with unactivated microglia, exhibit marked alterations in cell morphology and gene expression that differed from those seen in chronic gliosis. These Muller cells demonstrated in vitro (1) an upregulation of growth factors such as GDNF and LIF, and provide neuroprotection to photoreceptor cells, (2) increased pro-inflammatory factor production, which in turn increased microglial activation in a positive feedback loop, and (3) upregulated chemokine and adhesion protein expression, which allowed Muller cells to attract and adhere to microglia. In vivo activation of microglia by intravitreal injection of lipopolysaccharide (LPS) also induced increased Muller cell-microglia adhesion, indicating that activated microglia may translocate intraretinally in a radial direction using Muller cell processes as an adhesive scaffold. Conclusion: Our findings demonstrate that activated microglia are able to influence Muller cells directly, and initiate a program of bidirectional microglia-Muller cell signaling that can mediate adaptive responses within the retina following injury. In the acute aftermath following initial microglia activation, Muller cell responses may serve to augment initial inflammatory responses across retinal lamina and to guide the intraretinal mobilization of migratory microglia using chemotactic cues and adhesive cell contacts. Understanding adaptive microglia-Muller cell interactions in injury responses can help discover therapeutic cellular targets for intervention in retinal disease. C1 [Wang, Minhua; Ma, Wenxin; Zhao, Lian; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, Off Sci Director, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, Off Sci Director, NIH, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 NR 60 TC 42 Z9 43 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD DEC 7 PY 2011 VL 8 AR 173 DI 10.1186/1742-2094-8-173 PG 18 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 875SZ UT WOS:000299056500001 PM 22152278 ER PT J AU Elegheert, J Desfosses, A Shkumatov, AV Wu, XW Bracke, N Verstraete, K Van Craenenbroeck, K Brooks, BR Svergun, DI Vergauwen, B Gutsche, I Savvides, SN AF Elegheert, Jonathan Desfosses, Ambroise Shkumatov, Alexander V. Wu, Xiongwu Bracke, Nathalie Verstraete, Kenneth Van Craenenbroeck, Kathleen Brooks, Bernard R. Svergun, Dmitri I. Vergauwen, Bjorn Gutsche, Irina Savvides, Savvas N. TI Extracellular Complexes of the Hematopoietic Human and Mouse CSF-1 Receptor Are Driven by Common Assembly Principles SO STRUCTURE LA English DT Article ID STEM-CELL FACTOR; COLONY-STIMULATING FACTOR; SMALL-ANGLE SCATTERING; RAY SOLUTION SCATTERING; CRYSTAL-STRUCTURE; TYROSINE KINASES; ELECTRON-MICROSCOPY; FLT3 LIGAND; BIOLOGICAL MACROMOLECULES; TRANSMEMBRANE DOMAINS AB The hematopoietic colony stimulating factor-1 receptor (CSF-1R or FMS) is essential for the cellular repertoire of the mammalian immune system. Here, we report a structural and mechanistic consensus for the assembly of human and mouse CSF-1 :CSF-1R complexes. The EM structure of the complete extracellular assembly of the human CSF-1:CSF-1R complex reveals how receptor dimerization by CSF-1 invokes a ternary complex featuring extensive homotypic receptor contacts and striking structural plasticity at the extremities of the complex. Studies by small-angle X-ray scattering of unliganded hCSF-1R point to large domain rearrangements upon CSF-1 binding, and provide structural evidence for the relevance of receptor predimerization at the cell surface. Comparative structural and binding studies aiming to dissect the assembly principles of human and mouse CSF-1R complexes, including a quantification of the CSF-1/CSF-1R species cross-reactivity, show that bivalent cytokine binding to receptor coupled to ensuing receptor-receptor interactions are common denominators in extracellular complex formation. C1 [Desfosses, Ambroise; Gutsche, Irina] UMI 3265 UJF EMBL CNRS, Unit Virus Host Cell Interact, F-38042 Grenoble 9, France. [Elegheert, Jonathan; Bracke, Nathalie; Verstraete, Kenneth; Vergauwen, Bjorn; Savvides, Savvas N.] Univ Ghent, Lab Prot Biochem & Biomol Engn L ProBE, Unit Struct Biol, B-9000 Ghent, Belgium. [Van Craenenbroeck, Kathleen] Univ Ghent, LEGEST, B-9000 Ghent, Belgium. [Shkumatov, Alexander V.; Svergun, Dmitri I.] EMBL, Biol Small Angle Scattering Grp, D-22603 Hamburg, Germany. [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Gutsche, I (reprint author), UMI 3265 UJF EMBL CNRS, Unit Virus Host Cell Interact, 6 Rue Jules Horowitz,BP 181, F-38042 Grenoble 9, France. EM gutsche@embl.fr; savvas.savvides@ugent.be OI Svergun, Dmitri/0000-0003-0830-5696; Elegheert, Jonathan/0000-0002-4196-4813 FU Rhone-Alpes Region, France; HFSP [RGP 55/2006]; FWO [3G064307 G059710]; Ghent University; European Commission [226716] FX J.E., K.V., B.V., and K.V.C. are research fellows of the Research Foundation. Flanders, Belgium (FWO). A.D. was funded by a PhD fellowship of the Rhone-Alpes Region, France. A.V.S. and D.I.S. were supported by HFSP Research Grant Ref. RGP 55/2006. S.N.S. is supported by the FWO (Projects 3G064307 and G059710) and Ghent University (BOF instrument). We thank the EMBL-Hamburg for synchrotron beamtime allocation at DESY (Hamburg, Germany) and Clement Blanchet for technical support at beamline X33. Access to these synchrotron facilities is supported by the European Commission under the 7th Framework Programme: Research Infrastructures, Grant Agreement Number 226716. We further thank the SWITCH Laboratory at VIB-Belgium for access to FFF-MALLS facilities and Rodrigo Gallardo for help during data collection and analysis. J.E., A.D., A.V.S., X.W., N.B., B.R.B., D.I.S., B.V., and I.G. contributed to experimental design, performed research, analyzed data, and contributed to the writing of the manuscript. K.V. and K.V.C. provided experimental tools and technical assistance with tissue culture and mammalian protein expression. S.N.S. conceived and directed the study, contributed to experimental design, analyzed data, and contributed to the writing of the manuscript. NR 56 TC 16 Z9 17 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD DEC 7 PY 2011 VL 19 IS 12 BP 1762 EP 1772 DI 10.1016/j.str.2011.10.012 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 859XA UT WOS:000297907900010 PM 22153499 ER PT J AU Nishi, H Hashimoto, K Panchenko, AR AF Nishi, Hafumi Hashimoto, Kosuke Panchenko, Anna R. TI Phosphorylation in Protein-Protein Binding: Effect on Stability and Function SO STRUCTURE LA English DT Article ID EVOLUTIONARY CONSERVATION; REVEALS EVOLUTIONARY; SEQUENCE ALIGNMENT; GENE ONTOLOGY; HOT-SPOTS; DATABASE; SITES; INTERFACES; TYROSINE; DOMAIN AB Posttranslational modifications offer a dynamic way to regulate protein activity, subcellular localization, and stability. Here we estimate the effect of phosphorylation on protein binding and function for different types of complexes from human proteome. We find that phosphorylation sites tend to be located on binding interfaces in heterooligomeric and weak transient homooligomeric complexes. Analysis of molecular mechanisms of phosphorylation shows that phosphorylation may modulate the strength of interactions directly on interfaces and that binding hotspots tend to be phosphorylated in heterooligomers. Although the majority of complexes do not show significant estimated stability differences upon phosphorylation or dephosphorylation, for about one-third of all complexes it causes relatively large changes in binding energy. We discuss the cases where phosphorylation mediates the complex formation and regulates the function. We show that phosphorylation sites are more likely to be evolutionary conserved than other interfacial residues. C1 [Nishi, Hafumi; Hashimoto, Kosuke; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM panch@ncbi.nlm.nih.gov OI Nishi, Hafumi/0000-0002-0846-0330 FU Japan Society for the Promotion of Science; National Institutes of Health/Department of Health and Human Service (National Library of Medicine) FX The authors thank Michael Galperin and Tom Madej for helpful discussions. K.H. was partially supported by a Research Fellowship from the Japan Society for the Promotion of Science. This work was supported by National Institutes of Health/Department of Health and Human Service (Intramural Research program of the National Library of Medicine). NR 64 TC 60 Z9 61 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD DEC 7 PY 2011 VL 19 IS 12 BP 1807 EP 1815 DI 10.1016/j.str.2011.09.021 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 859XA UT WOS:000297907900014 PM 22153503 ER PT J AU Loria, CM Mussolino, ME Cogswell, ME Gillespie, C Gunn, JP Labarthe, DR Saydah, S Pavkov, ME AF Loria, Catherine M. Mussolino, Michael E. Cogswell, Mary E. Gillespie, Cathleen Gunn, Janelle P. Labarthe, Darwin R. Saydah, Sharon Pavkov, Meda E. TI Usual Sodium Intakes Compared With Current Dietary Guidelines-United States, 2005-2008 (Reprinted from MMWR, vol 60, pg 1413-1417, 2011) SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Reprint C1 [Cogswell, Mary E.; Gillespie, Cathleen; Gunn, Janelle P.; Labarthe, Darwin R.] CDC, Div Heart Dis & Stroke Prevent, Atlanta, GA 30333 USA. [Loria, Catherine M.; Mussolino, Michael E.] NHLBI, Div Cardiovasc Dis, NIH, Bethesda, MD 20892 USA. [Saydah, Sharon; Pavkov, Meda E.] CDC, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Cogswell, ME (reprint author), CDC, Div Heart Dis & Stroke Prevent, Atlanta, GA 30333 USA. EM mcogswell@cdc.gov NR 1 TC 0 Z9 0 U1 0 U2 1 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 DEC 7 PY 2011 VL 306 IS 21 BP 2322 EP 2324 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 856YH UT WOS:000297680300010 ER PT J AU Carlo, WA McDonald, SA Fanaroff, AA Vohr, BR Stoll, BJ Ehrenkranz, RA Andrews, WW Wallace, D Das, A Bell, EF Walsh, MC Laptook, AR Shankaran, S Poindexter, BB Hale, EC Newman, NS Davis, AS Schibler, K Kennedy, KA Sanchez, PJ Van Meurs, KP Goldberg, RN Watterberg, KL Faix, RG Frantz, ID Higgins, RD AF Carlo, Waldemar A. McDonald, Scott A. Fanaroff, Avroy A. Vohr, Betty R. Stoll, Barbara J. Ehrenkranz, Richard A. Andrews, William W. Wallace, Dennis Das, Abhik Bell, Edward F. Walsh, Michele C. Laptook, Abbot R. Shankaran, Seetha Poindexter, Brenda B. Hale, Ellen C. Newman, Nancy S. Davis, Alexis S. Schibler, Kurt Kennedy, Kathleen A. Sanchez, Pablo J. Van Meurs, Krisa P. Goldberg, Ronald N. Watterberg, Kristi L. Faix, Roger G. Frantz, Ivan D., III Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Association of Antenatal Corticosteroids With Mortality and Neurodevelopmental Outcomes Among Infants Born at 22 to 25 Weeks' Gestation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BIRTH-WEIGHT INFANTS; EXTREMELY PRETERM INFANTS; DEVELOPMENTAL-DISABILITY; AGE; SURVIVAL; CARE; MATURATION; VIABILITY; NETWORK; EPICURE AB Context Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care. Objective To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation. Design, Setting, and Participants Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N=10 541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables. Main Outcome Measures Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age. Results Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]). Conclusion Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months. JAMA. 2011;306(21):2348-2358 C1 [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Women & Infants Ctr 9380, Birmingham, AL 35249 USA. [Carlo, Waldemar A.; Andrews, William W.] Childrens Hosp Alabama, Birmingham, AL USA. [McDonald, Scott A.; Wallace, Dennis] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Fanaroff, Avroy A.; Walsh, Michele C.; Newman, Nancy S.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Vohr, Betty R.; Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Stoll, Barbara J.; Hale, Ellen C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.; Hale, Ellen C.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Poindexter, Brenda B.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN USA. [Davis, Alexis S.; Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Davis, Alexis S.; Van Meurs, Krisa P.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Schibler, Kurt] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. [Kennedy, Kathleen A.] Univ Texas Med Sch, Dept Pediat, Houston, TX USA. [Sanchez, Pablo J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Watterberg, Kristi L.] Univ New Mexico, Hlth Sci Ctr, Dept Pediat, Albuquerque, NM 87131 USA. [Faix, Roger G.] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT USA. [Frantz, Ivan D., III] Tufts Med Ctr, Floating Hosp Children, Div Newborn Med, Dept Pediat, Boston, MA USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Carlo, WA (reprint author), Univ Alabama Birmingham, Dept Pediat, Women & Infants Ctr 9380, 1700 6th Ave S, Birmingham, AL 35249 USA. EM wcarlo@peds.uab.edu RI Myers , Gary /I-4901-2013 OI Myers , Gary /0000-0003-4317-015X FU F. Hoffman-LaRoche Ltd; Astellas; Ikaria; Ikaria Biosynexus; National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Carlo reported that he is a board member of Mednax. Dr Sanchez reported that he received study funding from F. Hoffman-LaRoche Ltd and Astellas for his work on the Collaborative Antiviral Study Group. Dr van Meurs reported that she received consulting fees, honorarium, and equipment support from Ikaria; travel, accommodations, and meeting expenses paid for by Actelion and Ikaria; and payment from legal firms for expert testimony for various lawsuits. Dr Faix reported that he serves on a data and safety monitoring board and receives funding from Ikaria Biosynexus. No other authors reported disclosures.; The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network's Generic Database and Follow-up Studies. NR 30 TC 96 Z9 98 U1 1 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 7 PY 2011 VL 306 IS 21 BP 2348 EP 2358 DI 10.1001/jama.2011.1752 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 856YH UT WOS:000297680300020 PM 22147379 ER PT J AU Stevens, KN Garcia-Closas, M Fredericksen, Z Kosel, M Pankratz, VS Hopper, JL Dite, GS Apicella, C Southey, MC Schmidt, MK Broeks, A Van 't Veer, LJ Tollenaar, RAEM Fasching, PA Beckmann, MW Hein, A Ekici, AB Johnson, N Peto, J Silva, ID Gibson, L Sawyer, E Tomlinson, I Kerin, MJ Chanock, S Lissowska, J Hunter, DJ Hoover, RN Thomas, GD Milne, RL Perez, JIA Gonzalez-Neira, A Benitez, J Burwinkel, B Meindl, A Schmutzler, RK Bartrar, CR Hamann, U Ko, YD Bruning, T Chang-Claude, J Hein, R Wang-Gohrke, S Dork, T Schurmann, P Bremer, M Hillemanns, P Bogdanova, N Zalutsky, JV Rogov, YI Antonenkova, N Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, J Chenevix-Trench, G Chen, X Peterlongo, P Bonanni, B Bernard, L Manoukian, S Wang, X Cerhan, J Vachon, CM Olson, J Giles, GG Baglietto, L McLean, CA Severi, G John, EM Miron, A Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Andrulis, I Knight, JA Glendon, G Mulligan, AM Cox, A Brock, IW Elliott, G Cross, SS Pharoah, PP Dunning, AM Pooley, KA Humphreys, MK Wang, J Kang, D Yoo, KY Noh, DY Sangrajrang, S Gabrieau, V Brennan, P Mckay, J Anton-Culver, H Ziogas, A Couch, FJ Easton, DF AF Stevens, K. N. Garcia-Closas, M. Fredericksen, Z. Kosel, M. Pankratz, V. S. Hopper, J. L. Dite, G. S. Apicella, C. Southey, M. C. Schmidt, M. K. Broeks, A. Van 't Veer, L. J. Tollenaar, R. A. E. M. Fasching, P. A. Beckmann, M. W. Hein, A. Ekici, A. B. Johnson, N. Peto, J. Silva, I. dos Santos Gibson, L. Sawyer, E. Tomlinson, I. Kerin, M. J. Chanock, S. Lissowska, J. Hunter, D. J. Hoover, R. N. Thomas, G. D. Milne, R. L. Perez, J. I. Arias Gonzalez-Neira, A. Benitez, J. Burwinkel, B. Meindl, A. Schmutzler, R. K. Bartrar, C. R. Hamann, U. Ko, Y. D. Bruening, T. Chang-Claude, J. Hein, R. Wang-Gohrke, S. Doerk, T. Schuermann, P. Bremer, M. Hillemanns, P. Bogdanova, N. Zalutsky, J. V. Rogov, Y. I. Antonenkova, N. Lindblom, A. Margolin, S. Mannermaa, A. Kataja, V. Kosma, V-M Hartikainen, J. Chenevix-Trench, G. Chen, X. Peterlongo, P. Bonanni, B. Bernard, L. Manoukian, S. Wang, X. Cerhan, J. Vachon, C. M. Olson, J. Giles, G. G. Baglietto, L. McLean, C. A. Severi, G. John, E. M. Miron, A. Winqvist, R. Pylkaes, K. Jukkola-Vuorinen, A. Grip, M. Andrulis, I. Knight, J. A. Glendon, G. Mulligan, A. M. Cox, A. Brock, I. W. Elliott, G. Cross, S. S. Pharoah, P. P. Dunning, A. M. Pooley, K. A. Humphreys, M. K. Wang, J. Kang, D. Yoo, K-Y Noh, D-Y Sangrajrang, S. Gabrieau, V. Brennan, P. Mckay, J. Anton-Culver, H. Ziogas, A. Couch, F. J. Easton, D. F. CA GENICA Network kConFab Invest Australian Ovarian Cancer Study Gr TI Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk SO BRITISH JOURNAL OF CANCER LA English DT Article DE genetic susceptibility; neoplasms; association study ID PIK3CA MUTATIONS; POOR-PROGNOSIS; HIGH-FREQUENCY; PTEN LOSS; GENE; ASSOCIATION; CORRELATE; PATHWAY; OVARIAN AB BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR) = 0.97, 95% confidence interval (CI) 0.95-0.99, P = 4.6 x 10(-3)), but did not reach significance in the BCAC replication study alone (OR = 0.98, 95% CI 0.96-1.01, P = 0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer British Journal of Cancer (2011) 105, 1934 - 1939. doi: 10.1038/bjc.2011.448 www.bjcancer.com Published online 27 October 2011 (C) 2011 Cancer Research UK C1 [Couch, F. J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Stevens, K. N.; Fredericksen, Z.; Kosel, M.; Pankratz, V. S.; Wang, X.; Cerhan, J.; Vachon, C. M.; Olson, J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Garcia-Closas, M.] Inst Canc Res, Sect Epidemiol & Genet, London SW7 3RP, England. [Garcia-Closas, M.; Johnson, N.] Breakthrough Breast Canc Res Ctr, London SW7 3RP, England. [Hopper, J. L.; Dite, G. S.; Apicella, C.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Southey, M. C.] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Schmidt, M. K.; Broeks, A.; Van 't Veer, L. J.] Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Tollenaar, R. A. E. M.] Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands. [Fasching, P. A.] Univ Calif Los Angeles, Div Hematol & Oncol, Dept Med, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Fasching, P. A.; Beckmann, M. W.; Hein, A.] Univ Erlangen Nurnberg, Dept Gynecol & Obstet, Univ Breast Ctr Franconia, Comprehens Canc Ctr Erlangen Nuremberg, D-91054 Erlangen, Germany. [Ekici, A. B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Peto, J.; Silva, I. dos Santos; Gibson, L.] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1E 7HT, England. [Sawyer, E.] Kings Coll London, Natl Inst Hlth Res NIHR, Comprehens Biomed Res Ctr, Guys & St Thomas NHS Fdn Trust, London SE1 9RT, England. [Sawyer, E.] Kings Coll Hosp NHS Fdn Trust, Guys Hosp, London SE1 9RT, England. [Tomlinson, I.] Univ Oxford, Oxford Biomed Res Ctr Mol & Populat Genet, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Kerin, M. J.] Univ Hosp, NUIG Dept Surg, Inst Clin Sci, Galway 091524411, Ireland. [Chanock, S.; Hoover, R. N.; Thomas, G. D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, J.] M Sklodowska Curie Mem Canc Ctr, Inst Oncol, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Hunter, D. J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Milne, R. L.] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid 28029, Spain. [Perez, J. I. Arias] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo 33012, Spain. [Gonzalez-Neira, A.] Spanish Natl Canc Res Ctr CNIO, Human Gentyping Unit CeGen, Madrid, Spain. [Benitez, J.] Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Madrid 28029, Spain. [Burwinkel, B.] Univ Heidelberg Hosp, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany. [Burwinkel, B.] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany. [Meindl, A.] Tech Univ Munich, Dept Obstet & Gynaecol, D-80333 Munich, Germany. [Schmutzler, R. K.] Univ Hosp Cologne, Div Mol Gynecooncol, Dept Obstet & Gynaecol, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany. [Bartrar, C. R.] Univ Heidelberg, Inst Human Genet, D-69120 Heidelberg, Germany. [Hamann, U.] Deutsch Krebsforschungszentrum DKFZ, D-69120 Heidelberg, Germany. [Ko, Y. D.] Evangel Kliniken Bonn gGmbH, Betriebsstatte Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany. [Bruening, T.] German Social Accid Insurance IPA, Inst Prevent & Occupat Med, D-44789 Bochum, Germany. [Chang-Claude, J.; Hein, R.] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Wang-Gohrke, S.] Univ Ulm, Dept Obstet & Gynecol, D-89081 Ulm, Germany. [Doerk, T.; Schuermann, P.] Hannover Med Sch, Gynaecol Res Unit, D-30625 Hannover, Germany. [Bremer, M.; Bogdanova, N.] Hannover Med Sch, Clin Radiat Oncol, D-30625 Hannover, Germany. [Hillemanns, P.; Zalutsky, J. V.; Rogov, Y. I.; Antonenkova, N.] Hannover Med Sch, Clin Obstet & Gynaecol, D-30625 Hannover, Germany. [Lindblom, A.] Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden. [Margolin, S.] Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Mannermaa, A.; Kosma, V-M; Hartikainen, J.] Univ Eastern Finland, Inst Clin Med, Dept Pathol, FI-70211 Kuopio, Finland. [Mannermaa, A.; Kosma, V-M; Hartikainen, J.] Kuopio Univ Hosp, Bioctr Kuopio, FI-70211 Kuopio, Finland. [Kataja, V.] Univ Eastern Finland, Kuopio Univ Hosp, Inst Clin Med, Dept Oncol, FI-70211 Kuopio, Finland. [Chenevix-Trench, G.; Chen, X.] Queensland Inst Med Res, Herston, Qld 4029, Australia. [Peterlongo, P.] Fdn IRCCS Ist Nazl Tumori INT, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predicted Med, I-1620139 Milan, Italy. [Peterlongo, P.] Fdn Ist FIRC Oncol Mol, IFOM, I-1620139 Milan, Italy. [Bonanni, B.] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy. [Bernard, L.] Ist Europeo Oncol, Dept Expt Oncol, I-1620139 Milan, Italy. [Bernard, L.] Consortium Genom Technol Cogentech, I-1620139 Milan, Italy. [Manoukian, S.] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Prevent Med, I-20133 Milan, Italy. [Giles, G. G.; Baglietto, L.; Severi, G.] Canc Epidemiol Ctr, Canc Council Victoria, Carlton, Vic 3053, Australia. [Giles, G. G.; Baglietto, L.; Severi, G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Victoria 3010, Australia. [McLean, C. A.] Alfred Hosp, Dept Anat Pathol, Prahran, Vic 3181, Australia. [John, E. M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA. [Miron, A.] Dana Farber Canc Inst, Dept Surg, Boston, MA 02215 USA. [Winqvist, R.; Pylkaes, K.] Univ Oulu, Oulu Univ Hosp, Canc Genet Lab, Dept Clin Genet, Oulu 90220, Finland. [Winqvist, R.; Pylkaes, K.] Univ Oulu, Oulu Univ Hosp, Bioctr Oulu, Oulu 90220, Finland. [Jukkola-Vuorinen, A.] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu 90220, Finland. [Grip, M.] Univ Oulu, Oulu Univ Hosp, Dept Surg, Oulu 90220, Finland. [Andrulis, I.; Glendon, G.] Ontario Canc Genet Network, Toronto, ON M5G 2C1, Canada. [Andrulis, I.] Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Andrulis, I.] Univ Toronto, Dept Mol Genet, Toronto, ON M5A 2N4, Canada. [Knight, J. A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Knight, J. A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5A 2N4, Canada. [Mulligan, A. M.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5A 2N4, Canada. [Mulligan, A. M.] St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Mulligan, A. M.] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Cox, A.; Brock, I. W.] Univ Sheffield, Fac Med Dent & Hlth, Sheffield S10 2RX, S Yorkshire, England. [Elliott, G.] Univ Manchester, Med Genet Res Grp, Fac Med & Human Sci, Manchester M13 9PL, Lancs, England. [Cross, S. S.] Univ Sheffield, Dept Neurosci, Fac Med Dent & Hlth, Sheffield S10 2RX, S Yorkshire, England. [Pharoah, P. P.] United Kingdom Dept Oncol, Cambridge, England. [Pharoah, P. P.] Dept Publ Hlth, Cambridge, England. [Pharoah, P. P.] Primary Care Univ Cambridge, Cambridge, England. [Dunning, A. M.; Pooley, K. A.; Easton, D. F.] Univ Cambridge, Dept Oncol, Cambridge CB2 0RE, England. [Humphreys, M. K.; Wang, J.; Easton, D. F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Kang, D.; Yoo, K-Y; Noh, D-Y] Seoul Natl Univ, Coll Med, Seoul 110799, South Korea. [Sangrajrang, S.] Natl Canc Inst, Bangkok 10400, Thailand. [Gabrieau, V.; Brennan, P.; Mckay, J.] Int Agcy Res Canc, F-69372 Lyon 08, France. [Anton-Culver, H.; Ziogas, A.] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92697 USA. RP Couch, FJ (reprint author), Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55905 USA. EM couch.fergus@mayo.edu RI Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; manoukian, siranoush/E-7132-2017; Hartikainen, Jaana/E-6256-2015; Knight, Julia/A-6843-2012; Noh, Dong-Young/G-5531-2011; Kang, Dae Hee/E-8631-2012; Yoo, Keun-Young/J-5548-2012; Hein, Alexander/F-6999-2010; Kerin, Michael/D-6748-2013; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013; Dork, Thilo/J-8620-2012; Bernard, Loris/K-5953-2014; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015 OI Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; manoukian, siranoush/0000-0002-6034-7562; Dite, Gillian/0000-0002-2448-2548; Cerhan, James/0000-0002-7482-178X; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099; Hein, Alexander/0000-0003-2601-3398; Garcia-Closas, Montserrat /0000-0003-1033-2650 FU Dutch Cancer Society [NKI 2001-2423, NKI 2007-3839]; Dutch National Genomics Initiative; United States National Cancer Institute, National Institutes of Health (NIH) [RFA-CA-06-503]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; University Hospital Erlangen; Cancer Research UK; Breakthrough Breast Cancer; NIHR Biomedical Research Centre; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guy's & St Thomas' NHS Foundation Trust; Oxford Biomedical Research Centre; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI081583, PI081120]; Deutsche Krebshilfe [107054]; Dietmar-Hopp Foundation; Helmholtz society; German Cancer Research Center (DKFZ); Hannover Medical School; German Academic Exchange Program; Friends of Hannover Medical School; Finnish Cancer Society; Academy of Finland [127220]; Kuopio University Hospital [5654113, 5501]; University of Eastern Finland; NHMRC; National Breast Cancer Foundation and Cancer Australia [628333]; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC) [199600, 209057, 251553, 504711]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of Tasmania; Italian citizens; NIH [CA122340]; US Recovery act [CA122340Z]; VicHealth and Cancer Council Victoria; Finnish Cancer Foundation; Sigrid Juselius Foundation; Academy of Finland; University of Oulu; Oulu University Hospital; Breast Cancer Campaign and Yorkshire Cancer Research; National Institutes of Health, National Cancer Institute [CA-58860, CA-92044]; Lon V Smith Foundation [LVS-39420] FX The ABCS study was funded by the Dutch Cancer Society (grants NKI 2001-2423; NKI 2007-3839), the Dutch National Genomics Initiative; ABCS acknowledges all patients, and Sten Cornelissen, Richard van Hien, Flora van Leeuwen, Vincent Smit and other contributors to the 'BOSOM' study (ABCS). The ABCFS, NC-BCFR and OFBCR works were supported by the United States National Cancer Institute, National Institutes of Health (NIH) under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638). Samples from the NC-BCFR were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organisations imply endorsement by the US Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. JLH is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. MCS is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. BBCC is funded in part by the ELAN fund of the University Hospital Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI081583 and PI081120). We thank Charo Alonso, Tais Moreno, Guillermo Pita, Primitiva Menendez and Pilar Zamora for their contribution to this work. The GC-HBOC was collected within a project funded by the Deutsche Krebshilfe (Grant number: 107054). It was supported by the Dietmar-Hopp Foundation, the Helmholtz society and the German Cancer Research Center (DKFZ). We thank Sandrine Tchatchou for genotyping. The HABCS was supported by an intramural grant from Hannover Medical School. The HMBCS was supported by short-term fellowships from the German Academic Exchange Program (to NB), and the Friends of Hannover Medical School (to NB). KARBAC acknowledges The Swedish Cancer Society and The Stockholm Cancer Society. KBCP is supported by grants from the Finnish Cancer Society; the Academy of Finland (grant number 127220); the special Government Funding (EVO) of Kuopio University Hospital (grant number 5654113 and 5501) and by the strategic funding of the University of Eastern Finland. We thank Mrs Helena Kemilainen, Mrs Aija Parkkinen and Mrs Eija Myohanen for their skillful technical assistance.; We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded 2001-2009 by NHMRC and currently by theNational Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729); the Cancer Council of Tasmania and Cancer Foundation of Western Australia; and the NHMRC [199600]. GC-T is supported by the NHMRC. PP is supported by funds from Italian citizens who allocated the 5 x 1000 share of their tax payment to the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1000'). MBCSG thanks Paolo Radice, Bernard Peissel, Daniela Zaffaroni and Marco A Pierotti of the Fondazione IRCCS Istituto Nazionale Tumori and Monica Barile of the Istituto Europeo di Oncologia, Milano, Italy. MCBCS was supported by NIH grant CA122340 and US Recovery act award CA122340Z. Many people have contributed to the MCCS, including the original investigators and the diligent teams who recruited the participants and who continue working on follow-up. Finally, we express our gratitude to the many thousands of Melbourne residents who continue to participate in the study. Cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. OBCS was supported by research grants from the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Oulu and the Oulu University Hospital. SBCS was funded by the Breast Cancer Campaign and Yorkshire Cancer Research. The authors acknowledge Helen Cramp, Sue Higham, Dan Connley, Saba Balasubramanian. The UCIBCS is supported by the National Institutes of Health, National Cancer Institute grants CA-58860, CA-92044 and the Lon V Smith Foundation grant LVS-39420. NR 23 TC 2 Z9 2 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD DEC 6 PY 2011 VL 105 IS 12 BP 1934 EP 1939 DI 10.1038/bjc.2011.448 PG 6 WC Oncology SC Oncology GA 863CQ UT WOS:000298140800018 PM 22033276 ER PT J AU Kravitz, DJ Baker, CI AF Kravitz, Dwight J. Baker, Chris I. TI Toward a new model of scientific publishing: discussion and a proposal SO FRONTIERS IN COMPUTATIONAL NEUROSCIENCE LA English DT Article DE peer review; neuroscience; publishing ID REVIEWERS AB The current system of publishing in the biological sciences is notable for its redundancy, inconsistency, sluggishness, and opacity. These problems persist, and grow worse, because the peer review system remains focused on deciding whether or not to publish a paper in a particular journal rather than providing (1) a high-quality evaluation of scientific merit and( 2) the information necessary to organize and prioritize the literature. Online access has eliminated the need for journals as distribution channels, so their primary current role is to provide authors with feedback prior to publication and a quick way for other researchers to prioritize the literature based on which journal publishes a paper. However, the feedback provided by reviewers is not focused on scientific merit but on whether to publish in a particular journal, which is generally of little use to authors and an opaque and noisy basis for prioritizing the literature. Further, each submission of a rejected manuscript requires the entire machinery of peer review to creak to life anew. This redundancy incurs delays, inconsistency, and increased burdens on authors, reviewers, and editors. Finally, reviewers have no real incentive to review well or quickly, as their performance is not tracked, let alone rewarded. One of the consistent suggestions for modifying the current peer review system is the introduction of some form of post-publication reception, and the development of a marketplace where the priority of a paper rises and falls based on its reception from the field (see other articles in this special topics). However, the information that accompanies a paper into the marketplace is as important as the marketplace's mechanics. Beyond suggestions concerning the mechanisms of reception, we propose an update to the system of publishing in which publication is guaranteed, but pre-publication peer review still occurs, giving the authors the opportunity to revise their work following a mini pre-reception from the field. This step also provides a consistent set of rankings and reviews to the marketplace, allowing for early prioritization and stabilizing its early dynamics. We further propose to improve the general quality of reviewing by providing tangible rewards to those who do it well. C1 [Kravitz, Dwight J.; Baker, Chris I.] NIMH, Unit Learning & Plast, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Kravitz, DJ (reprint author), NIMH, Unit Learning & Plast, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM kravitzd@mail.nih.gov RI Kravitz, Dwight/B-8430-2012; OI Baker, Chris/0000-0001-6861-8964 NR 9 TC 23 Z9 23 U1 4 U2 13 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5188 J9 FRONT COMPUT NEUROSC JI Front. Comput. Neurosci. PD DEC 5 PY 2011 VL 5 AR 55 DI 10.3389/fncom.2011.00055 PG 12 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 882MY UT WOS:000299569100001 PM 22164143 ER PT J AU Helbing, CC Wagner, MJ Pettem, K Johnston, J Heimeier, RA Veldhoen, N Jirik, FR Shi, YB Browder, LW AF Helbing, Caren C. Wagner, Mary J. Pettem, Katherine Johnston, Jill Heimeier, Rachel A. Veldhoen, Nik Jirik, Frank R. Shi, Yun-Bo Browder, Leon W. TI Modulation of Thyroid Hormone-Dependent Gene Expression in Xenopus laevis by INhibitor of Growth (ING) Proteins SO PLOS ONE LA English DT Article ID PHD FINGER; BREAST-CANCER; PLANT HOMEODOMAIN; TUMOR-SUPPRESSOR; AXIS DISRUPTION; HISTONE H3; METAMORPHOSIS; RECEPTOR; FAMILY; CHROMATIN AB Background: INhibitor of Growth (ING) proteins belong to a large family of plant homeodomain finger-containing proteins important in epigenetic regulation and carcinogenesis. We have previously shown that ING1 and ING2 expression is regulated by thyroid hormone (TH) during metamorphosis of the Xenopus laevis tadpole. The present study investigates the possibility that ING proteins modulate TH action. Methodology/Principal Findings: Tadpoles expressing a Xenopus ING2 transgene (Trans(ING2)) were significantly smaller than tadpoles not expressing the transgene (Trans(GFP)). When exposed to 10 nM 3,5,3'-triiodothyronine (T(3)), premetamorphic Trans(ING2) tadpoles exhibited a greater reduction in tail, head, and brain areas, and a protrusion of the lower jaw than T(3)-treated Trans(GFP) tadpoles. Quantitative real time polymerase chain reaction (QPCR) demonstrated elevated TH receptor beta (TR beta) and TH/bZIP transcript levels in Trans(ING2) tadpole tails compared to Trans(GFP) tadpoles while TR alpha mRNAs were unaffected. In contrast, no difference in TR alpha, TR beta or insulin-like growth factor (IGF2) mRNA abundance was observed in the brain between Trans(ING2) and Trans(GFP) tadpoles. All of these transcripts, except for TR alpha mRNA in the brain, were inducible by the hormone in both tissues. Oocyte transcription assays indicated that ING proteins enhanced TR-dependent, T(3)-induced TR beta gene promoter activity. Examination of endogenous T(3)-responsive promoters (TR beta and TH/bZIP) in the tail by chromatin immunoprecipitation assays showed that ING proteins were recruited to TRE-containing regions in T(3)-dependent and independent ways, respectively. Moreover, ING and TR proteins coimmunoprecipitated from tail protein homogenates derived from metamorphic climax animals. Conclusions/Significance: We show for the first time that ING proteins modulate TH-dependent responses, thus revealing a novel role for ING proteins in hormone signaling. This has important implications for understanding hormone influenced disease states and suggests that the induction of ING proteins may facilitate TR function during metamorphosis in a tissue-specific manner. C1 [Helbing, Caren C.; Wagner, Mary J.; Pettem, Katherine; Veldhoen, Nik] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada. [Johnston, Jill; Jirik, Frank R.; Browder, Leon W.] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada. [Heimeier, Rachel A.; Shi, Yun-Bo] NICHHD, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, Program Cell Regulat & Metab,NIH, Bethesda, MD 20892 USA. [Jirik, Frank R.] Univ Calgary, McCaig Inst Bone & Joint Hlth, Calgary, AB, Canada. RP Helbing, CC (reprint author), Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada. EM chelbing@uvic.ca FU Natural Sciences and Engineering Research Council (NSERC); National Institute of Child Health and Human Development, NIH; NSERC-PGSM; Michael Smith Foundation for Health Research (MSFHR); PGSD FX This work was funded by Natural Sciences and Engineering Research Council (NSERC) Discovery grants to CCH and LWB, and also in part by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH (YBS). MJW was recipient of NSERC-PGSM and PGSD scholarships and a Michael Smith Foundation for Health Research (MSFHR) trainee award. CCH is a past MSFHR scholar and recipient of a NSERC University Faculty Award; and FRJ held a Canada Tier I Research Chair Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 4 Z9 4 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 5 PY 2011 VL 6 IS 12 AR e28658 DI 10.1371/journal.pone.0028658 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863NX UT WOS:000298172800054 PM 22163049 ER PT J AU Okorie, PN McKenzie, FE Ademowo, OG Bockarie, M Kelly-Hope, L AF Okorie, Patricia Nkem McKenzie, F. Ellis Ademowo, Olusegun George Bockarie, Moses Kelly-Hope, Louise TI Nigeria Anopheles Vector Database: An Overview of 100 Years' Research SO PLOS ONE LA English DT Article ID VILLAGE-SCALE TRIAL; POPULATION GENETIC-STRUCTURE; POLYMERASE-CHAIN-REACTION; SOUTH-WESTERN NIGERIA; PYRETHROID INSECTICIDE RESISTANCE; RESIDUAL FUMIGANT INSECTICIDE; AFRICAN MALARIA VECTORS; GAMBIAE-SENSU-STRICTO; SUB-SAHARAN AFRICA; NORTHERN NIGERIA AB Anopheles mosquitoes are important vectors of malaria and lymphatic filariasis (LF), which are major public health diseases in Nigeria. Malaria is caused by infection with a protozoan parasite of the genus Plasmodium and LF by the parasitic worm Wuchereria bancrofti. Updating our knowledge of the Anopheles species is vital in planning and implementing evidence based vector control programs. To present a comprehensive report on the spatial distribution and composition of these vectors, all published data available were collated into a database. Details recorded for each source were the locality, latitude/longitude, time/period of study, species, abundance, sampling/collection methods, morphological and molecular species identification methods, insecticide resistance status, including evidence of the kdr allele, and P. falciparum sporozoite rate and W. bancrofti microfilaria prevalence. This collation resulted in a total of 110 publications, encompassing 484,747 Anopheles mosquitoes in 632 spatially unique descriptions at 142 georeferenced locations being identified across Nigeria from 1900 to 2010. Overall, the highest number of vector species reported included An. gambiae complex (65.2%), An. funestus complex (17.3%), An. gambiae s.s. (6.5%). An. arabiensis (5.0%) and An. funestus s.s. (2.5%), with the molecular forms An. gambiae M and S identified at 120 locations. A variety of sampling/collection and species identification methods were used with an increase in molecular techniques in recent decades. Insecticide resistance to pyrethroids and organochlorines was found in the main Anopheles species across 45 locations. Presence of P. falciparum and W. bancrofti varied between species with the highest sporozoite rates found in An. gambiae s.s, An. funestus s.s. and An. moucheti, and the highest microfilaria prevalence in An. gambiae s.l., An. arabiensis, and An. gambiae s.s. This comprehensive georeferenced database provides an essential baseline on Anopheles vectors and will be an important resource for malaria and LF vector control programmes in Nigeria. C1 [Okorie, Patricia Nkem; Ademowo, Olusegun George] Univ Ibadan, Inst Adv Med Res & Training, Coll Med, Ibadan, Nigeria. [McKenzie, F. Ellis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bockarie, Moses; Kelly-Hope, Louise] Univ Liverpool, Liverpool Sch Trop Med, Ctr Neglected Trop Dis, Liverpool L3 5QA, Merseyside, England. RP Okorie, PN (reprint author), Univ Ibadan, Inst Adv Med Res & Training, Coll Med, Ibadan, Nigeria. EM triciaokoye@yahoo.com FU Medical Research Council [G1001337] NR 175 TC 13 Z9 14 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 5 PY 2011 VL 6 IS 12 AR e28347 DI 10.1371/journal.pone.0028347 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 863NX UT WOS:000298172800027 PM 22162764 ER PT J AU Sherman-Baust, CA Becker, KG Wood, WH Zhang, YQ Morin, PJ AF Sherman-Baust, Cheryl A. Becker, Kevin G. Wood, William H. Zhang, Yongqing Morin, Patrice J. TI Gene expression and pathway analysis of ovarian cancer cells selected for resistance to cisplatin, paclitaxel, or doxorubicin SO JOURNAL OF OVARIAN RESEARCH LA English DT Article ID PROSTATE SECRETORY PROTEIN; ANTICANCER DRUG CISPLATIN; MULTIDRUG-RESISTANCE; EXTRACELLULAR-MATRIX; PEPTIDE PCK3145; APOPTOSIS; GROWTH; OVEREXPRESSION; CHEMOTHERAPY; SUPPRESSES AB Background: Resistance to current chemotherapeutic agents is a major cause of therapy failure in ovarian cancer patients, but the exact mechanisms leading to the development of drug resistance remain unclear. Methods: To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of drug resistant ovarian cancer cell lines through repeated exposure to three chemotherapeutic drugs (cisplatin, doxorubicin, or paclitaxel), and identified changes in gene expression patterns using Illumina whole-genome expression microarrays. Validation of selected genes was performed by RT-PCR and immunoblotting. Pathway enrichment analysis using the KEGG, GO, and Reactome databases was performed to identify pathways that may be important in each drug resistance phenotype. Results: A total of 845 genes (p < 0.01) were found altered in at least one drug resistance phenotype when compared to the parental, drug sensitive cell line. Focusing on each resistance phenotype individually, we identified 460, 366, and 337 genes significantly altered in cells resistant to cisplatin, doxorubicin, and paclitaxel, respectively. Of the 845 genes found altered, only 62 genes were simultaneously altered in all three resistance phenotypes. Using pathway analysis, we found many pathways enriched for each resistance phenotype, but some dominant pathways emerged. The dominant pathways included signaling from the cell surface and cell movement for cisplatin resistance, proteasome regulation and steroid biosynthesis for doxorubicin resistance, and control of translation and oxidative stress for paclitaxel resistance. Conclusions: Ovarian cancer cells develop drug resistance through different pathways depending on the drug used in the generation of chemoresistance. A better understanding of these mechanisms may lead to the development of novel strategies to circumvent the problem of drug resistance. C1 [Sherman-Baust, Cheryl A.; Morin, Patrice J.] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Becker, Kevin G.; Wood, William H.; Zhang, Yongqing] NIA, Res Resource Branch, Baltimore, MD 21224 USA. [Morin, Patrice J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. RP Morin, PJ (reprint author), NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. EM morinp@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU NIH, National Institute on Aging FX We thank the members of our laboratory for useful comments on the manuscript. We thank Dr. Bingxue Yan for technical help on various aspects of this work. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 33 TC 25 Z9 26 U1 1 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-2215 J9 J OVARIAN RES JI J. Ovarian Res. PD DEC 5 PY 2011 VL 4 AR 21 DI 10.1186/1757-2215-4-21 PG 11 WC Reproductive Biology SC Reproductive Biology GA 876IT UT WOS:000299101900001 PM 22141344 ER PT J AU Wen, H Kemble, CK Bennett, EE AF Wen, Han Kemble, Camille K. Bennett, Eric E. TI Theory of oblique and grazing incidence Talbot-Lau interferometers and demonstration in a compact source x-ray reflective interferometer SO OPTICS EXPRESS LA English DT Article ID PHASE GRATINGS; ANGLE AB With the advent of Talbot-Lau interferometers for x-ray phase-contrast imaging, oblique and grazing incidence configurations are now used in the pursuit of sub-micron grating periods and high sensitivity. Here we address the question whether interferometers having oblique incident beams behave in the same way as the well-understood normal incidence ones, particularly when the grating planes are non-parallel. We derive the normal incidence equivalence of oblique incidence geometries from wave propagation modeling. Based on the theory, we propose a practical method to correct for non-parallelism of the grating planes, and demonstrate its effectiveness with a polychromatic hard x-ray reflective interferometer. (C) 2010 Optical Society of America C1 [Wen, Han; Kemble, Camille K.; Bennett, Eric E.] NHLBI, Imaging Phys Lab, NIH, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NHLBI, Imaging Phys Lab, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Bennett, Eric/A-2551-2013; Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [ZIA HL004606-15] NR 22 TC 7 Z9 7 U1 2 U2 21 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD DEC 5 PY 2011 VL 19 IS 25 BP 25093 EP 25112 DI 10.1364/OE.19.025093 PG 20 WC Optics SC Optics GA 857FN UT WOS:000297702400025 PM 22273901 ER PT J AU Zhang, LQ Collins, PL Lamb, RA Pickles, RJ AF Zhang, Liqun Collins, Peter L. Lamb, Robert A. Pickles, Raymond J. TI Comparison of differing cytopathic effects in human airway epithelium of parainfluenza virus 5 (W3A), parainfluenza virus type 3, and respiratory syncytial virus SO VIROLOGY LA English DT Article DE Parainfluenza virus; Respiratory syncytial virus; Airway epithelium; Cytopathic effect; Viral pathogenesis; Syncytia; Ciliated cell shedding; Viral persistence; Multi-potent progenitor cells; 3-Dimensional (3-D) image reconstruction ID SIMIAN-VIRUS-5 V-PROTEIN; INFLUENZA-A VIRUS; CILIATED CELLS; WILD-TYPE; INFECTION; INTERFERON; SV5; DISEASE; SYSTEM; DOMAIN AB Parainfluenza virus 5 (PIV5) infects a wide range of animals including dogs, pigs, cats, and humans: however, its association with disease in humans remains controversial. In contrast to parainfluenza virus 3 (PIV3) or respiratory syncytial virus (RSV), PIV5 is remarkably non-cytopathic in monolayer cultures of immortalized epithelial cells. To compare the cytopathology produced by these viruses in a relevant human tissue, we infected an in vitro model of human ciliated airway epithelium and measured outcomes of cytopathology. PIV5, PIV3 and, RSV all infected ciliated cells, and PIV5 and PIV3 infection was dependent on sialic acid residues. Only PIV5-infected cells formed syncytia. PIV5 infection resulted in a more rapid loss of infected cells by shedding of infected cells into the lumen. These studies revealed striking differences in cytopathology of PIV5 versus PIV3 or RSV and indicate the extent of cytopathology determined in cell-lines does not predict events in differentiated airway cells. (C) 2011 Elsevier Inc. All rights reserved. C1 [Zhang, Liqun; Pickles, Raymond J.] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC 27599 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Lamb, Robert A.] Northwestern Univ, Howard Hughes Med Inst, Dept Mol Biosci, Evanston, IL 60201 USA. RP Zhang, LQ (reprint author), UNC Cyst Fibrosis Ctr, 7021 Thurston Bowles,CB 7248, Chapel Hill, NC 27599 USA. EM liqun_zhang@med.unc.edu FU Cystic Fibrosis Foundation [Zhang03I0]; National Institutes of Health [R01 HL77844, P01 HL051818, P30 DK065988, P30 DK047757, R01 AI23173]; NIAID FX This work was supported in part by the Cystic Fibrosis Foundation (Zhang03I0) and the National Institutes of Health (R01 HL77844, P01 HL051818, P30 DK065988, P30 DK047757, and R01 AI23173). PLC was supported by the NIAID Intramural Program. RAL is an Investigator of the Howard Hughes Medical Institute. Sources of funding played no roles in study design, in the collection, analysis, and interpretation of the data, in the writing of the report, or in the decision to submit the paper for publication. NR 37 TC 17 Z9 17 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 5 PY 2011 VL 421 IS 1 BP 67 EP 77 DI 10.1016/j.virol.2011.08.020 PG 11 WC Virology SC Virology GA 847QZ UT WOS:000296988900009 PM 21986028 ER PT J AU Muzzio, M Huang, ZH Johnson, WD McCormick, DL Kapetanovic, IM AF Muzzio, Miguel Huang, Zhihua Johnson, William D. McCormick, David L. Kapetanovic, Izet M. TI Determination and stability of CP-31398 in plasma from experimental animals by LC-MS/MS SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE CP-31398; Plasma; Stability; Method validation; LC-MS/MS ID MUTANT P53; MICE AB A sensitive and accurate approach for the determination of CP-31398 (N-{2-[(E)-2-(4-methoxy-phenyl)-vinyl]-quinazolin-4-yl}-N',N'-dimethyl-propane-1,3-diamine hydrochloride) in rat and dog plasma by LC-MS/MS was validated to support preclinical toxicological and pharmacological studies. Based on the results of stability experiments with diluted CP-31398 solutions using NMR, LC-MS/MS and LC-Q-TOF, all sample preparation and handling steps were performed under yellow light to avoid CP-31398 decomposition. CP-31398 was extracted by protein precipitation with acetonitrile and separated using a Phenomenex Luna 3 mu m phenyl-hexyl, 100 angstrom, 30 x 2.0 mm column (rat plasma) or a Phenomenex Synergi 4 mu Polar-RP, 80 angstrom. 30 x 2.0 mm column (dog plasma) at a flow rate of 0.30 mL/min. The mobile phase consisted of A: 1% formic acid in water and B: 1% formic acid in methanol or acetonitrile. Total run times for rat and dog samples were 7 and 8 min, respectively, with accompanying retention times of 1.8 for both columns. A turbo ion spray interface was used as the ion source operating in positive mode. Calibration curves were linear from 5 to 1000 ng/mL. Linearity was assessed using the external standard method. Within-run and between-run accuracy was 93-109% of the true value for all analytes with precision (SD) of 8% or less for all experiments. The validated method was applied to preclinical toxicology studies in rats and dogs after oral administration of CP-31398. (C) 2011 Elsevier B.V. All rights reserved. C1 [Muzzio, Miguel; Huang, Zhihua; Johnson, William D.; McCormick, David L.] IIT Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Kapetanovic, Izet M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Muzzio, M (reprint author), IIT Res Inst, Life Sci Grp, Chicago, IL 60616 USA. EM mmuzzio@iitri.org FU Division of Cancer Prevention, National Cancer Institute [N01-CN-43304 (HHSN261200433004C)] FX This research was supported by contract N01-CN-43304 (HHSN261200433004C) from the Division of Cancer Prevention, National Cancer Institute. The authors thank Heidi Kreuzer for assistance with the manuscript. NR 11 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD DEC 5 PY 2011 VL 56 IS 4 BP 809 EP 814 DI 10.1016/j.jpba.2011.07.013 PG 6 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 819MX UT WOS:000294832100021 PM 21831553 ER PT J AU Nair, H Brooks, WA Katz, M Roca, A Berkley, JA Madhi, SA Simmerman, JM Gordon, A Sato, M Howie, S Krishnan, A Ope, M Lindblade, KA Carosone-Link, P Lucero, M Ochieng, W Kamimoto, L Dueger, E Bhat, N Vong, S Theodoratou, E Chittaganpitch, M Chimah, O Balmaseda, A Buchy, P Harris, E Evans, V Katayose, M Gaur, B O'Callaghan-Gordo, C Goswami, D Arvelo, W Venter, M Briese, T Tokarz, R Widdowson, MA Mounts, AW Breiman, RF Feikin, DR Klugman, KP Olsen, SJ Gessner, BD Wright, PF Rudan, I Broor, S Simoes, EAF Campbell, H AF Nair, Harish Brooks, W. Abdullah Katz, Mark Roca, Anna Berkley, James A. Madhi, Shabir A. Simmerman, James Mark Gordon, Aubree Sato, Masatoki Howie, Stephen Krishnan, Anand Ope, Maurice Lindblade, Kim A. Carosone-Link, Phyllis Lucero, Marilla Ochieng, Walter Kamimoto, Laurie Dueger, Erica Bhat, Niranjan Vong, Sirenda Theodoratou, Evropi Chittaganpitch, Malinee Chimah, Osaretin Balmaseda, Angel Buchy, Philippe Harris, Eva Evans, Valerie Katayose, Masahiko Gaur, Bharti O'Callaghan-Gordo, Cristina Goswami, Doli Arvelo, Wences Venter, Marietjie Briese, Thomas Tokarz, Rafal Widdowson, Marc-Alain Mounts, Anthony W. Breiman, Robert F. Feikin, Daniel R. Klugman, Keith P. Olsen, Sonja J. Gessner, Bradford D. Wright, Peter F. Rudan, Igor Broor, Shobha Simoes, Eric A. F. Campbell, Harry TI Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis SO LANCET LA English DT Review ID COMMUNITY-ACQUIRED PNEUMONIA; HUMAN-IMMUNODEFICIENCY-VIRUS; SYNCYTIAL VIRUS; HUMAN METAPNEUMOVIRUS; TRACT INFECTIONS; VIRAL ETIOLOGY; UNITED-STATES; STREPTOCOCCUS-PNEUMONIAE; PNEUMOCOCCAL PNEUMONIA; CHILDHOOD PNEUMONIA AB Background The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. Methods We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. Findings We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49-162 million) new cases of influenza (data from nine studies), 20 million (13-32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1-2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28 000-111 500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. Interpretation Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. C1 [Nair, Harish] Univ Edinburgh, Ctr Populat Hlth Sci, Sch Med, Global Hlth Acad, Edinburgh EH8 9AG, Midlothian, Scotland. [Nair, Harish] Publ Hlth Fdn India, New Delhi, India. [Brooks, W. Abdullah; Goswami, Doli] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Katz, Mark; Breiman, Robert F.; Feikin, Daniel R.] Kenya Govt Med Res Ctr, Nairobi, Kenya. [Katz, Mark; Breiman, Robert F.; Feikin, Daniel R.] Ctr Dis Control & Prevent Kenya, Nairobi, Kenya. [Roca, Anna; O'Callaghan-Gordo, Cristina] Univ Barcelona, Ctr Int Hlth Res CRESIB, Hosp Clin, IDIBAPS, Barcelona, Spain. [Berkley, James A.] Ctr Geog Med Res Coast, Kilin, Kenya. [Berkley, James A.] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford, England. [Madhi, Shabir A.] Univ Witwatersrand, Med Res Council, Resp & Meningeal Pathogens Res Unit, ZA-2050 Wits, South Africa. [Madhi, Shabir A.] Univ Witwatersrand, Dept Sci & Technol, ZA-2050 Wits, South Africa. [Madhi, Shabir A.] Univ Witwatersrand, Natl Res Fdn Vaccine Preventable Dis, ZA-2050 Wits, South Africa. [Simmerman, James Mark; Olsen, Sonja J.] US Ctr Dis Control & Prevent Thailand, Div & Int Emerging Infect Program, MOPH Collaborat, Nonthaburi, Thailand. [Gordon, Aubree; Harris, Eva] Univ Calif Berkeley, Div Infect Dis & Vaccinol, Berkeley, CA 94720 USA. [Gordon, Aubree] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Sato, Masatoki] Fukushima Med Univ, Dept Paediat, Sch Med, Fukushima, Japan. [Howie, Stephen; Chimah, Osaretin] Med Res Council UK Labs, Banjul, Gambia. [Krishnan, Anand; Gaur, Bharti] All India Inst Med Sci, New Delhi, India. [Lindblade, Kim A.; Arvelo, Wences] Ctr Dis Control & Prevent, Global Dis Detect Program, Reg Off Cent Amer & Panama, Guatemala City, Guatemala. [Carosone-Link, Phyllis; Simoes, Eric A. F.] Univ Colorado, Denver, CO 80202 USA. [Lindblade, Kim A.; Simoes, Eric A. F.] Childrens Hosp, Denver, CO 80218 USA. [Ochieng, Walter] Kenya Govt Med Res Ctr, Ctr Virus Res, Nairobi, Kenya. [Kamimoto, Laurie; Widdowson, Marc-Alain] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Dueger, Erica] Global Dis Detect & Response Ctr, Naval Med Res Unit 3, Cairo, Egypt. [Bhat, Niranjan] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Amer Indian Hlth, Baltimore, MD USA. [Chittaganpitch, Malinee] Minist Publ Hlth, Natl Inst Hlth, Nonthaburi, Thailand. [Chimah, Osaretin] Med Ctr, Asaba, Delta State, Nigeria. [Katayose, Masahiko] Soma Gen Hosp, Dept Paediat, Soma, Japan. [Venter, Marietjie] Natl Inst Communicable Dis, Resp Virus Unit, Natl Inflenza Ctr, Natl Hlth Lab Serv, Johannesburg, South Africa. [Venter, Marietjie] Univ Pretoria, Resp & Zoonot Virus Programme, Dept Med Virol, ZA-0002 Pretoria, South Africa. [Briese, Thomas; Tokarz, Rafal] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY USA. [Mounts, Anthony W.] World Hlth Org, Global Influenza Program, Geneva, Switzerland. [Klugman, Keith P.] Emory Univ, Dept Global Hlth, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Klugman, Keith P.] Emory Univ, Div Infect Dis, Sch Med, Atlanta, GA 30322 USA. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Wright, Peter F.] Dartmouth Med Sch, Div Infect Dis & Int Hlth, Lebanon, NH USA. [Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Fac Med, Split, Croatia. [Simoes, Eric A. F.] Univ Padjadjaram, Bandung, Indonesia. RP Nair, H (reprint author), Univ Edinburgh, Ctr Populat Hlth Sci, Sch Med, Global Hlth Acad, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. EM harish.nair@ed.ac.uk; harry.campbell@ed.ac.uk RI Nair, Harish/E-7431-2010; Krishnan, Anand/D-8537-2012; Rudan, Igor/I-1467-2012; Theodoratou, Evropi/C-3430-2014; Venter, Marietjie/P-9604-2016; OI Nair, Harish/0000-0002-9432-9100; Krishnan, Anand/0000-0002-9173-7811; Rudan, Igor/0000-0001-6993-6884; Theodoratou, Evropi/0000-0001-5887-9132; Venter, Marietjie/0000-0003-2696-824X; Widdowson, Marc-Alain/0000-0002-0682-6933; O'Callaghan-Gordo, Cristina/0000-0002-4229-2991; Gordon, Aubree/0000-0002-9352-7877; Berkley, James/0000-0002-1236-849X FU WHO [HQGIP1002906]; Bill & Melinda Gates Foundation [51285]; Wyeth; Pfizer; GSK; Sanofi Pasteur; GlaxoSmithKline; Merck; MedImmune; Roche; Aventis Pasteur; Evans-Powderject; US Centers for Disease Control and Prevention (CDC); Indian Council of Medical Research FX WHO; Bill & Melinda Gates Foundation.; SAM has received research funding from Wyeth for the Soweto study that contributed to the data. He has received consultancy from Pfizer, GSK, and Novartis and speaker fees from Pfizer and GSK. However, no honoraria were received for work included in this study. BDG has received consultancy from WHO and a travel grant from Sanofi Pasteur to attend a conference on influenza in 2010. He is employed by Agence de Medecine Preventive, which has received funding from WHO, Pfizer, GlaxoSmithKline, and Merck. In 2010, the Agence de Medecine Preventive was hired by Sanofi Pasteur to organize a conference on influenza. However, no grants or honoraria were received for work included in this study. EAFS has received speaker fees and consultancy from MedImmune and research grants from Roche and MedImmune. However, no grants or honoraria were received for work included in this study. NB is employed by Johns Hopkins University which has received funding from Aventis Pasteur and Evans-Powderject. All other authors declare that they have no conflicts of interest.; Financial support for this work was provided by WHO Global Influenza Program (grant number HQGIP1002906) and the Bill & Melinda Gates Foundation (grant number 51285). The study in Ballabgarh, India, received financial support from US Centers for Disease Control and Prevention (CDC) and Indian Council of Medical Research. This work was done as part of the wider programme of the Child Health Epidemiology Working Group (CHERG) to establish the major causes of global childhood disease burden. Walter Ochieng sadly died suddenly and unexpectedly while this paper was being prepared for publication. We would like to acknowledge his important contribution to this study and his role in strengthening influenza surveillance in Kenya. We thank Johannes Forster (Department of Paediatrics, St Josefskrankenhaus Freiburg and University of Freiburg, Freiburg, Germany), Gabriele Ihorst (Clinical Trials Center, University Medical Centre Freiburg, Freiburg, Germany), Terho Heikkinen (Turku University Hospital, Turku, Finland), Alex Ezeh, Samuel Oti, and Catherine Kyobutungi (African Population and Health Research Centre, Nairobi, Kenya), and the Influenza Emerging Infections Program Network, USA for providing additional data from their published papers; Vivek Gupta and Sanjay K Rai (Comprehensive Rural Health Services Project, Ballabgarh and All India Institute of Medical Sciences, New Delhi, India); Samander Kaushik and Yashpal Singh (Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India); National Institute of Virology, Pune, India; Wallace D Bulimo (National Influenza Centre, Nairobi, Kenya); Respiratory and Zoonosis group, Department of Medical Virology, University of Pretoria, South Africa; D James Nokes (KEMRI, Kilifi, Kenya); Locadiah Kuwanda (Chris Hani Baragwanath Hospital, Johannesburg, South Africa); Pedro L Alonso, Ll Quinto, Q Bassat (CRESIB, Hospital Clinic/IDIBAPS, Universitat de Barcelona, Barcelona, Spain and Centro de Investigacao em Saude da Manhica, Ministerio de Saude, Maputo, Mozambique); Jens Levy (Influenza Division and International Emerging Infections Program, US CDC-Thailand MOPH Collaboration, Nonthaburi, Thailand); Alejandra Estevez, Fabiola Moscoso, and Jennifer Gray (Centro de Estudios en Salud, Universidad del Valle de Guatemala); Lissette Reyes, Juan Carlos Moir (Ministerio de Salud Publica y Asistencia Social, Guatemala); Alicia M Fry (Influenza Division, CDC, Atlanta, USA); Hanna Nohynek, Taneli Puumalainen and Petri Ruutu (National Institute for Health and Welfare, Finland); Leilani Nillos (Research Institute for Tropical Medicine, Department of Health, Alabang, Muntinlupa, Philippines) and ARIVAC consortium; Ian Lipkin (University of Columbia, New York); Gerard Morris (University Witwatersrand, South Africa); Grant Mackenzie, Readon Ideh, Bernard Ebruke, Claire Oluwalana (MRC, Gambia) and the Gambia Severe Pneumonia Studies Group; Karen Fowler (University of Alabama at Birmingham, Birmingham, AL, USA); Katherine O'Brien (Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA) for their assistance; Jian Shayne F Zhang (Centre for Population Health Sciences, The University of Edinburgh, UK) for doing the literature search in Chinese language databases; Carolyn B Bridges (Influenza Division, National Center for Immunizations and Respiratory Disease, CDC, Atlanta, GA, USA) for critically reviewing the manuscript and providing helpful comments.; The findings and conclusions in this report are those of the authors and do not necessarily represent he views of the US CDC or WHO. NR 89 TC 229 Z9 238 U1 3 U2 45 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD DEC 3 PY 2011 VL 378 IS 9807 BP 1917 EP 1930 DI 10.1016/S0140-6736(11)61051-9 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 863AW UT WOS:000298136200026 PM 22078723 ER PT J AU Weinberger, DM Malley, R Lipsitch, M AF Weinberger, Daniel M. Malley, Richard Lipsitch, Marc TI Serotype replacement in disease after pneumococcal vaccination SO LANCET LA English DT Review ID STREPTOCOCCUS-PNEUMONIAE SEROTYPES; 7-VALENT CONJUGATE VACCINE; PLACEBO-CONTROLLED-TRIAL; CARE-CENTER ATTENDEES; ACUTE OTITIS-MEDIA; NASOPHARYNGEAL CARRIAGE; INVASIVE DISEASE; TEMPORAL TRENDS; ANTIMICROBIAL RESISTANCE; CHANGING EPIDEMIOLOGY AB Vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) has significantly reduced the burden of pneumococcal disease and has had an important public health benefit. Because this vaccine targets only seven of the more than 92 pneumococcal serotypes, concerns have been raised that non-vaccine serotypes (NVTs) could increase in prevalence and reduce the benefits of vaccination. Indeed, among asymptomatic carriers, the prevalence of NVTs has increased substantially, and consequently, there has been little or no net change in the bacterial carriage prevalence. In many populations, pneumococcal disease caused by NVT has increased, but in most cases this increase has been less than the increase in NVT carriage. We review the evidence for serotype replacement in carriage and disease, and address the surveillance biases that might affect these findings. We then discuss possible reasons for the discrepancy between near-complete replacement in carriage and partial replacement for disease, including differences in invasiveness between vaccine serotypes. We contend that the magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and biases in the disease surveillance systems that could underestimate the true amount of replacement. We conclude by discussing the future potential for serotype replacement in disease and the need for continuing surveillance. C1 [Weinberger, Daniel M.; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard Univ, Ctr Communicable Dis Dynam, Sch Publ Hlth, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Malley, Richard] Childrens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Malley, Richard] Harvard Univ, Sch Med, Boston, MA USA. [Weinberger, Daniel M.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Weinberger, DM (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 16,Room 37, Bethesda, MD 20892 USA. EM weinbergerdm@mail.nih.gov OI Lipsitch, Marc/0000-0003-1504-9213; Weinberger, Daniel/0000-0003-1178-8086 FU Pfizer; Novartis; NIH [R01 AI048935, R01 AI066013] FX DMW has no conflicts of interest to declare. RM is a member of the Scientific Advisory Board of Genocea Biosciences. ML has accepted honoraria or consulting fees from Pfizer and Novartis.; We thank Anthony Scott and Elizabeth Miller for helpful discussions, particularly on the topics of surveillance artifacts (EM) and design of surveillance in low-resource areas (AS), and for crucial feedback on the manuscript. This study was supported by NIH research grant R01 AI048935 to ML and R01 AI066013 to RM. NR 108 TC 294 Z9 301 U1 3 U2 34 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD DEC 3 PY 2011 VL 378 IS 9807 BP 1962 EP 1973 DI 10.1016/S0140-6736(10)62225-8 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 863AW UT WOS:000298136200030 PM 21492929 ER PT J AU Kim, YJ Kim, D Illuzzi, JL Delaplane, S Su, D Bernier, M Gross, ML Georgiadis, MM Wilson, DM AF Kim, Yun-Jeong Kim, Daemyung Illuzzi, Jennifer L. Delaplane, Sarah Su, Dian Bernier, Michel Gross, Michael L. Georgiadis, Millie M. Wilson, David M., III TI S-Glutathionylation of Cysteine 99 in the APE1 Protein Impairs Abasic Endonuclease Activity SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE APEX1; base excision DNA repair; posttranslational modification; cysteine glutathionylation; redox regulation ID BASE EXCISION-REPAIR; HUMAN APURINIC ENDONUCLEASE; REDOX REGULATION; DNA-REPAIR; APURINIC/APYRIMIDINIC ENDONUCLEASE; MAJOR HUMAN; PHOTOCHEMICAL OXIDATION; APE1/REF-1; BINDING; PHOSPHORYLATION AB Human apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is a central participant in the base excision repair pathway, exhibiting AP endonuclease activity that incises the DNA backbone 5' to an abasic site. Besides its prominent role as a DNA repair enzyme, APE1 was separately identified as a protein called redox effector factor 1, which is able to enhance the DNA binding activity of several transcription factors through a thiol-exchange-based reduction-oxidation mechanism. In the present study, we found that human APE1 is S-glutathionylated under conditions of oxidative stress both in the presence of glutathione in vitro and in cells. S-glutathionylated APE1 displayed significantly reduced AP endonuclease activity on abasic-site-containing oligonucleotide substrates, a result stemming from impaired DNA binding capacity. The combination of site-directed mutagenesis, biochemical assays, and mass spectrometric analysis identified Cys99 in human APE1 as the critical residue for the S-glutathionylation that leads to reduced AP endonuclease activity. This modification is reversible by reducing agents, which restore APE1 incision function. Our studies describe a novel posttranslational modification of APE1 that regulates the DNA repair function of the protein. Published by Elsevier Ltd. C1 [Kim, Yun-Jeong; Illuzzi, Jennifer L.; Wilson, David M., III] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Kim, Daemyung] Cheongju Univ, Dept Genet Engn, Cheongju 360764, South Korea. [Delaplane, Sarah; Georgiadis, Millie M.] Indiana Univ Purdue Univ, Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Delaplane, Sarah; Georgiadis, Millie M.] Indiana Univ Purdue Univ, Purdue Sch Sci, Dept Chem & Chem Biol, Indianapolis, IN 46202 USA. [Su, Dian; Gross, Michael L.] Washington Univ, Dept Chem, St Louis, MO 63130 USA. [Bernier, Michel] NIA, Clin Invest Lab, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov OI Bernier, Michel/0000-0002-5948-368X FU National Institutes of Health; National Institute on Aging; National Institutes of Health [CA114571]; National Center for Research Resources [2P41RR000954] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, as well as by grants from the National Institutes of Health (CA114571) to M.M.G. and from the National Center for Research Resources (2P41RR000954) to M.L.G. NR 56 TC 14 Z9 14 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD DEC 2 PY 2011 VL 414 IS 3 BP 313 EP 326 DI 10.1016/j.jmb.2011.10.023 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869UD UT WOS:000298622800001 PM 22024594 ER PT J AU McKenzie, M Tucker, EJ Compton, AG Lazarou, M George, C Thorburn, DR Ryan, MT AF McKenzie, Matthew Tucker, Elena J. Compton, Alison G. Lazarou, Michael George, Christa Thorburn, David R. Ryan, Michael T. TI Mutations in the Gene Encoding C8orf38 Block Complex I Assembly by Inhibiting Production of the Mitochondria-Encoded Subunit ND1 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE mitochondria; complex I assembly factor; Leigh syndrome; blue native-PAGE; mtDNA-encoded translation ID POLYACRYLAMIDE-GEL ELECTROPHORESIS; MOLECULAR CHAPERONE; LEIGH-SYNDROME; DEFICIENCY; MEMBRANE; DISEASE; NDUFAF1; ENCEPHALOPATHY; IDENTIFICATION; PROTEINS AB The assembly of complex I (NADH ubiquinone oxidoreductase) is a complicated process, requiring the integration of 45 subunits encoded by both nuclear and mitochondrial DNAs into a structure of approximately 1 MDa. A number of "assembly factors" that aid complex I biogenesis have recently been described, including C8orf38. This protein was identified as an assembly factor by its evolutionary conservation in organisms containing complex I and by a C8orf38 mutation in a patient presenting with Leigh syndrome and isolated complex I deficiency. In this report, we have undertaken the characterization of C8orf38 and its role in complex I assembly. Analysis of mitochondria from fibroblasts of a patient harboring a C8orf38 mutation showed almost undetectable levels of steady-state complex I and defective biogenesis of the mtDNA-encoded subunit ND1. Complementation with wild-type C8orf38 restored the levels of both ND1 and complex I, confirming the C8orf38 mutation as the cause of the complex I defect in the patient. In the absence of ND1 in patient cells, early- and mid-stage intermediate complexes were still formed; however, assembly of late-stage intermediates was impaired, indicating a convergence point in the assembly process. While C8orf38 appears to behave at a step in complex I biogenesis similar to that of the assembly factor C20orf7, complementation studies showed that both proteins are required for ND1 synthesis/stabilization. We conclude that C8orf38 is a crucial factor required for the translation and/or integration of ND1 into an early-stage assembly intermediate and that mutation of C8orf38 disrupts the initial stages of complex I biogenesis. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Lazarou, Michael; George, Christa; Ryan, Michael T.] La Trobe Univ, Dept Biochem, Melbourne, Vic 3086, Australia. [Ryan, Michael T.] La Trobe Univ, ARC Ctr Excellence Coherent Xray Sci, Melbourne, Vic 3086, Australia. [McKenzie, Matthew] Monash Inst Med Res, Ctr Reprod & Dev, Clayton, Vic 3168, Australia. [Tucker, Elena J.; Compton, Alison G.; Thorburn, David R.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Tucker, Elena J.; Thorburn, David R.] Univ Melbourne, Dept Paediat, Melbourne, Vic 3010, Australia. [Lazarou, Michael] NINDS, Bethesda, MD 20892 USA. RP Ryan, MT (reprint author), La Trobe Univ, Dept Biochem, Melbourne, Vic 3086, Australia. EM M.Ryan@latrobe.edu.au RI Tucker, Elena/B-3487-2012; Ryan, Michael/C-6673-2011; Thorburn, David/G-6266-2013; OI Ryan, Michael/0000-0003-2586-8829; thorburn, david/0000-0002-7725-9470; Lazarou, Michael/0000-0003-2150-5545; McKenzie, Matthew/0000-0001-7508-1800; Compton, Alison/0000-0002-2725-7055 FU National Health and Medical Research Council [433028, 541911, 436901, 436906]; Ramaciotti Foundation; James and Vera Lawson Trust; Australian Postgraduate Award; Victorian Government FX This work was supported by grants and fellowships from the National Health and Medical Research Council (433028 and 541911 to M.M.; 436901 and 436906 to D.T.), the Ramaciotti Foundation, the James and Vera Lawson Trust, an Australian Postgraduate Award (E.T.), and the Victorian Government's Operational Infrastructure Support Program. NR 49 TC 27 Z9 29 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD DEC 2 PY 2011 VL 414 IS 3 BP 413 EP 426 DI 10.1016/j.jmb.2011.10.012 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869UD UT WOS:000298622800008 PM 22019594 ER PT J AU Zeng, Y Liu, G Ma, Y Chen, XY Ito, Y AF Zeng, Yun Liu, Gang Ma, Ying Chen, Xiaoyuan Ito, Yoichiro TI Organic high ionic strength aqueous two-phase solvent system series for separation of ultra-polar compounds by spiral high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Organic-high ionic aqueous two-phase solvent systems; High-speed counter-current chromatography (HSCCC); Flat-twisted spiral column; Sulfonic acids; Zwitter ions; Catecholamines AB Existing two-phase solvent systems for high-speed countercurrent chromatography cover the separation of hydrophobic to moderately polar compounds, but often fail to provide suitable partition coefficient values for highly polar compounds, such as sulfonic acids, catecholamines and zwitter ions. The present paper introduces a new solvent series which can be applied for the separation of these polar compounds. It is composed of 1-butanol, ethanol, saturated ammonium sulfate and water at various volume ratios and consists of a series of 10 steps which are arranged according to the polarity of the solvent system so that the two-phase solvent system with suitable K values for the target compound(s) can be found in a few steps. Each solvent system gives proper volume ratio and high density difference between the two phases to provide a satisfactory level of retention of the stationary phase in the spiral column assembly. The method is validated by partition coefficient measurement of four typical polar compounds including methyl green (basic dye), tartrazine (sulfonic acid), tyrosine (zwitter ion) and epinephrine (a catecholamine), all of which show low partition coefficient values in the polar 1-butanol-water system. The capability of the method is demonstrated by separation of three catecholamines. Published by Elsevier B.V. C1 [Zeng, Yun; Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Zeng, Yun; Liu, Gang] N Sichuan Med Coll, Inst Mat Medica & Dept Pharmacol, Nanchong 637007, Sichuan Provinc, Peoples R China. [Liu, Gang; Ma, Ying; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, 10 Ctr Drive,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov FU National Institutes of Health (NIH); Sichuan Province [09ZA036, KFJJ0905/0807, 2011JQ0032]; National Natural Science Foundation of China [81101101] FX This work was supported by the Intramural Research Program (IRP) of the National Institutes of Health (NIH). The work also was partially supported by projects (No. 09ZA036, KFJJ0905/0807, and 2011JQ0032) of Sichuan Province and National Natural Science Foundation of China (81101101). The authors are indebted to Dr. Adrian Weisz of the U.S. Food and Drug Administration, Silver Spring, MD, USA for his kind gift of tartrazine. NR 15 TC 20 Z9 21 U1 5 U2 43 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD DEC 2 PY 2011 VL 1218 IS 48 BP 8715 EP 8717 DI 10.1016/j.chroma.2011.09.083 PG 3 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 852VV UT WOS:000297386500018 PM 22033108 ER PT J AU Ioannidis, JPA Khoury, MJ AF Ioannidis, John P. A. Khoury, Muin J. TI Improving Validation Practices in "Omics" Research SO SCIENCE LA English DT Editorial Material ID BIOINFORMATICS; PROTEOMICS AB "Omics" research poses acute challenges regarding how to enhance validation practices and eventually the utility of this rich information. Several strategies may be useful, including routine replication, public data and protocol availability, funding incentives, reproducibility rewards or penalties, and targeted repeatability checks. C1 [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Khoury, Muin J.] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD 20852 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Humanities & Sci, Dept Stat, Stanford, CA 94305 USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. EM muk1@cdc.gov NR 21 TC 99 Z9 101 U1 0 U2 30 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 2 PY 2011 VL 334 IS 6060 BP 1230 EP 1232 DI 10.1126/science.1211811 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 855HD UT WOS:000297553600037 PM 22144616 ER PT J AU Anastasiou, D Poulogiannis, G Asara, JM Boxer, MB Jiang, JK Shen, M Bellinger, G Sasaki, AT Locasale, JW Auld, DS Thomas, CJ Vander Heiden, MG Cantley, LC AF Anastasiou, Dimitrios Poulogiannis, George Asara, John M. Boxer, Matthew B. Jiang, Jian-kang Shen, Min Bellinger, Gary Sasaki, Atsuo T. Locasale, Jason W. Auld, Douglas S. Thomas, Craig J. Vander Heiden, Matthew G. Cantley, Lewis C. TI Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses SO SCIENCE LA English DT Article ID OXIDATIVE STRESS; TUMOR-SUPPRESSOR; CELLS; ROS; METABOLISM; CANCER; ISOFORM; PROTEIN AB Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys(358). This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys(358) to Ser(358) oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress. C1 [Anastasiou, Dimitrios; Poulogiannis, George; Asara, John M.; Bellinger, Gary; Sasaki, Atsuo T.; Locasale, Jason W.; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02115 USA. [Anastasiou, Dimitrios; Poulogiannis, George; Sasaki, Atsuo T.; Locasale, Jason W.; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Asara, John M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Boxer, Matthew B.; Jiang, Jian-kang; Shen, Min; Auld, Douglas S.; Thomas, Craig J.] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Bellinger, Gary; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cantley, LC (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02115 USA. EM lewis_cantley@hms.harvard.edu RI Cantley, Lewis/D-1800-2014; OI Cantley, Lewis/0000-0002-1298-7653; Locasale, Jason/0000-0002-7766-3502 FU Japanese Society for the Promotion of Science; Kanae Foundation for Research Abroad; NIH [R03MH085679, 1P30CA147882, R01-GM056203-13, P01-CA089021, P01-CA117969-04]; Burroughs Wellcome Fund; Damon Runyon Cancer Research Foundation; Smith family; Starr Cancer Consortium; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; National Human Genome Research Institute, NIH FX We thank V. Toxavidis and J. Tigges (Beth Israel Deaconess Medical Center flow cytometry facility) for support with flow cytometry applications; X. Yang and S. Breitkopf for technical assistance with mass spectrometry; Ross Dickins and Scott Lowe (Cold Spring Harbor Laboratory) for the gift of tamoxifen-inducible Cre-expressing retroviral plasmid; and C. Benes, N. Wu, A. Shaywitz, B. Emerling, A. Saci, G. DeNicola, K. Courtney, A. Couvillon, S. Soltoff, A. Carracedo, A. Grassian, J. Brugge, and members of the Cantley lab for helpful discussions. L. C. C. is a cofounder of Agios Pharmaceuticals, a company that seeks to develop novel therapeutics that target cancer metabolism. G. P. is a Pfizer Fellow of the Life Sciences Research Foundation. A. T. S. is a Genentech Fellow and supported by the Japanese Society for the Promotion of Science and the Kanae Foundation for Research Abroad. M. G. V. H. is supported by the NIH (R03MH085679 and 1P30CA147882), the Burroughs Wellcome Fund, the Damon Runyon Cancer Research Foundation, and the Smith family. This work was supported by grants from the NIH (R01-GM056203-13, P01-CA089021, and P01-CA117969-04 to L. C. C), the Starr Cancer Consortium (L. C. C. and M. G. V. H.), the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research, and the Intramural Research Program of the National Human Genome Research Institute, NIH (M. B. B., J. J., M. S., D. S. A., and C. J. T.). We apologize to colleagues whose work we could not cite because of space limitations. NR 28 TC 371 Z9 379 U1 10 U2 92 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD DEC 2 PY 2011 VL 334 IS 6060 BP 1278 EP 1283 DI 10.1126/science.1211485 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 855HD UT WOS:000297553600051 PM 22052977 ER PT J AU Stout, NL Pfalzer, LA Levy, E McGarvey, C Springer, B Gerber, LH Soballe, P AF Stout, Nicole L. Pfalzer, Lucinda A. Levy, Ellen McGarvey, Charles Springer, Barbara Gerber, Lynn H. Soballe, Peter TI Segmental Limb Volume Change as a Predictor of the Onset of Lymphedema in Women With Early Breast Cancer SO PM&R LA English DT Article ID POSTMASTECTOMY EDEMA; LYMPHATIC FUNCTION; ARM; SURGERY; SYMPTOMS; MELANOMA; DRAINAGE; VALIDITY; SWOLLEN AB Objective: To demonstrate that segmental changes along the upper extremity occur before the onset of breast cancer-related lymphedema (BCRL). These changes may be subclinical in nature and may be predictive of the onset of chronic lymphedema. Design: A retrospective subset analysis of a larger prospective cohort trial. Patient Cohort: A total of 196 patients provided consent and were enrolled in the prospective study. Subclinical lymphedema developed in 46 of these patients. Limb volume data were available for 45 of these 46 patients from visits before the onset of lymphedema and were used in this analysis. We compared this group with an age-matched control group without BCRL from the same cohort (n = 45). Setting: Military hospital outpatient breast care center. Methods: Women were enrolled and assessed preoperatively. Baseline measures of limb volume were obtained with the use of optoelectronic perometry, and reassessment was conducted at 1, 3, 6, 9, and 12 months postoperatively. BCRL was identified in 46 of 196 women at an average of 6.9 months postoperatively. A retrospective analysis was conducted in which we examined volume changes over four 10-cm segments of the limb at the visits before the onset of BCRL. By using repeated-measures multivariate analysis of variance, we compared segmental volumes between groups at preoperative baseline, time of diagnosis of BCRL, and time of follow-up after early intervention. Linear regression analysis was performed to determine the strength of the relationship between total limb volume change with segmental volumes at the time of diagnosis of BCRL. Main Outcome Measurements: We hypothesized that segmental volume changes occur and can be measured in the limb before the onset of lymphedema. Results: At arm segments 10-20 cm (P = .044) and 20-30 cm (P < .001), a significant volume increase was noted before the diagnosis of subclinical BCRL. Segmental volume changes correlated to the total limb volume (TLV) change. At segments 20-30 cm, the coefficient of determination was r(2) = 0.952, and at 10-20 cm it was r(2) = 0.845, suggesting that these segments predicted TLV changes. Conclusion: Serial interval assessment of limb volume segments may be an important clinical tool to detect early-onset lymphedema before TLV changes. PM R2011;3:1098-1105 C1 [Stout, Nicole L.; Soballe, Peter] Natl Naval Med Ctr, Breast Care Ctr, Bethesda, MD 20889 USA. [Pfalzer, Lucinda A.] Univ Michigan, Flint, MI 48503 USA. [Levy, Ellen; McGarvey, Charles; Gerber, Lynn H.] NIH, Bethesda, MD 20892 USA. [McGarvey, Charles] CLM Consulting Rockville, Rockville, MD USA. [Springer, Barbara] Off Surg Gen, Falls Church, VA USA. [Gerber, Lynn H.] George Mason Univ, Fairfax, VA 22030 USA. [Soballe, Peter] USN, San Diego Med Ctr, San Diego, CA USA. RP Stout, NL (reprint author), Natl Naval Med Ctr, Breast Care Ctr, 8901 Wisconsin Ave,Breast Care Ctr Bldg 19,3rd Fl, Bethesda, MD 20889 USA. EM Nicole.stout@med.navy.mil FU National Naval Medical Center, Bethesda, MD (protocol NNMC) [2001-052]; National Institutes of Health, Mark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, Physical Therapy Section, Bethesda, MD (protocol NIH) [02-CC-0044] FX This research was Institutional Review Board approved and funded by the National Naval Medical Center, Bethesda, MD (protocol NNMC# 2001-052) and the National Institutes of Health, Mark O. Hatfield Clinical Research Center, Rehabilitation Medicine Department, Physical Therapy Section, Bethesda, MD (protocol NIH# 02-CC-0044). The views expressed in this' article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of the Army, Department of Defense, or the U.S. Government. NR 41 TC 11 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD DEC PY 2011 VL 3 IS 12 BP 1098 EP 1105 DI 10.1016/j.pmrj.2011.07.021 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 966YG UT WOS:000305872700004 PM 21974905 ER PT J AU Pandiri, AR Sills, RC Hoenerhoff, MJ Peddada, SD Ton, TVT Hong, HHL Flake, GP Malarkey, DE Olson, GR Pogribny, IP Walker, NJ Boudreau, MD AF Pandiri, Arun R. Sills, Robert C. Hoenerhoff, Mark J. Peddada, Shyamal D. Ton, Thai-Vu T. Hong, Hue-Hua L. Flake, Gordon P. Malarkey, David E. Olson, Greg R. Pogribny, Igor P. Walker, Nigel J. Boudreau, Mary D. TI Aloe vera Non-Decolorized Whole Leaf Extract-Induced Large Intestinal Tumors in F344 Rats Share Similar Molecular Pathways with Human Sporadic Colorectal Tumors SO TOXICOLOGIC PATHOLOGY LA English DT Article DE Aloe vera; colon; F344 rat; human; colorectal tumors ID INDUCED COLON CARCINOGENESIS; GENE-EXPRESSION; BETA-CATENIN; CANCER-CELLS; SIGNALING PATHWAY; EPITHELIAL-CELLS; MUTATIONS; TUMORIGENESIS; ADENOMAS; INVASION AB Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-beta) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-beta signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels. C1 [Pandiri, Arun R.; Sills, Robert C.; Hoenerhoff, Mark J.; Ton, Thai-Vu T.; Hong, Hue-Hua L.; Flake, Gordon P.; Malarkey, David E.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Peddada, Shyamal D.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Olson, Greg R.] Toxicol Pathol Associates, Jefferson, AR USA. [Pogribny, Igor P.; Boudreau, Mary D.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Walker, Nigel J.] NTP NIEHS, Res Triangle Pk, NC USA. RP Pandiri, AR (reprint author), BG 101 RM B358 MSC B3-06,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM pandiriak@niehs.nih.gov RI Walker, Nigel/D-6583-2012; Peddada, Shyamal/D-1278-2012 OI Walker, Nigel/0000-0002-9111-6855; FU IAG [224-07-0007]; FDA; NTP; NIEHS/DHHS FX The authors would like to thank Dr. Darlene Dixon and Dr. Michael Devito for their review of this manuscript; Dr. Keith Shockley and Dr. Grace Kissling for help with statistics; and Ms. Natasha Clayton and Ms. Beth Mahler for their excellent technical assistance. This study was supported in part by IAG #224-07-0007 between the FDA and the NTP as well as by the intramural research program at NIEHS/DHHS. NR 49 TC 7 Z9 7 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2011 VL 39 IS 7 BP 1065 EP 1074 DI 10.1177/0192623311422081 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA 961IV UT WOS:000305459000005 PM 21937742 ER PT J AU Morens, DM AF Morens, David M. TI Remembering Daumier's Blue Period SO ECOHEALTH LA English DT Editorial Material ID CHALLENGE C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, Bldg 31,Room 7A-03,31 Ctr Dr,MSC 2520, Bethesda, MD 20892 USA. EM dmorens@niaid.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1612-9202 J9 ECOHEALTH JI EcoHealth PD DEC PY 2011 VL 8 IS 4 BP 527 EP 530 DI 10.1007/s10393-012-0745-y PG 4 WC Biodiversity Conservation; Ecology; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 947QR UT WOS:000304445100014 PM 22311099 ER PT J AU Weinsheimer, SM Xu, HC Achrol, AS Stamova, B McCulloch, CE Pawlikowska, L Tian, YF Ko, NU Lawton, MT Steinberg, GK Chang, SD Jickling, G Ander, BP Kim, H Sharp, FR Young, WL AF Weinsheimer, Shantel M. Xu, Huichun Achrol, Achal S. Stamova, Boryana McCulloch, Charles E. Pawlikowska, Ludmila Tian, Yingfang Ko, Nerissa U. Lawton, Michael T. Steinberg, Gary K. Chang, Steven D. Jickling, Glen Ander, Bradley P. Kim, Helen Sharp, Frank R. Young, William L. TI Gene Expression Profiling of Blood in Brain Arteriovenous Malformation Patients SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Arteriovenous malformation; Blood; Gene expression; Intracranial hemorrhage; Microarray analysis ID PERIPHERAL-BLOOD; INTRACRANIAL HEMORRHAGE; INTRACEREBRAL HEMORRHAGE; LONGITUDINAL RISK; AORTIC-ANEURYSMS; ISCHEMIC-STROKE; IDENTIFICATION; DISEASE; INVOLVEMENT; POPULATION AB Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. Gene expression profiling of blood has led to the identification of stroke biomarkers and may help identify BAVM biomarkers and illuminate BAVM pathogenesis. It is unknown whether blood gene expression profiles differ between (1) BAVM patients and healthy controls or (2) unruptured and ruptured BAVM patients at presentation. We characterized blood transcriptional profiles in 60 subjects (20 unruptured BAVM, 20 ruptured BAVM, and 20 healthy controls) using Affymetrix whole genome expression arrays. Expression differences between groups were tested by ANOVA, adjusting for potential confounders. Genes with absolute fold change >= 1.2 (false discovery rate corrected p <= 0.1) were selected as differentially expressed and evaluated for over-representation in KEGG biological pathways (p <= 0.05). Twenty-nine genes were differentially expressed between unruptured BAVM patients and controls, including 13 which may be predictive of BAVM. Patients with ruptured BAVM compared to unruptured BAVM differed in expression of 1,490 genes, with over-representation of genes in 8 pathways including MAPK, VEGF, Wnt signaling, and several inflammatory pathways. These results suggest clues to the pathogenesis of BAVM and/or BAVM rupture and point to potential biomarkers or new treatment targets. C1 [Weinsheimer, Shantel M.; Pawlikowska, Ludmila; Kim, Helen; Young, William L.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94110 USA. [Weinsheimer, Shantel M.; McCulloch, Charles E.; Pawlikowska, Ludmila; Ko, Nerissa U.; Lawton, Michael T.; Kim, Helen; Young, William L.] Univ Calif San Francisco, Ctr Cerebrovasc Res, San Francisco, CA 94110 USA. [Xu, Huichun; Stamova, Boryana; Tian, Yingfang; Jickling, Glen; Ander, Bradley P.; Sharp, Frank R.] Univ Calif Davis, Neurosci Program, Sacramento, CA 95817 USA. [Xu, Huichun; Stamova, Boryana; Tian, Yingfang; Jickling, Glen; Ander, Bradley P.; Sharp, Frank R.] Univ Calif Davis, Genet Program, Sacramento, CA 95817 USA. [Xu, Huichun] NHGRI, NIH, Bethesda, MD 20892 USA. [Achrol, Achal S.; Steinberg, Gary K.; Chang, Steven D.] Stanford Univ, Dept Neurosurg, Palo Alto, CA 94304 USA. [McCulloch, Charles E.; Kim, Helen] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94110 USA. [Ko, Nerissa U.; Young, William L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94110 USA. [Lawton, Michael T.; Young, William L.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94110 USA. [Xu, Huichun; Stamova, Boryana; Tian, Yingfang; Jickling, Glen; Ander, Bradley P.; Sharp, Frank R.] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. RP Young, WL (reprint author), Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, 1001 Potrero Ave,Room 3C-38, San Francisco, CA 94110 USA. EM ccr@anesthesia.ucsf.edu RI Jickling, Glen/K-4002-2013; OI Jickling, Glen/0000-0003-3543-0820 FU National Institutes of Health (NIH) [P01 NS044155, R01 NS034949, 3R01NS034949-14S1, K23 NS058357]; NIH/NIGMS [T32 GM08440]; NINDS; ARRA [NS056302]; American Heart Association Bugher Foundation Center for Stroke Prevention; Aneurysm and AVM Foundation FX We thank the patients who participated in this study and the members of the UCSF Brain AVM project for the assistance with patient recruitment, technical support, and data management. This study was supported by the National Institutes of Health (NIH) Grants P01 NS044155 and R01 NS034949 (WLY), supplement 3R01NS034949-14S1 (WLY, FRS), K23 NS058357 (HK), NIH/NIGMS T32 GM08440 (SW), NINDS and ARRA NS056302 (FRS); the American Heart Association Bugher Foundation Center for Stroke Prevention Research Grant (FRS, WLY); and The Aneurysm and AVM Foundation Award (WLY). NR 39 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD DEC PY 2011 VL 2 IS 4 SI SI BP 575 EP 587 DI 10.1007/s12975-011-0103-3 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 943YJ UT WOS:000304163700015 PM 22184505 ER PT J AU Zhang, LS Rahbari, R He, M Kebebew, E AF Zhang, Lisa Rahbari, Reza He, Mei Kebebew, Electron TI CDC23 regulates cancer cell phenotype and is overexpressed in papillary thyroid cancer SO ENDOCRINE-RELATED CANCER LA English DT Article ID GENE-EXPRESSION PROFILES; GENDER DISPARITY; HEPATOCELLULAR-CARCINOMA; RISK; PROTEOLYSIS; POPULATION; GENOMICS; SECURIN; TUMORS; ENTRY AB Cancer gender disparities have been observed for a variety of human malignancies. Thyroid cancer is one such example where there is a dramatic difference in the incidence, aggressiveness, and death rate by gender. The molecular basis for gender disparity is poorly understood. To address this, we performed genome-wide gene expression profiling in matched papillary thyroid cancer (PTC) samples and identified nine candidate genes differentially expressed by gender. One of these genes was CDC23 that was upregulated in PTC in men compared with women. Because the function and expression of CDC23 is unknown in eukaryotic cells, we further characterized the expression of CDC23 in normal, hyperplastic, and PTC tissue samples. We found CDC23 was overexpressed in PTC and absent in normal and hyperplastic thyroid tissue. In thyroid cancer cells, functional knockdown of CDC23 resulted in an increase in the number of cells in both the S and G(2)M phases of the cell cycle, and an inhibition of cellular proliferation, tumor spheroid formation, and anchorage-independent growth. Cellular arrest in both S and G(2)M phases was associated with significant cyclin B1 and securin protein accumulation after CDC23 knockdown. Moreover, the effect of CDC23 on cellular proliferation and cell cycle progression was reversed on triple knockdown studies of CDC23, cyclin B1, and securin. Our data taken together suggests CDC23 has important biologic effects on cell proliferation and cell cycle progression. The effect of CDC23 on cellular proliferation and cell cycle progression is mediated, at least in part, by cyclin B1 and securin protein levels. Therefore, we propose that CDC23 is a critical regulator of cell cycle and cell growth, and may be involved in thyroid cancer initiation and progression, and may explain the different tumor biology observed by gender. Endocrine-Related Cancer (2011) 18 731-742 C1 [Zhang, Lisa; Rahbari, Reza; He, Mei; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, NIH,HHS,Clin Res Ctr, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, NIH,HHS,Clin Res Ctr, Bldg 10-CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This study was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 37 TC 4 Z9 4 U1 0 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD DEC PY 2011 VL 18 IS 6 BP 731 EP 742 DI 10.1530/ERC-11-0181 PG 12 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 918IN UT WOS:000302242800015 PM 21990323 ER PT J AU Aguera-Gonzales, S Gross, CC Fernandez-Messina, L Ashiru, O Esteso, G Hang, HC Reyburn, HT Long, EO Vales-Gomez, M AF Aguera-Gonzales, Sonia Gross, Catharina C. Fernandez-Messina, Lola Ashiru, Omodele Esteso, Gloria Hang, Howard C. Reyburn, Hugh T. Long, Eric O. Vales-Gomez, Mar TI Palmitoylation of MICA, a ligand for NKG2D, mediates its recruitment to membrane microdomains and promotes its shedding SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE MHC-class I-related chain A; NK cell; NKG2D; Palmitoylation ID CHAIN-RELATED MOLECULE; I-RELATED CHAIN; CUTTING EDGE; MATRIX-METALLOPROTEINASE; CHEMICAL PROBES; DOWN-REGULATION; NK CELLS; T-CELLS; PROTEIN; RECEPTOR AB MICA and MICB (MHC-class-I-related chain A/B) are transmembrane proteins expressed in pathological conditions that are ligands for NKG2D, an activating receptor found on cytotoxic lymphocytes. The recognition on target cells of NKG2D ligands leads to the activation of lysis and cytokine secretion by NK cells and T cells. Besides being expressed at the cell surface, MICA/B can be released as soluble proteins. Soluble NKG2D ligands downmodulate expression of the NKG2D receptor on lymphocytes, leading to a diminished cytotoxic response. Prior studies suggested that recruitment of MICA/B molecules to cholesterol-enriched microdomains was an important factor regulating the proteolytic release of these molecules. We now show that recruitment of MICA to these microdomains depends on palmitoylation of two cysteine residues that allow MICA molecules to reside in the membrane in the same domains as caveolin-1. Compared with WT molecules, nonpalmitoylated mutant MICA molecules were shed to the supernatant with low efficiency; however, both WT and mutant MICA were able to trigger NK cell cytotoxicity. These data suggest that the presence of NKG2D ligands at the plasma membrane is sufficient to activate cytotoxicity and reflect the need of different ligands to exploit different cellular pathways to reach the cell surface upon different stress situations. C1 [Fernandez-Messina, Lola; Esteso, Gloria; Reyburn, Hugh T.; Vales-Gomez, Mar] CNB CSIC, Madrid 28049, Spain. [Gross, Catharina C.; Long, Eric O.] Natl Inst Hlth, Natl Inst Allerg & Infect Dis, Lab Immunogenet, Rockville, MD USA. [Hang, Howard C.] Rockefeller Univ, Lab Chem Biol & Microbiol Pathogen, New York, NY USA. [Aguera-Gonzales, Sonia; Fernandez-Messina, Lola; Ashiru, Omodele; Vales-Gomez, Mar] Univ Cambridge, Dept Pathol, Div Immunol, Cambridge, England. [Aguera-Gonzales, Sonia] Inst Pasteur, Dept Immunol, F-75724 Paris, France. [Gross, Catharina C.] Univ Hosp Munster, Dept Neurol Inflammat Dis Nervous Syst, D-48149 Munster, Germany. RP Vales-Gomez, M (reprint author), CNB CSIC, Darwin 3,Campus Cantoblanco, Madrid 28049, Spain. EM mvales@cnb.csic.es RI Long, Eric/G-5475-2011; Vales-Gomez, Mar/F-5351-2012; Reyburn, Hugh/B-4338-2009 OI Long, Eric/0000-0002-7793-3728; Vales-Gomez, Mar/0000-0001-7424-3206; FU Intramural NIH HHS; Medical Research Council [, G9800943]; NIGMS NIH HHS [GM087544, R01 GM087544] NR 42 TC 16 Z9 17 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2011 VL 41 IS 12 BP 3667 EP 3676 DI 10.1002/eji.20114165 PG 10 WC Immunology SC Immunology GA 853ZU UT WOS:000297465000031 PM 21928280 ER PT J AU Schisterman, EF Vexler, A Ye, AJ Perkins, NJ AF Schisterman, Enrique F. Vexler, Albert Ye, Aijun Perkins, Neil J. TI A COMBINED EFFICIENT DESIGN FOR BIOMARKER DATA SUBJECT TO A LIMIT OF DETECTION DUE TO MEASURING INSTRUMENT SENSITIVITY SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Measurement error; pooling; limit of detection; cost-efficient design; three-assay design; two-assay design; duplicate; one-pool design ID ROC CURVE ANALYSIS; POOLED ASSESSMENTS; MEASUREMENT ERROR; DIAGNOSTIC-ACCURACY; EXPOSURE; BIOSPECIMENS; SAMPLES AB Pooling specimens, a well-accepted sampling strategy in biomedical research, can be applied to reduce the cost of studying biomarkers. Even if the cost of a single assay is not a major restriction in evaluating biomarkers, pooling can be a powerful design that increases the efficiency of estimation based on data that is censored due to an instrument's lower limit of detection (LLOD). However, there are situations when the pooling design strongly aggravates the detection limit problem. To combine the benefits of pooled assays and individual assays, hybrid designs that involve taking a sample of both pooled and individual specimens have been proposed. We examine the efficiency of these hybrid designs in estimating parameters of two systems subject to a LLOD: (1) normally distributed biomarker with normally distributed measurement error and pooling error; (2) Gamma distributed biomarker with double exponentially distributed measurement error and pooling error. Three-assay design and two-assay design with replicates are applied to estimate the measurement and pooling error. The Maximum likelihood method is used to estimate the parameters. We found that the simple one-pool design, where all assays but one are random individuals and a single pooled assay includes the remaining specimens, under plausible conditions, is very efficient and can be recommended for practical use. C1 [Schisterman, Enrique F.; Ye, Aijun; Perkins, Neil J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. [Vexler, Albert] SUNY Buffalo, Buffalo, NY 14214 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd, Rockville, MD 20852 USA. EM schistee@mail.nih.gov; avexler@buffalo.edu; yea2@mail.nih.gov; perkinsn@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Epidemiology branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX Supported by the Intramural Research Program of the Epidemiology branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 22 TC 7 Z9 7 U1 1 U2 2 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD DEC PY 2011 VL 5 IS 4 BP 2651 EP 2667 DI 10.1214/11-AOAS490 PG 17 WC Statistics & Probability SC Mathematics GA 893UT UT WOS:000300382800018 ER PT J AU Barao, I Alvarez, M Redelman, D Weiss, JM Ortaldo, JR Wiltrout, RH Murphy, WJ AF Barao, Isabel Alvarez, Maite Redelman, Doug Weiss, Jonathan M. Ortaldo, John R. Wiltrout, Robert H. Murphy, William J. TI Hydrodynamic Delivery of Human IL-15 cDNA Increases Murine Natural Killer Cell Recovery after Syngeneic Bone Marrow Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Bone marrow transplantation; NK reconstitution; Gene therapy; IL-15 ID VERSUS-HOST-DISEASE; NK CELLS; IN-VIVO; IMMUNE RECONSTITUTION; TRANS-PRESENTATION; IL-15/IL-15R-ALPHA COMPLEXES; INTERLEUKIN-15; ACTIVATION; SURVIVAL; MICE AB Immune deficiency immediately following bone marrow transplantation (BMT) increases susceptibility to opportunistic infections as well as tumor relapse. Natural Killer (NK) cells play important roles in the resistance to virally infected and transformed cells. Interleukin (IL)-15 has been shown to be essential for NK cell development and survival. We administered human (h) IL-15 cDNA (pIL-15) via hydrodynamic delivery to murine recipients undergoing congenic BMT to determine its effects on NK cell reconstitution. Hydrodynamic pIL-15 delivery resulted in high levels of hIL-15 protein in the serum that lasted for several days and then quickly declined. The appearance of hIL-15 was followed by a significant increase of mature donor-derived NK cells within the bone marrow, spleens, and livers of the treated recipients. No accumulation of immature NK cell progenitors was observed. The NK cells from IL-15-treated recipients displayed an activated phenotype and were lytically active toward tumor targets in vitro to a similar degree as did those cells from recipients treated with control plasmid. This suggests that the predominant effect of IL-15 was a quantitative increase in total NK cell numbers and not qualitative changes in NK cell functions. No toxicities or adverse effects were observed. Studies performed in transplanted mice bearing renal carcinoma tumors demonstrated that this mode of hIL-15 gene delivery resulted in increased antitumor responses. These results support the use of cytokine gene transfer-based regimens as a platform to augment NK cell recovery after BMT. Biol Blood Marrow Transplant 17: 1754-1764 (2011) (C) 2011 American Society for Blood and Marrow Transplantation C1 [Murphy, William J.] Univ Calif Davis, Sch Med, CTSC IRC, Dept Dermatol, Sacramento, CA 95817 USA. [Barao, Isabel] Univ Nevada, Dept Microbiol & Immunol, Reno, NV 89557 USA. [Redelman, Doug] Univ Nevada, Dept Physiol, Reno, NV 89557 USA. [Weiss, Jonathan M.; Ortaldo, John R.; Wiltrout, Robert H.] SAIC Frederick Inc, Natl Canc Inst Frederick, Frederick, MD USA. [Murphy, William J.] Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. RP Murphy, WJ (reprint author), Univ Calif Davis, Sch Med, CTSC IRC, Dept Dermatol, Suite 1630,2921 Stockton Blvd, Sacramento, CA 95817 USA. EM wmjmurphy@ucdavis.edu FU National Institutes of Health (NIH) [R01HL089905, P20 RR016464, P20 RR018751, P01 DK041315] FX This study was supported by National Institutes of Health (NIH) Grants R01HL089905, P20 RR016464, P20 RR018751, and P01 DK041315. NR 38 TC 6 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2011 VL 17 IS 12 BP 1754 EP 1764 DI 10.1016/j.bbmt.2011.08.023 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 895CB UT WOS:000300472700006 PM 21906575 ER PT J AU McIver, ZA Melenhorst, JJ Grim, A Naguib, N Weber, G Fellowes, V Khuu, H Stroncek, DS Leitman, SF Battiwalla, M Barrett, AJ AF McIver, Zachariah A. Melenhorst, Jan J. Grim, Andrew Naguib, Nicholas Weber, Gerrit Fellowes, Vicki Khuu, Hahn Stroncek, David S. Leitman, Susan F. Battiwalla, Minoo Barrett, A. John TI Immune Reconstitution in Recipients of Photodepleted HLA-Identical Sibiing Donor Stem Cell Transplantations: T Cell Subset Frequencies Predict Outcome SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Transplantation; Photodepletion; TH9402; GVHD; CD4 central memory ID GRAFT-VERSUS-HOST; ANTIGEN-PRESENTING CELLS; SELECTIVE DEPLETION; P-GLYCOPROTEIN; LEUKEMIA; DISEASE; LYMPHOCYTES; CD4(+); PAIRS AB We evaluated an ex vivo photodepletion (PD) technique to selectively deplete graft-versus-host disease (GVHD) alloreacting T cells given to 24 human leukocyte antigen (HLA)-identical sibling stem cell transplantation (SCT) recipients. Donor lymphocytes were activated by 72-hour exposure to irradiated in vitro expanded recipient T lymphocytes and pulsed with a TH9402 photosensitizer. Alloactivated T cells preferentially retaining the photosensitizer were eliminated by light exposure. The PD product showed an inverted CD4(+)/CD8(+) ratio with greatest depletion occurring in the CD4(+) naive and central memory populations. In contrast, the CD8(+) naive and effector cells were relatively conserved, reflecting the differential extrusion of TH9402 by T cell subsets. Cytomegalovirus reactive T cells were reduced in the PD product and in recipient blood 100 days after SCT when compared with contemporaneous HLA-identical sibling donor T cell-depleted SCT recipients. Although PD SCTrecipients experienced similar absolute lymphocyte counts during the first 100 days after SCT, they achieved 100% donor T cell chimerism more rapidly and had higher CD8(+) naive T cell counts early after SCT. SCT recipients of PD products with the lowest CD4 central memory content had the highest risk of developing chronic GVHD (cGVHD) (P =.04) and a poorer survival (P =.03). Although the persistence of CD8(+) naive T cells may have contributed to important antileukemia responses resulting in a relatively low relapse rate, our findings emphasize the role of donor memory T cells and CD4 cells in establishing immune competence post-SCT. Although PD is associated with excellent outcomes in the haploidentical setting, the low frequency of alloactivations in HLA-matched pairs makes the PD approach used by our group for allodepletion in HLA-matched sibling transplantations an inefficient technique. Biol Blood Marrow Transplant 17: 1846-1854 (2011) Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation C1 [McIver, Zachariah A.; Melenhorst, Jan J.; Grim, Andrew; Naguib, Nicholas; Weber, Gerrit; Battiwalla, Minoo; Barrett, A. John] NHLBI, Allotransplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Fellowes, Vicki; Khuu, Hahn; Stroncek, David S.; Leitman, Susan F.] NIH, Cell Proc Sect, Dept Transfus Med, Bethesda, MD 20892 USA. RP McIver, ZA (reprint author), NHLBI, Allotransplantat Sect, Hematol Branch, NIH, 10 Ctr Dr,Room 3-5220, Bethesda, MD 20892 USA. EM mciverza@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 24 TC 18 Z9 18 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2011 VL 17 IS 12 BP 1846 EP 1854 DI 10.1016/j.bbmt.2011.05.017 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 895CB UT WOS:000300472700017 PM 21684345 ER PT J AU Mielke, S McIver, ZA Shenoy, A Fellowes, V Khuu, H Stroncek, DF Leitman, SF Childs, R Battiwalla, M Koklanaris, E Haggerty, J Savani, BN Rezvani, K Barrett, AJ AF Mielke, Stephan McIver, Zachariah A. Shenoy, Aarthy Fellowes, Vicki Khuu, Hahn Stroncek, David F. Leitman, Susan F. Childs, Richard Battiwalla, Minoo Koklanaris, Eleftheria Haggerty, Janice Savani, Bipin N. Rezvani, Katie Barrett, A. John TI Selectively T Cell-Depleted Allografts from HLA-Matched Sibling Donors Followed by Low-Dose Posttransplantation Immunosuppression to Improve Transplantation Outcome in Patients with Hematologic Malignancies SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Transplantation; Acute GVHD; Selective depletion; Allogeneic ID GRAFT-VERSUS-HOST; IMMUNE RECONSTITUTION; DISEASE; LEUKEMIA; LYMPHOCYTES; MARROW; PAIRS AB We evaluated a photodepletion technique to selectively deplete host-reacting T cells from human leukocyte antigen (HLA)-matched sibling stem cell transplantations with the goal of reducing posttransplantation immunosuppression to improve antimalignancy effects postallografting. Donor lymphocytes were stimulated with irradiated expanded recipient T lymphocytes in an ex vivo mixed lymphocyte reaction. Alloactivated T cells preferentially retaining the photosensitizer 4,5-dibromorhodamine 123 (TH9402) were eliminated by exposure to visible light. Twenty-four patients with hematologic malignancies (16 high risk) conditioned with fludarabine, cyclophosphamide, and totalbody irradiation received a CD34-selected stem cell allograft from an HLA-matched sibling along with 5 x 10(6)/kg selectively depleted donor T cells. Low-dose cyclosporine was used for posttransplantation immunosuppression. Eleven patients survived at a median of 30 months. Probabilities (+/- SEM) for overall and disease-free survival are 39% +/- 12% and 30% +/- 12%, respectively, whereas grade III-IV acute graft-versus-host disease (aGVHD) was 13% +/- 7%. Six patients relapsed, with a relapse probability of 27% +/- 10%. These results suggest that selectively photodepleted allografts in matched sibling transplantations followed by low-dose immunosuppression may protect against severe aGVHD but is associated with delayed immune recovery. Biol Blood Marrow Transplant 17: 1855-1861(2011) (C) Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation C1 [McIver, Zachariah A.; Childs, Richard; Battiwalla, Minoo; Koklanaris, Eleftheria; Haggerty, Janice; Barrett, A. John] NHLBI, Allotransplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Mielke, Stephan] Univ Hosp Wuerzburg, Div Hematol, Dept Internal Med 2, Wurzburg, Germany. [Shenoy, Aarthy] Washington Hosp Ctr, Inst Canc, Washington, DC 20010 USA. [Fellowes, Vicki; Khuu, Hahn; Stroncek, David F.; Leitman, Susan F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Rezvani, Katie] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Haematol, London, England. RP McIver, ZA (reprint author), NHLBI, Allotransplantat Sect, Hematol Branch, NIH, 10 Ctr Dr,Room 3-5220, Bethesda, MD 20892 USA. EM mciverza@nhlbi.nih.gov FU Kiadis Pharma; National Heart, Lung and Blood Institute at the National Institutes of Health, Bethesda, MD; The Netherlands FX Financial disclosure: This trial was supported in part by a research grant from Kiadis Pharrna under a clinical trial agreement with the National Heart, Lung and Blood Institute at the National Institutes of Health, Bethesda, MD.; S.M. designed research and wrote the article. Z.A.M. provided clinical care, analyzed data, and wrote the article. A.S. designed research and provided clinical care. V.F. supervised the preparation of clinical products. H.K. designed research and supervised the preparation of clinical products. D.F.S. designed research and supervised the preparation of clinical products. S.F.L. designed research and supervised the preparation of clinical products. R.C. provided clinical care. M.B. provided clinical care and wrote the article. E.K. provided clinical care. J.F[. provided clinical care. B.S. designed research. K.R. designed research. A.J.B. designed research, provided clinical care, and wrote the article. S.M. received research funding from Kiadis Pharma, The Netherlands. NR 17 TC 23 Z9 23 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2011 VL 17 IS 12 BP 1855 EP 1861 DI 10.1016/j.bbmt.2011.05.019 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 895CB UT WOS:000300472700018 PM 21684344 ER PT J AU Sholom, S DeWitt, R Simon, SL Bouville, A McKeever, SWS AF Sholom, S. DeWitt, R. Simon, S. L. Bouville, A. McKeever, S. W. S. TI Emergency optically stimulated luminescence dosimetry using different materials SO RADIATION MEASUREMENTS LA English DT Article DE OSL dosimeter; Individual emergency dosimetry; Teeth; Nails; Business cards; Plastic buttons ID ELECTRONIC COMPONENTS; ACCIDENT DOSIMETRY; TOOTH ENAMEL; OSL AB Several materials were tested as possible individual emergency dosimeters using Optically Stimulated Luminescence (OSL) as means to assess the exposure. Materials investigated included human nails, business cards and plastic buttons. The OSL properties of these materials were studied in comparison with those of teeth. Most samples revealed OSL signals only after exposure to ionizing radiation: some samples of business cards, however, displayed a strong initial "native" signal (i.e. existing in the samples prior to irradiation). The sensitivity (minimum measurable dose) of the samples was found to vary significantly from sample to sample of the same material and was in the range from several tens of mGy to a few dozens of Gy. The dose-response curves were linear for doses below 10 Gy. Fading of the OSL signals was estimated for different lenghts of times and found to be similar to 95%, 45%, 30% and 15% for samples of teeth, business cards, buttons and nails, respectively, following storage at room temperature in the dark for a period of 3 weeks after exposure. For samples stored under routine laboratory light, fading was much faster and the radiation-induced signals almost disappeared after a few hours of such illumination. It was concluded that the tested materials could be used in triage situations to detect and estimate the possible overexposure of individuals if the measurements can be performed soon enough after exposure. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Sholom, S.; DeWitt, R.; McKeever, S. W. S.] Oklahoma State Univ, Stillwater, OK 74074 USA. [Simon, S. L.; Bouville, A.] NCI, NIH, Bethesda, MD 20892 USA. RP Sholom, S (reprint author), Oklahoma State Univ, Venture 1,Suite 201,1110 S Innovat Way Dr, Stillwater, OK 74074 USA. EM Sergey.sholom@okstate.edu OI DeWitt, Regina/0000-0003-2876-5489 FU National Institute of Allergy and Infectious Diseases; National Cancer Institute, NIAID [Y2-Al-5077]; NCI [Y3-CO-5117] FX This work was supported by the Intra-Agency agreement between the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIAID agreement #Y2-Al-5077 and NCI agreement #Y3-CO-5117. NR 11 TC 13 Z9 13 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-4487 J9 RADIAT MEAS JI Radiat. Meas. PD DEC PY 2011 VL 46 IS 12 SI SI BP 1866 EP 1869 DI 10.1016/j.radmeas.2011.03.004 PG 4 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 894WY UT WOS:000300459400124 PM 22125409 ER PT J AU Borgmann, A Toth, TI Gruhn, M Daun-Gruhn, S Buschges, A AF Borgmann, Anke Toth, Tibor I. Gruhn, Matthias Daun-Gruhn, Silvia Bueschges, Ansgar TI Dominance of local sensory signals over inter-segmental effects in a motor system: experiments SO BIOLOGICAL CYBERNETICS LA English DT Article DE Locomotion; Walking; Central pattern generator; Campaniform sensilla; Inter-segmental coordination ID FEMUR-TIBIA JOINT; STICK INSECT LEG; CENTRAL NERVOUS-SYSTEM; RAT SPINAL-CORD; CAMPANIFORM SENSILLA; CARAUSIUS-MOROSUS; WALKING SYSTEM; NEONATAL-RAT; INTERSEGMENTAL COORDINATION; PATTERN GENERATION AB Legged locomotion requires that information local to one leg, and inter-segmental signals coming from the other legs are processed appropriately to establish a coordinated walking pattern. However, very little is known about the relative importance of local and inter-segmental signals when they converge upon the central pattern generators (CPGs) of different leg joints. We investigated this question on the CPG of the middle leg coxa-trochanter (CTr)-joint of the stick insect which is responsible for lifting and lowering the leg. We used a semi-intact preparation with an intact front leg stepping on a treadmill, and simultaneously stimulated load sensors of the middle leg. We found that middle leg load signals induce bursts in the middle leg depressor motoneurons (MNs). The same local load signals could also elicit rhythmic activity in the CPG of the middle leg CTr-joint when the stimulation of middle leg load sensors coincided with front leg stepping. However, the influence of front leg stepping was generally weak such that front leg stepping alone was only rarely accompanied by switching between middle leg levator and depressor MN activity. We therefore conclude that the impact of the local sensory signals on the levator-depressor motor system is stronger than the inter-segmental influence through front leg stepping. C1 [Borgmann, Anke; Toth, Tibor I.; Gruhn, Matthias; Daun-Gruhn, Silvia; Bueschges, Ansgar] Univ Cologne, Inst Zool, Dept Anim Physiol, D-50674 Cologne, Germany. RP Borgmann, A (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM anke.borgmann@uni-koeln.de FU DFG [Bu 857/8, 10, DA1182/1-1] FX The authors thank H.-P. Bollhagen, J. Sydow, and M. Dubbert for excellent technical support, and J. Schmidt and S.N. Zill for discussions in the course of the study. This study was supported by DFG grant Bu 857/8,10 to A. B. and by a DFG Emmy-Noether-Grant (DA1182/1-1) to S.G. NR 63 TC 13 Z9 13 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-1200 J9 BIOL CYBERN JI Biol. Cybern. PD DEC PY 2011 VL 105 IS 5-6 BP 399 EP 411 DI 10.1007/s00422-012-0473-y PG 13 WC Computer Science, Cybernetics; Neurosciences SC Computer Science; Neurosciences & Neurology GA 889TF UT WOS:000300095600009 PM 22290138 ER PT J AU Sofi, F Lova, RM Nucida, V Taviani, A Benvenuti, F Stuart, M Weinrich, M Cecchi, F Abbate, R Gensini, GF Macchi, C AF Sofi, F. Lova, R. Molino Nucida, V. Taviani, A. Benvenuti, F. Stuart, M. Weinrich, M. Cecchi, F. Abbate, R. Gensini, G. F. Macchi, C. TI Adaptive physical activity and back pain: a non-randomised community-based intervention trial SO EUROPEAN JOURNAL OF PHYSICAL AND REHABILITATION MEDICINE LA English DT Article DE Motor activity; Back pain; Exercise ID ACTIVITY PROGRAM; PREVALENCE; LIFE; AGE AB Background. Back pain is a significant problem due to the high healthcare utilization, rising costs of care and low effectiveness of many current treatments. Aim. Aim of this study was to determine the effects of a community-based Adapted Physical Activity (APA) program focused on chronic, non-specific back pain. Design. Open-label intervention study. Setting. Community. Population. All patients admitted to Empoli Rehabilitation Department for non-specific back pain for at least three months, were considered for APA. Exclusion criteria were: "red flags", difficulty/disability in basic daily living activities, severe/acute medical conditions, acute pain, psychiatric disease or cognitive impairment, severe visuoauditory deficit. Overall, 650 persons were enrolled. Methods. The APA program, including strength and flexibility training and exercises for improving posture was delivered for 12 months, with 1-hour group classes three times per week. Results. Overall 261 (40.2%) subjects completed the 12-month APA program and were compared to the 310 (47.7%) who were screened but failed to initiate or complete the study. There were no significant differences in baseline demographic and clinical characteristics between groups. Patients who followed the APA program reported significantly improved health status and significant back pain improvement, compared with those who did not adhere to the program. In the logistic regression analysis adjusted for age and gender, a distance from home to gymnasium greater than the median for the study population (2.6 kin) was the only baseline characteristic significantly associated with an increased risk of non-adherence (OR 1.44, 95%CI 1.01-2.13; P=0.04). Conclusion. This study suggests that a community-based APA program can improve back pain and health status in persons with chronic, non-specific low back pain. Clinical rehabilitation impact. These findings highlight the potential for new approaches to manage chronic disease and disability by facilitating a healthy lifestyle and promoting physical activity through implementation of community-based exercise programs. C1 [Sofi, F.; Abbate, R.; Gensini, G. F.] Univ Florence, Dept Med & Surg Crit Care, I-50134 Florence, Italy. [Sofi, F.; Lova, R. Molino; Cecchi, F.; Gensini, G. F.; Macchi, C.] Don Carlo Gnocchi Fdn, IRCCS, Florence, Italy. [Sofi, F.] Univ Careggi, Azienda Osped, Agcy Nutr, Florence, Italy. [Nucida, V.; Taviani, A.; Benvenuti, F.] Azienda Unita Sanit Locale 11, Dipartimento Riabilitaz & Fragilita, Empoli, Italy. [Stuart, M.] Univ Maryland Baltimore Cty, Hlth Adm & Policy Program, Baltimore, MD USA. [Weinrich, M.] NIH, Natl Ctr Med Rehabil Res, Bethesda, MD 20892 USA. RP Sofi, F (reprint author), Univ Florence, Dept Med & Surg Crit Care, Viale Morgagni 85, I-50134 Florence, Italy. EM francescosofi@gmail.com RI Sofi, Francesco/J-3941-2016 OI Sofi, Francesco/0000-0001-7113-7424 NR 23 TC 7 Z9 7 U1 1 U2 8 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 1973-9087 J9 EUR J PHYS REHAB MED JI Eur. J. Phys. Rehabil. Med. PD DEC PY 2011 VL 47 IS 4 BP 543 EP 549 PG 7 WC Rehabilitation SC Rehabilitation GA 890CT UT WOS:000300123400003 PM 21508911 ER PT J AU Choi, H Li, X Lau, ST Hu, CH Zhou, QF Shung, KK AF Choi, Hojong Li, Xiang Lau, Sien-Ting Hu, ChangHong Zhou, Qifa Shung, K. Kirk TI Development of Integrated Preamplifier for High-Frequency Ultrasonic Transducers and Low-Power Handheld Receiver SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID 2D CMUT ARRAYS; CIRCUIT; DESIGN; CMOS; CHIP AB This paper describes the design of a front-end circuit consisting of an integrated preamplifier with a Sallen-Key Butterworth filter for very-high-frequency ultrasonic transducers and a low-power handheld receiver. This preamplifier was fabricated using a 0.18-mu m 7WL SiGe bi-polar complementary metal oxide semiconductor (BiCMOS) process. The Sallen-Key filter is used to increase the voltage gain of the front-end circuit for high-frequency transducers which are generally low in sensitivity. The measured peak voltage gain of the front-end circuits for the BiCMOS preamplifier with the Sallen-Key filter was 41.28 dB at 100 MHz with a -6-dB bandwidth of 91%, and the dc power consumption of the BiCMOS preamplifier was 49.53 mW. The peak voltage gain of the front-end circuits for the CMOS preamplifier with the Sallen-Key filter was 39.52 dB at 100 MHz with a -6-dB bandwidth of 108%, and the dc power consumption of the CMOS preamplifier was 43.57 mW. Pulse-echo responses and wire phantom images with a single-element ultrasonic transducer have been acquired to demonstrate the performance of the front-end circuit. C1 [Choi, Hojong; Li, Xiang; Lau, Sien-Ting; Hu, ChangHong; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA USA. [Choi, Hojong; Li, Xiang; Lau, Sien-Ting; Hu, ChangHong; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH Resource Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. RP Choi, H (reprint author), Univ So Calif, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA USA. EM qifazhou@usc.edu RI Lau, Sien-Ting/B-6091-2013 FU NIH [P41-EB2182]; MOSIS MEP [4793-MEP-RES/USC-BE] FX Manuscript received June 21, 2011; accepted October 11, 2011. The authors acknowledge NIH Grant #P41-EB2182 and MOSIS MEP Research Program #4793-MEP-RES/USC-BE. NR 30 TC 15 Z9 15 U1 1 U2 13 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD DEC PY 2011 VL 58 IS 12 BP 2646 EP 2658 DI 10.1109/TUFFC.2011.2127 PG 13 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 889SF UT WOS:000300092800016 PM 23443700 ER PT J AU Sylvetsky, A Rother, KI Brown, R AF Sylvetsky, Allison Rother, Kristina I. Brown, Rebecca TI Artificial Sweetener Use Among Children: Epidemiology, Recommendations, Metabolic Outcomes, and Future Directions SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Artificial sweeteners; Non-nutritive sweeteners; Noncaloric sweeteners; Low-calorie sweeteners; Sugar substitutes; Obesity; Overweight ID FOOD-INTAKE; BEVERAGE CONSUMPTION; WEIGHT-GAIN; BODY-WEIGHT; CALORIC COMPENSATION; GLUCOSE-ABSORPTION; TASTE RECEPTORS; SELF-REGULATION; ENERGY-INTAKE; NONNUTRITIVE SWEETENERS AB This review summarizes the literature pertaining to the epidemiology and current recommendations for pediatric artificial sweetener use and presents the results of studies investigating metabolic responses to artificial sweeteners among children. An understanding of the research previously conducted and the gaps that remain will inform future clinical and translational research, to develop evidence-based recommendations for artificial sweetener use in the prevention and treatment of pediatric obesity. C1 [Sylvetsky, Allison] Emory Univ, Grad Div Biol & Biomed Sci, Atlanta, GA 30322 USA. [Rother, Kristina I.; Brown, Rebecca] NIDDKD, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. RP Sylvetsky, A (reprint author), Emory Univ, Grad Div Biol & Biomed Sci, 1462 Clifton Rd,Suite 314, Atlanta, GA 30322 USA. EM asylvet@emory.edu FU National Institutes of Health; National Institute of Diabetes, Digestive, and Kidney Diseases FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, and the National Institute of Diabetes, Digestive, and Kidney Diseases. NR 71 TC 19 Z9 19 U1 2 U2 44 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD DEC PY 2011 VL 58 IS 6 BP 1467 EP + DI 10.1016/j.pcl.2011.09.007 PG 15 WC Pediatrics SC Pediatrics GA 865LF UT WOS:000298311700011 PM 22093863 ER PT J AU Beatty, L AF Beatty, Lula TI Women & Addiction: A Comprehensive Handbook. SO PSYCHOLOGY OF WOMEN QUARTERLY LA English DT Book Review C1 [Beatty, Lula] Natl Inst Drug Abuse, Special Populat Off, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Beatty, L (reprint author), Natl Inst Drug Abuse, Special Populat Off, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0361-6843 J9 PSYCHOL WOMEN QUART JI Psychol. Women Q. PD DEC PY 2011 VL 35 IS 4 BP 636 EP 637 DI 10.1177/0361684311417403 PG 2 WC Psychology, Multidisciplinary; Women's Studies SC Psychology; Women's Studies GA 890OQ UT WOS:000300154500010 ER PT J AU Parvaz, MA Alia-Klein, N Woicik, PA Volkow, ND Goldstein, RZ AF Parvaz, Muhammad A. Alia-Klein, Nelly Woicik, Patricia A. Volkow, Nora D. Goldstein, Rita Z. TI Neuroimaging for drug addiction and related behaviors SO REVIEWS IN THE NEUROSCIENCES LA English DT Article DE dopamine; electroencephalography (EEG); event-related potentials (ERPs); magnetic resonance imaging (MRI); positron emission tomography (PET); prefrontal cortex ID EVENT-RELATED POTENTIALS; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; OBSESSIVE-COMPULSIVE DISORDER; ANTERIOR CINGULATE CORTEX; BRAIN GLUCOSE-METABOLISM; NEUROPSYCHOLOGICAL TEST-PERFORMANCE; AUDITORY-EVOKED-POTENTIALS; PROGRESSIVE RATIO SCHEDULE; ALCOHOL-DEPENDENT PATIENTS AB In this review, we highlight the role of neuroimaging techniques in studying the emotional and cognitive-behavioral components of the addiction syndrome by focusing on the neural substrates subserving them. The phenomenology of drug addiction can be characterized by a recurrent pattern of subjective experiences that includes drug intoxication, craving, bingeing, and withdrawal with the cycle culminating in a persistent preoccupation with obtaining, consuming, and recovering from the drug. In the past two decades, imaging studies of drug addiction have demonstrated deficits in brain circuits related to reward and impulsivity. The current review focuses on studies employing positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and electroencephalography (EEG) to investigate these behaviors in drug-addicted human populations. We begin with a brief account of drug addiction followed by a technical account of each of these imaging modalities. We then discuss how these techniques have uniquely contributed to a deeper understanding of addictive behaviors. C1 [Parvaz, Muhammad A.; Alia-Klein, Nelly; Woicik, Patricia A.; Goldstein, Rita Z.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, Dept Med, 30 Bell Ave,Bldg 490, Upton, NY 11973 USA. EM rgoldstein@bnl.gov OI Parvaz, Muhammad/0000-0002-2671-2327 FU National Institute on Drug Abuse [1R01DA023579]; General Clinical Research Center [5-MO1-RR-10710]; USA Department of Energy [DE-AC02-98CHI-886] FX This work was supported by grants from the National Institute on Drug Abuse [1R01DA023579 to R.Z.G.] and General Clinical Research Center [5-MO1-RR-10710].; This manuscript has been authored by Brookhaven Science Associates, LLC under Contract No. DE-AC02-98CHI-886 with the USA Department of Energy. The United States Government retains, and the publisher, by accepting the article for publication, acknowledges, a world-wide license to publish or reproduce the published form of this article, or allow others to do so, for the United States Government purposes. NR 243 TC 27 Z9 28 U1 8 U2 25 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-1763 J9 REV NEUROSCIENCE JI Rev. Neurosci. PD DEC PY 2011 VL 22 IS 6 BP 609 EP 624 DI 10.1515/RNS.2011.055 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 889QH UT WOS:000300087800003 PM 22117165 ER PT J AU Leon, LG Giovannetti, E Smid, K van Houte, BPP Hanauske, AR Giaccone, G Peters, GJ AF Leon, Leticia G. Giovannetti, Elisa Smid, Kees van Houte, Bart P. P. Hanauske, Axel R. Giaccone, Giuseppe Peters, Godefridus J. TI DNA Copy Number Profiles Correlate with Outcome in Colorectal Cancer Patients Treated with Fluoropyrimidine/Antifolate-based Regimens SO CURRENT DRUG METABOLISM LA English DT Review DE DNA copy number profile; colorectal cancer; 5-fluorouracil; capecitabine; pemetrexed; clinical outcome ID COMPARATIVE GENOMIC HYBRIDIZATION; HIGH-RESOLUTION ANALYSIS; CGH TUMOR PROFILES; LYMPH-NODE STATUS; THYMIDYLATE-SYNTHASE; COLON-CANCER; DIHYDROPYRIMIDINE DEHYDROGENASE; METHYLENETETRAHYDROFOLATE REDUCTASE; CARCINOMA PROGRESSION; MICROARRAY ANALYSIS AB For decades 5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colorectal cancer (CRC). The combinations of 5-FU or its oral prodrug capecitabine with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab increased responses. However, the overall prognosis is poor, and predictive biomarkers of cytotoxic drugs activity are missing. Pharmacogenetic studies focused on candidate determinants of drug activity/metabolism, such as thymidylate synthase or dihydropyrimidine dehydrogenase, but reported controversial results. Given the heterogeneous and complex nature of CRC, it is likely that many aberrations underlying its progression can also affect therapeutic response. Therefore, high-throughput arrays for genome-wide-DNA aberrations play a pivotal role for new markers discovery by moving from hypothesis-driven, targeted-research to unbiased screening of the whole genetic spectrum. Chromosomal aberrations are critical events in tumorigenesis, and genomic regions harbouring DNA gains/losses have been identified in 85% of CRC patients. These aberrations change the expression of many genes, which might explain the differential effects of specific chemotherapeutic agents. In particular, recent studies reported correlations between DNA copy-number profiles and response to fluoropyrimidine-based regimens, such as leucovorin-modulated-5-FU+irinotecan (FOLFIRI), capecitabine+irinotecan (CAPIRI) and pemetrexed+irinotecan (ALIRI). Genome-wide profiling by oligonucleotide-based array-comparative-genomic-hybridization (aCGH) revealed genomic loci, of which the copy-number status may serve as marker for outcome after FOLFIRI and CAPIRI. Larger randomized and prospective trials of these aCGH platforms in CRC patients treated with fluoropyrimidine-based regimens are ongoing, and will ultimately demonstrate whether these findings can be of actual value to predict clinical outcome and direct the choice of therapy. C1 [Leon, Leticia G.; Giovannetti, Elisa; Smid, Kees; Peters, Godefridus J.] Vrije Univ Amsterdam, Med Ctr, Dept Oncol, NL-1081 HV Amsterdam, Netherlands. [van Houte, Bart P. P.] Vrije Univ Amsterdam, Med Ctr, Ctr Integrat Bioinformat, NL-1081 HV Amsterdam, Netherlands. [Hanauske, Axel R.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Peters, Godefridus J.] Natl Canc Inst, Bethesda, MD USA. RP Giovannetti, E (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Canc Ctr Amsterdam CCA 1 52, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM elisa.giovannetti@gmail.com RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Giovannetti, Elisa/0000-0002-7565-7504 FU Spanish MSC-FIS; Netherlands Organization for Scientific Research (NWO); Lilly&Co., Netherlands; Centre-for-Medical-Systems-Biology-CMSG [134] FX Dr. Leticia G. Leon was supported by the Spanish MSC-FIS for a post-doctoral contract. Dr. Elisa Giovannetti would like to thank the Netherlands Organization for Scientific Research (NWO) for the VENI grant. Prof. Godefridus J. Peters and Prof. Giuseppe Giaccone were supported by Lilly&Co., Netherlands, and Centre-for-Medical-Systems-Biology-CMSG# 134. NR 87 TC 4 Z9 4 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2002 J9 CURR DRUG METAB JI Curr. Drug Metab. PD DEC PY 2011 VL 12 IS 10 BP 956 EP 965 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 883YR UT WOS:000299671900005 PM 21787269 ER PT J AU Shen, HW Jiang, XL Gonzalez, FJ Yu, AM AF Shen, Hong-Wu Jiang, Xi-Ling Gonzalez, Frank J. Yu, Ai-Ming TI Humanized Transgenic Mouse Models for Drug Metabolism and Pharmacokinetic Research SO CURRENT DRUG METABOLISM LA English DT Review DE Humanized; transgenic; mouse model; drug metabolism; pharmacokinetics; drug interaction; toxicity; cancer ID UDP-GLUCURONOSYLTRANSFERASE-1 UGT1 LOCUS; ARYL-HYDROCARBON RECEPTOR; MOTILITY FACTOR-RECEPTOR; HUMAN RISK-ASSESSMENT; INDUCED LIVER-INJURY; KNOCK-IN MICE; CYTOCHROME-P450 2D6; N-ACETYLTRANSFERASE; HUMAN CYP2D6; 5-METHOXY-N,N-DIMETHYLTRYPTAMINE METABOLISM AB Extrapolation of the metabolic, pharmacokinetic and toxicological data obtained from animals to humans is not always straightforward, given the remarkable species difference in drug metabolism that is due in large part to the differences in drug-metabolizing enzymes between animals and humans. Furthermore, genetic variations in drug-metabolizing enzymes may significantly alter pharmacokinetics, drug efficacy and safety. Thus, humanized transgenic mouse lines, in which the human drug-metabolizing enzymes are expressed in mouse tissues in the presence or absence of mouse orthologues, have been developed to address such challenges. These humanized transgenic mice are valuable animal models in understanding the significance of specific human drug-metabolizing enzymes in drug clearance and pharmacokinetics, as well as in predicting potential drug-drug interactions and chemical toxicity in humans. This review, therefore, aims to summarize the development and application of some humanized transgenic mouse models expressing human drug-metabolizing enzymes. The limitations of these genetically modified mouse models are also discussed. C1 [Shen, Hong-Wu; Jiang, Xi-Ling; Yu, Ai-Ming] SUNY Buffalo, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Yu, AM (reprint author), SUNY Buffalo, Dept Pharmaceut Sci, 541 Cooke Hall, Buffalo, NY 14260 USA. EM aimingyu@buffalo.edu RI Jiang, Xiling/E-9197-2012 FU National Institute On Drug Abuse, National Institutes of Health (NIH) [R01DA021172] FX The authors would like to thank financial support (award number R01DA021172) from the National Institute On Drug Abuse, National Institutes of Health (NIH). NR 105 TC 15 Z9 16 U1 1 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2002 J9 CURR DRUG METAB JI Curr. Drug Metab. PD DEC PY 2011 VL 12 IS 10 BP 997 EP 1006 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 883YR UT WOS:000299671900010 PM 22023319 ER PT J AU Malhotra, SV AF Malhotra, Sanjay V. TI Ionic Liquid Applications in the Synthesis of Organic Building Blocks SO CURRENT ORGANIC SYNTHESIS LA English DT Editorial Material C1 NCI, Lab Synthet Chem, SAIC Inc, Frederick, MD 21702 USA. RP Malhotra, SV (reprint author), NCI, Lab Synthet Chem, SAIC Inc, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1794 J9 CURR ORG SYNTH JI Curr. Org. Synth. PD DEC PY 2011 VL 8 IS 6 BP 776 EP 776 PG 1 WC Chemistry, Organic SC Chemistry GA 883DM UT WOS:000299613600001 ER PT J AU Kumar, V Parmar, VS Malhotra, SV AF Kumar, Vineet Parmar, Virinder S. Malhotra, Sanjay V. TI Ionic Liquids: Neoteric Solvents for Nucleoside Chemistry SO CURRENT ORGANIC SYNTHESIS LA English DT Article DE Nucleosides; ionic liquids; solubility; antiviral drugs ID PYRIMIDINE NUCLEOSIDES; EFFICIENT METHOD; ANTIVIRAL DRUGS; CARBOCYCLIC NUCLEOSIDES; SELECTIVE BENZOYLATION; ENZYMATIC RESOLUTION; BETA-ELIMINATION; ANALOGS; CATALYSIS; ACYLATION AB Nucleoside chemistry represents an important research area for drug discovery, as many nucleoside analogues are prominent drugs that have been widely applied in cancer and viral chemotherapy. However, the synthesis of modified nucleosides presents a major challenge. Most of the currently available methods require toxic, high-boiling solvents, long reaction times and tedious workup methods. The situation is further aggravated by the poor solubility of the nucleosides in common organic solvents. There is a constant effort to develop process chemistry in alternative media to limit the use of organic solvents that are hazardous to the environment and can be deleterious to human health. Ionic liquids (ILs) are 'designer materials' with unique physico-chemical properties. The methodologies utilizing ionic liquids for the synthesis of pharmaceutically important nucleoside analogues, including some antiviral drugs, are highly convenient and efficient. This article is focused on the recent developments made in nucleoside chemistry using ILs as a reaction medium. C1 [Kumar, Vineet; Malhotra, Sanjay V.] NCI Frederick, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. [Parmar, Virinder S.] Univ Delhi, Dept Chem, Delhi 110007, India. RP Malhotra, SV (reprint author), NCI Frederick, Lab Synthet Chem, SAIC Frederick Inc, 1050 Boyles St, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors acknowledge financial support from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 63 TC 2 Z9 2 U1 0 U2 8 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1794 J9 CURR ORG SYNTH JI Curr. Org. Synth. PD DEC PY 2011 VL 8 IS 6 BP 777 EP 786 PG 10 WC Chemistry, Organic SC Chemistry GA 883DM UT WOS:000299613600002 ER PT J AU DelBove, J Rosson, G Strobeck, M Chen, JG Archer, TK Wang, WD Knudsen, ES Weissman, BE AF DelBove, Jessica Rosson, Gary Strobeck, Matthew Chen, Jianguang Archer, Trevor K. Wang, Weidong Knudsen, Erik S. Weissman, Bernard E. TI Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene SO EPIGENETICS LA English DT Article DE SWI/SNF; BAF155; SMARCC1; tumor suppressor gene; cancer epigenetics ID CHROMATIN-REMODELING COMPLEX; SWI-SNF COMPLEX; CELL-CYCLE; PROTEASOMAL DEGRADATION; RETINOBLASTOMA PROTEIN; EXPRESSION ANALYSIS; RHABDOID TUMOR; GROWTH ARREST; BRG1; CANCER AB Recent studies have established that two core members of the SWI/SNF chromatin remodeling complex, BRG1 and SNF5/INI1, possess tumor-suppressor activity in human and mouse cancers. While the third core member, BAF155, has been implicated by several studies as having a potential role in tumor development, direct evidence for its tumor suppressor activity has remained lacking. Therefore, we screened for BAF155 deficiency in a large number of human tumor cell lines. We identified two cell lines, the SNUC2B colon carcinoma and the SKOV3 ovarian carcinoma, displaying a complete loss of protein expression while maintaining normal levels of mRNA expression. The SKOV3 cell line possesses a heterozygous 4 bp deletion that results in an 855AA truncated protein, while the cause of the loss of BAF155 expression in the SNUC2B cell line appears due to a post-transcriptional error. However, the lack of detectable BAF155 expression did not affect sensitivity to RB-mediated cell cycle arrest. Re-expression of full length but not a truncated form of BAF155 in the two cancer cell lines leads to reduced colony forming ability characterized by replicative senescence but not apoptosis. Collectively, these data suggest that loss of BAF155 expression represents another mechanism for inactivation of SWI/SNF complex activity in the development in human cancer. Our results further indicate that the c-terminus proline-glutamine rich domain plays a critical role in the tumor suppressor activity of this protein. C1 [DelBove, Jessica; Weissman, Bernard E.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27514 USA. [Rosson, Gary; Weissman, Bernard E.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Rosson, Gary] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Strobeck, Matthew; Knudsen, Erik S.] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA. [Strobeck, Matthew; Knudsen, Erik S.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Chen, Jianguang; Archer, Trevor K.] Natl Inst Environm Hlth Sci, Chromatin & Gene Express Sect, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC USA. [Wang, Weidong] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [DelBove, Jessica] Univ Utah, Sch Med, Dept Hematol, Salt Lake City, UT USA. RP Weissman, BE (reprint author), Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27514 USA. EM weissman@med.unc.edu FU National Institute on Aging, National Institutes of Health [AG000650-10]; National Institute of Environmental Health Sciences, National Institutes of Health [Z01 ES071006-11]; National Institutes of Health [T32ES007017]; [R01CA91048]; [R01CA138841]; [R01CA127387] FX This work was supported, in part, by R01CA91048 and R01CA138841 (B.E.W.), by the Intramural Research Program of the National Institute on Aging (grant AG000650-10), National Institutes of Health (W.W.), by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01 ES071006-11), National Institutes of Health (T.K.A.) and by R01CA127387 (E.S.K.). Dr. Delbove was supported, in part, by a training grant from the National Institutes of Health T32ES007017. NR 47 TC 20 Z9 21 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 J9 EPIGENETICS-US JI Epigenetics PD DEC PY 2011 VL 6 IS 12 BP 1444 EP 1453 DI 10.4161/epi.6.12.18492 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 886CI UT WOS:000299828200005 PM 22139574 ER PT J AU Munoz, M Chadwick, M Perez-Hernandez, E Vargha-Khadem, F Mishkin, M AF Munoz, M. Chadwick, M. Perez-Hernandez, E. Vargha-Khadem, F. Mishkin, M. TI Novelty preference in patients with developmental amnesia SO HIPPOCAMPUS LA English DT Article DE hippocampus; developmental amnesia; novelty preference; memory; incidental recognition ID MEDIAL TEMPORAL-LOBE; PAIRED-COMPARISON TASK; SELECTIVE HIPPOCAMPAL-LESIONS; RECOGNITION MEMORY; DECLARATIVE MEMORY; ITEM RECOGNITION; SEMANTIC MEMORY; TO-SAMPLE; RECOLLECTION; DAMAGE AB To re-examine whether or not selective hippocampal damage reduces novelty preference in visual paired comparison (VPC), we presented two different versions of the task to a group of patients with developmental amnesia (DA), each of whom sustained this form of pathology early in life. Compared with normal control participants, the DA group showed a delay-dependent reduction in novelty preference on one version of the task and an overall reduction on both versions combined. Because VPC is widely considered to be a measure of incidental recognition, the results appear to support the view that the hippocampus contributes to recognition memory. A difficulty for this conclusion, however, is that according to one current view the hippocampal contribution to recognition is limited to task conditions that encourage recollection of an item in some associated context, and according to another current view, to recognition of an item with the high confidence judgment that reflects a strong memory. By contrast, VPC, throughout which the participant remains entirely uninstructed other than to view the stimuli, would seem to lack such task conditions and so would likely lead to recognition based on familiarity rather than recollection or, alternatively, weak memories rather than strong. However, before concluding that the VPC impairment therefore contradicts both current views regarding the role of the hippocampus in recognition memory, two possibilities that would resolve this issue need to be investigated. One is that some variable in VPC, such as the extended period of stimulus encoding during familiarization, overrides its incidental nature, and, because this condition promotes either recollection- or strength-based recognition, renders the task hippocampal-dependent. The other possibility is that VPC, rather than providing a measure of incidental recognition, actually assesses an implicit, information-gathering process modulated by habituation, for which the hippocampus is also partly responsible, independent of its role in recognition. (C) 2010 Wiley Periodicals, Inc. C1 [Munoz, M.; Vargha-Khadem, F.] UCL Inst Child Hlth, Dev Cognit Neurosci Unit, London WC1N 1EH, England. [Chadwick, M.] Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Perez-Hernandez, E.] Complutense Sch Educ, Madrid 28040, Spain. [Mishkin, M.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Munoz, M (reprint author), UCL Inst Child Hlth, Dev Cognit Neurosci Unit, 30 Guilford St, London WC1N 1EH, England. EM Monica.munoz@ich.ucl.ac.uk RI Munoz-Lopez, Monica/F-3154-2016; Perez-Hernandez, Elena/H-5619-2015; OI Perez-Hernandez, Elena/0000-0001-8822-6423; Munoz Lopez, Monica/0000-0002-5530-2394 FU Marie Curie International Re-Integration [041428]; Medical Research Council [G0300117/65439]; National Institute of Mental Health, NIH/DHHS FX Grant sponsor: Marie Curie International Re-Integration; Grant number: 041428; Grant sponsor: Medical Research Council; Grant number: G0300117/65439; Grant sponsor: Intramural Research Program of the National Institute of Mental Health, NIH/DHHS. NR 43 TC 6 Z9 6 U1 2 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1050-9631 J9 HIPPOCAMPUS JI Hippocampus PD DEC PY 2011 VL 21 IS 12 BP 1268 EP 1276 DI 10.1002/hipo.20836 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 851RE UT WOS:000297287800002 PM 20882542 ER PT J AU Kagan, JM Gupta, N Varghese, S Virkar, H AF Kagan, Jonathan M. Gupta, Nitin Varghese, Suresh Virkar, Hemant TI The NIAID Division of AIDS enterprise information system: integrated decision support for global clinical research programs SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article AB The National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) Enterprise Information System (DAIDS-ES) is a web-based system that supports NIAID in the scientific, strategic, and tactical management of its global clinical research programs for HIV/AIDS vaccines, prevention, and therapeutics. Different from most commercial clinical trials information systems, which are typically protocol-driven, the DAIDS-ES was built to exchange information with those types of systems and integrate it in ways that help scientific program directors lead the research effort and keep pace with the complex and ever-changing global HIV/AIDS pandemic. Whereas commercially available clinical trials support systems are not usually disease-focused, DAIDS-ES was specifically designed to capture and incorporate unique scientific, demographic, and logistical aspects of HIV/AIDS treatment, prevention, and vaccine research in order to provide a rich source of information to guide informed decision-making. Sharing data across its internal components and with external systems, using defined vocabularies, open standards and flexible interfaces, the DAIDS-ES enables NIAID, its global collaborators and stakeholders, access to timely, quality information about NIAID-supported clinical trials which is utilized to: (1) analyze the research portfolio, assess capacity, identify opportunities, and avoid redundancies; (2) help support study safety, quality, ethics, and regulatory compliance; (3) conduct evidence-based policy analysis and business process re-engineering for improved efficiency. This report summarizes how the DAIDS-ES was conceptualized, how it differs from typical clinical trial support systems, the rationale for key design choices, and examples of how it is being used to advance the efficiency and effectiveness of NIAID's HIV/AIDS clinical research programs. C1 [Kagan, Jonathan M.] NIAID, Div Clin Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Gupta, Nitin; Varghese, Suresh; Virkar, Hemant] Digital Infuz Inc, Gaithersburg, MD USA. RP Kagan, JM (reprint author), NIAID, Div Clin Res, Dept Hlth & Human Serv, NIH, 6700B Rockledge Dr,Room 1102, Bethesda, MD 20892 USA. EM jkagan@niaid.nih.gov FU NIAID; 'DAIDS Enterprise System (DAIDS-ES) Development', from the National Institute of Allergy & Infectious Diseases, National Institutes of Health, Department of Health and Human Services, United States government [N01-AI-30060] FX The authors gratefully acknowledge the following: Dr Edmund C Tramont (NIAID) for his vision and support in initiating the project; the leadership and members of the NIAIDS HIV/AIDS clinical trials networks and collaborating organizations; Ms Lisa Chatterjee and Mr Thomas McCartan (Digital Infuzion, Inc) for their contributions to the DAIDS-ES business and technical architectures; Mr Raj Shah (CTIS, Inc) and Dr John Silva, MD (Silva Consulting) for thoughtful perspectives and discussions; Mr Sanjeev Bhagowalia (Deputy Associate Administrator, Office of Citizen Services and Innovative Technologies, US General Services Administration) for valuable insights into assessing business impacts of enterprise systems; and Mr Richard Rabil (Digital Infuzion, Inc) for help with editing and assembling the manuscript.; This work was supported by contract N01-AI-30060, 'DAIDS Enterprise System (DAIDS-ES) Development', from the National Institute of Allergy & Infectious Diseases, National Institutes of Health, Department of Health and Human Services, United States government. NR 8 TC 4 Z9 4 U1 0 U2 10 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD DEC PY 2011 VL 18 SU 1 BP I161 EP I165 DI 10.1136/amiajnl-2011-000114 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 886RJ UT WOS:000299871300026 PM 21816958 ER PT J AU Vilar, S Harpaz, R Chase, HS Costanzi, S Rabadan, R Friedman, C AF Vilar, Santiago Harpaz, Rave Chase, Herbert S. Costanzi, Stefano Rabadan, Raul Friedman, Carol TI Facilitating adverse drug event detection in pharmacovigilance databases using molecular structure similarity: application to rhabdomyolysis SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID MALIGNANT NEUROLEPTIC SYNDROME; SEVERE MYOPATHY; FUSIDIC ACID; MECHANISMS; OMEPRAZOLE; DISCOVERY; TOXICITY; NETWORK; PATIENT AB Background Adverse drug events (ADE) cause considerable harm to patients, and consequently their detection is critical for patient safety. The US Food and Drug Administration maintains an adverse event reporting system (AERS) to facilitate the detection of ADE in drugs. Various data mining approaches have been developed that use AERS to detect signals identifying associations between drugs and ADE. The signals must then be monitored further by domain experts, which is a time-consuming task. Objective To develop a new methodology that combines existing data mining algorithms with chemical information by analysis of molecular fingerprints to enhance initial ADE signals generated from AERS, and to provide a decision support mechanism to facilitate the identification of novel adverse events. Results The method achieved a significant improvement in precision in identifying known ADE, and a more than twofold signal enhancement when applied to the ADE rhabdomyolysis. The simplicity of the method assists in highlighting the etiology of the ADE by identifying structurally similar drugs. A set of drugs with strong evidence from both AERS and molecular fingerprint-based modeling is constructed for further analysis. Conclusion The results demonstrate that the proposed methodology could be used as a pharmacovigilance decision support tool to facilitate ADE detection. C1 [Vilar, Santiago; Harpaz, Rave; Chase, Herbert S.; Rabadan, Raul; Friedman, Carol] Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY 10032 USA. [Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Friedman, C (reprint author), Columbia Univ, Med Ctr, Dept Biomed Informat, 622 W 168th St VC, New York, NY 10032 USA. EM friedman@dbmi.columbia.edu RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332; Vilar Varela, Santiago/0000-0003-2663-4370 FU National Library of Medicine [R01 LM010016, R01 LM010016-0S1, R01 LM010016-0S2, R01 LM008635, 1R01LM010140-01]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health FX This work was supported by grants R01 LM010016 (CF), R01 LM010016-0S1 (CF), R01 LM010016-0S2 (CF), R01 LM008635 (CF) and 1R01LM010140-01 (RR), from the National Library of Medicine and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. NR 50 TC 22 Z9 22 U1 1 U2 13 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD DEC PY 2011 VL 18 SU 1 BP I73 EP I80 DI 10.1136/amiajnl-2011-000417 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 886RJ UT WOS:000299871300012 PM 21946238 ER PT J AU Geller, NL AF Geller, Nancy L. TI Statistics: An All-Encompassing Discipline SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Editorial Material C1 [Geller, Nancy L.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Geller, NL (reprint author), NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. EM nancylgeller@gmail.com NR 10 TC 6 Z9 6 U1 0 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2011 VL 106 IS 496 BP 1225 EP 1229 DI 10.1198/jasa.2011.ap11592 PG 5 WC Statistics & Probability SC Mathematics GA 883VL UT WOS:000299662900001 ER PT J AU Davidov, O Peddada, S AF Davidov, Ori Peddada, Shyamal TI Order-Restricted Inference for Multivariate Binary Data With Application to Toxicology SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Dose-response study; Multivariate binary data; Order-restricted statistical inference; Stochastic order relation ID HISTORICAL CONTROL DATA; TUMOR-INCIDENCE RATES; MULTINOMIAL POPULATIONS; LOGISTIC-MODELS; RESPONSES; TESTS; DISTRIBUTIONS; VARIABLES; OUTCOMES AB In many applications, researchers collect multivariate binary response data under two or more naturally ordered experimental conditions. In such situations, one is often interested in using all binary outcomes simultaneously to detect an ordering among the experimental conditions. To make such comparisons, we develop a general methodology for testing for the multivariate stochastic order between K >= 2 multivariate binary distributions. Our proposed test uses order-restricted estimators, which, according to our simulation study, are more efficient than the unrestricted estimators in terms of their mean squared error. We compared the power of the proposed test with that of several alternative tests, including procedures that combine individual univariate tests for order, such as union-intersection tests and a Bonferroni-based test. We also compared the proposed test with an unrestricted Hotel ling T-2-type test. Our simulations suggest that the proposed method competes well with these alternatives. The gain in power is often substantial. The proposed methodology is illustrated by applying it to a two-year rodent cancer bioassay data obtained from the U.S. National Toxicology Program. Supplemental materials are available online. C1 [Davidov, Ori] Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. [Peddada, Shyamal] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Davidov, O (reprint author), Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. EM davidov@stat.haifa.ac.il; peddada@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 FU Israeli Science Foundation [875/09]; National Institute of Environmental Health Sciences [Z01 ES101744-04] FX Ori Davidov is Associate Professor, Department of Statistics, University of Haifa, Mount Carmel, Haifa 31905, Israel (E-mail: davidov@stat.haifa.ac.il). Shyamal Peddada is Senior Investigator, Biostatistics Branch, National Institute of Environmental Health Sciences, Alexander Drive, Research Triangle Park, NC 27709 (E-mail: peddada@niehs.nih.gov). The research of On Davidov was partially supported by the Israeli Science Foundation (grant 875/09) and was conducted when visiting Shyamal Das Peddada. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (grant Z01 ES101744-04). We thank Professor Doron Zeilberger (Rutgers University) for pointing out the connection between the number of upper sets and the Dedekind numbers and Drs. Grace Kissling (NIEHS) and Wenge Guo (New Jersey Institute of Technology) for several useful comments that improved the presentation. We would also like to thank the editors and reviewers for constructive comments that helped improve many aspects of the article. NR 46 TC 11 Z9 11 U1 0 U2 14 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2011 VL 106 IS 496 BP 1394 EP 1404 DI 10.1198/jasa.2011.tm10322 PG 11 WC Statistics & Probability SC Mathematics GA 883VL UT WOS:000299662900014 PM 22973069 ER PT J AU Qin, J Ning, J Liu, H Shen, Y AF Qin, Jing Ning, Jing Liu, Hao Shen, Yu TI Maximum Likelihood Estimations and EM Algorithms With Length-Biased Data SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Cox regression model; Increasing failure rate; Nonparametric likelihood; Profile likelihood; Right-censored data ID PREVALENT COHORT DATA; NONPARAMETRIC-ESTIMATION; REGRESSION-MODELS; HAZARDS REGRESSION; ASYMPTOTIC THEORY; TRUNCATED DATA; FRAILTY MODEL; SURVIVAL-DATA; CENSORED-DATA; FAILURE RATE AB Length-biased sampling has been well recognized in economics, industrial reliability, etiology applications, and epidemiological, genetic, and cancer screening studies. Length-biased right-censored data have a unique data structure different from traditional survival data. The nonparametric and semiparametric estimation and inference methods for traditional survival data are not directly applicable for length-biased right-censored data. We propose new expectation-maximization algorithms for estimations based on full likelihoods involving infinite-dimensional parameters under three settings for length-biased data: estimating nonparametric distribution function, estimating nonparametric hazard function under an increasing failure rate constraint, and jointly estimating baseline hazards function and the covariate coefficients under the Cox proportional hazards model. Extensive empirical simulation studies show that the maximum likelihood estimators perform well with moderate sample sizes and lead to more efficient estimators compared to the estimating equation approaches. The proposed estimates are also more robust to various right-censoring mechanisms. We prove the strong consistency properties of the estimators, and establish the asymptotic normality of the semiparametric maximum likelihood estimators under the Cox model using modern empirical processes theory. We apply the proposed methods to a prevalent cohort medical study. Supplemental materials are available online. C1 [Qin, Jing] NIAID, Bethesda, MD 20817 USA. [Ning, Jing; Shen, Yu] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Liu, Hao] Baylor Coll Med, Div Biostat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. RP Qin, J (reprint author), NIAID, Bethesda, MD 20817 USA. EM jingqin@niaid.nih.gov; jning@mdanderson.org; haol@bcm.edu; yshen@mdanderson.org OI Shen, Yu/0000-0002-3899-7868 FU Seniors' Independence Research Program, through the National Health Research and Development Program of Health Canada [6606-3954-MC(S)]; Pfizer Canada through Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity [6603-1417-302(R)]; Bayer Incorporated; British Columbia Health Research Foundation [38(93-2), 34(96-1)]; National Institute of Health [R01-CA079466] FX ling Qin is Mathematical Statistician, National Institution of Allergy and Infectious Diseases, Bethesda, MD 20817 (E-mail: jingqin@niaid.nih.gov). Jing Ning is Assistant Professor, Department of Biostatistics, M. D. Anderson Cancer Center, Houston, TX 77030 (E-mail: jning@mdanderson.org). Hao Liu is Associate Professor, Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030 (E-mail: haol@bcm.edu). Yu Shen is Professor, Department of Biostatistics, M. D. Anderson Cancer Center, Houston, TX 77030 (E-mail: yshen@mdanderson.org). We thank one associate editor and two referees for their very constructive comments. We also thank Professor Masoud Asgharian and investigators of the Canadian Study of Health and Aging (CHSA) for providing us the dementia data from CHSA. The data reported in the example were collected as part of the CHSA. The core study was funded by the Seniors' Independence Research Program, through the National Health Research and Development Program of Health Canada (Project 6606-3954-MC(S)). Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program. NHRDP Project 6603-1417-302(R), Bayer Incorporated, and the British Columbia Health Research Foundation Projects 38(93-2) and 34(96-1). The study was coordinated through the University of Ottawa and the Division of Aging and Seniors, Health Canada. This research was supported in part by National Institute of Health grant R01-CA079466. NR 60 TC 14 Z9 14 U1 0 U2 11 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2011 VL 106 IS 496 BP 1434 EP 1449 DI 10.1198/jasa.2011.tm10156 PG 16 WC Statistics & Probability SC Mathematics GA 883VL UT WOS:000299662900017 PM 22323840 ER PT J AU Li, PF Qin, J AF Li, Pengfei Qin, Jing TI A New Nuisance-Parameter Elimination Method With Application to the Unordered Homologous Chromosome Pairs Problem SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Degenerate Fisher information; Double-blinded clinical trials; Empirical likelihood; Interim analysis; Shannon's mutual information ID EMPIRICAL LIKELIHOOD; TESTS; REGRESSION; DIFFER AB Motivated by applications of the case control model or exponential tilting model in the unordered homologous chromosome pairs problem in genetic studies and in the interim analysis in double-blinded clinical trials, we develop a new nuisance-parameter elimination method based on the empirical Shannon's mutual information. The asymptotic behaviors of the maximum empirical Shannon's mutual information estimation and the empirical Shannon's mutual information test are similar to those of the maximum likelihood estimation and the likelihood ratio test, respectively. Interestingly, we have found a connection between the empirical Shannon's mutual information and the profile empirical likelihood (Owen 1988) under some constraints. In the test of the null hypothesis that the unordered pairs come from the same distribution, the maximum Shannon's mutual information estimation has a degenerate information matrix. As a result, we have to expand the empirical Shannon's mutual information test statistic up to the fourth order to find the limiting distribution of the mixture of a distribution with point mass at zero and a chi-squared distribution with one degree of freedom. A real genetic dataset is employed for illustration. We also outline another application of Shannon's mutual information in general genetic mixture models. C1 [Li, Pengfei] Univ Alberta, Dept Math & Stat Sci, Edmonton, AB T6G 2G1, Canada. [Qin, Jing] NIAID, NIH, Bethesda, MD 20892 USA. RP Li, PF (reprint author), Univ Alberta, Dept Math & Stat Sci, Edmonton, AB T6G 2G1, Canada. EM pengfei@stat.ualberta.ca; jingqin@niaid.nih.gov FU Natural Sciences and Engineering Research Council of Canada FX Pengfei Li is Assistant Professor, Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, AB, Canada, T6G 2G1 (E-mail: pengfei@stat.ualberta.ca). Jing Qin is Mathematical Statistician, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 (E-mail: jingqin@niaid.nih.gov). The authors thank the editor, the associate editor, and a referee for constructive comments and suggestions that have improved the article. The research is supported by the Natural Sciences and Engineering Research Council of Canada. NR 21 TC 0 Z9 0 U1 1 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2011 VL 106 IS 496 BP 1476 EP 1484 DI 10.1198/jasa.2011.tm10670 PG 9 WC Statistics & Probability SC Mathematics GA 883VL UT WOS:000299662900020 ER PT J AU Ozarslan, E Komlosh, ME Lizak, MJ Horkay, F Basser, PJ AF Oezarslan, E. Komlosh, M. E. Lizak, M. J. Horkay, F. Basser, P. J. TI Double pulsed field gradient (double-PFG) MR imaging (MRI) as a means to measure the size of plant cells SO MAGNETIC RESONANCE IN CHEMISTRY LA English DT Article DE diffusion; plant cell; pulsed field gradient; microscopic; anisotropy; cell size; general gradient waveform; double; multiple; wavevector ID SPIN-ECHO; DIFFUSION-TENSOR; WHITE-MATTER; NMR; ANISOTROPY; TISSUES; WATER; SIGNAL; BRAIN AB Measurement of diffusion in porous materials and biological tissues with the pulsed field gradient (PFG) MR techniques has proven useful in characterizing the microstructure of such specimens noninvasively. A natural extension of the traditional PFG technique comprises multiple pairs of diffusion gradients. This approach has been shown to provide the ability to characterize anisotropy at different length scales without the need to employ very strong gradients. In this work, the double-PFG imaging technique was used on a specimen involving a series of glass capillary arrays with different diameters. The experiments on the phantom demonstrated the ability to create a quantitative and accurate map of pore sizes. The same technique was subsequently employed to image a celery stalk. A diffusion tensor image (DTI) of the same specimen was instrumental in accurately delineating the regions of vascular tissue and determining the local orientation of cells. This orientation information was incorporated into a theoretical double-PFG framework and the technique was employed to estimate the cell size in the vascular bundles of the celery stalk. The findings suggest that the double-PFG MRI framework could provide important new information regarding the microstructure of many plants and other food products. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Oezarslan, E.; Komlosh, M. E.; Horkay, F.; Basser, P. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Oezarslan, E.; Komlosh, M. E.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Lizak, M. J.] Natl Inst Neurol Disorders & Stroke, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. RP Ozarslan, E (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM evren@helix.nih.gov RI Ozarslan, Evren/B-4858-2013; Basser, Peter/H-5477-2011 OI Ozarslan, Evren/0000-0003-0859-1311; FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH); Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM); Henry M. Jackson Foundation (HJF) FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). Support for this work included funding from Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) and the Henry M. Jackson Foundation (HJF). NR 31 TC 8 Z9 8 U1 0 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0749-1581 J9 MAGN RESON CHEM JI Magn. Reson. Chem. PD DEC PY 2011 VL 49 SU 1 SI SI BP S79 EP S84 DI 10.1002/mrc.2797 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 884EL UT WOS:000299687600011 PM 22290713 ER PT J AU Izzotti, A Larghero, P Longobardi, M Cartiglia, C Camoirano, A Steele, VE De Flora, S AF Izzotti, Alberto Larghero, Patrizia Longobardi, Mariagrazia Cartiglia, Cristina Camoirano, Anna Steele, Vernon E. De Flora, Silvio TI Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Cigarette smoke; Micro RNAs; DNA adducts; 8-Oxo-7,8-dihydro-2 '-deoxyguanosine; Mouse lung ID GENE-EXPRESSION; N-ACETYLCYSTEINE; DNA-DAMAGE; MICE; LIGHT; CHEMOPREVENTION; TRANSCRIPTOME; RESISTANCE; CANCER; TUMORS AB Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m(3) of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) were measured by P-32 postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used. (C) 2011 Elsevier B.V. All rights reserved. C1 [Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Steele, Vernon E.] NCI, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Genoa, Italy. EM sdf@unige.it OI izzotti, alberto/0000-0002-8588-0347 FU NIH National Cancer Institute [N01-CN-53301] FX This work was supported by the NIH National Cancer Institute (Contract N01-CN-53301). NR 23 TC 45 Z9 47 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD DEC 1 PY 2011 VL 717 IS 1-2 SI SI BP 9 EP 16 DI 10.1016/j.mrfmmm.2010.12.008 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 858FQ UT WOS:000297781700002 PM 21185844 ER PT J AU Izzotti, A Larghero, P Balansky, R Pfeffer, U Steele, VE De Flora, S AF Izzotti, Alberto Larghero, Patrizia Balansky, Roumen Pfeffer, Ulrich Steele, Vernon E. De Flora, Silvio TI Interplay between histopathological alterations, cigarette smoke and chemopreventive agents in defining microRNA profiles in mouse lung SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE MicroRNAs; Cigarette smoke; Chemopreventive agents; Lung carcinogenesis ID GENE-EXPRESSION; NEONATAL MICE; STEM-CELLS; PHENETHYL ISOTHIOCYANATE; REGULATE EXPRESSION; N-ACETYLCYSTEINE; UP-REGULATION; CANCER; MODULATION; GROWTH AB We have investigated alterations of microRNA expression profiles in the apparently healthy lung of mice and rats as an early response to exposure to cigarette smoke, either mainstream (MCS) or environmental, and/or to treatment with chemopreventive agents. Further on, we evaluated microRNA alterations at a later stage, when lung tumors were detectable in MCS-exposed mice. Lung samples were available from previous studies, in which strain H mice had been exposed to MCS for 4 months, starting immediately after birth, and then kept in filtered air for an additional 3 months. Some samples were from MCS-exposed mice treated either with N-acetyl-L-cysteine during pregnancy or with phenethyl isothiocyanate after weaning. The analysis of 576 mouse microRNAs showed that MCS strongly dysregulated microRNA expression and that both chemopreventive agents efficiently attenuated this trend, especially in noncancer tissue. MicroRNA expression was affected by histopathology, with specific signatures related to occurrence of pneumonia, adenoma, or bronchoalveolar carcinoma. Within pairs of samples from individual mice, microRNA analysis discriminated adenomatous tissue and especially carcinomatous tissue from the surrounding normal appearing tissue. A series of microRNA alterations characterized the sequential stages of pulmonary carcinogenesis. The involved functions included oncogene activation, inhibition of oncosuppressor genes, recruitment of undifferentiated stem cells, inflammation, inhibition of gap-junctional intercellular communications, angiogenesis, invasiveness, and metastatization. Thus, microRNA expression profiles in lung are dysregulated by MCS along all steps of the carcinogenesis process and depend on the interplay among exposure to noxious agents, treatment with dietary and pharmacological agents, and occurrence of pulmonary diseases. (C) 2010 Elsevier B.V. All rights reserved. C1 [Izzotti, Alberto; Larghero, Patrizia; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Balansky, Roumen] Natl Oncol Ctr, BU-1157 Sofia, Bulgaria. [Pfeffer, Ulrich] Natl Canc Res Inst IST, Funct Genom Unit, Genoa, Italy. [Steele, Vernon E.] NCI, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Genoa, Italy. EM sdf@unige.it RI Pfeffer, Ulrich/J-7064-2016 OI izzotti, alberto/0000-0002-8588-0347; Pfeffer, Ulrich/0000-0003-0872-4671 FU NIH National Cancer Institute [N01-CN-53301]; Associazione Italiana per la Ricerca sul Cancro (AIRC) [8909] FX The authors thank Ilaria Righi for assistance in bibliographic search and assistance in preparation of the manuscript. This work was supported by the NIH National Cancer Institute (Contract N01-CN-53301) and by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Contract 8909). NR 62 TC 21 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD DEC 1 PY 2011 VL 717 IS 1-2 SI SI BP 17 EP 24 DI 10.1016/j.mrfmmm.2010.10.003 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 858FQ UT WOS:000297781700003 PM 20974155 ER PT J AU Yong, RL Lonser, RR AF Yong, Raymund L. Lonser, Russell R. TI Surgery for Glioblastoma Multiforme: Striking a Balance SO WORLD NEUROSURGERY LA English DT Editorial Material DE Brain neoplasms; Neurosurgery; Quality control ID SUPRATENTORIAL GLIOMAS; RESECTION; SURVIVAL C1 [Yong, Raymund L.; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov FU Intramural NIH HHS [Z01 NS003052-01] NR 17 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 J9 WORLD NEUROSURG JI World Neurosurg. PD DEC PY 2011 VL 76 IS 6 BP 528 EP 530 DI 10.1016/j.wneu.2011.06.053 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 885XL UT WOS:000299814600010 PM 22251498 ER PT J AU Meltzer, PS Helman, LJ AF Meltzer, Paul S. Helman, Lee J. TI Genomic Investigation of Dedifferentiated Liposarcoma Suggests a Role for Therapeutic Targeting of the Tumor Epigenome SO CANCER DISCOVERY LA English DT Editorial Material AB A comprehensive genetic analysis of dedifferentiated liposarcomas suggests that epigenetic modifications are common and may alter the differentiation capacity in these tumors. Furthermore, these data suggest that treatment strategies aimed at altering histone acetylation and/or DNA methylation are worthy of further study. Cancer Discovery; 1(7); 555-6. (C)2011 AACR. C1 [Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Helman, Lee J.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Helman, LJ (reprint author), 10 Ctr DR,MSC 1106,Bldg 10,Room 1W-3750, Bethesda, MD 20892 USA. EM helmanl@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2011 VL 1 IS 7 BP 555 EP 556 DI 10.1158/2159-8290.CD-11-0291 PG 2 WC Oncology SC Oncology GA 880MX UT WOS:000299412300024 PM 22586679 ER PT J AU Juergens, RA Wrangle, J Vendetti, FP Murphy, SC Zhao, M Coleman, B Sebree, R Rodgers, K Hooker, CM Franco, N Lee, B Tsai, S Delgado, IE Rudek, MA Belinsky, SA Herman, JG Baylin, SB Brock, MV Rudin, CM AF Juergens, Rosalyn A. Wrangle, John Vendetti, Frank P. Murphy, Sara C. Zhao, Ming Coleman, Barbara Sebree, Rosa Rodgers, Kristen Hooker, Craig M. Franco, Noreli Lee, Beverly Tsai, Salina Delgado, Igor Espinoza Rudek, Michelle A. Belinsky, Steven A. Herman, James G. Baylin, Stephen B. Brock, Malcolm V. Rudin, Charles M. TI Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non-Small Cell Lung Cancer SO CANCER DISCOVERY LA English DT Article ID HISTONE DEACETYLASE INHIBITION; DNA METHYLATION; SOLID TUMORS; PHASE-I; 5-AZACYTIDINE NSC-102816; PROMOTER HYPERMETHYLATION; CIRCULATING DNA; MALIGNANCIES; AZACITIDINE; PLASMA AB Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy. SIGNIFICANCE: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit. Cancer Discovery; 1(7); 598-607. (C) 2011 AACR. C1 [Juergens, Rosalyn A.; Wrangle, John; Murphy, Sara C.; Zhao, Ming; Coleman, Barbara; Sebree, Rosa; Hooker, Craig M.; Franco, Noreli; Lee, Beverly; Rudek, Michelle A.; Herman, James G.; Baylin, Stephen B.; Rudin, Charles M.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21231 USA. [Rodgers, Kristen; Brock, Malcolm V.] Johns Hopkins Univ, Dept Surg, Baltimore, MD 21231 USA. [Vendetti, Frank P.] Johns Hopkins Univ, Anticanc Drug Dev Grad Training Program, Baltimore, MD 21231 USA. [Tsai, Salina] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21231 USA. [Delgado, Igor Espinoza] NCI, Invest Drug Branch, Bethesda, MD 20892 USA. [Belinsky, Steven A.] Lovelace Resp Res Inst, Albuquerque, NM USA. RP Rudin, CM (reprint author), Johns Hopkins Univ, Dept Oncol, Canc Res Bldg 2,Room 544,1550 Orleans St, Baltimore, MD 21231 USA. EM mbrock1@jhmi.edu; rudin@jhmi.edu FU Cancer Therapy Evaluation Program; National Institutes of Health [R21 CA126265, UO1 CA70095, P50 CA058184, P30 CA006973, S10RR026824, UL1 RR 025005]; Flight Attendant Medical Research Institute; American Association for Cancer Research/Stand Up to Cancer Dream Team Translational Cancer Research [SU2C-AACR-DT0109] FX This study was sponsored through the Cancer Therapy Evaluation Program with grant support from the National Institutes of Health (R21 CA126265, UO1 CA70095, P50 CA058184, P30 CA006973, S10RR026824, and UL1 RR 025005), the Flight Attendant Medical Research Institute, and American Association for Cancer Research/Stand Up to Cancer Dream Team Translational Cancer Research Grant, grant number SU2C-AACR-DT0109. NR 50 TC 212 Z9 219 U1 4 U2 33 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2011 VL 1 IS 7 BP 598 EP 607 DI 10.1158/2159-8290.CD-11-0214 PG 10 WC Oncology SC Oncology GA 880MX UT WOS:000299412300031 PM 22586682 ER PT J AU Kelly, RJ Lopez-Chavez, A Szabo, E AF Kelly, Ronan J. Lopez-Chavez, Ariel Szabo, Eva TI Criteria of Evidence to Move Potential Chemopreventive Agents into Late Phase Clinical Trials SO CURRENT DRUG TARGETS LA English DT Review DE Chemoprevention; clinical trials; cancer ID SPORADIC COLORECTAL ADENOMAS; CANCER PREVENTION TRIAL; BREAST-CANCER; LUNG-CANCER; RANDOMIZED-TRIAL; VITAMIN-E; CYCLOOXYGENASE-2 INHIBITOR; BETA-CAROTENE; IIB TRIAL; RISK AB Preclinical models and data from clinical trials suggest that cancer is a preventable disease. However, demonstration of a preventive effect requires large phase III clinical trials of long duration and involves many thousands of participants. The decision to proceed with phase III studies therefore must be informed by robust efficacy and safety data. This requires a systematic review of all available preclinical, epidemiological, and clinical data, along with a mechanistic understanding of the biology of the disease under study. In this review we identify the issues that are critical to decision-making prior to embarking on late phase prevention clinical trials and provide a framework for making such decisions. C1 [Szabo, Eva] NCI, LUACRG, DCP, Bethesda, MD 20892 USA. [Kelly, Ronan J.; Lopez-Chavez, Ariel] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Szabo, E (reprint author), NCI, LUACRG, DCP, 6130 Execut Blvd,Rm 2132, Bethesda, MD 20892 USA. EM szaboe@mail.nih.gov NR 44 TC 3 Z9 3 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-4501 J9 CURR DRUG TARGETS JI Curr. Drug Targets PD DEC PY 2011 VL 12 IS 13 BP 1983 EP 1988 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 883DD UT WOS:000299612100010 PM 21158704 ER PT J AU Malhotra, SV AF Malhotra, Sanjay V. TI Hot Topic: Trends in Drug Discovery and Development SO CURRENT MOLECULAR MEDICINE LA English DT Editorial Material C1 NCI, Lab Synthet Chem, SAIC Inc, Frederick, MD 21702 USA. RP Malhotra, SV (reprint author), NCI, Lab Synthet Chem, SAIC Inc, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD DEC PY 2011 VL 11 IS 9 BP 708 EP 708 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 883EX UT WOS:000299618000001 PM 22126792 ER PT J AU Garg, H Viard, M Jacobs, A Blumenthal, R AF Garg, Himanshu Viard, Mathias Jacobs, Amy Blumenthal, Robert TI Targeting HIV-1 gp41-induced Fusion and Pathogenesis for Anti-viral Therapy SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE HIV; gp41; fusion; lipophilic; apoptosis; antiviral ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 ENVELOPE GLYCOPROTEIN; PROXIMAL EXTERNAL REGION; MEMBRANE-SPANNING DOMAIN; NUCLEAR-MAGNETIC-RESONANCE; BETA-STRAND CONFORMATION; INFECTED SOOTY MANGABEYS; CHEMOKINE RECEPTOR CXCR4; GP41 CYTOPLASMIC TAIL; HUMAN LYMPHOID-TISSUE AB HIV gp41 is a metastable protein whose native conformation is maintained in the form of a heterodimer with gp120. The non-covalently associated gp41/gp120 complex forms a trimer on the virus surface. As gp120 engages with HIV's receptor, CD4, and coreceptor, CXCR4 or CCR5, gp41 undergoes several conformational changes resulting in fusion between the viral and cellular membranes. Several lipophilic and amphiphilic domains have been shown to be critical in that process. While the obvious function of gp41 in viral entry is well-established its role in cellular membrane fusion and the link with pathogenesis are only now beginning to appear. Recent targeting of gp41 via fusion inhibitors has revealed an important role of this protein not only in viral entry but also in bystander apoptosis and HIV pathogenesis. Studies by our group and others have shown that the phenomenon of gp41-mediated hemifusion initiates apoptosis in bystander cells and correlates with virus pathogenesis. More interestingly, recent clinical evidence suggests that gp41 mutants arising after Enfuvirtide therapy are associated with CD4 cell increase and immunological benefits. This has in turn been correlated to a decrease in bystander apoptosis in our in vitro as well as in vivo assays. Although a great deal of work has been done to unravel HIV-1 gp41-mediated fusion mechanisms, the factors that regulate gp41-mediated fusion versus hemifusion and the mechanism by which hemifusion initiates bystander apoptosis are not fully understood. Further insight into these issues will open new avenues for drug development making gp41 a critical anti-HIV target both for neutralization and virus attenuation. C1 [Garg, Himanshu] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Ctr Excellence Infect Dis, El Paso, TX 79905 USA. [Garg, Himanshu] Texas Tech Univ, Hlth Sci Ctr, Dept Pediat, El Paso, TX 79905 USA. [Viard, Mathias; Blumenthal, Robert] Natl Canc Inst Frederick, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. [Viard, Mathias] NCI Frederick, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. [Jacobs, Amy] SUNY Buffalo, Sch Med & Biomed Sci, Dept Microbiol & Immunol, Buffalo, NY 14260 USA. RP Blumenthal, R (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Ctr Excellence Infect Dis, El Paso, TX 79905 USA. EM blumenthalr@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 155 TC 12 Z9 13 U1 1 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD DEC PY 2011 VL 11 IS 24 BP 2947 EP 2958 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 883NY UT WOS:000299642200002 PM 22044225 ER PT J AU Paez, A Farber, S Wheeler, D AF Paez, Antonio Farber, Steven Wheeler, David TI A simulation-based study of geographically weighted regression as a method for investigating spatially varying relationships SO ENVIRONMENT AND PLANNING A LA English DT Article DE GWR; correlation; locally linear estimation; simulation; goodness of fit; inference ID COEFFICIENT MODELS; GWR; NONSTATIONARITY; TESTS AB Large variability and correlations among the coefficients obtained from the method of geographically weighted regression (GWR) have been identified in previous research. This is an issue that poses a serious challenge for the utility of the method as a tool to investigate multivariate relationships. The objectives of this paper are to assess: (1) the ability of GWR to discriminate between a spatially constant processes and one with spatially varying relationships; and (2) to accurately retrieve spatially varying relationships. Extensive numerical experiments are used to investigate situations where the underlying process is stationary and nonstationary, and to assess the degree to which spurious intercoefficient correlations are introduced. Two different implementations of GWR and cross-validation approaches are assessed. Results suggest that judicious application of GWR can be used to discern whether the underlying process is nonstationary. Furthermore, evidence of spurious correlations indicates that caution must be exercised when drawing conclusions regarding spatial relationships retrieved using this approach, particularly when working with small samples. C1 [Paez, Antonio] McMaster Univ, Ctr Spatial Anal, Sch Geog & Earth Sci, Hamilton, ON L8S 4K1, Canada. [Farber, Steven] Univ Utah, Dept Geog, Salt Lake City, UT 84112 USA. [Wheeler, David] Virginia Commonwealth Univ, Dept Biostat, Sch Med, Richmond, VA USA. [Wheeler, David] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Paez, A (reprint author), McMaster Univ, Ctr Spatial Anal, Sch Geog & Earth Sci, Hamilton, ON L8S 4K1, Canada. EM paezha@mcmaster.ca; steven.farber@geog.utah.edu; dcwheels@gmail.com RI Paez, Antonio/A-1894-2008; Farber, Steven/L-9356-2013 OI Paez, Antonio/0000-0001-6912-9919; Farber, Steven/0000-0002-3870-5984 NR 31 TC 50 Z9 52 U1 1 U2 31 PU PION LTD PI LONDON PA 207 BRONDESBURY PARK, LONDON NW2 5JN, ENGLAND SN 0308-518X J9 ENVIRON PLANN A JI Environ. Plan. A PD DEC PY 2011 VL 43 IS 12 BP 2992 EP 3010 DI 10.1068/a44111 PG 19 WC Environmental Studies; Geography SC Environmental Sciences & Ecology; Geography GA 880YV UT WOS:000299447400018 ER PT J AU Wright, JT Li, Y Suggs, C Kuehl, MA Kulkarni, AB Gibson, CW AF Wright, J. Tim Li, Yong Suggs, Cynthia Kuehl, Melissa A. Kulkarni, Ashok B. Gibson, Carolyn W. TI The role of amelogenin during enamel-crystallite growth and organization in vivo SO EUROPEAN JOURNAL OF ORAL SCIENCES LA English DT Article; Proceedings Paper CT 8th International Symposium on Development, Properties and Pathology of Tooth Enamel CY JUN 12-18, 2011 CL N Utica, IL DE amelogenesis imperfecta; amelogenin; crystallite; transgenic mice ID IMPERFECTA PHENOTYPE; MICE DISPLAY; EXPRESSION; DEFECTS; DIFFERENTIATION; AMELOBLASTIN; PROTEINS; MUTATION; SHAPE AB Amelogenin is critical for enamel formation, and human amelogenin gene (AMELX) mutations cause hypoplastic and/or hypomaturation enamel phenotypes. The Amelx null (AKO) mouse has a severe hypoplastic phenotype. This study evaluated the effect of amelogenin loss on enamel formation and crystallite morphology. Enamel from AKO and wild-type (WT) mice was used. The AKO mice were mated with transgenic mice expressing the most abundant known amelogenin isoform, TgM180-87, to rescue (KOM180-87) the enamel crystallite phenotype. Molar enamel was embedded, sectioned with a diamond microtome, and images were obtained by transmission electron microscopy. The crystallite sizes from multiple sections were measured using Image J. The mean thicknesses (WT = 26 nm, AKO = 16 nm, and KOM180-87 = 25 nm) and the mean widths (WT = 96 nm, AKO = 59 nm, KOM180-87 = 85 nm) of crystallites were measured. Despite a complete loss of amelogenin in AKO mice, a mineralized enamel layer with well-defined and organized crystallites is formed. In the absence of amelogenin, enamel crystallites were reduced in thickness and width. For the first time we show that introduction of the m180 amelogenin isoform into the AKO mouse through cross-breeding rescues the crystallite phenotype. We conclude that amelogenin is essential for the development of normal crystallite size. C1 [Wright, J. Tim; Suggs, Cynthia] Univ N Carolina, Dept Pediat Dent, Sch Dent, Chapel Hill, NC 27599 USA. [Li, Yong; Kuehl, Melissa A.; Gibson, Carolyn W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Wright, JT (reprint author), Univ N Carolina, Dept Pediat Dent, Sch Dent, CB 7450 Brauer Hall, Chapel Hill, NC 27599 USA. EM tim_wright@dentistry.unc.edu FU NIDCR NIH HHS [DE011089, R01 DE011089, R01 DE011089-11] NR 33 TC 5 Z9 5 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0909-8836 J9 EUR J ORAL SCI JI Eur. J. Oral Sci. PD DEC PY 2011 VL 119 SU 1 SI SI BP 65 EP 69 DI 10.1111/j.1600-0722.2011.00883.x PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 875YB UT WOS:000299070300014 PM 22243229 ER PT J AU Gibson, CW Li, Y Suggs, C Kuehl, MA Pugach, MK Kulkarni, AB Wright, JT AF Gibson, Carolyn W. Li, Yong Suggs, Cynthia Kuehl, Melissa A. Pugach, Megan K. Kulkarni, Ashok B. Wright, John T. TI Rescue of the murine amelogenin null phenotype with two amelogenin transgenes SO EUROPEAN JOURNAL OF ORAL SCIENCES LA English DT Article; Proceedings Paper CT 8th International Symposium on Development, Properties and Pathology of Tooth Enamel CY JUN 12-18, 2011 CL N Utica, IL DE amelogenesis imperfecta; amelogenin; phenotypic rescue; transgenic mice ID DENTAL ENAMEL; EXPRESSION; PEPTIDE; GENE; MICE; MATRIX; IDENTIFICATION; PROTEINASES; TRANSCRIPT; IMPERFECTA AB The amelogenin proteins are required for normal enamel development, and the most abundant amelogenins expressed from alternatively spliced mRNAs are M180 and leucine-rich amelogenin protein (LRAP). The X-Chromosomal Amelogenin (Amelx) null [knockout (KO)] mouse has an enamel defect similar to human X-linked amelogenesis imperfecta. The disorganized enamel layer in KO mice is 10-20% of the thickness of wild-type (WT) enamel and lacks prismatic structures. When the KO mice were mated with mice that express the transgene M180-87, (TgM180-87) partial rescue of the phenotype was observed such that enamel thickness, volume, and density increased. A second transgene was introduced by mating TgM180 KO mice with TgLRAP mice, and male offspring were characterized for genotype and tooth phenotype was evaluated by scanning electron microscopy. The molar enamel thickness of TgM180-LRAP KO mice was further increased, and the structure was improved, with a more defined decussation pattern compared with singly rescued mice. We conclude that TgM180 provides significant rescue of the KO phenotype. Although the effectiveness of the LRAP transgene, alone, to rescue is less obvious, the addition of the LRAP transgene to the M180 transgene in KO enamel leads to an added improvement in both amount and structure and thus these transgenes function in a complementary manner. Together, the two most abundant amelogenins lead to the formation of obvious enamel decussation patterns. C1 [Gibson, Carolyn W.; Li, Yong; Kuehl, Melissa A.; Pugach, Megan K.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Suggs, Cynthia; Wright, John T.] Univ N Carolina, Sch Dent, Dept Pediat Dent, Chapel Hill, NC USA. [Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Gibson, CW (reprint author), Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, 240 S 40th St, Philadelphia, PA 19104 USA. EM cgibson@dental.upenn.edu FU NIDCR NIH HHS [DE011089, R01 DE011089, R01 DE011089-12] NR 26 TC 13 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0909-8836 EI 1600-0722 J9 EUR J ORAL SCI JI Eur. J. Oral Sci. PD DEC PY 2011 VL 119 SU 1 SI SI BP 70 EP + DI 10.1111/j.1600-0722.2011.00882.x PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 875YB UT WOS:000299070300003 PM 22243230 ER PT J AU Lu, XY Ito, Y Kulkarni, A Gibson, C Luan, XH Diekwisch, TGH AF Lu, Xuanyu Ito, Yoshihiro Kulkarni, Ashok Gibson, Carolyn Luan, Xianghong Diekwisch, Thomas G. H. TI Ameloblastin-rich enamel matrix favors short and randomly oriented apatite crystals SO EUROPEAN JOURNAL OF ORAL SCIENCES LA English DT Article; Proceedings Paper CT 8th International Symposium on Development, Properties and Pathology of Tooth Enamel CY JUN 12-18, 2011 CL N Utica, IL DE ameloblastin (AMBN); amelogenin (AMELX); apatite; enamel; evolution ID SECRETORY CALCIUM-BINDING; AMELOGENIN; EVOLUTION; TEETH; TISSUE; GENE; MINERALIZATION; PROTEINS; GROWTH AB Molecular evolution studies suggest that amelogenin (AMELX), the principal component of the mammalian enamel matrix, emerged considerably later than ameloblastin (AMBN), and enamelin. Here, we created a transgenic mouse model to ask the question how a conceivable basal enamel lacking AMELX and enriched in the more basal AMBN might compare with recent mouse enamel. To answer this question we overexpressed AMBN using a keratin 14 (K14) promoter and removed AMELX from the genetic background by crossbreeding with amelx(-/-) mice. Enamel coverings of amelx(-/-) mice and of the squamate Iguana iguana were used for comparison. Scanning electron microscopic analysis documented that AMBN transgenic (TG) x amelx(-/-) mouse molars were covered by a 5 mu m thin 'enameloid' layer resembling the thin enamel of the Iguana squamate. Transmission electron microscopy revealed that the enamel of developing AMBN TG x amelx(-/-) mouse molars contained short (approximately 70 nm) and randomly oriented crystals, while WT controls, AMBN overexpressors, and amelx(-/-) mice all featured elongated and parallel oriented crystals measuring between 300 and 600 nm in average length. Together, these studies illustrate that AMBN promotes the growth of a crystalline enamel layer with short and randomly oriented crystals, but lacks the ability to facilitate the formation of long and parallel oriented apatite crystals. C1 [Lu, Xuanyu; Ito, Yoshihiro; Luan, Xianghong; Diekwisch, Thomas G. H.] Univ Illinois, Brodie Lab Craniofacial Genet, Chicago, IL 60607 USA. [Kulkarni, Ashok] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Gibson, Carolyn] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. RP Diekwisch, TGH (reprint author), Univ Illinois, Brodie Lab Craniofacial Genet, Chicago, IL 60607 USA. EM tomdkw@uic.edu FU NIDCR NIH HHS [DE13378, DE18057, DE18900, R01 DE013378, R01 DE018900, R01 DE019155, R03 DE018057] NR 28 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0909-8836 J9 EUR J ORAL SCI JI Eur. J. Oral Sci. PD DEC PY 2011 VL 119 SU 1 SI SI BP 254 EP 260 DI 10.1111/j.1600-0722.2011.00905.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 875YB UT WOS:000299070300038 PM 22243254 ER PT J AU Vourganti, S Shuch, B Bratslavsky, G AF Vourganti, Srinivas Shuch, Brian Bratslavsky, Gennady TI Surgical management of large renal tumors SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE cytoreductive; high stage; large; nephrectomy; nephron sparing; systemic therapy; T2 ID NEPHRON-SPARING SURGERY; LAPAROSCOPIC PARTIAL NEPHRECTOMY; FACTOR-TARGETED THERAPY; LYMPH-NODE DISSECTION; CANCER-CENTER EXPERIENCE; CHRONIC KIDNEY-DISEASE; CELL-CARCINOMA; CYTOREDUCTIVE NEPHRECTOMY; RADICAL NEPHRECTOMY; PATHOLOGICAL FEATURES AB The surgical management of patients with renal cell carcinoma has undergone many changes. With equivalent oncologic outcomes and appreciation of the importance of renal functional preservation, the utilization of nephron-sparing partial nephrectomy has increased in recent years. Nevertheless, tumors of larger size continue to be preferentially treated with radical nephrectomy. Here, we present evidence that improvements in techniques and durability of oncologic outcomes has justified the use of nephron sparing to accomplish renal functional preservation even in patients with large renal tumors. In addition, surgical technical considerations when managing such tumors are discussed. Finally, we discuss cytoreductive surgery and the evolving role of systemic targeted therapies in the management of advanced metastatic disease. C1 [Vourganti, Srinivas; Shuch, Brian; Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Bratslavsky, Gennady] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. RP Bratslavsky, G (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1107,Bldg 10,CRC,Room 2W-5942, Bethesda, MD 20892 USA. EM bratslag@upstate.edu NR 119 TC 1 Z9 1 U1 0 U2 1 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD DEC PY 2011 VL 11 IS 12 BP 1889 EP 1900 DI 10.1586/ERA.11.129 PG 12 WC Oncology SC Oncology GA 879WR UT WOS:000299364100016 PM 22117156 ER PT J AU Allen, J Levintova, M Mohatt, G AF Allen, James Levintova, Marya Mohatt, Gerald TI Suicide and alcohol-related disorders in the US Arctic: boosting research to address a primary determinant of health disparities SO INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH LA English DT Review DE Arctic; Alaska; Alaska Native; suicide; alcohol; US Arctic research; research infrastructure ID ALASKA NATIVES; SUBSTANCE USE; PREVENTION; ABUSE AB Objectives. To review the existing epidemiological literature on suicide and alcohol-related disorders and their social determinants in the U.S. Arctic, as it relates to U.S. government research and evaluation efforts, and to offer recommendations to boost research capacity in the U.S. Arctic and collaborations across the circumpolar Arctic as part of global health initiatives. Study design. Synthetic literature review. Methods. Published literature; federal and state reports on suicide and alcohol-related disorders; and federal databases on research and program evaluation in the U.S Arctic were reviewed, with a focus on epidemiological trends over the past 50 years. Results. Suicide and alcohol-related disorders play a significant role in health disparities in the U.S. Arctic, with evidence of a disturbing prevalence trend over the past 50 years. Important variations exist in suicide rates across different regions of Alaska with different majority populations of Alaska Native cultural groups - and, in selected key instances, within these regions - with immense implications for guiding effective prevention efforts. Consequences of alcohol abuse are severe and particularly significant in their impact upon Alaska Native people. Health-related conditions associated with alcohol abuse are among the leading causes of mortality. Conclusions. Recommendations to boost research capacity in behavioural health in the U.S. Arctic are offered, specifically on strategies and methods of inquiry and analysis; distinctions between populations and communities in rural circumpolar contexts; and future epidemiological and implementation research. (Int J Circumpolar Health 2011; 70(5):473-487) C1 [Allen, James; Mohatt, Gerald] Univ Alaska, Dept Psychol, Fairbanks, AK 99775 USA. [Allen, James; Mohatt, Gerald] Univ Alaska, Ctr Alaska Native Hlth Res, Fairbanks, AK 99775 USA. [Levintova, Marya] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Allen, J (reprint author), Univ Alaska, Dept Psychol, Fairbanks, AK 99775 USA. EM jrallen@alaska.edu RI Allen, James/B-1349-2013 OI Allen, James/0000-0002-5567-6302 FU National Center for Minority Health Disparities [R24 MD001626]; National Institute of Neurological Disease and Stroke [01 NS0406904-04, U01NS048069-04S1, U01NS048069-04S2]; National Science Foundation [ARC-0756211]; National Center for Research Resources [P20RR061430] FX This article is dedicated to Gerald V. Mohatt, who started work on this paper, but passed away during the early preparation of the manuscript. For the past 30 years, Jerry was a champion of Arctic research, the health of people living in the Arctic, and the rights of Indigenous people. Jerry served as founding director of the Center for Alaska Native Health Research. His contribution to circumpolar research has been immense, and he will be missed by all of us whose lives he touched. Work on this manuscript was supported in part by National Center for Minority Health Disparities (R24 MD001626), National Institute of Neurological Disease and Stroke (01 NS0406904-04 Revised, U01NS048069-04S1; U01NS048069-04S2), National Science Foundation (ARC-0756211) and National Center for Research Resources (P20RR061430) awards to the first author. NR 41 TC 20 Z9 21 U1 1 U2 4 PU INT ASSOC CIRCUMPOLAR HEALTH PUBL PI OULU PA AAPISTIE1, OULU, FIN-90220, FINLAND SN 1239-9736 J9 INT J CIRCUMPOL HEAL JI Int. J. Circumpolar Health PD DEC PY 2011 VL 70 IS 5 BP 473 EP 487 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 879UD UT WOS:000299356800007 PM 22067096 ER PT J AU Shabason, JE Tofilon, PJ Camphausen, K AF Shabason, Jacob E. Tofilon, Philip J. Camphausen, Kevin TI Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE glioblastoma multiforme; GBM; histone deacetylase inhibitor; HDAC inhibitor; valproic acid; VPA; radiosensitization; radiosensitizer ID HISTONE DEACETYLASE INHIBITORS; SUBEROYLANILIDE HYDROXAMIC ACID; PHASE-II TRIAL; INCREASING THERAPEUTIC GAIN; CELL LUNG-CANCER; VALPROIC ACID; GLIOBLASTOMA-MULTIFORME; GAMMA-H2AX FOCI; ADJUVANT TEMOZOLOMIDE; EPIGENETIC THERAPY AB Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumour. Patients afflicted with this disease unfortunately have a very poor prognosis, and fewer than 5% of patients survive for 5 years from the time of diagnosis. Therefore, improved therapies to treat this disease are sorely needed. One such class of drugs that have generated great enthusiasm for the treatment of numerous malignancies, including GBM, is histone deacetylase (HDAC) inhibitors. Pre-clinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging pre-clinical data, numerous HDAC inhibitors are under investigation in clinical trials, either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy or radiation therapy. In fact, two actively studied HDAC inhibitors, vorinostat and depsipeptide, were recently approved for the treatment of refractory cutaneous T cell lymphoma. In this review, we first present a patient with GBM, and then discuss the pathogenesis, epidemiology and current treatment options of GBM. Finally, we examine the translation of pre-clinical studies that have demonstrated HDAC inhibitors as potent radiosensitizers in in vitro and in vivo models, to a phase II clinical trial combining the HDAC inhibitor, valproic acid, along with temozolomide and radiation therapy for the treatment of GBM. C1 [Shabason, Jacob E.; Tofilon, Philip J.; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Shabason, Jacob E.] Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD 20817 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, NIH, 10 Ctr Dr 3B42, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 65 TC 36 Z9 36 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD DEC PY 2011 VL 15 IS 12 BP 2735 EP 2744 DI 10.1111/j.1582-4934.2011.01296.x PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 859DS UT WOS:000297855700019 PM 21362133 ER PT J AU Drake, RR Boggs, SR Drake, SK AF Drake, Richard R. Boggs, Sarah R. Drake, Steven K. TI Pathogen identification using mass spectrometry in the clinical microbiology laboratory SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE MALDI-TOF; Biotyper; PCR-ESI; bacteria; sepsis ID DESORPTION IONIZATION-TIME; RESISTANT STAPHYLOCOCCUS-AUREUS; ASSISTED-LASER-DESORPTION/IONIZATION; BLOOD CULTURE BOTTLES; ROUTINE IDENTIFICATION; RAPID IDENTIFICATION; SPECIES IDENTIFICATION; NONFERMENTING BACTERIA; YEAST; PCR AB The recent application of Matrix-assisted Laser Desorption/Ionization Time-of-Flight and Polymerase Chain Reaction Electrospray Ionization Quadrupole Time-of-Flight mass spectrometry approaches to microbial identification has initiated a revolution in the clinical microbiology lab. The commercial application of these technologies to pathogen identification has only begun in the last five years, and already new potentially life-saving applications of these technologies are rapidly identifying organisms that in the past have proven notoriously difficult to identify. In this review, we will provide a brief historical perspective on how these developments arose, describe why they are being successfully applied now and provide an overview of current approaches. Using examples involving clinical isolates of Staphylococcus aureus, a perspective on future use and developments of mass spectrometry in the identification of microbial organisms is provided. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Drake, Richard R.] Med Univ S Carolina, Dept Cell & Mol Pharmacol, MUSC Prote Ctr, Charleston, SC 29425 USA. [Drake, Richard R.; Boggs, Sarah R.] Eastern Virginia Med Sch, Dept Pediat, Norfolk, VA 23507 USA. [Boggs, Sarah R.] Childrens Hosp Kings Daughters, Dept Pediat, Norfolk, VA 23507 USA. [Drake, Steven K.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Drake, RR (reprint author), Med Univ S Carolina, Dept Cell & Mol Pharmacol, MUSC Prote Ctr, 173 Ashley Ave, Charleston, SC 29425 USA. EM draker@musc.edu NR 59 TC 11 Z9 11 U1 1 U2 18 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD DEC PY 2011 VL 46 IS 12 BP 1223 EP 1232 DI 10.1002/jms.2008 PG 10 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 869MA UT WOS:000298601000004 PM 22223412 ER PT J AU Reiter, DA Roque, RA Lin, PC Doty, SB Pleshko, N Spencer, RG AF Reiter, David A. Roque, Remigio A. Lin, Ping-Chang Doty, Stephen B. Pleshko, Nancy Spencer, Richard G. TI Improved specificity of cartilage matrix evaluation using multiexponential transverse relaxation analysis applied to pathomimetically degraded cartilage SO NMR IN BIOMEDICINE LA English DT Article DE cartilage MRI; transverse relaxation; multiexponential T2; proteoglycan; cartilage degradation ID FIXED CHARGE-DENSITY; ARTICULAR-CARTILAGE; MAGNETIC-RESONANCE; T-2 RELAXATION; SPATIAL VARIATION; NMR RELAXATION; SOLID-STATE; MRI; COLLAGEN; TISSUE AB The noninvasive early detection of specific matrix alterations in degenerative cartilage disease would be of substantial use in basic science studies and clinically, but remains an elusive goal. Recently developed MRI methods exhibit some specificity, but require contrast agents or nonstandard pulse sequences and hardware. We present a multiexponential approach which does not require contrast agents or specialized hardware, and uses a standard multiple-echo spin-echo sequence. Experiments were performed on tissue models of degenerative cartilage using enzymes with distinct actions. MR results were validated using histologic, biochemical and infrared spectroscopic analyses. The sulfated glycosaminoglycan per dry weight (dw) in bovine nasal cartilage was 0.72 +/- 0.06 mg/mg dw and was reduced through chondroitinase AC and collagenase digestion to 0.56 +/- 0.12 and 0.58 +/- 0.13 mg/mg dw, respectively. Multiexponential analysis of data obtained at 9.4 T permitted the identification of tissue compartments assigned to the proteoglycan component of the matrix and to bulk water. Enzymatic treatment resulted in a significant reduction in the ratio of proteoglycan-bound to free water from 0.13 +/- 0.02 in control cartilage to 0.03 +/- 0.02 and 0.05 +/- 0.06 under chondroitinase AC and collagenase treatment, respectively. As expected, monoexponential T2 increased with both degradation protocols, but without further specificity to the nature of the degradation. An important eventual extension of this approach may be to map articular cartilage degeneration in the clinical setting. As an initial step towards this, localized multiexponential T2 analysis was performed on control and trypsin treated excised bovine patella. The results obtained on this articular cartilage sample were readily interpretable in terms of proteoglycan-associated and relatively free water compartments. In potential clinical applications, signal-to-noise ratio constraints will define the threshold for the detection of macromolecular compartment changes at a given spatial scale. The multiexponential approach has potential application to the early detection of cartilage degradation with the use of appropriate pulse parameters under high signal-to-noise ratio conditions. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Reiter, David A.; Roque, Remigio A.; Lin, Ping-Chang; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spectroscopy Sect, NIH, Baltimore, MD 21224 USA. [Doty, Stephen B.] Hosp Special Surg, Div Res, Microscopy Core Facil, New York, NY 10021 USA. [Pleshko, Nancy] Temple Univ, Dept Mech Engn, Philadelphia, PA 19122 USA. RP Reiter, DA (reprint author), NIA, Magnet Resonance Imaging & Spectroscopy Sect, NIH, GRC 4D-08, Baltimore, MD 21224 USA. EM reiterda@mail.nih.gov OI Lin, Ping-Chang/0000-0003-0918-4072 FU National Institutes on Health (NIH), National Institute on Aging; NIH [R01 EB000744, AR046121] FX This work was supported in part by the Intramural Research Program of the National Institutes on Health (NIH), National Institute on Aging, and by NIH R01 EB000744 (NP). We acknowledge Mila Spevak and Orla O'Shea of the Hospital for Special Surgery for assistance with the collection of histologic and FT-IRIS data through the HSS Musculoskeletal Repair and Regeneration Core Facility funded by NIH AR046121. NR 48 TC 17 Z9 17 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD DEC PY 2011 VL 24 IS 10 BP 1286 EP 1294 DI 10.1002/nbm.1690 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 871NT UT WOS:000298745600013 PM 21465593 ER PT J AU de Wit, E Bushmaker, T Scott, D Feldmann, H Munster, VJ AF de Wit, Emmie Bushmaker, Trenton Scott, Dana Feldmann, Heinz Munster, Vincent J. TI Nipah Virus Transmission in a Hamster Model SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TO-PERSON TRANSMISSION; NOSOCOMIAL TRANSMISSIBILITY; VERTICAL TRANSMISSION; FLYING-FOXES; INFECTION; BANGLADESH; PARAMYXOVIRUS; OUTBREAK; ENCEPHALITIS; MALAYSIA AB Based on epidemiological data, it is believed that human-to-human transmission plays an important role in Nipah virus outbreaks. No experimental data are currently available on the potential routes of human-to-human transmission of Nipah virus. In a first dose-finding experiment in Syrian hamsters, it was shown that Nipah virus was predominantly shed via the respiratory tract within nasal and oropharyngeal secretions. Although Nipah viral RNA was detected in urogenital and rectal swabs, no infectious virus was recovered from these samples, suggesting no viable virus was shed via these routes. In addition, hamsters inoculated with high doses shed significantly higher amounts of viable Nipah virus particles in comparison with hamsters infected with lower inoculum doses. Using the highest inoculum dose, three potential routes of Nipah virus transmission were investigated in the hamster model: transmission via fomites, transmission via direct contact and transmission via aerosols. It was demonstrated that Nipah virus is transmitted efficiently via direct contact and inefficiently via fomites, but not via aerosols. These findings are in line with epidemiological data which suggest that direct contact with nasal and oropharyngeal secretions of Nipah virus infected individuals resulted in greater risk of Nipah virus infection. The data provide new and much-needed insights into the modes and efficiency of Nipah virus transmission and have important public health implications with regards to the risk assessment and management of future Nipah virus outbreaks. C1 [de Wit, Emmie; Bushmaker, Trenton; Feldmann, Heinz; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Scott, Dana] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP de Wit, E (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. EM emmie.dewit@nih.gov OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 17 Z9 17 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2011 VL 5 IS 12 AR e1432 DI 10.1371/journal.pntd.0001432 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 870KI UT WOS:000298667700035 PM 22180802 ER PT J AU Giorgobiani, E Chitadze, N Chanturya, G Grdzelidze, M Jochim, RC Machablishvili, A Tushishvili, T Zedginidze, Y Manjgaladze, MK Iashvili, N Makharadze, MP Zakaraya, T Kikaleishvili, K Markhvashvili, I Badashvili, G Daraselia, T Fay, MP Kamhawi, S Sacks, D AF Giorgobiani, Ekaterina Chitadze, Nazibrola Chanturya, Gvantsa Grdzelidze, Marina Jochim, Ryan C. Machablishvili, Anna Tushishvili, Tsiuri Zedginidze, Yulia Manjgaladze, Marina K. Iashvili, Nino Makharadze, Manana P. Zakaraya, Tsiuri Kikaleishvili, Konstantin Markhvashvili, Ivan Badashvili, Goderdzi Daraselia, Teymuraz Fay, Michael P. Kamhawi, Shaden Sacks, David TI Epidemiologic Aspects of an Emerging Focus of Visceral Leishmaniasis in Tbilisi, Georgia SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DIRECT AGGLUTINATION-TEST; ASYMPTOMATIC HUMAN CARRIERS; POLYMERASE-CHAIN-REACTION; FREEZE-DRIED ANTIGEN; CANINE LEISHMANIASIS; ENTOMOLOGICAL SURVEY; DONOVANI INFECTION; SEQUENCE ALIGNMENT; SUBCLINICAL FORM; KINETOPLAST DNA AB Background: Over the last 15 years, visceral leishmaniasis (VL) has emerged as a public health concern in Tbilisi, the capital of Georgia. Methodology/Principal Findings: Seroepidemiological surveys were conducted to determine the prevalence and incidence of infection in children and dogs within the main focus of VL, and to identify risk factors associated with human infection. Of 4,250 children investigated, 7.3% were positive by direct agglutination test in a baseline survey; an apparent incidence rate of 6.0% was estimated by one year follow-up. None of the seropositive children progressed to VL during the survey. Increased seropositivity at one year was predicted by presence at baseline of clustered flying insects (OR = 1.49; P = 0.001), perceived satisfactory sanitation (OR = 1.65; P<0.001), stray dogs (OR = 1.33; P = 0.023), and by persistent fever during the 6 months prior to baseline survey (OR = 14.2; P<0.001). Overall, 18.2% (107/588) of domestic and 15.3% (110/718) of stray dogs were seropositive by the rk39 dipstick test. Clinical VL signs were found in 1.3% of domestic and 2.9% of stray, seropositive dogs. Parasites isolated from human and dog samples were identified by PCR and phylogenetic analysis of the Leishmania 70 kDa heat-shock protein (HSP70) gene as Leishmania infantum. Conclusions/Significance: There is an active focus of L. infantum transmission in Tbilisi with a high prevalence of human and canine infections. C1 [Giorgobiani, Ekaterina; Chitadze, Nazibrola; Chanturya, Gvantsa; Grdzelidze, Marina; Machablishvili, Anna; Tushishvili, Tsiuri; Zedginidze, Yulia; Kikaleishvili, Konstantin; Markhvashvili, Ivan; Daraselia, Teymuraz] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Jochim, Ryan C.; Kamhawi, Shaden] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Grdzelidze, Marina; Jochim, Ryan C.; Machablishvili, Anna; Tushishvili, Tsiuri; Badashvili, Goderdzi] Res Inst Med Parasitol & Trop Med, Tbilisi, Rep of Georgia. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Giorgobiani, E (reprint author), Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. EM egiorgobiani@yahoo.com RI Jochim, Ryan/C-6756-2013; OI Fay, Michael P./0000-0002-8643-9625 FU US Department of Health and Human Services (DHHS) through the International Science and Technology Center [ISTC G-1081/BTEP N89] FX This study was supported by the US Department of Health and Human Services (DHHS) Biotechnology Engagement Program through the International Science and Technology Center (grant ISTC G-1081/BTEP N89). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 5 Z9 5 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2011 VL 5 IS 12 AR e1415 DI 10.1371/journal.pntd.0001415 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 870KI UT WOS:000298667700021 PM 22180796 ER PT J AU Lakdawala, SS Lamirande, EW Suguitan, AL Wang, WJ Santos, CP Vogel, L Matsuoka, Y Lindsley, WG Jin, H Subbarao, K AF Lakdawala, Seema S. Lamirande, Elaine W. Suguitan, Amorsolo L., Jr. Wang, Weijia Santos, Celia P. Vogel, Leatrice Matsuoka, Yumiko Lindsley, William G. Jin, Hong Subbarao, Kanta TI Eurasian-Origin Gene Segments Contribute to the Transmissibility, Aerosol Release, and Morphology of the 2009 Pandemic H1N1 Influenza Virus SO PLOS PATHOGENS LA English DT Article ID GUINEA-PIG MODEL; SINGLE AMINO-ACID; A VIRUS; RECEPTOR-BINDING; SWINE INFLUENZA; FERRET MODEL; M2 PROTEIN; HEMAGGLUTININ; HUMANS; MICE AB The epidemiological success of pandemic and epidemic influenza A viruses relies on the ability to transmit efficiently from person-to-person via respiratory droplets. Respiratory droplet (RD) transmission of influenza viruses requires efficient replication and release of infectious influenza particles into the air. The 2009 pandemic H1N1 (pH1N1) virus originated by reassortment of a North American triple reassortant swine (TRS) virus with a Eurasian swine virus that contributed the neuraminidase (NA) and M gene segments. Both the TRS and Eurasian swine viruses caused sporadic infections in humans, but failed to spread from person-to-person, unlike the pH1N1 virus. We evaluated the pH1N1 and its precursor viruses in a ferret model to determine the contribution of different viral gene segments on the release of influenza virus particles into the air and on the transmissibility of the pH1N1 virus. We found that the Eurasian-origin gene segments contributed to efficient RD transmission of the pH1N1 virus likely by modulating the release of influenza viral RNA-containing particles into the air. All viruses replicated well in the upper respiratory tract of infected ferrets, suggesting that factors other than viral replication are important for the release of influenza virus particles and transmission. Our studies demonstrate that the release of influenza viral RNA-containing particles into the air correlates with increased NA activity. Additionally, the pleomorphic phenotype of the pH1N1 virus is dependent upon the Eurasian-origin gene segments, suggesting a link between transmission and virus morphology. We have demonstrated that the viruses are released into exhaled air to varying degrees and a constellation of genes influences the transmissibility of the pH1N1 virus. C1 [Lakdawala, Seema S.; Lamirande, Elaine W.; Santos, Celia P.; Vogel, Leatrice; Matsuoka, Yumiko; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Suguitan, Amorsolo L., Jr.; Wang, Weijia; Jin, Hong] MedImmune, Mountain View, CA USA. [Lindsley, William G.] NIOSH, Morgantown, WV USA. RP Lakdawala, SS (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM kanta.subbarao@nih.gov OI Lindsley, William/0000-0003-0720-5829 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (NIAID). This research was performed as part of a Cooperative Research and Development Agreement between the Laboratory of Infectious Diseases, NIAID and MedImmune. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 76 Z9 78 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2011 VL 7 IS 12 AR e1002443 DI 10.1371/journal.ppat.1002443 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 876LH UT WOS:000299108500052 PM 22241979 ER PT J AU Laliberte, JP Weisberg, AS Moss, B AF Laliberte, Jason P. Weisberg, Andrea S. Moss, Bernard TI The Membrane Fusion Step of Vaccinia Virus Entry Is Cooperatively Mediated by Multiple Viral Proteins and Host Cell Components SO PLOS PATHOGENS LA English DT Article ID INTRACELLULAR MATURE VIRION; RESPIRATORY SYNCYTIAL VIRUS; SURFACE HEPARAN-SULFATE; POXVIRUS L1 PROTEIN; 2 INFECTIOUS FORMS; INFLUENZA HEMAGGLUTININ; MONOCLONAL-ANTIBODIES; ENTRY/FUSION COMPLEX; PROMOTES HEMIFUSION; TYROSINE KINASE AB For many viruses, one or two proteins allow cell attachment and entry, which occurs through the plasma membrane or following endocytosis at low pH. In contrast, vaccinia virus (VACV) enters cells by both neutral and low pH routes; four proteins mediate cell attachment and twelve that are associated in a membrane complex and conserved in all poxviruses are dedicated to entry. The aim of the present study was to determine the roles of cellular and viral proteins in initial stages of entry, specifically fusion of the membranes of the mature virion and cell. For analysis of the role of cellular components, we used well characterized inhibitors and measured binding of a recombinant VACV virion containing Gaussia luciferase fused to a core protein; viral and cellular membrane lipid mixing with a self-quenching fluorescent probe in the virion membrane; and core entry with a recombinant VACV expressing firefly luciferase and electron microscopy. We determined that inhibitors of tyrosine protein kinases, dynamin GTPase and actin dynamics had little effect on binding of virions to cells but impaired membrane fusion, whereas partial cholesterol depletion and inhibitors of endosomal acidification and membrane blebbing had a severe effect at the later stage of core entry. To determine the role of viral proteins, virions lacking individual membrane components were purified from cells infected with members of a panel of ten conditional-lethal inducible mutants. Each of the entry protein-deficient virions had severely reduced infectivity and except for A28, L1 and L5 greatly impaired membrane fusion. In addition, a potent neutralizing L1 monoclonal antibody blocked entry at a post-membrane lipid-mixing step. Taken together, these results suggested a 2-step entry model and implicated an unprecedented number of viral proteins and cellular components involved in signaling and actin rearrangement for initiation of virus-cell membrane fusion during poxvirus entry. C1 [Laliberte, Jason P.; Weisberg, Andrea S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Laliberte, JP (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX The work has been supported by the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 31 Z9 32 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2011 VL 7 IS 12 AR e1002446 DI 10.1371/journal.ppat.1002446 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 876LH UT WOS:000299108500054 PM 22194690 ER PT J AU Ruckwardt, TJ Malloy, AMW Gostick, E Price, DA Dash, P McClaren, JL Thomas, PG Graham, BS AF Ruckwardt, Tracy J. Malloy, Allison M. W. Gostick, Emma Price, David A. Dash, Pradyot McClaren, Jennifer L. Thomas, Paul G. Graham, Barney S. TI Neonatal CD8 T-cell Hierarchy Is Distinct from Adults and Is Influenced by Intrinsic T cell Properties in Respiratory Syncytial Virus Infected Mice SO PLOS PATHOGENS LA English DT Article ID RECEPTOR-BETA-CHAINS; EARLY-LIFE; JUNCTIONAL SEQUENCES; IMMUNE-RESPONSE; MOUSE MODEL; N-REGIONS; EPITOPE; REINFECTION; DIVERSITY; VACCINES AB Following respiratory syncytial virus infection of adult CB6F1 hybrid mice, a predictable CD8+ T cell epitope hierarchy is established with a strongly dominant response to a K(d)-restricted peptide (SYIGSINNI) from the M2 protein. The response to K(d)M2(82-90) is similar to 5-fold higher than the response to a subdominant epitope from the M protein (NAITNAKII, D(b)M(187-195)). After infection of neonatal mice, a distinctly different epitope hierarchy emerges with codominant responses to K(d)M2(82-90) and D(b)M(187-195). Adoptive transfer of naive CD8+ T cells from adults into congenic neonates prior to infection indicates that intrinsic CD8+ T cell factors contribute to age-related differences in hierarchy. Epitope-specific precursor frequency differs between adults and neonates and influences, but does not predict the hierarchy following infection. Additionally, dominance of K(d)M2(82-90) -specific cells does not correlate with TdT activity. Epitope-specific V beta repertoire usage is more restricted and functional avidity is lower in neonatal mice. The neonatal pattern of codominance changes after infection at 10 days of age, and rapidly shifts to the adult pattern of extreme K(d)M2(82-90) -dominance. Thus, the functional properties of T cells are selectively modified by developmental factors in an epitope-specific and age-dependent manner. C1 [Ruckwardt, Tracy J.; Malloy, Allison M. W.; Price, David A.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff, S Glam, Wales. [Dash, Pradyot; McClaren, Jennifer L.; Thomas, Paul G.] St Jude Childrens Hosp, Memphis, TN 38105 USA. RP Ruckwardt, TJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov RI Price, David/C-7876-2013; OI Thomas, Paul G./0000-0001-7955-0256; Price, David/0000-0001-9416-2737; Dash, Pradyot/0000-0001-5467-0657 FU National Institute of Allergy and Infectious Diseases FX This work was supported by intramural funding from the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 37 Z9 37 U1 2 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2011 VL 7 IS 12 AR e1002377 DI 10.1371/journal.ppat.1002377 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 876LH UT WOS:000299108500008 PM 22144888 ER PT J AU Safronetz, D Zivcec, M LaCasse, R Feldmann, F Rosenke, R Long, D Haddock, E Brining, D Gardner, D Feldmann, H Ebihara, H AF Safronetz, David Zivcec, Marko LaCasse, Rachel Feldmann, Friederike Rosenke, Rebecca Long, Dan Haddock, Elaine Brining, Douglas Gardner, Donald Feldmann, Heinz Ebihara, Hideki TI Pathogenesis and Host Response in Syrian Hamsters following Intranasal Infection with Andes Virus SO PLOS PATHOGENS LA English DT Article ID HANTAVIRUS PULMONARY SYNDROME; REGULATORY T-CELLS; SIN-NOMBRE-VIRUS; VIRAL HEMORRHAGIC-FEVER; NEW-WORLD HANTAVIRUSES; INTERFERON RESPONSES; PERSON TRANSMISSION; GOLDEN-HAMSTER; RENAL SYNDROME; NITRIC-OXIDE AB Hantavirus pulmonary syndrome (HPS), also referred to as hantavirus cardiopulmonary syndrome (HCPS), is a rare but frequently fatal disease caused by New World hantaviruses. In humans HPS is associated with severe pulmonary edema and cardiogenic shock; however, the pathogenesis of this disease remains unclear largely due to a lack of suitable animal models for the study of disease progression. In this study we monitored clinical, virological, pathophysiological parameters and host immunological responses to decipher pathological factors and events in the lethal Syrian hamster model of HPS following intranasal inoculation of Andes virus. Transcriptional profiling of the host gene responses demonstrated a suppression of innate immune responses in most organs analyzed during the early stage of infection, except for in the lung which had low level activation of several pro-inflammatory genes. During this phase Andes virus established a systemic infection in hamsters, with viral antigen readily detectable in the endothelium of the majority of tissues analyzed by 7-8 days post-inoculation. Despite wide-spread infection, histological analysis confirmed pathological abnormalities were almost exclusively found in the lungs. Immediately preceding clinical signs of disease, intense activation of pro-inflammatory and Th1/Th2 responses were observed in the lungs as well as the heart, but not in peripheral organs, suggesting that localized immune-modulations by infection is paramount to pathogenesis. Throughout the course of infection a strong suppression of regulatory T-cell responses was noted and is hypothesized to be the basis of the aberrant immune activations. The unique and comprehensive monitoring of host immune responses to hantavirus infection increases our understanding of the immuno-pathogenesis of HPS and will facilitate the development of treatment strategies targeting deleterious host immunological responses. C1 [Safronetz, David; Zivcec, Marko; Haddock, Elaine; Feldmann, Heinz; Ebihara, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Zivcec, Marko; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada. [LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Brining, Douglas; Gardner, Donald] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Feldmann, Friederike] NIAID, Off Operat & Management, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Safronetz, D (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM feldmannh@niaid.nih.gov; ebiharah@niaid.nih.gov OI Zivcec, Marko/0000-0003-4337-8487 FU National Institutes of Health FX This work was funded by the Intramural Research Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 27 Z9 27 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2011 VL 7 IS 12 AR e1002426 DI 10.1371/journal.ppat.1002426 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 876LH UT WOS:000299108500038 PM 22194683 ER PT J AU Schaller, T Ocwieja, KE Rasaiyaah, J Price, AJ Brady, TL Roth, SL Hue, S Fletcher, AJ Lee, K KewalRamani, VN Noursadeghi, M Jenner, RG James, LC Bushman, FD Towers, GJ AF Schaller, Torsten Ocwieja, Karen E. Rasaiyaah, Jane Price, Amanda J. Brady, Troy L. Roth, Shoshannah L. Hue, Stephane Fletcher, Adam J. Lee, KyeongEun KewalRamani, Vineet N. Noursadeghi, Mahdad Jenner, Richard G. James, Leo C. Bushman, Frederic D. Towers, Greg J. TI HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PREINTEGRATION COMPLEX; NUCLEOPORIN NUP153; NONDIVIDING CELLS; DNA INTEGRATION; PORE COMPLEX; PROTEIN; INFECTION; BINDING; MACROPHAGES AB Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment. C1 [Schaller, Torsten; Rasaiyaah, Jane; Hue, Stephane; Fletcher, Adam J.; Noursadeghi, Mahdad; Jenner, Richard G.; Towers, Greg J.] UCL, Med Res Council, Ctr Med Mol Virol, Div Infect & Immun, London, England. [Ocwieja, Karen E.; Brady, Troy L.; Roth, Shoshannah L.; Bushman, Frederic D.] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Price, Amanda J.; James, Leo C.] MRC, Mol Biol Lab, Prot & Nucle Acid Chem Div, Cambridge, England. [Lee, KyeongEun; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Schaller, T (reprint author), Kings Coll London, Guys Hosp, KCL Dept Infect Dis, London WC2R 2LS, England. EM g.towers@ucl.ac.uk RI Jenner, Richard/J-8683-2012; Towers, Greg/H-8892-2012; OI Hue, Stephane/0000-0002-8580-6905; Bushman, Frederic/0000-0003-4740-4056; Towers, Gregory/0000-0002-7707-0264; Schaller, Torsten/0000-0001-9597-4112 FU Wellcome Trust [WT090940]; National Institute of Health Research UCL/UCLH Comprehensive Biomedical Research Centre; Medical Research Council; NIH [AI52845, AI082020]; University of Pennsylvania Center for AIDS Research; Penn Genome Frontiers Institute via the Pennsylvania Department of Health FX This work was funded by Wellcome Trust fellowship (WT090940) to GJT and grants from the National Institute of Health Research UCL/UCLH Comprehensive Biomedical Research Centre and the Medical Research Council (GJT) and NIH grants AI52845 and AI082020, the University of Pennsylvania Center for AIDS Research, and the Penn Genome Frontiers Institute via a grant with the Pennsylvania Department of Health (FDB). The United States Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 161 Z9 161 U1 3 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2011 VL 7 IS 12 AR e1002439 DI 10.1371/journal.ppat.1002439 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 876LH UT WOS:000299108500049 PM 22174692 ER PT J AU Cmarik, JL Troxler, JA Hanson, CA Zhang, X Ruscetti, SK AF Cmarik, Joan L. Troxler, Jami A. Hanson, Charlotte A. Zhang, Xiang Ruscetti, Sandra K. TI The Human Lung Adenocarcinoma Cell Line EKVX Produces an Infectious Xenotropic Murine Leukemia Virus SO VIRUSES-BASEL LA English DT Article DE EKVX; NCI-60; human cell line; xenotropic murine leukemia virus; gammaretrovirus ID HUMAN-MALIGNANT-MELANOMA; LONG TERMINAL REPEAT; NUDE-MICE; HUMAN-TUMOR; BREAST CARCINOMA; LEUKEMOGENIC ACTIVITY; RETROVIRUS XMRV; GENE-EXPRESSION; C RETROVIRUSES; OVARIAN-CANCER AB The cell lines of the NCI-60 panel represent different cancer types and have been widely utilized for drug screening and molecular target identification. Screening these cell lines for envelope proteins or gene sequences related to xenotropic murine leukemia viruses (X-MLVs) revealed that one cell line, EKVX, was a candidate for production of an infectious gammaretrovirus. The presence of a retrovirus infectious to human cells was confirmed by the cell-free transmission of infection to the human prostate cancer cell line LNCaP. Amplification and sequencing of additional proviral sequences from EKVX confirmed a high degree of similarity to X-MLV. The cell line EKVX was established following passage of the original tumor cells through nude mice, providing a possible source of the X-MLV found in the EKVX cells. C1 [Cmarik, Joan L.; Troxler, Jami A.; Hanson, Charlotte A.; Zhang, Xiang; Ruscetti, Sandra K.] NCI, Lab Canc Prevent, Frederick, MD 21702 USA. RP Cmarik, JL (reprint author), NCI, Lab Canc Prevent, Frederick, MD 21702 USA. EM cmarikj@mail.nih.gov; ruscetts@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Frank Ruscetti, Kathryn Jones, Ying Huang, John Coffin, and Michael Alley for helpful discussions. We appreciate the materials provided by the tumor repository of the NCI Developmental Therapeutics Program, Frank Ruscetti, and Michael Lerman, and are grateful for the technical assistance provided by Cari Sadowski and Dan Bertolette. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 97 TC 4 Z9 4 U1 0 U2 2 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2011 VL 3 IS 12 BP 2442 EP 2461 DI 10.3390/v3122442 PG 20 WC Virology SC Virology GA 882CF UT WOS:000299538200005 PM 22355448 ER PT J AU Chen, G Cho, SJ Huang, XP Jensen, NH Svennebring, A Sassano, MF Roth, BL Kozikowski, AP AF Chen, Gang Cho, Sung Jin Huang, Xi-Ping Jensen, Niels H. Svennebring, Andreas Sassano, Maria F. Roth, Bryan L. Kozikowski, Alan P. TI Rational Drug Design Leading to the Identification of a Potent 5-HT2C Agonist Lacking 5-HT2B Activity SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Serotonin; 5-HT2c receptor; 5-HT2B receptor; agonist; hydrophobic interactions ID RECEPTOR AGONISTS; SEROTONIN RECEPTORS; HALLUCINOGENS; DISORDER; BIOLOGY AB The 5-HT2C receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT2C receptor agonists. After expanding our structure-function library, we were able to combine our data sets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT2B/5-HT2C agonists, which has led to the identification of a highly selective 5-HT2C agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC50 of 55 nM and no detectable agonism at the 5-HT2B receptor. C1 [Chen, Gang; Cho, Sung Jin; Svennebring, Andreas; Kozikowski, Alan P.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Drug Discovery Program, Chicago, IL 60612 USA. [Huang, Xi-Ping; Jensen, Niels H.; Sassano, Maria F.; Roth, Bryan L.] Univ N Carolina, Sch Med, Ctr Comprehens Canc,Drug Screening Program, Dept Pharmacol,Ctr Neurobiol,Div NIMH Psychoact, Chapel Hill, NC 27599 USA. RP Kozikowski, AP (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Drug Discovery Program, M-C781,833 S Wood St, Chicago, IL 60612 USA. EM kozikowa@uic.edu RI sassano, maria/G-4941-2013; Chen, Gang/B-6320-2014; Roth, Bryan/F-3928-2010 FU NIH [R01 DA022317, R01 MH61887, N01 MH80032, U19 MH82441] FX This work was supported by NIH Grants R01 DA022317 (A.P.K.) and R01 MH61887, N01 MH80032, and U19 MH82441 (B.L.R.). NR 24 TC 11 Z9 11 U1 0 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD DEC PY 2011 VL 2 IS 12 BP 929 EP 932 DI 10.1021/ml200206z PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 860KK UT WOS:000297947000011 PM 22778800 ER PT J AU Kim, MK Yang, ST Lee, KH Um, JH Liu, MY Kang, H Park, SJ Chung, JH AF Kim, Myung K. Yang, Shutong Lee, Kyoung-Hwa Um, Jee-Hyun Liu, Mengyang Kang, Hyeog Park, Sung Jun Chung, Jay H. TI Promyelocytic leukemia inhibits adipogenesis, and loss of promyelocytic leukemia results in fat accumulation in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE adipogenesis ID ACTIVATED PROTEIN-KINASE; 3T3-L1 PREADIPOCYTE DIFFERENTIATION; MITOTIC CLONAL EXPANSION; DIET-INDUCED OBESITY; ADIPOCYTE DIFFERENTIATION; ADIPOSE-TISSUE; INSULIN SENSITIVITY; ENERGY-EXPENDITURE; PPAR-GAMMA; TRANSCRIPTIONAL REPRESSION AB Kim MK, Yang S, Lee K, Um J, Liu M, Kang H, Park SJ, Chung JH. Promyelocytic leukemia inhibits adipogenesis, and loss of promyelocytic leukemia results in fat accumulation in mice. Am J Physiol Endocrinol Metab 301: E1130-E1142, 2011. First published August 16, 2011; doi: 10.1152/ajpendo.00092.2011.-The function of the tumor suppressor promyelocytic leukemia (PML) protein is disrupted in promyelocytic leukemia. PML has been reported to function as a negative regulator of mTOR (mammalian target of rapamycin) and nuclear Akt under some conditions. mTOR and Akt pathways regulate a diverse array of pathways, including those that control insulin signaling, energy metabolism, growth, cellular survival, and lifespan. Although the PML-mTOR/Akt link suggests that PML may have metabolic functions in the whole organism, very little is known about the metabolic functions of PML. Here we report that PML(-/-) mice did not show any significant metabolic defects. There was no impairment in the mTOR/Akt or AMPK signaling in white adipose tissue, liver, or muscle. However, despite having normal food intake and activity levels, PML(-/-) mice gained body weight faster and had more fat mass, particularly subcutaneous fat mass, in the diet-induced obesity model. Using in vitro adipogenesis models, we discovered that PML is a suppressor of adipogenesis. PML expression decreased during adipogenesis and was undetectable in fully differentiated adipocytes. Loss of PML increased expression of the adipogenic transcription factors CCAAT/enhancer binding protein-alpha and peroxisome proliferator-activated receptor-gamma. We found that the Sirt1-NCor-SMRT corepressor complex, which represses pparg transcription, does not bind to the pparg promoter efficiently upon PML depletion. On the basis of these findings, we propose that PML is a negative regulator of the adipogenic transcription factors and that, in times of energy excess, PML may limit fat accumulation by suppressing the differentiation of preadipocytes into adipocytes. C1 [Kim, Myung K.; Yang, Shutong; Lee, Kyoung-Hwa; Um, Jee-Hyun; Liu, Mengyang; Kang, Hyeog; Park, Sung Jun; Chung, Jay H.] NHLBI, Lab Obes & Aging Res, NIH, Bethesda, MD 20892 USA. [Lee, Kyoung-Hwa] Seoul Natl Univ, Ischem Hypox Dis Inst, Med Res Ctr, Seoul, South Korea. [Liu, Mengyang] Duke Univ, Trinity Sch Arts & Sci, Durham, NC USA. RP Kim, MK (reprint author), NHLBI, Lab Obes & Aging Res, NIH, Bldg 10,Rm 7D18,10 Ctr Dr, Bethesda, MD 20892 USA. EM KimMK@mail.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 80 TC 9 Z9 9 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD DEC PY 2011 VL 301 IS 6 BP E1130 EP E1142 DI 10.1152/ajpendo.00092.2011 PG 13 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 863CT UT WOS:000298141100010 PM 21846906 ER EF