FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Jonas, MM Balistreri, WF Gonzalez-Peralta, RP Haber, B Mohan, P Molleston, JP Murray, KF Narkewicz, M Rosenthal, P Schwarz, KB Smith, LJ Barton, B Shepherd, JA Robuck, PR Duggan, C AF Jonas, Maureen M. Balistreri, William F. Gonzalez-Peralta, Regino P. Haber, Barbara Mohan, Parvathi Molleston, Jean P. Murray, Karen F. Narkewicz, Michael Rosenthal, Philip Schwarz, Kathleen B. Smith, Lesley J. Barton, Bruce Shepherd, John A. Robuck, Patricia R. Duggan, Christopher TI CHANGES IN BODY MASS INDEX AND BODY COMPOSITION IN CHILDREN TREATED WITH PEGINTERFERON FOR CHRONIC HEPATITIS C IN THE PEDS-C TRIAL SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Jonas, Maureen M.; Duggan, Christopher] Childrens Hosp, Boston, MA 02115 USA. [Balistreri, William F.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Gonzalez-Peralta, Regino P.] Univ Florida, Gainesville, FL USA. [Haber, Barbara] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Mohan, Parvathi] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Molleston, Jean P.] Indiana Univ, Indianapolis, IN 46204 USA. [Murray, Karen F.] Seattle Childrens Hosp, Seattle, WA USA. [Narkewicz, Michael] Univ Colorado, Denver, CO 80202 USA. [Rosenthal, Philip; Shepherd, John A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schwarz, Kathleen B.] Johns Hopkins Univ, Baltimore, MD USA. [Smith, Lesley J.] Univ Miami, Miami, FL USA. [Barton, Bruce] Maryland Med Res Inst, Baltimore, MD USA. [Robuck, Patricia R.] NIDDK, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 708 BP 636A EP 637A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000707 ER PT J AU Ananthanarayanan, M Li, YF Walsh, M Surapureddi, S Goldstein, J Suchy, FJ AF Ananthanarayanan, Meena Li, Yanfeng Walsh, Martin Surapureddi, Sailesh Goldstein, Joyce Suchy, Frederick J. TI IDENTIFICATION OF NUCLEAR RECEPTOR COACTIVATOR 6 (NCOA6/ASC-2) AND MIXED MYELOID LINEAGE LEUKEMIA 3 (MLL3), A HISTONE H3K4 METHYL TRANSFERASE, AS PARTNERS OF THE ASCOM COMPLEX IN FXR TRANSACTIVATION OF BSEP PROMOTER SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Ananthanarayanan, Meena; Li, Yanfeng; Walsh, Martin; Suchy, Frederick J.] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. [Surapureddi, Sailesh; Goldstein, Joyce] NIEHS, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 763 BP 662A EP 662A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000762 ER PT J AU Katsounas, A Frank, AC Yang, J Lempicki, RA Neumann, AU Polis, MA Kottilil, S AF Katsounas, Antonios Frank, Astrid C. Yang, Jun Lempicki, Richard A. Neumann, Avidan U. Polis, Michael A. Kottilil, Shyam TI DIFFERENTIAL SPECIFICITY OF INNATE HOST GENE EXPRESSION ON INTERFERON-MEDIATED ANTIVIRAL EFFECT ON HCV AND HIV SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Katsounas, Antonios; Yang, Jun; Lempicki, Richard A.] NCI, SAIC, Frederick, MD 21701 USA. [Frank, Astrid C.; Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Neumann, Avidan U.] Bar Ilan Univ, Ramat Dan, Israel. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 797 BP 678A EP 678A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000796 ER PT J AU Lempicki, RA Yang, J Masur, H Polis, MA Kottilil, S AF Lempicki, Richard A. Yang, Jun Masur, Henry Polis, Michael A. Kottilil, Shyam TI EXHAUSTION OF TYPE-I INTERFERON SIGNALING PATHWAY AS A MAJOR MECHANISM FOR LACK OF RESPONSE TO PEG-INTERFERON AND RIBAVIRIN THERAPY IN HIV/HCV CO-INFECTED SUBJECTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Lempicki, Richard A.; Yang, Jun] SAIC Frederick, Frederick, MD USA. [Masur, Henry] NIH, CCMD, CC, Bethesda, MD 20892 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 804 BP 681A EP 681A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000803 ER PT J AU Wang, HH Schlaak, JF Masur, H Polis, MA Suffredini, AF Kottilil, S AF Wang, Honghui Schlaak, Joerg F. Masur, Henry Polis, Michael A. Suffredini, Anthony F. Kottilil, Shyam TI APPLIED PROTEOMICS IN HCV CO-INFECTION: DIFFERENTIAL EXPRESSION OF SERUM PROTEINS PRIOR TO TREATMENT IS ASSOCIATED WITH RESPONSE TO HCV THERAPY IN HIV CO-INFECTED INDIVIDUALS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Wang, Honghui; Masur, Henry; Suffredini, Anthony F.] NIH, CCMD, CC, Bethesda, MD 20892 USA. [Schlaak, Joerg F.] Univ Essen Gesamthsch, Essen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 809 BP 683A EP 683A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000808 ER PT J AU Lempicki, RA Schlaak, JF Masur, H Polis, MA Kottilil, S AF Lempicki, Richard A. Schlaak, Joerg F. Masur, Henry Polis, Michael A. Kottilil, Shyam TI GENOME-WIDE SINGLE NUCLEOTIDE POLYMORPHISM ANALYSIS IDENTIFIES A UNIQUE CCL-5 HALPLOTYPE IN HIV/HCV CO-INFECTED NON-RESPONDERS TO PEGYLATED-INTERFERON (PEG-IFN) AND RIBAVIRIN (RBV) THERAPY SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Masur, Henry] NIH, CCMD, CC, Bethesda, MD 20892 USA. [Lempicki, Richard A.] SAIC Frederick, Frederick, MD USA. [Schlaak, Joerg F.] Univ Essen Gesamthsch, Essen, Germany. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 824 BP 690A EP 690A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000823 ER PT J AU Noureddin, M Rotman, Y Feld, J Koh, C Abdalla, A Thomas, E Park, Y Heller, T Ghany, MG Hoofnagle, JH Liang, TJ AF Noureddin, Mazen Rotman, Yaron Feld, Jordan Koh, Christopher Abdalla, Adil Thomas, Emmanuel Park, Yoon Heller, Theo Ghany, Marc G. Hoofnagle, Jay H. Liang, T. Jake TI THE EFFECTS OF RIBAVIRIN ON SERUM HCV LEVELS BEFORE AND DURING COMBINATION TREATMENT WITH PEGINTERFERON SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Noureddin, Mazen; Rotman, Yaron; Feld, Jordan; Koh, Christopher; Abdalla, Adil; Thomas, Emmanuel; Park, Yoon; Heller, Theo; Ghany, Marc G.; Hoofnagle, Jay H.; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 835 BP 695A EP 695A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000834 ER PT J AU Murphy, A Daucher, M Subramanian, M Polis, MA Kottilil, S AF Murphy, Alison Daucher, Marybeth Subramanian, Mani Polis, Michael A. Kottilil, Shyam TI COMPARATIVE ANALYSIS OF IN VIVO ANTIVIRAL EFFECTS AND INDUCTION OF INTERFERON-INDUCIBLE GENES BY PEGYLATED-INTERFERON AND ALBINTERFERON ALFA-2B IN HIV/HCV CO-INFECTED SUBJECTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Murphy, Alison; Daucher, Marybeth; Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Subramanian, Mani] Human Genome Sci, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 846 BP 701A EP 701A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000845 ER PT J AU Burbelo, P Kovacs, JA Schlaak, JF Masur, H Polis, MA Kottilil, S AF Burbelo, Peter Kovacs, Joseph A. Schlaak, Joerg F. Masur, Henry Polis, Michael A. Kottilil, Shyam TI PROTEOME-WIDE ANTI-HCV AND ANTI-HIV ANTIBODY PROFILING USING A NOVEL HIGH THROUGHPUT LUCIFERASE IMMUNOPRECIPITATION SYSTEM FOR PREDICTING AND MONITORING RESPONSE TO HCV TREATMENT IN HIV CO-INFECTED PATIENTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Burbelo, Peter] NIDCR, NIH, DHHS, Bethesda, MD USA. [Schlaak, Joerg F.] Univ Essen Gesamthsch, Essen, Germany. [Kovacs, Joseph A.; Masur, Henry] NIH, CCMD, CC, Bethesda, MD 20892 USA. RI Burbelo, Peter/B-1027-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 864 BP 710A EP 710A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000863 ER PT J AU Herrmann, E Subramanian, M Polis, MA Kottilil, S AF Herrmann, Eva Subramanian, Mani Polis, Michael A. Kottilil, Shyam TI COMPARATIVE SAFETY TOLERABILITY, VIRAL AND PHARMACODYNAMIC EFFICACY OF PEGYLATED-INTERFERONS AND ALBINTERFERON ALFA-2B IN HIV/HCV GENOTYPE-1 INFECTED PATIENTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Herrmann, Eva] Goethe Univ Frankfurt, Dept Med, Inst Biostat, Frankfurt, Germany. [Subramanian, Mani] Human Genome Sci Inc, Rockville, MD USA. [Polis, Michael A.] NIAID, LIR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 870 BP 714A EP 714A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000869 ER PT J AU Murphy, A Polis, MA Neumann, AU Kottilil, S AF Murphy, Alison Polis, Michael A. Neumann, Avidan U. Kottilil, Shyam TI TWICE WEEKLY PEG IFN-ALPHA-2A WITH RIBAVIRIN IMPROVES EARLY VIRAL KINETICS OVER STANDARD THERAPY AMONG HIV/HCV CO-INFECTED AFRICAN AMERICAN PATIENTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Murphy, Alison; Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Neumann, Avidan U.] Bar Ilan Univ, Ramat Dan, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 905 BP 731A EP 731A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000904 ER PT J AU Heller, T Rotman, Y Haynes-Williams, V Kleiner, DE Ghany, MG Liang, TJ Hoofnagle, JH AF Heller, Theo Rotman, Yaron Haynes-Williams, Vanessa Kleiner, David E. Ghany, Marc G. Liang, T. Jake Hoofnagle, Jay H. TI LONG-TERM, HIGH-DOSE PEGINTERFERON ALFA-2A IS AN EFFECTIVE TREATMENT FOR CHRONIC HEPATITIS D SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Heller, Theo; Rotman, Yaron; Haynes-Williams, Vanessa; Ghany, Marc G.; Liang, T. Jake; Hoofnagle, Jay H.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 911 BP 734A EP 734A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000910 ER PT J AU Aouizerat, BE Bambha, K Unalp-Arida, A Ferrell, L Bass, NM AF Aouizerat, Bradley E. Bambha, Kiran Unalp-Arida, Aynur Ferrell, Linda Bass, Nathan M. TI GENETIC VARIATION IN HORMONE SENSITIVE LIPASE AND ADIPONECTIN CONFERS SUSCEPTIBILITY TO NONALCOHOLIC FATTY LIVER DISEASE SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Aouizerat, Bradley E.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Bambha, Kiran; Bass, Nathan M.] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Unalp-Arida, Aynur] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Ferrell, Linda] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA. [Aouizerat, Bradley E.; Bambha, Kiran; Unalp-Arida, Aynur; Ferrell, Linda; Bass, Nathan M.] NIDDK, NASH Clin Res Network, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 987 BP 768A EP 768A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000985 ER PT J AU Bambha, K Aouizerat, BE Unalp-Arida, A Ferrell, L Bass, NM AF Bambha, Kiran Aouizerat, Bradley E. Unalp-Arida, Aynur Ferrell, Linda Bass, Nathan M. TI GENETIC VARIATION IN ADIPONECTIN CONFERS SUSCEPTIBILITY TO NONALCOHOLIC FATTY LIVER DISEASE IN LATINO CAUCASIANS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Bambha, Kiran; Bass, Nathan M.] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Aouizerat, Bradley E.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Unalp-Arida, Aynur] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Ferrell, Linda] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA. [Bambha, Kiran; Aouizerat, Bradley E.; Unalp-Arida, Aynur; Ferrell, Linda; Bass, Nathan M.] NIDDK, NASH Clin Res Network, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 995 BP 771A EP 772A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000992 ER PT J AU Kleiner, DE Berk, PD Hsu, JY Belle, SH Courcoulas, AP Pomp, A Roerig, JL Smith, MD Wolfe, BM AF Kleiner, David E. Berk, Paul D. Hsu, Jesse Y. Belle, Steven H. Courcoulas, Anita P. Pomp, Alfons Roerig, James L. Smith, Mark D. Wolfe, Bruce M. TI SPECTRUM OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN BARIATRIC SURGERY PATIENTS WITH NORMAL ALANINE AMINOTRANSFERASE (ALT) SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Berk, Paul D.] Columbia Univ, New York, NY USA. [Hsu, Jesse Y.; Belle, Steven H.; Courcoulas, Anita P.] Univ Pittsburgh, Pittsburgh, PA USA. [Pomp, Alfons] Cornell Univ, New York, NY 10021 USA. [Roerig, James L.] Univ N Dakota, Fargo, ND USA. [Smith, Mark D.] Oregon Weight Loss Surg, Portland, OR USA. [Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 994 BP 771A EP 771A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456000991 ER PT J AU Katsounas, A Trippler, M Wang, B Lempicki, RA Bein, S Gerken, G Schlaak, JF AF Katsounas, Antonios Trippler, Martin Wang, Bo Lempicki, Richard A. Bein, Sabine Gerken, Guido Schlaak, Joerg F. TI CCL5 EXPRESSION IS A MARKER FOR THE STAGE OF LIVER FIBROSIS IN CHRONIC HEPATITIS C AND IS REGULATED BY THE INNATE IMMUNE SYSTEM SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Katsounas, Antonios; Trippler, Martin; Wang, Bo; Bein, Sabine; Gerken, Guido; Schlaak, Joerg F.] Univ Hosp Essen, Dept Gastroenterol & Hepatol, Essen, Germany. [Katsounas, Antonios; Lempicki, Richard A.] NIAID, Lab Bioinformat & Immunopathogenesis, SAIC Frederick Inc, Frederick, MD USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1087 BP 813A EP 813A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001084 ER PT J AU Modi, AA Feld, JJ Park, Y Kleiner, DE Everhart, JE Liang, JT Hoofnagle, JH AF Modi, Apurva A. Feld, Jordan J. Park, Yoon Kleiner, David E. Everhart, James E. Liang, Jake T. Hoofnagle, Jay H. TI REDUCED LIVER FIBROSIS: COFFEE OR CAFFEINE? SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Modi, Apurva A.; Park, Yoon; Liang, Jake T.; Hoofnagle, Jay H.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Feld, Jordan J.] Univ Toronto, Div Gastroenterol, Toronto, ON, Canada. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Everhart, James E.] NIDDK, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1097 BP 817A EP 817A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001094 ER PT J AU Marquardt, JU Raggi, C Andersen, JB Seo, D Avital, I Holczbauer, A Factor, VM Thorgeirsson, SS AF Marquardt, Jens U. Raggi, Chiara Andersen, Jesper B. Seo, Deakwan Avital, Itzhak Holczbauer, Agnes Factor, Valentina M. Thorgeirsson, Snorri S. TI GENE EXPRESSION SIGNATURE OF PUTATIVE CANCER STEM CELLS PREDICTS SURVIVAL OF HCC PATIENTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Marquardt, Jens U.; Raggi, Chiara; Andersen, Jesper B.; Seo, Deakwan; Holczbauer, Agnes; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, LEC, NIH, Bethesda, MD 20892 USA. [Avital, Itzhak] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1182 BP 854A EP 855A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001179 ER PT J AU Zeissig, S Murata, K Hu, ZY Kaser, A Dougan, SK Scapa, E Cohen, DE Liang, JT Blumberg, RS AF Zeissig, Sebastian Murata, Kazumoto Hu, Zongyi Kaser, Arthur Dougan, Stephanie K. Scapa, Erez Cohen, David E. Liang, Jake T. Blumberg, Richard S. TI MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN REGULATES CD1D-RESTRICTED ANTIGEN PRESENTATION OF HEPATOCYTES AND CONTROLS NKT CELL HOMEOSTASIS VIA CD1D-MEDIATED APOPTOSIS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Zeissig, Sebastian; Dougan, Stephanie K.; Scapa, Erez; Cohen, David E.; Blumberg, Richard S.] Dept Med, Div Gastroenterol, Boston, MA USA. [Kaser, Arthur] Innsbruck Med Univ, Div Gastroenterol, Innsbruck, Austria. [Murata, Kazumoto; Hu, Zongyi; Liang, Jake T.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. RI Zeissig, Sebastian/B-6297-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1202 BP 863A EP 864A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001199 ER PT J AU Wang, H Park, O Lafdil, F Shen, KZ Horiguchi, N Yin, S Fu, XY Kunos, G Gao, B AF Wang, Hua Park, Ogyi Lafdil, Fouad Shen, Kezhen Horiguchi, Norio Yin, Shi Fu, Xin-Yuan Kunos, George Gao, Bin TI INTERPLAY OF HEPATIC AND MYELOID STAT3 IN FACILITATING LIVER REGENERATION VIA TEMPERING INNATE IMMUNITY SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Wang, Hua; Park, Ogyi; Lafdil, Fouad; Shen, Kezhen; Horiguchi, Norio; Yin, Shi; Kunos, George; Gao, Bin] NIAAA, NIH, Bethesda, MD 46202 USA. [Fu, Xin-Yuan] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1220 BP 871A EP 871A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001217 ER PT J AU Horiguchi, N Lafdil, F Park, O Wang, H Mukhopadhyay, P Pacher, P Gao, B AF Horiguchi, Norio Lafdil, Fouad Park, Ogyi Wang, Hua Mukhopadhyay, Partha Pacher, Pal Gao, Bin TI DISSOCIATION OF LIVER INFLAMMATION AND NECROSIS INDUCED BY HEPATOTOXIN CARBON TETRACHLORIDE IN MYELOID CELL-SPECIFIC STAT3 KNOCKOUT MICE SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Horiguchi, Norio; Lafdil, Fouad; Park, Ogyi; Wang, Hua; Mukhopadhyay, Partha; Pacher, Pal; Gao, Bin] NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1244 BP 881A EP 881A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001241 ER PT J AU Lafdil, F Wang, H Park, O Zhang, WC Moritoki, Y Yin, S Gershwin, ME Lian, ZX Gao, B AF Lafdil, Fouad Wang, Hua Park, Ogyi Zhang, Weici Moritoki, Yuki Yin, Shi Gershwin, M. Eric Lian, Zhe-Xiong Gao, Bin TI MYELOID STAT3 DEFICIENCY EXACERBATES T CELL HEPATITIS VIA PROMOTING PREFERENTIALLY TH1 RESPONSE AND TH17 TO A LESSER EXTENT SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Lafdil, Fouad; Wang, Hua; Park, Ogyi; Yin, Shi; Gao, Bin] NIAAA, Sect Liver Biol, NIH, Rockville, MD 20852 USA. [Zhang, Weici; Moritoki, Yuki; Gershwin, M. Eric; Lian, Zhe-Xiong] Univ Calif Davis, Div Rheumatol, Davis, CA 95616 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1252 BP 884A EP 885A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001249 ER PT J AU Katsounas, A Rasimas, JJ Lempicki, RA Yang, J Kottilil, S AF Katsounas, Antonios Rasimas, Joseph J. Lempicki, Richard A. Yang, Jun Kottilil, Shyam TI PSYCHIATRIC SIDE EFFECTS TO INTERFERON-alpha/RIBAVIRIN ARE ASSOCIATED WITH DISTINCT ISG20 AND FNBP-1 EXPRESSION PROFILES IN THERAPEUTIC RESPONDERS (SVR) AND NON-RESPONDERS (NR) IN HIV AND HCV CO-INFECTION SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Katsounas, Antonios; Lempicki, Richard A.; Yang, Jun] NCI Frederick, SAIC, Bethesda, MD USA. [Rasimas, Joseph J.] NIMH, NIH, Bethesda, MD 20892 USA. [Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1329 BP 917A EP 918A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001326 ER PT J AU Kottilil, S Zhang, XZ Yang, J Lempicki, RA Sneller, M AF Kottilil, Shyam Zhang, Xiaozhen Yang, Jun Lempicki, Richard A. Sneller, Michael TI WHOLE GENOME TRANSCRIPTIONAL PROFILING IN PBMC ILLUSTRATES UNIQUE PATHOGENIC CHARACTERISTICS OF B CELL DEPLETION THERAPY IN HCV MIXED CRYOGLOBULINEMIC VASCULITIS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Kottilil, Shyam; Zhang, Xiaozhen; Sneller, Michael] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Yang, Jun; Lempicki, Richard A.] SAIC Frederick, Frederick, MD USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1342 BP 923A EP 923A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001339 ER PT J AU Kottilil, S Migone, T Rao, K Subramanian, M Sneller, M AF Kottilil, Shyam Migone, Thi Rao, Koneti Subramanian, Mani Sneller, Michael TI CHANGES IN PLASMA BLYS LEVELS IN PATIENTS WITH HCV MIXED CRYOGLOBULINEMIC VASCULITIS DURING TREATMENT WITH RITUXIMAB SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Kottilil, Shyam; Sneller, Michael] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Rao, Koneti] NIAID, LCID, NIH, Bethesda, MD 20892 USA. [Migone, Thi; Subramanian, Mani] Human Genome Sci, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1345 BP 924A EP 925A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001342 ER PT J AU Derbala, MF Shebl, FM Rashid, AH Amer, AM Bener, A AF Derbala, Moutaz F. Shebl, Fatma M. Rashid, Awad H. Amer, Aliaa M. Bener, Abdulbari TI MICROALBUMINURIA IN HEPATITIS C GENOTYPE 4: RELATION TO LIVER HISTOLOGY, VIRAL LOAD, AND EFFECT OF TREATMENT SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Shebl, Fatma M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Rashid, Awad H.] Hamad Med Corp, Dept Nephrol, Doha, Qatar. [Amer, Aliaa M.] Hamad Med Corp, Dept Lab Med & Histopathol, Hematol Sect, Doha, Qatar. [Bener, Abdulbari] Hamad Med Corp, Dept Med Stat & Epidemiol, Doha, Qatar. [Derbala, Moutaz F.] Hamad Med Corp, Dept Gastroenterol & Hepatol, Doha, Qatar. [Derbala, Moutaz F.] Weill Cornell Med Coll Qatar, Doha, Qatar. [Shebl, Fatma M.] Natioal Liver Inst, Dept Epidemiol, Menoufia, Egypt. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1352 BP 927A EP 927A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001348 ER PT J AU Katsounas, A Lempicki, RA Schlaak, JF Gerken, G Polis, MA Kottilil, S AF Katsounas, Antonios Lempicki, Richard A. Schlaak, Joerg F. Gerken, Guido Polis, Michael A. Kottilil, Shyam TI HIGH ISG-15 EXPRESSION 15 CORRELATED WITH NON-RESPONSE (NR) IN HIV/HCV CO-INFECTED SUBJECTS TREATED WITH PEG-INTERFERON AND RIBAVIRIN SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Katsounas, Antonios; Lempicki, Richard A.] SAIC, NCI Frederick, Bethesda, MD USA. [Polis, Michael A.] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Katsounas, Antonios; Schlaak, Joerg F.; Gerken, Guido; Kottilil, Shyam] Univ Essen Gesamthsch, Dept Gastroenterol & Hepatol, Essen, Germany. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1377 BP 938A EP 939A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001373 ER PT J AU Natarajan, V Hazen, A Polis, MA Kovacs, JA Kottilil, S AF Natarajan, Ven Hazen, Allison Polis, Michael A. Kovacs, Joseph A. Kottilil, Shyam TI HCV IN PERIPHERAL BLOOD MONONUCLEAR CELLS ARE PREDOMINANTLY CARRIED ON THE SURFACE OF NATURAL KILLER CELLS IN HIV/HCV CO-INFECTED INDIVIDUALS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Polis, Michael A.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Natarajan, Ven; Hazen, Allison] SAIC Frederick, Mol Cell Biol Lab, Frederick, MD USA. [Kovacs, Joseph A.] NIH, CCMD, CC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1384 BP 941A EP 942A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001380 ER PT J AU Lempicki, RA Schlaak, JF Murphy, A Kottilil, S AF Lempicki, Richard A. Schlaak, Joerg F. Murphy, Alison Kottilil, Shyam TI GENOME-WIDE SINGLE NUCLEOTIDE POILYMORPHISM ANALYSIS IDENTIFIES A UNIQUE INTEGRIN BETA 5 (ITGB5) HAPLOTYPE IN ADVANCED LIVER FIBROSIS PATIENTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Murphy, Alison; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Lempicki, Richard A.] SAIC Frederick, Frederick, MD USA. [Schlaak, Joerg F.] Univ Essen Hosp, Essen, Germany. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1385 BP 942A EP 942A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001381 ER PT J AU Zhang, XZ Daucher, M Kottilil, S AF Zhang, Xiaozhen Daucher, Marybeth Kottilil, Shyam TI HIV ENHANCES HCV REPLICATION BY ITS INTERACTION WITH MADCAM EXPRESSING HEPATOCELLULAR CARCINOMA CELLS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Zhang, Xiaozhen; Daucher, Marybeth; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1397 BP 947A EP 948A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001393 ER PT J AU Li, QS Brass, AL Ng, A Xavier, R Liang, TJ Elledge, SJ AF Li, Qisheng Brass, Abraham L. Ng, Aylwin Xavier, Ramnik Liang, T. Jake Elledge, Stephen J. TI A GENOME-WIDE GENETIC SCREEN FOR HOST FACTORS REQUIRED FOR HEPATITIS C VIRUS PROPAGATION SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Li, Qisheng; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Brass, Abraham L.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Brass, Abraham L.] Harvard Univ, Sch Med, Boston, MA USA. [Brass, Abraham L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. [Ng, Aylwin; Xavier, Ramnik] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Elledge, Stephen J.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet,Div Genet,Brigham & Womens Hosp, Boston, MA 02115 USA. RI Li, Qisheng/K-1909-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1404 BP 950A EP 951A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001400 ER PT J AU Zhang, XZ Daucher, M Yang, J Lempicki, RA Kottilil, S AF Zhang, Xiaozhen Daucher, Marybeth Yang, Jun Lempicki, Richard A. Kottilil, Shyam TI GENOME WIDE TRANSRIPTIONAL PROFILING OF HEPATOMA CELLS IDENTIFIES GENES SIGNIFICANT FOR HCV ENTRY, PATHOGENESIS AND RESPONSE TO INTERFERON SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Zhang, Xiaozhen; Daucher, Marybeth; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Yang, Jun; Lempicki, Richard A.] SAIC Frederick, Frederick, MD USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1407 BP 951A EP 952A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001403 ER PT J AU Zeremski, M Hooker, G Shu, MA Brown, Q Des Jarlais, DC Tobler, LH Rehermann, B Busch, MP Edlin, BR Talal, A AF Zeremski, Marija Hooker, Giles Shu, Marla A. Brown, Queenie Des Jarlais, Don C. Tobler, Leslie H. Rehermann, Barbara Busch, Michael P. Edlin, Brian R. Talal, Andrew TI INDUCTION OF CXCR3-AND CCR5-ASSOCIATED CHEMOKINES DURING ACUTE HEPATITIS C VIRUS (HCV) INFECTION SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Zeremski, Marija; Brown, Queenie; Talal, Andrew] Weill Cornell Med Coll, Ctr Study Hepatitis C, Med GI, New York, NY USA. [Hooker, Giles] Cornell Univ, Ithaca, NY USA. [Shu, Marla A.; Edlin, Brian R.] SUNY Downstate Coll Med, Brooklyn, NY USA. [Des Jarlais, Don C.] Beth Israel Deaconess Med Ctr, Baron Edmond de Rothschild Chem Dependency Inst, New York, NY 10003 USA. [Tobler, Leslie H.; Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH, Bethesda, MD USA. [Busch, Michael P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 SU S MA 1408 BP 952A EP 952A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001404 ER PT J AU Lagaye, S Nascimbeni, M Triyatni, M Bourdoncle, P Pol, S Saunier, B AF Lagaye, Sylvie Nascimbeni, Michelina Triyatni, Miriam Bourdoncle, Pierre Pol, Stanislas Saunier, Bertrand TI EVIDENCE FOR REPLICATION AND RELEASE OF HEPATITIS C VIRUS FOLLOWING THE EX VIVO INFECTION OF CULTURED HUMAN LIVER SLICES WITH VIRAL STRAINS OF GENOTYPES 1 AND 2 SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Lagaye, Sylvie; Nascimbeni, Michelina; Bourdoncle, Pierre; Pol, Stanislas; Saunier, Bertrand] Inst Cochin, Paris, France. [Triyatni, Miriam] NIAID, MSS, LVD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1419 BP 957A EP 957A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001415 ER PT J AU Frank, AC Katsounas, A Bharucha, J Imamichi, T Kottilil, S AF Frank, Astrid C. Katsounas, Antonios Bharucha, Jennifer Imamichi, Tomozumi Kottilil, Shyam TI AN INTERLEUKIN-12 FAMILY CYTOKINE, IL-27 INHIBITS HEPATITIS C VIRUS REPLICATION IN VITRO BOTH DIRECTLY AND SYNERGISTICALLY WITH INTERFeRON ALPHA SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Katsounas, Antonios; Bharucha, Jennifer; Imamichi, Tomozumi] NCI, SAIC, Bethesda, MD 20892 USA. [Frank, Astrid C.; Kottilil, Shyam] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1423 BP 959A EP 959A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001419 ER PT J AU Zhang, XZ Daucher, M Kottilil, S AF Zhang, Xiaozhen Daucher, Marybeth Kottilil, Shyam TI IDENTIFICATION OF HOST MICRORNAS THAT BLOCK HCV REPLICATION IN VITRO AS POTENTIAL TARGETS FOR TREATMENT OF HCV SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Zhang, Xiaozhen; Daucher, Marybeth; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1430 BP 962A EP 962A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001426 ER PT J AU Mi, LJ Karsdon, J Huang, WM Chiang, B Ghany, MG Del Priore, G Poon, E Leong, M Brown, RS AF Mi, Li-Jun Karsdon, Jeffrey Huang, William M. Chiang, Betty Ghany, Marc G. Del Priore, Giuseppe Poon, Eric Leong, Michelle Brown, Robert S. TI HEPATITIS B VIRUS (HBV) TRANSMISSION RATE AMONG CHILDREN BORN TO CHINESE-AMERICAN MOTHERS WITH CHRONIC HEPATITIS B (CHB) IN THE NEW YORK DOWNTOWN AREA SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Mi, Li-Jun] New York Downtown Hosp, Dept Med, Out Patient Div, New York, NY USA. [Karsdon, Jeffrey; Poon, Eric] New York Downtown Hosp, Dept Pediat, New York, NY USA. [Huang, William M.] New York Downtown Hosp, Dept Obstet & Gynecol, New York, NY USA. [Chiang, Betty] Gilead Sci Inc, Hepatitis Med Sci, Foster City, CA 94404 USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Del Priore, Giuseppe] New York Downtown Hosp, Dept Obstet & Gynecol, New York, NY USA. [Poon, Eric; Leong, Michelle] Chinese Community Partnership Hlth, New York, NY USA. [Brown, Robert S.] Columbia Univ, Med Ctr, Div Liver Dis & Transplantat, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 SU S MA 1438 BP 966A EP 966A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001434 ER PT J AU Pati, NT Daucher, M Murphy, A Sarin, SK Davey, RT Kottilil, S AF Pati, Nirupma Trehan Daucher, Marybeth Murphy, Alison Sarin, Shiv K. Davey, Richard T. Kottilil, Shyam TI IL-15 STIMULATION WITH PD-1/PD-L1/2 BLOCKADE ENHANCES HBV-SPECIFIC EFFECTOR CD8+T CELL IMMUNITY IN HIV POSITIVE AND NEGATIVE HBEAG NEGATIVE CHRONIC HEPATITIS B PATIENTS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Daucher, Marybeth; Murphy, Alison; Davey, Richard T.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Pati, Nirupma Trehan; Sarin, Shiv K.] Inst Liver & Biliary Sci, New Delhi, India. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1455 BP 974A EP 974A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001451 ER PT J AU Curto, TM Lok, AS Lagier, RJ Rowland, CM Sninsky, J Everhart, JE AF Curto, Teresa M. Lok, Anna S. Lagier, Robert J. Rowland, Charles M. Sninsky, John Everhart, James E. TI VALIDATION OF A PANEL OF GENETIC MARKERS (CRS7) IN PREDICTING CIRRHOSIS, FIBROSIS PROGRESSION (FP) AND CLINICAL OUTCOMES IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) IN THE HALT-C TRIAL SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Curto, Teresa M.] New England Res Inst, Watertown, MA 02172 USA. [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Everhart, James E.] NIDDK, Bethesda, MD USA. [Lagier, Robert J.; Rowland, Charles M.; Sninsky, John] Celera, Alameda, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1620 BP 1054A EP 1054A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001615 ER PT J AU Fontana, RJ Lok, AS Dienstag, JL Naishadham, D Bonkovsky, HL Wright, EC Goodman, ZD Sterling, RK AF Fontana, Robert J. Lok, Anna S. Dienstag, Jules L. Naishadham, Deepa Bonkovsky, Herbert L. Wright, Elizabeth C. Goodman, Zachary D. Sterling, Richard K. TI SERUM FIBROSIS MARKERS ARE ASSOCIATED WITH CLINICAL OUTCOMES AND HISTOLOGICAL PROGRESSION IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) AND ADVANCED FIBROSIS SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Fontana, Robert J.; Lok, Anna S.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Bonkovsky, Herbert L.] Carolina Med Ctr, Dept Med, Charlotte, NC USA. [Goodman, Zachary D.] Armed Forces Inst Pathol, Dept Pathol, Washington, DC 20306 USA. [Sterling, Richard K.] Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Naishadham, Deepa] New England Res Inst, Boston, MA USA. [Wright, Elizabeth C.] NIH, Liver Dis Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1625 BP 1056A EP 1057A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001620 ER PT J AU Everson, GT Hoefs, JC Shiffman, ML Morgan, TR Sterling, RK Curto, TM Wagner, D Wright, EC Everhart, JE AF Everson, Gregory T. Hoefs, John C. Shiffman, Mitchell L. Morgan, Timothy R. Sterling, Richard K. Curto, Teresa M. Wagner, David Wright, Elizabeth C. Everhart, James E. TI HEPATIC IMPAIRMENT MEASURED BY QUANTITATIVE TESTS OF LIVER FUNCTION (QLFTS) PREDICTS CLINICAL OUTCOME IN PATIENTS WITH ADVANCED FIBROSIS: RESULTS FROM THE HEPATITIS C ANTIVIRAL LONG-TERM TREATMENT AGAINST CIRRHOSIS (HALT-C) TRIAL SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Everson, Gregory T.] Univ Colorado, Transplant Ctr & Hepatol, Aurora, CO USA. [Hoefs, John C.; Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol & Hepatol, Irvine, CA USA. [Shiffman, Mitchell L.; Sterling, Richard K.] VCU, Sect Hepatol, Richmond, VA USA. [Wagner, David] Metab Solut, Nashua, NH USA. [Curto, Teresa M.] New England Res Inst, Watertown, MA 02172 USA. [Wright, Elizabeth C.; Everhart, James E.] NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1627 BP 1057A EP 1058A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001622 ER PT J AU Marrero, J Schwartz, ME Nguyen, MH Befeler, A Reddy, KR Roberts, LR Harnois, DM Wang, YH Wagner, P Feng, ZD AF Marrero, Jorge Schwartz, Myron E. Nguyen, Mindie H. Befeler, Alex Reddy, K. Rajender Roberts, Lewis R. Harnois, Denise M. Wang, Yinghui Wagner, Paul Feng, Ziding TI ALPHA-FETOPROTEIN AND DES-GAMMA CARBOXYPROTHROMBIN ARE INDEPENDENT PREDICTORS OF EARLY STAGE HEPATOCELLULAR CARCINOMA SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Marrero, Jorge] Univ Michigan, Ann Arbor, MI 48109 USA. [Schwartz, Myron E.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Nguyen, Mindie H.] Stanford Univ, Palo Alto, CA 94304 USA. [Befeler, Alex] St Louis Univ, St Louis, MO 63103 USA. [Reddy, K. Rajender] Univ Penn, Philadelphia, PA 19104 USA. [Roberts, Lewis R.] Mayo Clin, Rochester, MN USA. [Harnois, Denise M.] Mayo Clin, Jacksonville, FL 32224 USA. [Wang, Yinghui; Feng, Ziding] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Wagner, Paul] Natl Canc Inst, Bethesda, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1699 BP 1091A EP 1092A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001693 ER PT J AU Rabenhorst, U Beinoraviciute-Kellner, R Brezniceanu, ML Joos, S Devens, F Lichter, P Rieker, RJ Trojan, J Chung, HJ Levens, DL Zornig, M AF Rabenhorst, Uta Beinoraviciute-Kellner, Rasa Brezniceanu, Marie-Luise Joos, Stefan Devens, Frauke Lichter, Peter Rieker, Ralf J. Trojan, Joerg Chung, Hye-Jung Levens, David L. Zoernig, Martin TI Overexpression of the Far Upstream Element Binding Protein 1 in Hepatocellular Carcinoma Is Required for Tumor Growth SO HEPATOLOGY LA English DT Article ID C-MYC EXPRESSION; CELL-DEATH; DNA; CANCER; MECHANISM; APOPTOSIS; RESECTION; TARGETS; VIRUS; TFIIH AB We identified the far upstream element binding protein 1 (FBP1), an activator of transcription of the proto-oncogene c-myc, in a functional yeast survival screen for tumor-related antiapoptotic proteins and demonstrated strong overexpression of FBP1 in human hepatocellular carcinoma (HCC). Knockdown of the protein in HCC cells resulted in increased sensitivity to apoptotic stimuli, reduced cell proliferation, and impaired tumor formation in a mouse xenograft transplantation model. Interestingly, analysis of gene regulation in these cells revealed that c-myc levels were not influenced by FBP1 in HCC cells. Instead, we identified the cell cycle inhibitor p21 as a direct target gene repressed by FBP1, and in addition, expression levels of the proapoptotic genes tumor necrosis factor a, tumor necrosis factor-related apoptosis-inducing ligand, Noxa, and Bik were elevated in the absence of FBP1. Conclusion: Our data establish FBP1 as an important oncoprotein overexpressed in HCC that induces tumor propagation through direct or indirect repression of cell cycle inhibitors and proapoptotic target genes. (HEPATOLOGY 2009;50:1121-1129.) C1 [Rabenhorst, Uta; Beinoraviciute-Kellner, Rasa; Brezniceanu, Marie-Luise; Zoernig, Martin] Chemotherapeut Forschungsinst Georg Speyer Haus, D-60596 Frankfurt, Germany. [Joos, Stefan; Devens, Frauke; Lichter, Peter] German Canc Res Ctr, Div Mol Genet, D-6900 Heidelberg, Germany. [Rieker, Ralf J.] Univ Hosp, Dept Pathol, Heidelberg, Germany. [Rieker, Ralf J.] Med Univ Innsbruck, Dept Pathol, Innsbruck, Austria. [Trojan, Joerg] Goethe Univ Frankfurt, Dept Internal Med 1, Frankfurt, Germany. [Chung, Hye-Jung; Levens, David L.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zornig, M (reprint author), Chemotherapeut Forschungsinst Georg Speyer Haus, Paul Ehrlich Str 42-44, D-60596 Frankfurt, Germany. EM zoernig@em.uni-frankfurt.de RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural NIH HHS [ZIA SC009144-26] NR 31 TC 42 Z9 46 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 BP 1121 EP 1129 DI 10.1002/hep.23098 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JU UT WOS:000270455800019 PM 19637194 ER PT J AU Jeannot, E Boorman, GA Shymonyak, S Kosyk, O Rusyn, I AF Jeannot, Emmanuelle Boorman, Gary A. Shymonyak, Svitlana Kosyk, Oksana Rusyn, Ivan TI INCIDENCE OF AFLATOXIN B1-INDUCED HEPATIC TUMORS IS INCREASED IN HEPATITIS VIRUS C TRANSGENIC MICE AS COMPARED TO WILD TYPE C57BL/6J STRAIN SO HEPATOLOGY LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 30-NOV 03, 2009 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Jeannot, Emmanuelle; Shymonyak, Svitlana; Kosyk, Oksana; Rusyn, Ivan] UNC, ESE, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Boorman, Gary A.] Natl Inst Environm Hlth Sci, Environm Toxicol Program, Res Triangle Pk, NC USA. RI Rusyn, Ivan/S-2426-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 MA 1812 BP 1141A EP 1141A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JV UT WOS:000270456001806 ER PT J AU Hikita, H Takehara, T Shimizu, S Kodama, T Li, W Miyagi, T Hosui, A Ishida, H Ohkawa, K Kanto, T Hiramatsu, N Yin, XM Hennighausen, L Tatsumi, T Hayashi, N AF Hikita, Hayato Takehara, Tetsuo Shimizu, Satoshi Kodama, Takahiro Li, Wei Miyagi, Takuya Hosui, Atsushi Ishida, Hisashi Ohkawa, Kazuyoshi Kanto, Tatsuya Hiramatsu, Naoki Yin, Xiao-Ming Hennighausen, Lothar Tatsumi, Tomohide Hayashi, Norio TI Mcl-1 and Bcl-xL Cooperatively Maintain Integrity of Hepatocytes in Developing and Adult Murine Liver SO HEPATOLOGY LA English DT Article ID HUMAN HEPATOCELLULAR CARCINOMAS; DEFICIENT MICE; CELL-DEATH; PROTEIN FAMILY; APOPTOSIS; FAS; SUPPRESSION; DISRUPTION; INJURY; HAIR AB Anti-apoptotic members of the Bd-2 family, including Bcl-2, Bcl-xL, Mcl-1, Bd-w and Bfl-1, inhibit the mitochondrial pathway of apoptosis. Bd-xL and Mcl-1 are constitutively expressed in the liver. Although previous research established Bcl-xL as a critical apoptosis antagonist in differentiated hepatocytes, the significance of Mcl-1 in the liver, especially in conjunction with Bcl-xL, has not been clear. To examine this question, we generated hepatocyte-specific Mcl-1-deficient mice by crossing mcl-1(flox/flox) mice and AlbCre mice and further crossed them with bcl-x(flox/flox) mice, giving Mcl-1/Bcl-xL-deficient mice. The mcl-1(flox/flox) mice showed spontaneous apoptosis of hepatocytes after birth, as evidenced by elevated levels of serum alanine aminotransferase (ALT) and caspase-3/7 activity and an increased number of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL)positive cells in the liver; these phenotypes were very close to those previously found in hepatocyte-specific Bcl-xL-deficient mice. Although mcl-1(flox/+) AlbCre mice did not display apoptosis, their susceptibility to Fas-mediated liver injury significantly increased. Further crossing of Mcl-1 mice with Bd-xL mice showed that bcl-x(flox+) mcl-1(flox)/(+) AlbCre mice also showed spontaneous hepatocyte apoptosis similar to Bcl-xL-deficient or Mcl-1-deficient mice. In contrast, bcl-x(flox/flox) mcl-1(flox/+) AlbCre, bcl-x(flox/+) mcl-1(flox/flox) AlbCre, and bcl-x(flox/flox) mcl-1(flox/flox) AlbCre mice displayed a decreased number of hepatocytes and a reduced volume of the liver on day 18.5 of embryogenesis and rapidly died within I day after birth, developing hepatic failure evidenced by increased levels of blood ammonia and bilirubin. Conclusion: Mcl-1 is critical for blocking apoptosis in adult liver and, in the absence of Bcl-xL, is essential for normal liver development. Mcl-1 and Bcl-xL are two major anti-apoptotic Bd-2 family proteins expressed in the liver and cooperatively control hepatic integrity during liver development and in adult liver homeostasis in a gene dose-dependent manner. (HEPATOLOGY 2009;50:1217-1226.) C1 [Hikita, Hayato; Takehara, Tetsuo; Shimizu, Satoshi; Kodama, Takahiro; Li, Wei; Miyagi, Takuya; Hosui, Atsushi; Ishida, Hisashi; Ohkawa, Kazuyoshi; Kanto, Tatsuya; Hiramatsu, Naoki; Tatsumi, Tomohide; Hayashi, Norio] Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Suita, Osaka 5650871, Japan. [Yin, Xiao-Ming] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Hayashi, N (reprint author), Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM hayashin@gh.med.osaka-u.ac.jp OI Kodama, Takahiro/0000-0002-6250-1324 FU Ministry of Educatin, Culture, Sports, and Technology, Japan FX Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Educatin, Culture, Sports, and Technology, Japan (to T. Tak). NR 34 TC 41 Z9 42 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD OCT PY 2009 VL 50 IS 4 BP 1217 EP 1226 DI 10.1002/hep.23126 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 502JU UT WOS:000270455800029 PM 19676108 ER PT J AU Rutter, L Carver, FW Holroyd, T Nadar, SR Mitchell-Francis, J Apud, J Weinberger, DR Coppola, R AF Rutter, Lindsay Carver, Frederick W. Holroyd, Tom Nadar, Sreenivasan Rajamoni Mitchell-Francis, Judy Apud, Jose Weinberger, Daniel R. Coppola, Richard TI Magnetoencephalographic Gamma Power Reduction in Patients with Schizophrenia During Resting Condition SO HUMAN BRAIN MAPPING LA English DT Article DE default network; synthetic aperture magnetometry; baseline; precuneus; cuneus; SAM; magnetoencephalography; unaffected siblings; default mode ID VISUOSPATIAL WORKING-MEMORY; TASK-INDUCED DEACTIVATION; MEDIAL PREFRONTAL CORTEX; FALSE DISCOVERY RATE; DEFAULT-MODE; ALZHEIMERS-DISEASE; FUNCTIONAL CONNECTIVITY; BRAIN-FUNCTION; CORTICAL NETWORKS; STATE FMRI AB Objective: The "default network" represents a baseline condition of brain function and is of interest in schizophrenia research because its component brain regions are believed to be aberrant in the disorder. We hypothesized that magnetoencephalographic (MEG) source localization analysis would reveal abnormal resting activity within particular frequency bands in schizophrenia. Experimental Design: Eyes-closed resting state MEG signals were collected for two comparison groups. Patients with schizophrenia (N = 38) were age-gender matched with healthy control subjects (N = 38), and with a group of unmedicated unaffected siblings of patients with schizophrenia (N = 38). To localize 3D-brain regional differences, svnthetic aperture magnetometry was calculated across established frequency bands as follows: delta (0.9-4 Hz), theta (4-8 Hz), alpha (8-14 Hz), beta (14-30 Hz), gamma (30-80 Hz), and super-gamma (80-150 Hz). Principle Observations: Patients with schizophrenia showed significantly reduced activation in the gamma frequency band in the posterior region of the medial parietal cortex. As a group, unaffected siblings of schizophrenia patients also showed significantly reduced activation in the gamma bandwidth across similar brain regions. Moreover, using the significant region for the patients and examining the gamma band power gave an odds ratio of 6:1 for reductions of two standard deviations from the mean. This suggests that the measure might be the basis of an intermediate phenotype. Conclusions: MEG resting state analysis adds to the evidence that schizophrenic patients experience this condition very differently than healthy controls. Whether this baseline difference relates to network abnormalities remains to be seen. Hum Brain Mapp 30:3254-3264, 2009. (C) 2009 Wile-Liss, Inc. C1 [Rutter, Lindsay; Carver, Frederick W.; Holroyd, Tom; Nadar, Sreenivasan Rajamoni; Mitchell-Francis, Judy; Coppola, Richard] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Apud, Jose; Weinberger, Daniel R.; Coppola, Richard] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Coppola, R (reprint author), NIH, 301-402-7345,Bldg 10 Magnuson CC,4S235,9000 Rockv, Bethesda, MD 20892 USA. EM coppolar@mail.nih.gov FU NIMH Intramural Research program FX Contract Grant sponsor: NIMH Intramural Research program. NR 59 TC 49 Z9 50 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD OCT PY 2009 VL 30 IS 10 BP 3254 EP 3264 DI 10.1002/hbm.20746 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 507LB UT WOS:000270853700014 PM 19288463 ER PT J AU Yerys, BE Jankowski, KF Shook, D Rosenberger, LR Barnes, KA Berl, MM Ritzl, EK VanMeter, J Vaidya, CJ Gaillard, WD AF Yerys, Benjamin E. Jankowski, Kathryn F. Shook, Devon Rosenberger, Lisa R. Barnes, Kelly Anne Berl, Madison M. Ritzl, Eva K. VanMeter, John Vaidya, Chandan J. Gaillard, William D. TI The fMRI Success Rate of Children and Adolescents: Typical Development, Epilepsy, Attention Deficit/Hyperactivity Disorder, and Autism Spectrum Disorders SO HUMAN BRAIN MAPPING LA English DT Article DE autism; epilepsy; ADHD; children; success ID INTERVIEW AB Functional magnetic resonance imaging (fMRI) in children is increasingly used in clinical application and in developmental research; however, little is known how pediatric patient and typically developing populations successfully complete studies. We examined pediatric Success rates with epilepsy, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and typically developing children (TYP). We also examined the affect of age, and, for ADHD populations, medication status On success rates. We defined a successful fMRI individual run when the data were interpretable and included in group statistics. For unsuccessful runs, datasets with excessive motion or floor task performance were categorized when possible. All clinical groups scanned less successfully than controls; medication status did not affect ADHD success (epilepsy, 80%; ADHD (off methylphenidate), 77%; ADHD (on methylphenidate), 81%; ASD, 70%; TYP, 87%). Ten to 18-year-old had a significantly greater scan success rate than 4- to 6-year-old; adolescents (13- to 18-year-old) demonstrated greater scan success rates than 7- to 9-year-old. Success rate for completing an entire battery of experimental runs (n = 2-6), varied between 50-59%, for patient populations and 69% for TYP (79%, when excluding 4- to 6-year-old). Success rate for completing one run from a battery was greater than 90% for all groups, except for ASD (81%). These data Suggest 20-30% more children should be recruited in these patient groups, but only 10-20% for TYP for research studies. Studies with 4- to 6-year-olds may require 20-40% additional participants; studies with 10- to 18-year-olds may require 10-15% additional participants. Hum Brain Mapp 30:3426-3435, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Yerys, Benjamin E.] George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Neurosci,Childrens Res Inst, Washington, DC 20052 USA. [Yerys, Benjamin E.; Jankowski, Kathryn F.] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. [Shook, Devon; Barnes, Kelly Anne; Vaidya, Chandan J.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Ritzl, Eva K.] Johns Hopkins Univ Hosp, Dept Neurol, Washington, DC USA. [Ritzl, Eva K.; Gaillard, William D.] NINDS, Clin Epilepsy Sect, NIH, Washington, DC USA. [VanMeter, John; Gaillard, William D.] Georgetown Univ, Dept Neurol, Washington, DC USA. RP Yerys, BE (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Neurosci,Childrens Res Inst, Washington, DC 20052 USA. EM byerys@cnmc.org FU National Institute of Neurological Disorders and Stroke [R01-NS44280]; National Institute of Mental Health [R01-MH65395]; Studies for the Advancement of Autism Research and Treatment (STAART) [NIMH U54 MH0664 17]; Intellectual and Developmental Disabilities Research Center (Children's National Medical Center) [NIH IDDRC P30HD40677]; General Clinic Research Center [NIH GCRC M01-RR13297]; IDDRC T-32 Fellowship [NIH T32HD046388]; Frederick and Elizabeth Singer Foundation FX Contract grant sponsor: National Institute of Neurological Disorders and Stroke; Contract grant number: R01-NS44280; Contract grant sponsor: National Institute of Mental Health; Contract grant number: R01-MH65395; Contract grant sponsor: Studies for the Advancement of Autism Research and Treatment (STAART); Contract grant number: NIMH U54 MH0664 17; Contract grant sponsor: Intellectual and Developmental Disabilities Research Center (Children's National Medical Center); Contract grant number: NIH IDDRC P30HD40677; Contract grant sponsor: General Clinic Research Center; Contract grant number: NIH GCRC M01-RR13297; Contract grant sponsor: IDDRC T-32 Fellowship; Contract grant number: NIH T32HD046388; Contractgrant sponsors: Frederick and Elizabeth Singer Foundation, Avery Scholar Award. NR 9 TC 43 Z9 43 U1 2 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD OCT PY 2009 VL 30 IS 10 BP 3426 EP 3435 DI 10.1002/hbm.20767 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 507LB UT WOS:000270853700029 PM 19384887 ER PT J AU Kraynyak, KA Kutzler, MA Cisper, NJ Laddy, DJ Morrow, MP Waldmann, TA Weiner, DB AF Kraynyak, Kimberly A. Kutzler, Michele A. Cisper, Neil J. Laddy, Dominick J. Morrow, Matthew P. Waldmann, Thomas A. Weiner, David B. TI Plasmid-Encoded Interleukin-15 Receptor alpha Enhances Specific Immune Responses Induced by a DNA Vaccine In Vivo SO HUMAN GENE THERAPY LA English DT Article ID CD8(+) T-CELLS; VIRUS TYPE-1 INFECTION; MARROW-DERIVED CELLS; LONG-TERM SURVIVORS; IL-15 PLASMID; NATURAL-KILLER; TRANS-PRESENTATION; CARBOXYL-TERMINUS; DENDRITIC CELLS; CUTTING EDGE AB Plasmid-encoded DNA vaccines appear to be a safe and effective method for delivering antigen; however, the immunogenicity of such vaccines is often suboptimal. Cytokine adjuvants including interleukin (IL)-12, RANTES, granulocyte-macrophage colony-stimulating factor, IL-15, and others have been used to augment the immune response against DNA vaccines. In particular, IL-15 binds to a unique high-affinity receptor, IL-15R alpha; is trans-presented to CD8(+) T cells expressing the common beta gamma chain; and has been shown to play a role in the generation, maintenance, and proliferation of antigen-specific CD8(+) T cells. In this study, we took the unique approach of using both a cytokine and its receptor as an adjuvant in an HIV-1 vaccine strategy. To study IL-15R alpha expression, a unique monoclonal antibody (KK1.23) was generated to confirm receptor expression in vitro. Coimmunization of IL-15 and IL-15R alpha plasmids with HIV-1 antigenic plasmids in mice enhanced the antigen-specific immune response 2-fold over IL-15 immunoadjuvant alone. Furthermore, plasmid-encoded IL-15R alpha augments immune responses in the absence of IL-15, suggesting its role as a novel adjuvant. Moreover, pIL-15R alpha enhanced the cellular, but not the humoral, immune response as measured by antigen-specific IgG antibody. This is the first report describing that IL-15R alpha itself can act as an adjuvant by enhancing an antigen-specific T cell response. Uniquely, pIL-15 and pIL-15R alpha adjuvants combined, but not the receptor a chain alone, may be useful as a strategy for generating and maintaining memory CD8(+) T cells in a DNA vaccine. C1 [Kraynyak, Kimberly A.; Cisper, Neil J.; Laddy, Dominick J.; Morrow, Matthew P.; Weiner, David B.] Univ Penn, Dept Pathol & Lab Med, Sch Med, Philadelphia, PA 19104 USA. [Kutzler, Michele A.] Drexel Univ, Coll Med, Div Infect Dis & HIV Med, Philadelphia, PA 19102 USA. [Waldmann, Thomas A.] NCI, NIH, Bethesda, MD 20892 USA. RP Weiner, DB (reprint author), Univ Penn, Dept Pathol & Lab Med, Sch Med, 422 Curie Blvd,505 Stellar Chance Labs, Philadelphia, PA 19104 USA. EM dbweiner@mail.med.upenn.edu RI Weiner, David/H-8579-2014 FU NIH [1-T32-A107632]; HIVRAD FX The authors acknowledge helpful discussions with Jean Boyer, Ph.D. ( University of Pennsylvania, Philadelphia, PA), and Julia Conicello of the Wistar Institute Hybridoma Facility ( Philadelphia, PA) for help in generating and purifying the KK1.23 monoclonal antibody. The authors also thank the Penn Pathology Flow Cytometry and Biomedical Imaging core facilities. K. A. K. acknowledges the support of NIH grants 1-T32-A107632. D. B. W. acknowledges support from the NIH, including HIVRAD funding. NR 63 TC 15 Z9 16 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD OCT PY 2009 VL 20 IS 10 BP 1143 EP 1156 DI 10.1089/hum.2009.025 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 509OH UT WOS:000271026800006 PM 19530914 ER PT J AU Luo, M Simons, SS AF Luo, Min Simons, S. Stoney, Jr. TI Modulation of glucocorticoid receptor induction properties by cofactors in peripheral blood mononuclear cells SO HUMAN IMMUNOLOGY LA English DT Article DE Glucocorticoid hormone action; Modulation of induction parameters; Steroid potency vs. efficacy; Antisteroids; Gene-selective responses ID TRANSACTIVATION; RESISTANCE; SENSITIVITY; MUTATION; MICE AB Glucocorticoids are widely used for their anti-inflammatory and immumosuppressive properties. Changing concentrations of transcriptional cofactors or chemicals in transiently transfected tissue culture cells modify several properties of glucocorticoid receptor-regulated gene expression including total activity (A(max)), agonist steroid potency (EC(50)), and the percentage of full agonist activity for antisteroids (percent partial agonist activity). However, no reports exist for endogenous genes in primary human cells. Here we document that reduced concentrations of TIF2, a p160 coactivator, in peripheral blood mononuclear cells modulate these parameters for endogenous genes in a gene-selective manner, thus establishing the physiological relevance of this behavior. Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. C1 [Luo, Min; Simons, S. Stoney, Jr.] NIDDKD, Steroid Hormones Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDKD, Steroid Hormones Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Christian Grant [National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH)] for assistance with the transfection of PBMCs and Jon Ashwell (National Cancer Institute, NIH) for constructive criticism. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 19 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD OCT PY 2009 VL 70 IS 10 BP 785 EP 789 DI 10.1016/j.humimm.2009.07.029 PG 5 WC Immunology SC Immunology GA 503YI UT WOS:000270577900004 PM 19665040 ER PT J AU Ahn, J Schumacher, FR Berndt, SI Pfeiffer, R Albanes, D Andriole, GL Ardanaz, E Boeing, H Bueno-de-Mesquita, B Chanock, SJ Clavel-Chapelon, F Diver, WR Feigelson, HS Gaziano, JM Giovannucci, E Haiman, CA Henderson, BE Hoover, RN Kolonel, LN Kraft, P Ma, J Le Marchand, L Overvad, K Palli, D Stattin, P Stampfer, M Stram, DO Thomas, G Thun, MJ Travis, RC Trichopoulos, D Virtamo, J Weinstein, SJ Yeager, M Kaaks, R Hunter, DJ Hayes, RB AF Ahn, Jiyoung Schumacher, Fredrick R. Berndt, Sonja I. Pfeiffer, Ruth Albanes, Demetrius Andriole, Gerald L. Ardanaz, Eva Boeing, Heiner Bueno-de-Mesquita, Bas Chanock, Stephen J. Clavel-Chapelon, Francoise Diver, W. Ryan Feigelson, Heather Spencer Gaziano, J. Michael Giovannucci, Edward Haiman, Christopher A. Henderson, Brian E. Hoover, Robert N. Kolonel, Laurence N. Kraft, Peter Ma, Jing Le Marchand, Loic Overvad, Kim Palli, Domenico Stattin, Paer Stampfer, Meir Stram, Daniel O. Thomas, Gilles Thun, Michael J. Travis, Ruth C. Trichopoulos, Dimitrios Virtamo, Jarmo Weinstein, Stephanie J. Yeager, Meredith Kaaks, Rudolf Hunter, David J. Hayes, Richard B. TI Quantitative trait loci predicting circulating sex steroid hormones in men from the NCI-Breast and Prostate Cancer Cohort Consortium (BPC3) SO HUMAN MOLECULAR GENETICS LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; SERUM ANDROGENS; RISK; GENE; POLYMORPHISMS; ASSOCIATION AB Twin studies suggest a heritable component to circulating sex steroid hormones and sex hormone-binding globulin (SHBG). In the NCI-Breast and Prostate Cancer Cohort Consortium, 874 SNPs in 37 candidate genes in the sex steroid hormone pathway were examined in relation to circulating levels of SHBG (N = 4720), testosterone (N = 4678), 3 alpha-androstanediol-glucuronide (N = 4767) and 17 beta-estradiol (N = 2014) in Caucasian men. rs1799941 in SHBG is highly significantly associated with circulating levels of SHBG (P = 4.52 x 10(-21)), consistent with previous studies, and testosterone (P = 7.54 x 10(-15)), with mean difference of 26.9 and 14.3%, respectively, comparing wild-type to homozygous variant carriers. Further noteworthy novel findings were observed between SNPs in ESR1 with testosterone levels (rs722208, mean difference = 8.8%, P = 7.37 x 10(-6)) and SRD5A2 with 3 alpha-androstanediol-glucuronide (rs2208532, mean difference = 11.8%, P = 1.82 x 10(-6)). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones. C1 [Ahn, Jiyoung; Berndt, Sonja I.; Pfeiffer, Ruth; Albanes, Demetrius; Chanock, Stephen J.; Hoover, Robert N.; Thomas, Gilles; Weinstein, Stephanie J.; Yeager, Meredith; Hayes, Richard B.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ahn, Jiyoung; Hayes, Richard B.] NYU, Sch Med, Dept Environm Med, Div Epidemiol, New York, NY 10016 USA. [Schumacher, Fredrick R.; Haiman, Christopher A.; Henderson, Brian E.; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO USA. [Ardanaz, Eva] Publ Hlth Inst Navarra, Pamplona, Spain. [Ardanaz, Eva] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Boeing, Heiner] German Inst Human Nutr, Dept Epidemiol, Potsdam, Germany. [Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Clavel-Chapelon, Francoise] INSERM, ERI 20, Paris EA 4045, Paris, France. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, F-94805 Villejuif, France. [Diver, W. Ryan; Feigelson, Heather Spencer; Thun, Michael J.] Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30303 USA. [Gaziano, J. Michael; Giovannucci, Edward; Ma, Jing; Stampfer, Meir; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA. [Gaziano, J. Michael; Giovannucci, Edward; Ma, Jing; Stampfer, Meir; Trichopoulos, Dimitrios] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gaziano, J. Michael; Giovannucci, Edward; Ma, Jing; Stampfer, Meir; Trichopoulos, Dimitrios] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Overvad, Kim] Aarhus Univ Hosp, Aalborg Hosp, Dept Clin Epidemiol & Cardiol, Aalborg, Denmark. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Stattin, Paer] Umea Univ, Umea, Sweden. [Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FIN-00300 Helsinki, Finland. [Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany. RP Hayes, RB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM richard.b.hayes@nyumc.org RI Pfeiffer, Ruth /F-4748-2011; Perez , Claudio Alejandro/F-8310-2010; Clavel-Chapelon, Francoise/G-6733-2014; Albanes, Demetrius/B-9749-2015; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Hayes, Richard/0000-0002-0918-661X; PALLI, Domenico/0000-0002-5558-2437 FU Intramural NIH HHS; NCI NIH HHS [R01 CA097193, UO1-CA98216, UO1-CA98233, UO1-CA98710, UO1-CA98758] NR 25 TC 27 Z9 27 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2009 VL 18 IS 19 BP 3749 EP 3757 DI 10.1093/hmg/ddp302 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 505PZ UT WOS:000270707900019 PM 19574343 ER PT J AU Choi, BY Alper, SL Griffith, AJ AF Choi, Byung Yoon Alper, Seth L. Griffith, Andrew J. TI Response to: The c.-103T > C Variant in the 5 '-ATR of SLC26A4 Gene: A Pathogenic Mutation or Coincidental Polymorphism? SO HUMAN MUTATION LA English DT Letter ID VESTIBULAR AQUEDUCT; PENDRED-SYNDROME; HEARING-LOSS; ENLARGEMENT; DFNB4 C1 [Griffith, Andrew J.] NIDCD, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. [Alper, Seth L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Choi, Byung Yoon] NIDCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), NIDCD, Otolaryngol Branch, NIH, 5 Res Court,Room 1A-13D, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov NR 6 TC 4 Z9 4 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD OCT PY 2009 VL 30 IS 10 BP 1471 EP 1471 DI 10.1002/humu.21098 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 507LQ UT WOS:000270855400014 ER PT J AU Roessler, E El-Jaick, KB Dubourg, C Velez, JI Solomon, BD Pineda-Alvarez, DE Lacbawan, F Zhou, N Ouspenskaia, M Paulussen, A Smeets, HJ Hehr, U Bendavid, C Bale, S Odent, S David, V Muenke, M AF Roessler, Erich El-Jaick, Kenia B. Dubourg, Christele Velez, Jorge I. Solomon, Benjamin D. Pineda-Alvarez, Daniel E. Lacbawan, Felicitas Zhou, Nan Ouspenskaia, Maia Paulussen, Aimee Smeets, Hubert J. Hehr, Ute Bendavid, Claude Bale, Sherri Odent, Sylvie David, Veronique Muenke, Maximilian TI The Mutational Spectrum of Holoprosencephaly-Associated Changes within the SHH Gene in Humans Predicts Loss-of-Function Through Either Key Structural Alterations of the Ligand or Its Altered Synthesis SO HUMAN MUTATION LA English DT Article DE holoprosencephaly; mutation spectrum; SHH; protein processing ID MAXILLARY CENTRAL INCISOR; SONIC-HEDGEHOG GENE; BRACHYDACTYLY TYPE A1; HUMAN SIX3 GENE; GONADAL-DYSGENESIS; DESERT-HEDGEHOG; INDIAN HEDGEHOG; HETEROZYGOUS MUTATION; CRYSTAL-STRUCTURE; TERMINAL DOMAIN AB Mutations within either the SHH gene or its related pathway components are the most common, and best understood, pathogenetic changes observed in holoprosencephaly patients; this fact is consistent with the essential functions of this gene during forebrain development and patterning. Here we summarize the nature and types of deleterious sequence alterations among over one hundred distinct mutations in the SHH gene (64 novel mutations) and compare these to over a dozen mutations in disease-related Hedgehog family members IHH and DHH. This combined structural analysis suggests that dysfunction of Hedgehog signaling in human forebrain development can occur through truncations or major structural changes to the signaling domain, SHH-N, as well as due to defects in the processing of the mature ligand from its pre-pro-precursor or defective post-translation bi-lipid modifications with palmitate and cholesterol (C) 2009 WileyLiss, Inc. C1 [Roessler, Erich; El-Jaick, Kenia B.; Velez, Jorge I.; Solomon, Benjamin D.; Pineda-Alvarez, Daniel E.; Lacbawan, Felicitas; Zhou, Nan; Ouspenskaia, Maia; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Dubourg, Christele; Bendavid, Claude; David, Veronique] CHU Pontchaillou, Genet Mol Lab, Rennes, France. [Dubourg, Christele; Bendavid, Claude; Odent, Sylvie; David, Veronique] Univ Rennes 1, CNRS, Genet & Dev UMR6061, IFR140, F-35014 Rennes, France. [Paulussen, Aimee; Smeets, Hubert J.] Univ Maastricht, Acad Hosp, Maastricht, Netherlands. [Paulussen, Aimee; Smeets, Hubert J.] Univ Maastricht, Dept Clin Genet, Maastricht, Netherlands. [Hehr, Ute] Univ Regensburg, Ctr Human Genet, D-8400 Regensburg, Germany. [Hehr, Ute] Univ Regensburg, Dept Human Genet, D-8400 Regensburg, Germany. [Bale, Sherri] GeneDx, Gaithersburg, MD USA. [Odent, Sylvie] CHU Hop Sud, Serv Genet Clin, Rennes, France. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov FU National Human Genome Research Institute, National Institutes of Health; GIS Institut des Maladies Rares; COREC (CHU, Faculte de Medecine, Rennes, France) FX The authors wish to thank the patients who participated in this research and the many clinicians who referred them. This research was supported by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health, and by the GIS Institut des Maladies Rares, COREC (CHU, Faculte de Medecine, Rennes, France). NR 66 TC 32 Z9 34 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD OCT PY 2009 VL 30 IS 10 BP E921 EP E935 DI 10.1002/humu.21090 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 626QC UT WOS:000279980600003 PM 19603532 ER PT J AU Mattai, A Fung, L Bakalar, J Overman, G Tossell, J Miller, R Rapoport, J Gogtay, N AF Mattai, Anand Fung, Lawrence Bakalar, Jennifer Overman, Gerald Tossell, Julia Miller, Rachel Rapoport, Judith Gogtay, Nitin TI Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children SO HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL LA English DT Article DE clozapine; lithium; childhood-onset schizophrenia; neutropenia ID CHILDHOOD-ONSET SCHIZOPHRENIA; COLONY-STIMULATING FACTOR; INDUCED AGRANULOCYTOSIS; ADOLESCENTS; RECHALLENGE; OLANZAPINE; EFFICACY; DISORDER; THERAPY; IRELAND AB Objective Clozapine, a dibenzodiazepine antipsychotic, is the most effective medication for treatment-resistant schizophrenia. However, its use has been limited by the high risk of neutropenia. In children, the rate of neutropenia is higher when compared to adults. We decided to explore the use of lithium to manage neutropenia in childhood-onset schizophrenia (COS) through a systematic audit of COS cases. Methods Medical records were reviewed for patients with COS who had been treated with the combination of clozapine and lithium carbonate. Results Seven patients were found to have been treated with both clozapine and lithium. After initiation of lithium, ANC increased significantly in six out of seven subjects by 29 to 106% with a mean of 66%. In addition, six out of seven subjects continued using both clozapine and lithium for over 2 years (range: 2.0-7.2 years) and do not have immediate plans for discontinuation of either medications. Conclusions Our study bolsters support for the use of lithium in the management of neutropenia in children treated with clozapine. Although the coadministration of lithium and clozapine appears effective in the management of neutropenia, it is not without its risks and clinicians must be diligent in their joint use of these medications. Published in 2009 by John Wiley & Sons, Ltd. C1 [Mattai, Anand; Fung, Lawrence; Bakalar, Jennifer; Overman, Gerald; Tossell, Julia; Miller, Rachel; Rapoport, Judith; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Mattai, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,BN202,10 Ctr Dr, Bethesda, MD 20892 USA. EM mattaia@mail.nih.gov RI Gogtay, Nitin/A-3035-2008; OI Fung, Lawrence/0000-0002-5738-0396 FU Intramural NIH HHS [Z99 MH999999] NR 36 TC 5 Z9 5 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0885-6222 J9 HUM PSYCHOPHARM CLIN JI Hum. Psychopharmacol.-Clin. Exp. PD OCT PY 2009 VL 24 IS 7 BP 584 EP 589 DI 10.1002/hup.1056 PG 6 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology GA 507XT UT WOS:000270889900009 PM 19743394 ER PT J AU Ohtsubo, T Matsumura, K Sakagami, K Fujii, K Tsuruya, K Noguchi, H Rovira, II Finkel, T Iida, M AF Ohtsubo, Toshio Matsumura, Kiyoshi Sakagami, Kanae Fujii, Koji Tsuruya, Kazuhiko Noguchi, Hideko Rovira, Ilsa I. Finkel, Toren Iida, Mitsuo TI Xanthine Oxidoreductase Depletion Induces Renal Interstitial Fibrosis Through Aberrant Lipid and Purine Accumulation in Renal Tubules SO HYPERTENSION LA English DT Article DE xanthine oxidoreductase; lipid; uric acid; xanthine; renal interstitial fibrosis; epithelial mesenchymal transition; oxidative stress ID SERUM URIC-ACID; CARDIOVASCULAR-DISEASE; REPERFUSION INJURY; IMMUNE-SYSTEM; OXIDASE; EXPRESSION; GENE; IDENTIFICATION; HYPERTENSION; MOUSE AB Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species production, and adipogenesis. XOR gene-disrupted (XOR-/-) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR-/- mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR-/- mice was accompanied by deposition of crystals and lipid-rich substances. Triglyceride content in renal homogenates was significantly increased in XOR-/- mice. The level of lipogenesis-related gene expression was comparable in XOR+/+ and XOR-/- mice, whereas the expression of adipogenesis-related gene expression was significantly elevated in XOR-/- mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR-/- mice. Immunohistochemical analysis, Western blotting, and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia, and oxidative stress were increased in XOR-/- mice. Finally, we demonstrate that primary renal epithelial cells from XOR-/- mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in the renal tubules. We believe that these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia, and reactive oxygen species production, ultimately resulting in renal failure through increased renal interstitial fibrosis. (Hypertension. 2009; 54: 868-876.) C1 [Ohtsubo, Toshio; Matsumura, Kiyoshi; Sakagami, Kanae; Fujii, Koji; Tsuruya, Kazuhiko; Noguchi, Hideko; Iida, Mitsuo] Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan. [Rovira, Ilsa I.; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Ohtsubo, T (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Maidashi 3-1-1, Fukuoka 8128582, Japan. EM tohtsubo@intmed2.med.kyushu-u.ac.jp FU Ministry of Education, Science, Sports, and Culture of Japan [19590954] FX This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (No. 19590954). NR 39 TC 24 Z9 24 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD OCT PY 2009 VL 54 IS 4 BP 868 EP U371 DI 10.1161/HYPERTENSIONAHA.109.135152 PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 494XJ UT WOS:000269852600033 PM 19667249 ER PT J AU Gauthier, KM Chawengsub, Y Zeldin, DC Campbell, WB AF Gauthier, Kathryn M. Chawengsub, Yuttana Zeldin, Darryl C. Campbell, William B. TI Role of Soluble Epoxide Hydrolase in Flow-Induced Dilations of Mouse Mesenteric Arteries SO HYPERTENSION LA English DT Meeting Abstract CT 63rd High Blood Pressure Research Conference CY SEP 23-26, 2009 CL Chicago, IL C1 [Gauthier, Kathryn M.; Chawengsub, Yuttana; Campbell, William B.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Zeldin, Darryl C.] NIEHS, Rsch Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2009 VL 54 IS 4 BP E124 EP E125 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 494XJ UT WOS:000269852600506 ER PT J AU Montefusco, MC Kelley-Hedgepeth, A Merlo, K Bryan, CD Housman, DE Levy, D Mendelsohn, ME Huggins, GS AF Montefusco, Maria Claudia Kelley-Hedgepeth, Alyson Merlo, Kristen Bryan, Crystal D. Housman, David E. Levy, Daniel Mendelsohn, Michael E. Huggins, Gordon S. TI Little ROCK1 Is a Variant of the ROCK1 Gene Expressed in Human Smooth Muscle Cells SO HYPERTENSION LA English DT Meeting Abstract CT 63rd High Blood Pressure Research Conference CY SEP 23-26, 2009 CL Chicago, IL C1 [Montefusco, Maria Claudia; Kelley-Hedgepeth, Alyson; Merlo, Kristen; Bryan, Crystal D.; Mendelsohn, Michael E.; Huggins, Gordon S.] Tufts Med Cntr, Boston, MA USA. [Housman, David E.] MIT, Cambridge, MA 02139 USA. [Levy, Daniel] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2009 VL 54 IS 4 BP E62 EP E62 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 494XJ UT WOS:000269852600207 ER PT J AU Westphal, C Schmidt, C Konkel, A Schubert, C Fischer, R Dechend, R Luft, FC Regitz-Zagrosek, V Zeldin, DC Schunck, WH Muller, DN AF Westphal, Christina Schmidt, Cosima Konkel, Anne Schubert, Carola Fischer, Robert Dechend, Ralf Luft, Friedrich C. Regitz-Zagrosek, Vera Zeldin, Darryl C. Schunck, Wolf-Hagen Muller, Dominik N. TI CYP2J2 Overexpression Improves Cardiac Hypertrophy in Male But Not Female Mice SO HYPERTENSION LA English DT Meeting Abstract CT 63rd High Blood Pressure Research Conference CY SEP 23-26, 2009 CL Chicago, IL C1 [Westphal, Christina; Schubert, Carola; Regitz-Zagrosek, Vera] Charite, Cntr Gender Med & Cardiovasc Dis Women, D-13353 Berlin, Germany. [Schmidt, Cosima; Konkel, Anne; Dechend, Ralf; Luft, Friedrich C.; Schunck, Wolf-Hagen; Muller, Dominik N.] Max Delbruck Ctr Mol Med, Berlin, Germany. [Zeldin, Darryl C.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD OCT PY 2009 VL 54 IS 4 BP E53 EP E53 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 494XJ UT WOS:000269852600163 ER PT J AU Joshi, RP Song, J Schoenbach, KH Sridhara, V AF Joshi, R. P. Song, J. Schoenbach, K. H. Sridhara, V. TI Aspects of Lipid Membrane Bio-responses to Subnanosecond, Ultrahigh Voltage Pulsing SO IEEE TRANSACTIONS ON DIELECTRICS AND ELECTRICAL INSULATION LA English DT Article DE Bioelectric phenomena; dielectric breakdown; modeling; biomembranes ID MOLECULAR-DYNAMICS SIMULATIONS; REVERSIBLE ELECTRICAL BREAKDOWN; PLANAR BILAYER-MEMBRANES; CELL-MEMBRANES; ELECTROPORATION; ALAMETHICIN; FIELD; PERMEABILIZATION; VESICLES; CHANNELS AB Membrane electroporation is probably one of the best-known effects of applying external voltages to biological cells. Reports in the literature have focused on relatively long voltage pulse durations (100 ns-1 ms). Here we probe the very short (< 1 ns), but intense electric field (> 500 kV/cm) regime that is made possible by advances in pulsed power technology. Our analyses based on continuum Smoluchowski and Molecular Dynamics (MD) approaches, predict two new aspects. First, it is shown that pore formation rates would be dramatically lower than predicted by conventional theory due to their dependence on local pore area. Second, such high fields are predicted to affect membrane proteins and ion-channels, without causing electroporation in regions between the proteins. Hence, such high voltage, short duration pulsing should not be associated with electroporation alone, but rather be viewed as a novel vehicle that opens possibilities for a range of new electrically-driven bio-response phenomena. C1 [Joshi, R. P.; Song, J.; Schoenbach, K. H.] Old Dominion Univ, Dept Elect & Comp Engn, Norfolk, VA 23529 USA. [Joshi, R. P.; Song, J.; Schoenbach, K. H.] Old Dominion Univ, Frank Reidy Ctr Bioelect, Norfolk, VA 23529 USA. [Sridhara, V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Joshi, RP (reprint author), Old Dominion Univ, Dept Elect & Comp Engn, Norfolk, VA 23529 USA. FU AFOSR-MURI [F49620-02-1-0320] FX The authors would like to thank J. Weaver (MIT), W. Krassowska (Duke University), E. Neumann (Univ. of Bielefeld), and A. Pakhomov (ODU) for useful discussions. This work was sponsored in part by an AFOSR-MURI grant (#F49620-02-1-0320) on Subcellular Responses to Narrowband and Wideband Radio Frequency Radiation, managed by Dr. Robert J. Barker. NR 72 TC 10 Z9 11 U1 0 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1070-9878 J9 IEEE T DIELECT EL IN JI IEEE Trns. Dielectr. Electr. Insul. PD OCT PY 2009 VL 16 IS 5 BP 1243 EP 1250 PG 8 WC Engineering, Electrical & Electronic; Physics, Applied SC Engineering; Physics GA 509MU UT WOS:000271022800004 ER PT J AU Voss, CY Deola, S Fleisher, TA Marincola, FM AF Voss, Ching Y. Deola, Sara Fleisher, Thomas A. Marincola, Francesco M. TI Increased effector-target cell conjugate formation due to HLA restricted specific antigen recognition SO IMMUNOLOGIC RESEARCH LA English DT Article DE Effector-target conjugate formation; HLA-restricted antigen recognition; TCR/HLA/epitopes; Intracellular cytokines; Adhesion molecules ID PARAMETER FLOW-CYTOMETRY; CYTOTOXIC T-LYMPHOCYTES; MELANOMA-CELLS; ADHESION; ACTIVATION; EXPRESSION; PATHWAYS; VACCINE; LFA-1; CD2 AB The T cell receptor (TCR) orchestrates T cell mediated-cytotoxicity through a complex interaction that results in an antigen-specific effector-target cell conjugate formation. While it is well recognized that specific TCR/antigen interactions generate the immunological synapse, their direct contribution to the effector-target cell conjugate has not been conclusively demonstrated. Moreover, since human cytotoxic T lymphocyte (CTL) clones are also susceptible to antigen-independent adhesion to target cells, it remains unclear whether effector-target cell conjugate formation can serve as an indicator of specific antigen recognition by the TCR. To address this question, a well-characterized epitope-specific CTL clone recognizing the melanoma-associated antigen epitope gp100:209-217 in association with HLA-A*0201 was tested against melanoma cell lines lacking or expressing the HLA-A*0201 allele and/or gp100. In this model, TCR/HLA/antigen interactions cooperated with accessory/adhesion molecules to facilitate effector-target cell conjugate formation. HLA-restricted antigen recognition played a dominant role resulting in up to 2-fold increases in conjugate frequency, and a 50% increase of CTL binding to tumor cells over background. The increased number of CTL contained in conjugates correlated with the number of IFN-gamma producing CTL. These results warrant further investigation to evaluate conjugate assays as a potential tool to detect and isolate viable and functionally active CTL. Since conjugate formation analysis does not require knowledge of the target antigen, this assay could potentially be used for enrichment of CTL directed against novel antigens. C1 [Deola, Sara; Marincola, Francesco M.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Voss, Ching Y.; Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM FMarincola@cc.nih.gov FU NIH FX This work was supported by the NIH intramural program. NR 22 TC 1 Z9 1 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD OCT PY 2009 VL 45 IS 1 BP 13 EP 24 DI 10.1007/s12026-008-8041-1 PG 12 WC Immunology SC Immunology GA 495OV UT WOS:000269904000002 PM 18696013 ER PT J AU Qi, CF Li, ZY Raffeld, M Wang, HS Kovalchuk, AL Morse, HC AF Qi, Chen-Feng Li, Zhaoyang Raffeld, Mark Wang, Hongsheng Kovalchuk, Alexander L. Morse, Herbert C., III TI Differential expression of IRF8 in subsets of macrophages and dendritic cells and effects of IRF8 deficiency on splenic B cell and macrophage compartments SO IMMUNOLOGIC RESEARCH LA English DT Article DE Germinal center; Follicular dendritic cells; B cells; IRF8 ID SEQUENCE-BINDING PROTEIN; IFN REGULATORY FACTOR-4; LEUKEMIA-LIKE SYNDROME; MARGINAL-ZONE; TRANSCRIPTION FACTORS; GERMINAL-CENTERS; CUTTING EDGE; ICSBP; GENE; MICE AB IRF8, a transcription factor restricted primarily to hematopoietic cells, is known to influence the differentiation and function of dendritic cells (DC), macrophages, granulocytes and B cells. In human tonsil, IRF8 is expressed at high levels by intrafollicular macrophages and DC, but at much lower levels by tingible body macrophages in germinal centers (GCs) and little, if at all, by follicular DC. Spleens of IRF8-deficient mice had reduced numbers of white pulp follicles and GCs that were irregular in shape. The frequency of follicular B cells was significantly reduced while the population of marginal zone (MZ) B cells was increased. In addition, MZ macrophages were reduced in number and abnormally distributed, while metallophilic macrophages were normal. These findings demonstrate differential requirements for IRF8 among distinct subsets of B cells, DC, and macrophages. C1 [Qi, Chen-Feng; Li, Zhaoyang; Wang, Hongsheng; Kovalchuk, Alexander L.; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. [Raffeld, Mark] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Qi, CF (reprint author), NIAID, Immunopathol Lab, NIH, 5640 Fishers Lane,Twinbrook 1,Room 1528, Rockville, MD 20852 USA. EM cqi@niaid.nih.gov; hmorse@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 FU Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases FX We gratefully acknowledge the editorial assistance of B. Marshall, photographic support from Rick Dreyfuss, and the provision of mice by K. Ozato. This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 41 TC 13 Z9 13 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD OCT PY 2009 VL 45 IS 1 BP 62 EP 74 DI 10.1007/s12026-008-8032-2 PG 13 WC Immunology SC Immunology GA 495OV UT WOS:000269904000006 PM 18663414 ER PT J AU Simkus, C Bhattacharyya, A Zhou, M Veenstra, TD Jones, JM AF Simkus, Carrie Bhattacharyya, Anamika Zhou, Ming Veenstra, Timothy D. Jones, Jessica M. TI Correlation between recombinase activating gene 1 ubiquitin ligase activity and V(D)J recombination SO IMMUNOLOGY LA English DT Article DE CDC34; recombinase activating gene 1; ubiquitin ligase; V(D)J recombination ID POLYUBIQUITIN CHAINS; CONJUGATING ENZYME; PROTEIN BREAKDOWN; RAG MUTATIONS; CELL-CYCLE; SUBSTRATE; DOMAIN; DEFECTS; COMPLEX; BINDING AB P>The really interesting new gene (RING) finger ubiquitin ligase domain of the recombinase activating gene 1 (RAG1) V(D)J recombinase protein adopts a standard cross-brace architecture but co-ordinates three zinc ions as opposed to the canonical two. We demonstrated previously that disruption of the conserved zinc co-ordination sites resulted in loss of structural integrity and ubiquitin ligase (E3) activity and interfered with the ability of full-length RAG1 to support recombination. Here we present evidence that amino acids surrounding the third, non-canonical site also contribute to functional interaction with the ubiquitin conjugating (E2) enzyme CDC34, while certain residues on the RING domain's surface important for interaction between other E2-E3 pairs are less critical to the functional RAG1-CDC34 interaction in this assay. Partial reduction of ubiquitin ligase activity was significantly correlated with reduction in the ability of RAG1 to support recombination of extra-chromosomal substrates (r = 0 center dot 805, P = 0 center dot 009). While poly-ubiquitin chains could be generated, RAG1 did not promote rapid chain extension following mono-ubiquitylation of substrate, regardless of the E2 enzyme used. No single ubiquitin lysine mutant disrupted the ability of CDC34 to form ubiquitin chains on RAG1, and mass spectrometric analysis of the poly-ubiquitylated products indicated ubiquitin chain linkages through lysines 48 and 11. These data suggest that RAG1 promotes a mono-ubiquitylation reaction that is required for optimal levels of V(D)J recombination. C1 [Simkus, Carrie; Bhattacharyya, Anamika; Jones, Jessica M.] Georgetown Univ, Dept Biochem Mol & Cellular Biol, Washington, DC 20057 USA. [Zhou, Ming; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Jones, JM (reprint author), Georgetown Univ, Dept Biochem Mol & Cellular Biol, Washington, DC 20057 USA. EM jonesj5@georgetown.edu FU National Cancer Institute; National Institutes of Health [N01-CO-12400, P30CA051008, AI062854-01] FX The authors wish to thank Dr Wei Yang, National Institute for Diabetes, Digestive and Kidney Diseases, for assistance with preparation of Fig. 2. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400 and Award Number P30CA051008. 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 United States Government. This project was supported in part by a grant to J.M.J. from the National Institutes of Health (AI062854-01). The content is solely the responsibility of the authors. NR 38 TC 12 Z9 12 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD OCT PY 2009 VL 128 IS 2 BP 206 EP 217 DI 10.1111/j.1365-2567.2009.03101.x PG 12 WC Immunology SC Immunology GA 491LM UT WOS:000269580300006 PM 19740377 ER PT J AU Greenaway, HY Kurniawan, M Price, DA Douek, DC Davenport, MP Venturi, V AF Greenaway, Hui Yee Kurniawan, Monica Price, David A. Douek, Daniel C. Davenport, Miles P. Venturi, Vanessa TI Extraction and characterization of the rhesus macaque T-cell receptor beta-chain genes SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article DE T-cell; T-cell receptor; T-cell receptor repertoire ID SIMIAN IMMUNODEFICIENCY VIRUS; SIV INFECTION; ANIMAL-MODEL; REPERTOIRE DIVERSITY; IMMUNE-RESPONSE; INFLUENZA-VIRUS; TCR REPERTOIRE; CTL ESCAPE; CD8(+); MONKEYS AB Rhesus macaque models have been instrumental in the development and testing of vaccines before human studies and have provided fundamental insights into the determinants of immune efficacy in a variety of infectious diseases. However, the characterization of antigen-specific T-cell receptor (TCR) repertoires during adaptive immune responses in these models has earlier relied on human TCR gene assignments. Here, we extracted and characterized TCR beta-chain (TRB) genes from the recently sequenced rhesus macaque genome that are homologous to the human TRB genes. Comparison of the rhesus macaque TRB genes with the human TRB genes showed an average best match similarity of 92.9%. Furthermore, we confirmed the usage of most rhesus macaque TRB genes by expressed TCR beta sequences within epitope-specific TCR repertoires. This primary description of the rhesus macaque TRB genes will provide a standardized nomenclature and enable better characterization of TCR usage in studies that use this species. Immunology and Cell Biology (2009) 87, 546-553; doi: 10.1038/icb.2009.38; published online 9 June 2009 C1 [Greenaway, Hui Yee; Kurniawan, Monica; Davenport, Miles P.; Venturi, Vanessa] Univ New S Wales, Ctr Vasc Res, Complex Syst Biol Grp, Kensington, NSW 2052, Australia. [Price, David A.] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff, S Glam, Wales. [Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Venturi, V (reprint author), Univ New S Wales, Ctr Vasc Res, Complex Syst Biol Grp, Wallace Wurth Bldg, Kensington, NSW 2052, Australia. EM v.venturi@unsw.edu.au RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU James S McDonnell Foundation 21st Century Research Award/Studying Complex Systems; Australian Research Council (ARC); National Institutes of Health (NIH); Medical Research Council (UK) FX We thank Dr Mark Tanaka for assistance with the phylogenetic analysis and Associate Professor Andrew Collins for helpful discussions. This work was supported by the James S McDonnell Foundation 21st Century Research Award/Studying Complex Systems, the Australian Research Council (ARC) and the National Institutes of Health (NIH). MPD is a Sylvia and Charles Viertel Senior Medical Research Fellow and DAP is a Medical Research Council (UK) Senior Clinical Fellow. NR 50 TC 7 Z9 8 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD OCT PY 2009 VL 87 IS 7 BP 546 EP 553 DI 10.1038/icb.2009.38 PG 8 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 506NN UT WOS:000270782300011 PM 19506572 ER PT J AU Newman, ZL Leppla, SH Moayeri, M AF Newman, Zachary L. Leppla, Stephen H. Moayeri, Mahtab TI CA-074Me Protection against Anthrax Lethal Toxin SO INFECTION AND IMMUNITY LA English DT Article ID INDEPENDENT PHOSPHOLIPASE A(2); TUMOR-NECROSIS-FACTOR; CELL-DEATH PATHWAY; CATHEPSIN-B; BACILLUS-ANTHRACIS; CASPASE-1 ACTIVATION; NALP3 INFLAMMASOME; METHYL-ESTER; LYSOSOMAL PERMEABILIZATION; MEDIATED ACTIVATION AB Anthrax lethal toxin (LT) activates the NLRP1b (NALP1b) inflammasome and caspase-1 in macrophages from certain inbred mouse strains, but the mechanism by which this occurs is poorly understood. We report here that similar to several NLRP3 (NALP3, cryopyrin)-activating stimuli, LT activation of the NLRP1b inflammasome involves lysosomal membrane permeabilization (LMP) and subsequent cytoplasmic cathepsin B activity. CA-074Me, a potent cathepsin B inhibitor, protects LT-sensitive macrophages from cell death and prevents the activation of caspase-1. RNA interference knockdown of cathepsin B expression, however, cannot prevent LT-mediated cell death, suggesting that CA-074Me may also act on other cellular proteases released during LMP. CA-074Me appears to function downstream of LT translocation to the cytosol (as assessed by mitogen-activated protein kinase kinase cleavage), K+ effluxes, and proteasome activity. The initial increase in cytoplasmic activity of cathepsin B occurs at the same time or shortly before caspase-1 activation but precedes a larger-scale lysosomal destabilization correlated closely with cytolysis. We present results suggesting that LMP may be involved in the activation of the NLRP1b inflammasome. C1 [Newman, Zachary L.; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Bacterial Toxins & Therapeut Sect, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIAID, Bacterial Toxins & Therapeut Sect, Lab Bacterial Dis, NIH, Bldg 33,Room 1W20B, Bethesda, MD 20892 USA. EM mmoayeri@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 64 TC 56 Z9 59 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2009 VL 77 IS 10 BP 4327 EP 4336 DI 10.1128/IAI.00730-09 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 496ER UT WOS:000269952800016 PM 19635822 ER PT J AU Zelazny, AM Ding, L Elloumi, HZ Brinster, LR Benedetti, F Czapiga, M Ulrich, RL Ballentine, SJ Goldberg, JB Sampaio, EP Holland, SM AF Zelazny, Adrian M. Ding, Li Elloumi, Houda Z. Brinster, Lauren R. Benedetti, Fran Czapiga, Meggan Ulrich, Ricky L. Ballentine, Samuel J. Goldberg, Joanna B. Sampaio, Elizabeth P. Holland, Steven M. TI Virulence and Cellular Interactions of Burkholderia multivorans in Chronic Granulomatous Disease SO INFECTION AND IMMUNITY LA English DT Article ID RESPIRATORY EPITHELIAL-CELLS; CEPACIA COMPLEX; CYSTIC-FIBROSIS; HOST-DEFENSE; INTRACELLULAR SURVIVAL; PSEUDOMONAS-CEPACIA; LUNG INFECTION; GENE-TRANSFER; MURINE MODEL; IN-VITRO AB Chronic granulomatous disease (CGD) patients are susceptible to life-threatening infections by the Burkholderia cepacia complex. We used leukocytes from CGD and healthy donors and compared cell association, invasion, and cytokine induction by Burkholderia multivorans strains. A CGD isolate, CGD1, showed higher cell association than that of an environmental isolate, Env1, which correlated with cell entry. All B. multivorans strains associated significantly more with cells from CGD patients than with those from healthy donors. Similar findings were observed with another CGD pathogen, Serratia marcescens, but not with Escherichia coli. In a mouse model of CGD, strain CGD1 was virulent while Env1 was avirulent. B. multivorans organisms were found in the spleens of CGD1-infected mice at levels that were 1,000 times higher than those found in Env1-infected mice, which was coincident with higher levels of the proinflammatory cytokine interleukin-1 beta. Taken together, these results may shed light on the unique susceptibility of CGD patients to specific pathogens. C1 [Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Zelazny, Adrian M.; Ding, Li; Elloumi, Houda Z.; Ballentine, Samuel J.; Sampaio, Elizabeth P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Brinster, Lauren R.; Benedetti, Fran] NIAID, Div Vet Resources, Bethesda, MD 20892 USA. [Czapiga, Meggan] NIAID, Biol Imaging Sect, Bethesda, MD 20892 USA. [Ulrich, Ricky L.] USA, Med Res Inst Infect Dis, Bacteriol Div, Ft Detrick, MD 21702 USA. [Goldberg, Joanna B.] Univ Virginia Hlth Syst, Dept Microbiol, Charlottesville, VA USA. [Sampaio, Elizabeth P.] Fiocruz MS, Leprosy Lab, Inst Oswaldo Cruz, BR-21045900 Rio De Janeiro, Brazil. RP Zelazny, AM (reprint author), NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, 10 Ctr Dr,Bldg 10-2C-385, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was financially supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 46 TC 12 Z9 13 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2009 VL 77 IS 10 BP 4337 EP 4344 DI 10.1128/IAI.00259-09 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 496ER UT WOS:000269952800017 PM 19635825 ER PT J AU Wilbur, WJ Kim, W AF Wilbur, W. John Kim, Won TI The ineffectiveness of within-document term frequency in text classification SO INFORMATION RETRIEVAL LA English DT Article DE Within-document frequency; Bag-of-words; Word burstiness AB For the purposes of classification it is common to represent a document as a bag of words. Such a representation consists of the individual terms making up the document together with the number of times each term appears in the document. All classification methods make use of the terms. It is common to also make use of the local term frequencies at the price of some added complication in the model. Examples are the na < ve Bayes multinomial model (MM), the Dirichlet compound multinomial model (DCM) and the exponential-family approximation of the DCM (EDCM), as well as support vector machines (SVM). Although it is usually claimed that incorporating local word frequency in a document improves text classification performance, we here test whether such claims are true or not. In this paper we show experimentally that simplified forms of the MM, EDCM, and SVM models which ignore the frequency of each word in a document perform about at the same level as MM, DCM, EDCM and SVM models which incorporate local term frequency. We also present a new form of the na < ve Bayes multivariate Bernoulli model (MBM) which is able to make use of local term frequency and show again that it offers no significant advantage over the plain MBM. We conclude that word burstiness is so strong that additional occurrences of a word essentially add no useful information to a classifier. C1 [Wilbur, W. John; Kim, Won] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Wilbur, WJ (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM wilbur@ncbi.nlm.nih.gov; wonkim@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX The authors are supported by the Intramural Research Program of the NIH, National Library of Medicine. The authors would like to thank the anonymous referees for numerous helpful comments which improved the work reported here. NR 25 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-4564 J9 INFORM RETRIEVAL JI Inf. Retr. PD OCT PY 2009 VL 12 IS 5 BP 509 EP 525 DI 10.1007/s10791-008-9069-5 PG 17 WC Computer Science, Information Systems SC Computer Science GA 488AF UT WOS:000269320200001 PM 19802376 ER PT J AU Laky, K Annaert, W Fowlkes, BJ AF Laky, Karen Annaert, Willem Fowlkes, B. J. TI Amyloid precursor family proteins are expressed by thymic and lymph node stromal cells but are not required for lymphocyte development SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE APP-deficient mice; APLP2-deficient mice; T cells; thymocytes; gamma-secretase ID GAMMA-SECRETASE ACTIVITY; HEMATOPOIETIC PROGENITOR CELLS; RECEPTOR-RELATED PROTEIN; NF-KAPPA-B; INTRACELLULAR DOMAIN; ALZHEIMERS-DISEASE; THYMOCYTE DEVELOPMENT; NOTCH LIGANDS; IN-VITRO; PRESENILIN/GAMMA-SECRETASE AB Pharmacological inhibitors that block amyloid precursor protein (APP) cleavage and the formation of senile plaques are under development for the treatment of familial Alzheimer's disease. Unfortunately, many inhibitors that block gamma-secretase-mediated cleavage of APP also have immunosuppressive side effects. In addition to APP, numerous other proteins undergo gamma-secretase-mediated cleavage. In order to develop safer inhibitors, it is necessary to determine which of the gamma-secretase substrates contribute to the immunosuppressive effects. Because APP family members are widely expressed and are reported to influence calcium flux, transcription and apoptosis, they could be important for normal lymphocyte maturation. We find that APP and amyloid precursor-like protein 2 are expressed by stromal cells of thymus and lymph nodes, but not by lymphocytes. Although signals provided by thymic stromal cells are critical for normal T cell differentiation, lymphocyte development proceeds unperturbed in mice deficient for these APP family members. C1 [Laky, Karen; Fowlkes, B. J.] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. [Annaert, Willem] Ctr Human Genet KULeuven & VIB, Lab Membrane Trafficking, Louvain, Belgium. RP Fowlkes, BJ (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 111, Bethesda, MD 20892 USA. EM bfowlkes@nih.gov FU NIAID FX National Institutes of Health Intramural Research Program of the NIAID. NR 73 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD OCT PY 2009 VL 21 IS 10 BP 1163 EP 1174 DI 10.1093/intimm/dxp083 PG 12 WC Immunology SC Immunology GA 499KH UT WOS:000270218500008 PM 19710207 ER PT J AU Miller, MA Barr, BC Nordhausen, R James, ER Magargal, SL Murray, M Conrad, PA Toy-Choutka, S Jessup, DA Grigg, ME AF Miller, M. A. Barr, B. C. Nordhausen, R. James, E. R. Magargal, S. L. Murray, M. Conrad, P. A. Toy-Choutka, S. Jessup, D. A. Grigg, M. E. TI Ultrastructural and molecular confirmation of the development of Sarcocystis neurona tissue cysts in the central nervous system of southern sea otters (Enhydra lutris nereis) SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Sea otter; Sarcocystis neurona; Tissue cyst; Central nervous system; Brain; Ultrastructure; 18S rDNA; ITS1 ID OPOSSUMS DIDELPHIS-VIRGINIANA; EQUINE PROTOZOAL MYELOENCEPHALITIS; TOXOPLASMA-GONDII INFECTION; PHOCA-VITULINA-RICHARDSI; N-SP PROTOZOA; INTERMEDIATE HOST; MEPHITIS-MEPHITIS; PROCYON-LOTOR; LIFE-CYCLE; MENINGOENCEPHALITIS AB In 2004, three wild sea otters were diagnosed with putative Sarcocystis neurona-associated meningoencephalitis by histopathology and immunohistochemistry. Schizonts, free merozoites and tissue cysts were observed in the brains of all three infected animals. Tissue cysts walls from sea otter I (SO1) stained positively using anti-S. neurona polyclonal antiserum. However, positive staining does not preclude infection by closely related or cross-reactive tissue cyst-forming coccidian parasites. Two immature tissue cysts in the brain of SO1 were examined using transmission electron microscopy. Ultrastructural features included cyst walls with thin villous projections up to I pm long with tapered ends and a distinctive, electron-dense outer lining layer composed of linearly-arranged, semi-circular structures with a "hob-nailed" surface contour. Small numbers of microtubules extended down through the villi into the underlying granular layer. Metrocytes were short and plump with an anterior apical complex, 22 sub-pellicular microtubules, numerous free ribosomes and no rhoptries. Some metrocytes appeared to be dividing, with two adjacent nuclear profiles. Collectively these ultrastructural features were compatible with developing protozoal cysts and were similar to prior descriptions of S. neurona tissue cysts. Panspecific 18S rDNA primers were utilized to identify protozoa infecting the brains of these otters and DNA amplification and additional sequencing at the ITS1 locus confirmed that all three otters were infected with S. neurona. No other Sarcocystis spp. were detected in the brains or skeletal muscles of these animals by immunohistochemistry or PCR. We believe this is the first ultrastructural and molecular confirmation of the development of S. neurona tissue cysts in the CNS of any animal. Published by Elsevier Ltd. on behalf of Australian Society for Parasitology Inc. C1 [Miller, M. A.; Toy-Choutka, S.; Jessup, D. A.] Calif Dept Fish & Game, Marine Wildlife Vet Care & Res Ctr, Santa Cruz, CA 95060 USA. [Barr, B. C.; Nordhausen, R.] Univ Calif Davis, Calif Anim Hlth & Food Safety Serv Lab, Davis, CA 95617 USA. [James, E. R.] Univ British Columbia, Dept Med, Vancouver, BC V5Z 3J5, Canada. [Magargal, S. L.; Grigg, M. E.] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Murray, M.] Monterey Bay Aquarium, Monterey, CA 93940 USA. [Conrad, P. A.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. RP Miller, MA (reprint author), Calif Dept Fish & Game, Marine Wildlife Vet Care & Res Ctr, 1451 Shaffer Rd, Santa Cruz, CA 95060 USA. EM MMiller@ospr.dfg.ca.gov; grggm@niaid.nih.gov RI James, Erick/D-4725-2012 FU California Department of Fish and Game-Department of Oil Spill Prevention and Response (CDFG); NIH; NIAID FX This project was funded and completed by the California Department of Fish and Game-Department of Oil Spill Prevention and Response (CDFG) and by the Intramural Research Program of the NIH and NIAID (MEG). Staff and volunteers of CDFG, Monterey Bay Aquarium, the Marine Mammal Center, United States Geological Survey and the United States Fish and Wildlife Service helped recover and transport live and dead sea otters along the central California coast. We appreciate the assistance of the CDFG Petroleum Chemistry Laboratory, especially Dr. Susan Sugarman for completing the petroleum fingerprint testing on otter #3. Technical staff from CDFG assisted with otter necropsy, specimen collection and storage and data collection. Bacterial and protozoal cultures and protozoal serology were completed at the UC Davis School of Veterinary Medicine. Immunohistochemical stains for S. neurona and T. gondii and domoic acid testing were prepared at the California Animal Health and Food Safety (CAHFS) Laboratory. NR 54 TC 15 Z9 16 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD OCT PY 2009 VL 39 IS 12 BP 1363 EP 1372 DI 10.1016/j.ijpara.2009.04.014 PG 10 WC Parasitology SC Parasitology GA 491RW UT WOS:000269598100007 PM 19527725 ER PT J AU Thomas, KJ Cookson, MR AF Thomas, Kelly Jean Cookson, Mark R. TI The role of PTEN-induced kinase 1 in mitochondrial dysfunction and dynamics SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Review DE Parkinsonism; Parkin; Drp1; Fission; Fusion; Oxidative stress ID EARLY-ONSET PARKINSONISM; CYTOCHROME-C RELEASE; DEPENDENT PROTEIN-KINASE; SUBSTANTIA-NIGRA NEURONS; PINK1 MUTATIONS; CELL-DEATH; PERMEABILITY TRANSITION; OXIDATIVE STRESS; SUBCELLULAR-DISTRIBUTION; RECESSIVE PARKINSONISM AB Mutations in parkin, PTEN-induced kinase 1 (PINK1) and DJ-1 can all cause autosomal recessive forms of Parkinson's disease. Recent data suggest that these recessive parkinsonism-associated genes converge within a single pathogenic pathway whose dysfunction leads to the loss of substantia nigra pars compacta neurons. The major common functional effects of all three genes relate to mitochondrial and oxidative damage, with a possible additional involvement of the ubiquitin proteasome system. This review highlights the role of the mitochondrial kinase, PINK1, in protection against mitochondrial dysfunction and how this might relate to loss of substaintia nigra neurons in recessive parkinsonism. Published by Elsevier Ltd. C1 [Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20982 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, Bldg 35,Room 1A116,MSC 3707,35 Convent Dr, Bethesda, MD 20982 USA. EM Cookson@mail.nih.gov FU National Institutes on Aging, Intramural Research Program, NIH FX This work was supported by the National Institutes on Aging, Intramural Research Program, NIH. NR 181 TC 22 Z9 22 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD OCT PY 2009 VL 41 IS 10 BP 2025 EP 2035 DI 10.1016/j.biocel.2009.02.018 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 501AZ UT WOS:000270351100029 PM 19703660 ER PT J AU Castle, PE Rodriguez, AC Burk, RD Herrero, R Hildesheim, A Solomon, D Sherman, ME Jeronimo, J Alfaro, M Morales, J Guillen, D Hutchinson, ML Wacholder, S Schiffman, M AF Castle, Philip E. Rodriguez, Ana C. Burk, Robert D. Herrero, Rolando Hildesheim, Allan Solomon, Diane Sherman, Mark E. Jeronimo, Jose Alfaro, Mario Morales, Jorge Guillen, Diego Hutchinson, Martha L. Wacholder, Sholom Schiffman, Mark TI Neither one-time negative screening tests nor negative colposcopy provides absolute reassurance against cervical cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical cancer; human papillomavirus; cytology; Pap smear; cervical intraepithelial neoplasia; loop electrosurgical excision procedure; Guanacaste ID HUMAN-PAPILLOMAVIRUS DNA; SQUAMOUS INTRAEPITHELIAL LESIONS; LOOP ELECTROSURGICAL EXCISION; COSTA-RICA; FOLLOW-UP; INCIDENCE TRENDS; CLINICAL-TRIAL; HIGH-RISK; WOMEN; NEOPLASIA AB A population sample of 10,049 women living in Guanacaste, Costa Rica, was recruited into a natural history of human papillomavirus (HPV) and cervical neoplasia study in 1993-1994. At the enrollment visit, we applied multiple state-of-the-art cervical cancer screening methods to detect prevalent cervical cancer and to prevent subsequent cervical cancers by the timely detection an treatment of precancerous lesions. Women were screened at enrollment with 3 kinds of cytology (often reviewed by more than one pathologist), visual inspection and cervicography. Any positive screening test led to colposcopic referral and biopsy and/or excisional treatment of CIN2 or worse. We retrospectively tested stored specimens with an early HPV test (hybrid capture tube test) and for >40 HPV genotypes using a research PCR assay. We followed women typically 5-7 years and some up to 11 years. Nonetheless, 16 cases of Invasive cervical cancer were diagnosed during follow-up. Six cancer cases were failures at enrollment to detect abnormalities by cytology screening; 3 of the 6 were also negative at enrollment by sensitive HPV DNA testing. Seven cancers represent failures of colposcopy to diagnose cancer or a precancerous lesion in screen-positive women. Finally, 3 cases arose despite attempted excisional treatment of precancerous lesions. Based on this evidence, we suggest that no current secondary cervical cancer prevention technologies applied once in a previously under-screened population is likely to be 100% efficacious in preventing incident diagnoses of invasive cervical cancer. (C) 2009 UICC C1 [Castle, Philip E.; Hildesheim, Allan; Sherman, Mark E.; Jeronimo, Jose; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Rodriguez, Ana C.; Herrero, Rolando; Morales, Jorge; Guillen, Diego] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA. [Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY USA. [Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Obstet & Gynecol, Bronx, NY USA. [Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Womens Hlth, Bronx, NY USA. [Burk, Robert D.] Yeshiva Univ, Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Jeronimo, Jose] Program Appropriate Technol Hlth, Seattle, WA USA. [Alfaro, Mario] Caja Costarricense Seguro Social, Lab Nacl Citol, San Jose, Costa Rica. [Hutchinson, Martha L.] Women & Infants Hosp Rhode Isl, Dept Pathol & Lab Med, Providence, RI 02908 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd Room 5030,EPS MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NIH/National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH/National Cancer Institute. NR 49 TC 9 Z9 9 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2009 VL 125 IS 7 BP 1649 EP 1656 DI 10.1002/ijc.24525 PG 8 WC Oncology SC Oncology GA 491GB UT WOS:000269565400018 PM 19569231 ER PT J AU Cornfield, J Haenszel, W Hammond, EC Lilienfeld, AM Shimkin, MB Wynder, EL AF Cornfield, Jerome Haenszel, William Hammond, E. Cuyler Lilienfeld, Abraham M. Shimkin, Michael B. Wynder, Ernst L. TI Smoking and lung cancer: recent evidence and a discussion of some questions SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article ID CIGARETTE-SMOKE; BRONCHIAL EPITHELIUM; AIR POLLUTION; TOBACCO TAR; DEATH RATES; MORTALITY; CONDENSATE; BENZPYRENE; CARCINOMA AB This report reviews some of the more recent epidemiologic and experimental findings on the relationship of tobacco smoking to lung cancer, and discusses some criticisms directed against the conclusion that tobacco smoking, especially cigarettes, has a causal role in the increase in broncho-genic carcinoma. The magnitude of the excess lung-cancer risk among cigarette smokers is so great that the results can not be interpreted as arising from an indirect association of cigarette smoking with some other agent or characteristic, since this hypothetical agent would have to be at least as strongly associated with lung cancer as cigarette use; no such agent has been found or suggested. The consistency of all the epidemiologic and experimental evidence also supports the conclusion of a causal relationship with cigarette smoking, while there are serious inconsistencies in reconciling the evidence with other hypotheses which have been advanced. Unquestionably there are areas where more research is necessary, and, of course, no single cause accounts for all lung cancer. The information already available, however, is sufficient for planning and activating public health measures. - J. Nat. Cancer Inst. 22:173-203, 1959. C1 [Cornfield, Jerome] Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Biostat, Baltimore, MD 21218 USA. [Haenszel, William; Shimkin, Michael B.] US PHS, Natl Canc Inst, Dept Hlth Educ & Welf, Bethesda, MD USA. [Hammond, E. Cuyler] Amer Canc Soc Inc, New York, NY USA. [Wynder, Ernst L.] Sloan Kettering Inst Canc Res, New York, NY USA. RP Cornfield, J (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Biostat, Baltimore, MD 21218 USA. NR 81 TC 58 Z9 59 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2009 VL 38 IS 5 BP 1175 EP 1191 DI 10.1093/ije/dyp289 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 510PH UT WOS:000271101800003 PM 19773415 ER PT J AU Hazra, R Stoszek, SK Hance, LF Pinto, J Marques, H Peixoto, M Alarcon, J Mussi-Pinhata, M Serchuck, L AF Hazra, Rohan Stoszek, Sonia K. Hance, Laura Freimanis Pinto, Jorge Marques, Heloisa Peixoto, Mario Alarcon, Jorge Mussi-Pinhata, Marisa Serchuck, Leslie CA NISDI Pediat Study Grp 2008 TI Cohort Profile: NICHD International Site Development Initiative (NISDI): a prospective, observational study of HIV-exposed and HIV-infected children at clinical sites in Latin American and Caribbean countries SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID INFANT TRANSMISSION; ZIDOVUDINE; WOMEN C1 [Hazra, Rohan; Serchuck, Leslie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. [Stoszek, Sonia K.; Hance, Laura Freimanis] Westat Corp, Rockville, MD USA. [Pinto, Jorge] Univ Fed Minas Gerais, Dept Pediat, Div Immunol, Belo Horizonte, MG, Brazil. [Peixoto, Mario] Hosp Femina, Grp Hosp Conceicao, Porto Alegre, RS, Brazil. [Pinto, Jorge] Univ Nacl Mayor San Marcos, Inst Med Trop Daniel Alcides Carrion, Lima 14, Peru. [Mussi-Pinhata, Marisa] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. RP Hazra, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, 6100 Execut Blvd,Room 4B11, Bethesda, MD 20892 USA. EM hazrar@mail.nih.gov RI Mussi-Pinhata, Marisa/G-6568-2012; OI Mofenson, Lynne/0000-0002-2818-9808; moye, john/0000-0001-9976-8586; Alarcon, Jorge/0000-0002-0800-2380 FU NICHD NIH HHS [#N01-HD-3-3345]; NIDDK NIH HHS [#N01-DK-8-0001] NR 8 TC 22 Z9 22 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2009 VL 38 IS 5 BP 1207 EP 1214 DI 10.1093/ije/dyn239 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 510PH UT WOS:000271101800009 PM 19036797 ER PT J AU Rice, NE Bandinelli, S Corsi, AM Ferrucci, L Guralnik, JM Miller, MA Kumari, M Murray, A Frayling, TM Melzer, D AF Rice, Neil E. Bandinelli, Stefania Corsi, Anna Maria Ferrucci, Luigi Guralnik, Jack M. Miller, Michelle A. Kumari, Meena Murray, Anna Frayling, Tim M. Melzer, David TI The paraoxonase (PON1) Q192R polymorphism is not associated with poor health status or depression in the ELSA or INCHIANTI studies SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE PON1 Q192R polymorphism; rs662; organophosphates; detoxification; paraoxonase activity; depression; Mendelian randomization ID GENOME-WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; GENETIC EPIDEMIOLOGY; SUSCEPTIBILITY; DISEASE; SHEEP; DISORDER AB Background The human paraoxonase (PON1) protein detoxifies certain organophosphates, and the PON1 Q192R polymorphism (rs662) affects PON1 activity. Groups with higher dose exposure to organophosphate sheep dips or first Gulf War nerve toxins reported poorer health if they had 192R, and these associations have been used to exemplify Mendelian randomization analysis. However, a reported association of 192R with depression in a population-based study of older women recently cast doubt on the specificity of the higher dose findings. We aimed to examine associations between the PON1 Q192R polymorphism and self-reported poor health and depression in two independent population-based studies. Methods We used logistic regression models to examine the associations in men and women aged 60-79 years from the English Longitudinal Study of Ageing (ELSA, n = 3158) and InCHIANTI (n = 761) population studies. Outcomes included the Center for Epidemiologic Studies Depression (CES-D) scale, self-rated general health status and (in ELSA only) diagnoses of depression. Results The PON1 Q192R polymorphism was not associated with self-reported poor health {meta-analysis: odds ratio (OR)= 1.01 [confidence interval (CI) 0.91-1.13], P = 0.801} or depressive symptoms in either study or in meta-analyses [CES-D: OR = 1.01 (CI 0.87-1.17), P = 0.90]. There was also no association with histories of diagnosed depression in ELSA [OR = 1.03 (CI 0.82-1.30), P = 0.80]. Conclusions We found no evidence of an association between the PON1 Q192R polymorphism, and poor general or mental health in two independent population-based studies. Neither the claimed Q192R association with depression in the general population nor its theoretical implications were supported. C1 [Rice, Neil E.; Murray, Anna; Melzer, David] Peninsula Med Sch, Epidemiol & Publ Hlth Grp, Exeter EX2 5DW, Devon, England. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Corsi, Anna Maria] Tuscany Reg Hlth Agcy, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Miller, Michelle A.] CSB, Clin Sci Res Inst, Warwick Med Sch, Coventry, W Midlands, England. [Kumari, Meena] UCL, Dept Epidemiol & Publ Hlth, London, England. RP Melzer, D (reprint author), Peninsula Med Sch, Epidemiol & Publ Hlth Grp, RD&E Site,Barrack Rd, Exeter EX2 5DW, Devon, England. EM david.melzer@pms.ac.uk RI Miller, Michelle/D-1840-2009; OI Murray, Anna/0000-0002-2351-2522; Kumari, Meena/0000-0001-9716-1035; Melzer, David/0000-0002-0170-3838 FU US National Institute on Aging [R01AG24233, R01AG1764406S1] FX US National Institute on Aging [grant numbers R01AG24233, R01AG1764406S1 to English Longitudinal Study of Ageing DNA Repository (EDNAR)]; the Intramural Research Program, US National Institute on Aging, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 8 Z9 8 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD OCT PY 2009 VL 38 IS 5 BP 1374 EP 1379 DI 10.1093/ije/dyp265 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 510PH UT WOS:000271101800031 PM 19651761 ER PT J AU Stetler-Stevenson, M Yuan, CM AF Stetler-Stevenson, M. Yuan, C. M. TI Myelodysplastic syndromes: the role of flow cytometry in diagnosis and prognosis SO INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY LA English DT Review DE Flow cytometry; Myelodysplastic Syndromes; Cytopenia; Idiopathic Cytopenia of Uncertain Significance; Prognosis ID BONE-MARROW; ABNORMALITIES; CYTOGENETICS; EXPRESSION; DYSPLASIA; CELLS AB P>Flow cytometric immunophenotypic analysis is a well-recognized and widely accepted adjuvant test to increase the sensitivity and specificity of diagnosis in potential myelodysplastic syndrome (MDS) cases. In addition, flow cytometric analysis provides prognostic information in MDS that is not available from other sources. The flow cytometric findings indicative of MDS and its value is a diagnostic adjunct are discussed. C1 [Stetler-Stevenson, M.; Yuan, C. M.] NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20895 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2A-33,Mail Stop 1500, Bethesda, MD 20895 USA. EM stetler@mail.nih.gov FU NIH; NCI FX This was supported in part by the Intramural Research Program of the NIH, NCI. NR 22 TC 10 Z9 11 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1751-5521 J9 INT J LAB HEMATOL JI Int. J. Lab. Hematol. PD OCT PY 2009 VL 31 IS 5 BP 479 EP 483 DI 10.1111/j.1751-553X.2009.01176.x PG 5 WC Hematology SC Hematology GA 487IQ UT WOS:000269265900001 PM 19555363 ER PT J AU Ando, H Ichihashi, M Hearing, VJ AF Ando, Hideya Ichihashi, Masamitsu Hearing, Vincent J. TI Role of the Ubiquitin Proteasome System in Regulating Skin Pigmentation SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE fatty acid; melanin; melanocyte; tyrosinase; skin; pigmentation ID OCULOCUTANEOUS ALBINISM TYPE-1; MOUSE MELANOMA-CELLS; FATTY-ACIDS; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; MULTICATALYTIC PROTEINASE; SECRETORY PATHWAY; MOLECULAR-BASIS; LINOLEIC-ACID; TYROSINASE AB Pigmentation of the skin, hair and eyes is regulated by tyrosinase, the critical rate-limiting enzyme in melanin synthesis by melanocytes. Tyrosinase is degraded endogenously, at least in part, by the ubiquitin proteasome system ( UPS). Several types of inherited hypopigmentary diseases, such as oculocutaneous albinism and Hermansky-Pudlak syndrome, involve the aberrant processing and/or trafficking of tyrosinase and its subsequent degradation which can occur due to the quality-control machinery. Studies on carbohydrate modifications have revealed that tyrosinase in the endoplasmic reticulum (ER) is proteolyzed via ER-associated protein degradation and that tyrosinase degradation can also occur following its complete maturation in the Golgi. Among intrinsic factors that regulate the UPS, fatty acids have been shown to modulate tyrosinase degradation in contrasting manners through increased or decreased amounts of ubiquitinated tyrosinase that leads to its accelerated or decelerated degradation by proteasomes. C1 [Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Ando, Hideya; Ichihashi, Masamitsu] Doshisha Univ, Skin Aging & Photoaging Res Ctr, Kyoto 6190225, Japan. [Ando, Hideya; Ichihashi, Masamitsu] Kobe Skin Res Inst, Kobe, Hyogo 6500047, Japan. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM hideyaando@aol.com; mm_ichihashi@hotmail.com; hearingv@nih.gov FU NIH, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 39 TC 15 Z9 17 U1 0 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD OCT PY 2009 VL 10 IS 10 BP 4428 EP 4434 DI 10.3390/ijms10104428 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA 512UJ UT WOS:000271276000014 PM 20057953 ER PT J AU Hyodo, F Chandramouli, GVR Matsumoto, S Matsumoto, KI Mitchell, JB Krishna, MC Munasinghe, JP AF Hyodo, Fuminori Chandramouli, Gadisetti V. R. Matsumoto, Shingo Matsumoto, Ken-Ichiro Mitchell, James B. Krishna, Murali C. Munasinghe, Jeeva P. TI Estimation of tumor microvessel density by MRI using a blood pool contrast agent SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE angiogenesis; blood volume; microvascular density; MRI; Sunitinib; tumor; USPIO ID IRON-OXIDE; ENHANCED MRI; VOLUME; ANGIOGENESIS; BRAIN; MICE; FLOW; VASCULATURE; CARCINOMA; THERAPY AB Recognition of importance of angiogenesis to tumor growth, metastasis, and treatment outcome has led to efforts to develop non-invasive methods for longitudinal monitoring of tumor microvasculature. We describe a steady-state MRI technique to determine absolute blood volume (BV) as a marker of microvascular density with improved spatial and temporal resolution using an ultra small super paramagnetic iron oxide (USPIO). A noise reduction scheme for BV imaging was also proposed based on weighting factors derived by pre-contrast signal level as an adjustable additive constant. Gradient echo sequence was used for BV imaging with MRI at 7T. Optimal imaging conditions (USPIO dose and echo time) were determined by USPIO dose-dependent studies ex vivo and in vivo. Improved analysis strategies were at first applied for cerebral BV estimation in mice, which were found in good agreement with the literature values. These methods were then used to determine tumor BV in mice. The optimal concentration of USPIO for BV estimates was found to range from 3.6 to 4.48 mM (estimated as Fe concentration) in ex vivo experiments corresponding to an in vivo dosage of 215-287 mu mol/kg body weight, whereas a USPIO dose of 287 mu mol/kg leads to higher cerebral BV estimate in vivo than the reported values. Application of the BV imaging method to evaluation of anti-angiogenic effect of Sunitinib in squamous cell carcinoma (SCC) tumor bearing mice revealed similar to 46% reduction in tumor BV 4 days after start of Sunitinib treatment. The results show that the MRI. approach using USPIO yields high-resolution absolute BV images and the method can be conveniently applied to monitor longitudinal tumor microvessel density changes as a function of growth or in response to treatment. C1 [Hyodo, Fuminori; Chandramouli, Gadisetti V. R.; Matsumoto, Shingo; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hyodo, Fuminori] Kyushu Univ, Innovat Ctr Med Redox Nav, Fukuoka 812, Japan. [Matsumoto, Ken-Ichiro] Natl Inst Radiol Sci, Heavy Ion Radiobiol Res Grp, Chiba 260, Japan. [Munasinghe, Jeeva P.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM murali@helix.nih.gov NR 29 TC 16 Z9 16 U1 1 U2 5 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 OCT PY 2009 VL 35 IS 4 BP 797 EP 804 DI 10.3892/ijo_00000392 PG 8 WC Oncology SC Oncology GA 494AD UT WOS:000269780600015 PM 19724915 ER PT J AU Vikram, B AF Vikram, Bhadrasain TI CYBERKNIFE AND PROSTATE CANCER. IN REGARD TO KING ET AL. (INT J RADIAT ONCOL BIOL PHYS 2009;73:1043-1048) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter ID THERAPY C1 NCI, Clin Radiat Oncol Branch, Rockville, MD USA. RP Vikram, B (reprint author), NCI, Clin Radiat Oncol Branch, Rockville, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2009 VL 75 IS 2 BP 632 EP 632 DI 10.1016/j.ijrobp.2009.05.064 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 496AZ UT WOS:000269941600045 PM 19735890 ER PT J AU Lamm, AS Khare, A Conville, P Lau, PCK Bergeron, H Rosazza, JPN AF Lamm, Andrew S. Khare, Arshdeep Conville, Patricia Lau, Peter C. K. Bergeron, Helene Rosazza, John P. N. TI Nocardia iowensis sp nov., an organism rich in biocatalytically important enzymes and nitric oxide synthase SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article ID RIBOSOMAL-RNA GENE; ALDEHYDE OXIDOREDUCTASE; PHYLOGENETIC TREES; IDENTIFICATION; SEQUENCES; PURIFICATION; ACIDS; METABOLISM; EXPRESSION; NRRL-5646 AB Nocardia strain NRRL 5646, isolated from a garden soil sample in Osceola, Iowa, USA, was initially of interest as an antibiotic producer. It contained biocatalytically important enzymes and represented the first described nitric oxide synthase enzyme system in bacteria. The present polyphasic taxonomic study was undertaken to differentiate strain NRRL 5646 T from related species of the genus Nocardia. Chemotaxonomic analyses included determinations of the fatty acid methyl ester profile (C(16:1)omega 6c/C(16:1)omega 7c, C(16:0), C(18:1)omega 9c and C(18:0) 10-methyl as major components), quinone [cyclo, MK-8(H(4)) as the major component], polar lipid (diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside as major components) and mycolic acid. These results supported its placement within the genus Nocardia. Biochemical testing and 16S rRNA, 65-kDa heat-shock protein (hsp65) and preprotein translocase (secA1) gene sequence analyses differentiated strain NRRL 5646(T) from recognized Nocardia species. Previous studies have demonstrated that other genetic sequences (carboxylic acid reductase, Nocardia phosphopantetheinyl transferase and GTP cyclohydrolase I) from strain NRRL 5646(T) can also be used to substantiate its uniqueness. The level of 16S rRNA gene sequence similarity between strain NRRL 5646(T) and the type strains of Nocardia tenerifensis and Nocardia brasiliensis was 98.8 %. However, strain NRRL 5646 T could be clearly distinguished from these Nocardia species based on DNA-DNA hybridization data. Consequently, strain NRRL 5646(T) is considered to represent a novel species of the genus Nocardia, for which the name Nocardia iowensis sp. nov. is proposed. The type strain is NRRL 5646(T) (=UI 122540(T) =NRRL B-24671(T) =DSM 45197(T)). C1 [Lamm, Andrew S.; Khare, Arshdeep; Rosazza, John P. N.] Univ Iowa, Ctr Biocatalysis & Bioproc, Iowa City, IA 52242 USA. [Conville, Patricia] NIH, Microbiol Serv, Dept Lab Med, Warren G Magnuson Clin Ctr,US Dept Hlth & Human S, Bethesda, MD 20892 USA. [Lau, Peter C. K.; Bergeron, Helene] Natl Res Council Canada, Biotechnol Res Inst, Montreal, PQ H4P 2R2, Canada. RP Rosazza, JPN (reprint author), Univ Iowa, Ctr Biocatalysis & Bioproc, 2501 Crosspk Rd,Suite C100,Oakdale Res Pk, Iowa City, IA 52242 USA. EM john-rosazza@uiowa.edu FU Iowa Biotechnology Byproducts Consortium; US Department of Agriculture [2002-34188-12035, 2004-34188-15067]; NIH Warren G. Magnuson Clinical Center FX We acknowledge the assistance of Claude Pujol and Jean Ross at the University of Iowa. This work was supported by the Iowa Biotechnology Byproducts Consortium, through the Cooperative State Research, Education and Extension Service, US Department of Agriculture, under Agreement nos 2002-34188-12035 and 2004-34188-15067. Any opinions, findings, conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the US Department of Agriculture. In addition, this research was supported in part by the Intramural Research Program of the NIH Warren G. Magnuson Clinical Center. The views expressed herein are those of the authors and should not be construed as those of the US Department of Health and Human Services. NR 39 TC 4 Z9 4 U1 0 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD OCT PY 2009 VL 59 BP 2408 EP 2414 DI 10.1099/ijs.0.007427-0 PG 7 WC Microbiology SC Microbiology GA 511ZL UT WOS:000271211000006 PM 19622667 ER PT J AU Gericke, A Mayer, VGA Steege, A Patzak, A Neumann, U Grus, FH Joachim, SC Choritz, L Wess, J Pfeiffer, N AF Gericke, Adrian Mayer, Veronique G. A. Steege, Andreas Patzak, Andreas Neumann, Ulrike Grus, Franz H. Joachim, Stephanie C. Choritz, Lars Wess, Juergen Pfeiffer, Norbert TI Cholinergic Responses of Ophthalmic Arteries in M(3) and M(5) Muscarinic Acetylcholine Receptor Knockout Mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ISCHEMIC OPTIC NEUROPATHY; OCULAR BLOOD-FLOW; ENDOTHELIAL DYSFUNCTION; MACULAR DEGENERATION; CHOROIDAL CIRCULATION; DIABETIC-RETINOPATHY; RETROBULBAR HEMODYNAMICS; ISOMETRIC-EXERCISE; NITRIC-OXIDE; NERVE HEAD AB PURPOSE. To determine the functional role of M(3) and M(5) muscarinic acetylcholine receptor subtypes in ophthalmic arteries using gene-targeted mice. METHODS. Muscarinic receptor gene expression was quantified in murine ophthalmic arteries using real-time PCR. To test the functional relevance of M(3) and M(5) receptors, ophthalmic arteries from mice deficient in either subtype (M3R(-/-), M5R(-/-), respectively) and wild-type controls were isolated, cannulated with micropipettes, and pressurized. Changes in luminal vessel diameter in response to muscarinic and nonmuscarinic receptor agonists were measured by video microscopy. RESULTS. With the use of real-time PCR, all five muscarinic receptor subtypes were detected in ophthalmic arteries. However, mRNA levels of M(1), M(3), and M(5) receptors were higher than those of M(2) and M(4) receptors. In functional studies, after preconstriction with phenylephrine, acetylcholine and carbachol produced concentration-dependent dilations of ophthalmic arteries that were similar in M5R(-/-) and wild-type mice. Strikingly, cholinergic dilation of ophthalmic arteries was almost completely abolished in M3R(-/-) mice. Deletion of either M(3) or M(5) receptor did not affect responses to nonmuscarinic vasodilators such as bradykinin or nitroprusside. CONCLUSIONS. These findings provide the first evidence that M(3) receptors are critically involved in cholinergic regulation of diameter in murine ophthalmic arteries. (Invest Ophthalmol Vis Sci.2009;50:4822-4827) DOI: 10.1167/iovs.09-3600 C1 [Gericke, Adrian; Mayer, Veronique G. A.; Grus, Franz H.; Joachim, Stephanie C.; Choritz, Lars; Pfeiffer, Norbert] Johannes Gutenberg Univ Mainz, Univ Med, Dept Ophthalmol, D-55101 Mainz, Germany. [Steege, Andreas; Patzak, Andreas; Neumann, Ulrike] Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany. [Wess, Juergen] NIDDKD, Mol Signalling Lab, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gericke, A (reprint author), Johannes Gutenberg Univ Mainz, Univ Med, Dept Ophthalmol, D-55101 Mainz, Germany. EM adrian.gericke@gmx.net RI Steege, Andreas/F-3885-2010; Choritz, Lars/G-1859-2013 FU Ernst und Berta Grimmke Stiftung [5/08] FX Supported by Grant 5/08 from the Ernst und Berta Grimmke Stiftung. NR 50 TC 8 Z9 8 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2009 VL 50 IS 10 BP 4822 EP 4827 DI 10.1167/iovs.09-3600 PG 6 WC Ophthalmology SC Ophthalmology GA 497XE UT WOS:000270097200040 PM 19407017 ER PT J AU Ding, XY Patel, M Shen, DF Herzlich, AA Cao, XG Villasmil, R Klupsch, K Tuo, JS Downward, J Chan, CC AF Ding, Xiaoyan Patel, Mrinali Shen, Defen Herzlich, Alexandra A. Cao, Xiaoguang Villasmil, Rafael Klupsch, Kristina Tuo, Jingsheng Downward, Julian Chan, Chi-Chao TI Enhanced HtrA2/Omi Expression in Oxidative Injury to Retinal Pigment Epithelial Cells and Murine Models of Neurodegeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID HTRA1 PROMOTER POLYMORPHISM; SERINE-PROTEASE OMI/HTRA2; MACULAR DEGENERATION; NEUROPROTECTIVE ROLE; FAMILY PROTEINS; APOPTOSIS; DISEASE; DEATH; RPE; MITOCHONDRIA AB PURPOSE. To investigate the role of HtrA2/Omi, a nuclear-encoded mitochondrial serine protease with a proapoptosis function, under H(2)O(2)-induced oxidative stress in human RPE, in the Ccl2(-/-) Cx3cr1(-/-) double-knockout (DKO) mouse retina, and the HtrA2/Omi-deficient mice. METHODS. Oxidative stress was induced in ARPE-19 cells by 1 mM H(2)O(2) for 2 hours. HtrA2/Omi and caspase-3 expression was evaluated using RQ-PCR, immunohistochemistry, or Western blot. Cell viability was detected by MTT assay. HtrA2/Omi expression in the subcellular components and activated caspase-3 were measured. These processes were also evaluated in cells treated with UCF-101, an HtrA2/Omi inhibitor or in cells subjected to RNAi against HtrA2/Omi. Oxidative stress was assayed and compared in retinas of DKO and wild-type (WT) mice by determining serum NADPH oxidase subunits and nitrite levels. Transmission electron microscopy was used to view the retinal ultrastructure of the HtrA2/Omi-deficient mice. RESULTS. H(2)O(2)-induced oxidative damage resulted in HtrA2/Omi translocation from mitochondria to cytosol, leading to RPE cell apoptosis via a caspase-mediated pathway. Treatment of RPE cells with UCF-101 reduced the cytosolic translocation of HtrA2/Omi, attenuated caspase-3 activation, and decreased apoptosis. After specific HtrA2 downregulation, increased cell viability was measured in H(2)O(2)-treated ARPE-19 cells. Retina of DKO mice exhibit increased oxidative stress and upregulation of HtrA2/Omi. Fewer and abnormal mitochondria were found in HtrA2/Omi(-/-) photoreceptors and RPE. CONCLUSIONS. These findings suggest that HtrA2/Omi is related to RPE apoptosis due to oxidative stress, which may play an important role in the integrity of mitochondria and the pathogenesis of AMD. (Invest Ophthalmol Vis Sci. 2009; 50: 4957-4966) DOI: 10.1167/iovs.09-3381 C1 [Ding, Xiaoyan; Patel, Mrinali; Shen, Defen; Herzlich, Alexandra A.; Cao, Xiaoguang; Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Ding, Xiaoyan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Patel, Mrinali] Howard Hughes Med Inst, Chevy Chase, MD USA. [Cao, Xiaoguang] Peking Univ, Peoples Hosp, Dept Ophthalmol, Beijing 100871, Peoples R China. [Klupsch, Kristina; Downward, Julian] Canc Res UK London Res Inst, Signal Transduct Lab, London, England. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov OI Tuo, Jingsheng/0000-0002-1372-7810; Downward, Julian/0000-0002-2331-4729 FU National Institutes of Health Intramural Research Foundation FX Supported by the National Institutes of Health Intramural Research Foundation. NR 51 TC 20 Z9 20 U1 1 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2009 VL 50 IS 10 BP 4957 EP 4966 DI 10.1167/iovs.09-3381 PG 10 WC Ophthalmology SC Ophthalmology GA 497XE UT WOS:000270097200057 PM 19443712 ER PT J AU Blum, A Costello, R Samsel, L Zalos, G McCoy, P Csako, G Waclawiw, MA Cannon, RO AF Blum, Arnon Costello, Rene Samsel, Leigh Zalos, Gloria McCoy, Phil Csako, Gyorgy Waclawiw, Myron A. Cannon, Richard O., III TI Variability of C-Reactive Protein Levels among Patients with Stable Coronary Artery Disease and on Statin Therapy SO ISRAEL MEDICAL ASSOCIATION JOURNAL LA English DT Article DE C-reactive protein; coronary artery disease; statin therapy; vascular inflammation; risk stratification ID MIDDLE-AGED MEN; HEART-DISEASE; CARDIOVASCULAR-DISEASE; FUTURE RISK; MYOCARDIAL-INFARCTION; CHOLESTEROL LEVELS; HEALTHY-MEN; INFLAMMATION; MARKERS; EVENTS AB Background: High sensitivity C-reactive protein, a marker of inflammation, has been proposed to stratify coronary artery disease risk and is lowered by HMG-CoA reductase (statin) therapy. However, the reproducibility of persistently elevated hs-CRP levels and association with other markers of inflammation in patients with stable CAD on aggressive statin therapy is unknown. Objectives: To determine the reproducibility of hs-CRP levels measured within 2 weeks in patients with documented CAD with stable symptoms and to identify associations with other markers of inflammation. Methods: Levels of hs-CRP were measured twice within 14 days (7 +/- 4) in 23 patients (22 mates and 1 female, average age 66 +/- 10 years) with stable CAD and hs-CRP >= 2.0 mg/L but <= 10 mg/L at visit 1. All patients had received statins for cholesterol management (low density lipoprotein-cholesterol 84 +/- 25 mg/dl) with no dose change for > 3 months. None had a history or evidence of malignancy, chronic infection or inflammation, or recent trauma. There was no change in medications between visits 1 and 2, and no patient reported a change in symptoms or general health during this interval. White blood cell count and pro- and anti-inflammatory cytokines were measured at both visits. Results: hs-CRP levels tended to be lower at visit 2 (median 2.4 mg/L, range 0.8-11 mg/L) than at visit 1 (median 3.3 mg/L, range 2.0-9.7; P = 0.1793). However, between the two visits hs-CRP levels decreased by more than 1.0 mg/L in 10 patients and increased by more than 1.0 mg/L in 4 patients. Changes in hs-CRP levels were unrelated to changes in levels of white blood cells (P= 0.4353). Of the cytokines tested, only the anti-inflammatory cytokine interleukin-1 receptor antagonist and the pro-inflammatory cytokine interleukin-8 were above tower limits of detection, but there were no correlations between changes in these values and changes in hs-CRP (both P > 0.5). Conclusions: In stable CAD patients on aggressive statin therapy, hs-CRP levels may fluctuate over brief periods in the absence of changes in health, cardiac symptom status and medications, and without corroboration with other measures of inflammation. Accordingly, elevated hs-CRP levels should be interpreted with caution in this setting. C1 [Blum, Arnon; Zalos, Gloria; Cannon, Richard O., III] NIH, Ctr Clin, Translat Med Branch, Bethesda, MD 20892 USA. [Samsel, Leigh; McCoy, Phil] NIH, Ctr Clin, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. [Waclawiw, Myron A.] NHLBI, Off Biostat Res, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Costello, Rene; Csako, Gyorgy] NIH, Ctr Clin, Med Lab, Bethesda, MD 20892 USA. RP Blum, A (reprint author), Baruch Padeh Poria Med Ctr, Dept Internal Med, IL-15208 Galilee, Israel. EM navablum@hotmail.com NR 25 TC 2 Z9 3 U1 0 U2 0 PU ISRAEL MEDICAL ASSOC JOURNAL PI RAMAT GAN PA 2 TWIN TOWERS, 11TH FL, 35 JABOTINSKY ST, PO BOX 3604, RAMAT GAN 52136, ISRAEL SN 1565-1088 J9 ISR MED ASSOC J JI Isr. Med. Assoc. J. PD OCT PY 2009 VL 11 IS 10 BP 602 EP 605 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 545SU UT WOS:000273757900005 PM 20077946 ER PT J AU Galliher-Beckley, AJ Cidlowski, JA AF Galliher-Beckley, Amy J. Cidlowski, John A. TI Emerging Roles of Glucocorticoid Receptor Phosphorylation in Modulating Glucocorticoid Hormone Action in Health and Disease SO IUBMB LIFE LA English DT Review DE CDK; glucocorticoid receptor; ERK; GSK-3 beta; JNK; p38 MAPK; phosphorylation ID N-TERMINAL KINASE; GENE-EXPRESSION; PROTEIN-KINASE; TRANSCRIPTIONAL ACTIVATION; CELLS; SITES; CROSSTALK; APOPTOSIS; ISOFORMS AB Glucocorticoids (GCs) are hormones naturally released when the body perceives stress and function to return homeostatic balance within various tissues. Synthetic GCs are widely prescribed therapeutics for the treatment of numerous inflammatory disorders and cancers. The effects of GCs are mediated by their binding and activation of the GC receptor (GR), a transcription factor that is subject to hormone-dependent and -independent phosphorylation on several serine and threonine residues. The GR is phosphorylated by kinases such as MAPKs, CDKs, and GSK-3 beta, and these modifications modulate the transcriptional activity of the GR within cells. Here, we discuss the phosphorylation status of the GR as a mechanism to dictate how cells will ultimately respond to GCs. In doing so, we will review current knowledge about each phosphorylated residue within the GR and their contributions to modulating GC signaling in normal homeostatic physiology and during the progression of disease. (C) 2009 IUBMB IUBMB Life, 61(10): 979-986, 2009 C1 [Galliher-Beckley, Amy J.; Cidlowski, John A.] NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, Dept Hlth & Human Serv,NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, Dept Hlth & Human Serv,NIH, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIH National Institute of Environmental Health Sciences [Z01E5090057-12] FX We would like to thank Carl Bortner, Robert H. Oakley, arid Harriet Kinyarnu for their critical reading of this review. This research was Supported by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences (Z01E5090057-12). The authors declare no conflicts of interest. NR 35 TC 66 Z9 70 U1 1 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1521-6543 J9 IUBMB LIFE JI IUBMB Life PD OCT PY 2009 VL 61 IS 10 BP 979 EP 986 DI 10.1002/iub.245 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 507DX UT WOS:000270832600006 PM 19787703 ER PT J AU Aissani, B Ogwaro, KM Shrestha, S Tang, JM Breen, EC Wong, HL Jacobson, LP Rabkin, CS Ambinder, RF Martinez-Maza, O Kaslow, RA AF Aissani, Brahim Ogwaro, Kisani M. Shrestha, Sadeep Tang, Jianming Breen, Elizabeth C. Wong, Hui-lee Jacobson, Lisa P. Rabkin, Charles S. Ambinder, Richard F. Martinez-Maza, Otoniel Kaslow, Richard A. TI The Major Histocompatibility Complex Conserved Extended Haplotype 8.1 in AIDS-Related Non-Hodgkin Lymphoma SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE CD4; human leukocyte antigen; HIV; NHL; TNF ID TUMOR-NECROSIS-FACTOR; ACTIVE ANTIRETROVIRAL THERAPY; TNF-ALPHA PRODUCTION; GENETIC POLYMORPHISMS; MULTIPLE-SCLEROSIS; HIV-1 INFECTION; MHC HAPLOTYPES; RISK-FACTORS; ASSOCIATION; IMMUNODEFICIENCY AB Background: Two single nucleotide polymorphisms (SNPs) in adjacent genes, lymphotoxin alpha (LTA + 252G, rs909253 A>G) and tumor necrosis factor (TNF - 308A, rs1800629 G>A), form the G-A haplotype repeatedly associated with increased risk of non-Hodgkin lymphoma (NHL) in individuals uninfected with HTV-1. This association has been observed alone or in combination with human leukocyte antigens HLA-B*08 or HLA-DRB1*03 in the major histocompatibility complex (MHC). Which gene variant on this highly conserved extended haplotype (CEH 8.1) in whites most likely represents a true etiologic factor remains uncertain. Objective: We aimed to determine whether the reported association of the G-A haplotype of LTA-TNF with non-AIDS NHL also occurs with AIDS-related NHL. Methods: SNPs in LTA and TNF and in 6 other genes nearby were typed in 140 non-Hispanic European American pairs of AIDS-NHL cases and matched controls selected from HIV-infected men in the Multicenter AIDS Cohort Study. Results: The G-A haplotype and a 4-SNP haplotype in the neighboring gene cluster (rs537160 (A) rs1270942 (G), rs2072633 (A), and rs6467 (C)) were associated with AIDS-NHL (odds ratio = 2.7, 95% confidence interval: 1.5 to 4.8, P = 0.0009; and odds ratio = 3.2, 95% confidence interval: 1.6 to 6.6, P = 0.0008; respectively). These 2 haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1. Conclusion: The CEH 8.1-specific haplotype association of MHC class HI variants with AIDS-NHL closely resembles that observed for non-AIDS NHL. Corroboration of an MHC determinant of AIDS and non-AIDS NHL alike would imply an important pathogenetic mechanism common to both. C1 [Aissani, Brahim] Univ Alabama, Program Epidemiol Infect & Immun, Dept Epidemiol, Birmingham, AL 35294 USA. [Ogwaro, Kisani M.] Univ Alabama, Dept Psychiat, Birmingham, AL 35294 USA. [Tang, Jianming; Kaslow, Richard A.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Wong, Hui-lee; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Jacobson, Lisa P.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Ambinder, Richard F.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Breen, Elizabeth C.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. RP Aissani, B (reprint author), Univ Alabama, Program Epidemiol Infect & Immun, Dept Epidemiol, 1665 Univ Blvd,RPHB Room 220A, Birmingham, AL 35294 USA. EM baissani@uab.edu; rkaslow@uab.edu RI Martinez-Maza, Otoniel/B-2667-2009; OI Martinez-Maza, Otoniel/0000-0003-1364-0675; Tang, Jianming/0000-0003-0137-7486 FU NCI NIH HHS [P50 CA096888, P50 CA096888-01, P50-CA96888, R01 CA073475, R01 CA073475-03, R01 CA106168, R01 CA106168-01A1, R01-CA106168, R01-CA73475]; NCRR NIH HHS [5-M01-RR-00722, M01 RR000722]; NIAID NIH HHS [U01 AI037613, P30 AI 045008, P30 AI045008, P30 AI045008-01, U01 AI035039, U01 AI035040, U01 AI035041, U01 AI035042, U01 AI035043, U01 AI037984, UO1-AI-35039, UO1-AI-35040,, UO1-AI-35041, UO1-AI-35042, UO1-AI-35043, UO1-AI-37613, UO1-AI-37984] NR 53 TC 12 Z9 13 U1 0 U2 3 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 OCT 1 PY 2009 VL 52 IS 2 BP 170 EP 179 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 499GQ UT WOS:000270206500004 PM 19654554 ER PT J AU Busse, KH Hadigan, C Chairez, C Alfaro, RM Formentini, E Kovacs, JA Penzak, SR AF Busse, Kristin H. Hadigan, Colleen Chairez, Cheryl Alfaro, Raul M. Formentini, Elizabeth Kovacs, Joseph A. Penzak, Scott R. TI Gemfibrozil Concentrations Are Significantly Decreased in the Presence of Lopinavir-Ritonavir SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT 25, 2008 CL Washington, DC SP Infect Dis Soc Amer DE drug interaction; lopinavir-ritonavir; gemfibrozil; HIV ID INHIBITOR-ASSOCIATED HYPERTRIGLYCERIDEMIA; FIBRIC ACID-DERIVATIVES; CLINICAL PHARMACOKINETICS; MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK; LOPINAVIR/RITONAVIR; THERAPY; DISEASE; ABNORMALITIES; DYSLIPIDEMIA AB Objective: The objective of this study was to determine the influence of a 2-week course of lopinavir-ritonavir on the pharmacokinetics of the triglyceride-lowering agent, gemfibrozil. Methods: The study was conducted as an open label, single-sequence pharmacokinetic. study in healthy human volunteers. Gemfibrozil pharmacokinetic parameter values were compared using a Student t test after a single 600-mg dose was administered to healthy volunteers before and after 2 weeks of lopinavir-ritonavir (400/100 mg) twice daily. Results: Fifteen healthy volunteers (eight males) completed the study. All study drugs were generally well tolerated and no subjects withdrew participation. The geometric mean ratio (90% confidence interval) for gemfibrozil area under the plasma concentration-time curve after 14 days of lopinavir-ritonavir compared with baseline was 0.59 (0.52, 0.67) (P < 0.001). All 15 study subjects experienced a reduction in gemfibrozil area under the plasma concentration-time curve after lopinavir-ritonavir (range, - 6% to - 74%). The geometric mean ratios for gemfibrozil apparent oral clearance and maximum concentration were 1.69 (1.41, 1.97) and 0.67 (0.49, 0.86) after 14 days of lopinavir-ritonavir versus baseline, respectively (P < 0.0001 and 0.01, respectively). Gemfibrozil elimination half-life did not change after lopinavir-ritonavir administration (P = 0.60). Conclusion: Lopinavir-ritonavir significantly reduced the systemic exposure of gemfibrozil by reducing gemfibrozil absorption. Clinicians treating HIV-infected patients with hypertriglyceridemia should be aware of this drug interaction. C1 [Busse, Kristin H.; Alfaro, Raul M.; Penzak, Scott R.] NIH, Clin Pharmacokinet Res Lab, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Hadigan, Colleen; Chairez, Cheryl] NIAID, NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. [Formentini, Elizabeth; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Penzak, SR (reprint author), 9000 Rockville Pike,Bldg 10,Room 1N257, Bethesda, MD 20892 USA. EM spenzak@cc.nih.gov FU Intramural NIH HHS [Z01 CL006000-01] NR 37 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2009 VL 52 IS 2 BP 235 EP 239 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 499GQ UT WOS:000270206500010 PM 19648824 ER PT J AU Giedd, JN AF Giedd, Jay N. TI Linking Adolescent Sleep, Brain Maturation, and Behavior SO JOURNAL OF ADOLESCENT HEALTH LA English DT Editorial Material ID PREFRONTAL CORTEX; SCHIZOPHRENIA C1 NIMH, Brain Imaging Unit, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Giedd, JN (reprint author), NIMH, Brain Imaging Unit, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Sanguansri, Luz/B-6630-2011; Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Sanguansri, Luz/0000-0003-1908-7604; Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS [Z99 MH999999] NR 10 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD OCT PY 2009 VL 45 IS 4 BP 319 EP 320 DI 10.1016/j.jadohealth.2009.07.007 PG 2 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 502AM UT WOS:000270426200001 PM 19766933 ER PT J AU Wang, J Iannotti, RJ Nansel, TR AF Wang, Jing Iannotti, Ronald J. Nansel, Tonja R. TI School Bullying Among Adolescents in the United States: Physical, Verbal, Relational, and Cyber SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE School bullying; Cyber bullying; Relational bullying; Parental support; Peers; Sociodemographic characteristics ID PEER VICTIMIZATION; INDIRECT AGGRESSION; PERCEIVED FAMILY; INVOLVEMENT; ADJUSTMENT; FRIENDSHIP; PREVALENCE; VICTIMS; BULLIES; GENDER AB Purpose: Four forms of school bullying behaviors among US adolescents and their association with sociodemographic characteristics, parental support, and friends were examined. Methods: Data were obtained from the Health Behavior in School-Aged Children (HBSC) 2005 Survey, a nationally representative sample of grades 6-10 (N = 7,182). The revised Olweus Bully/Victim Questionnaire was used to measure physical, verbal, and relational forms of bullying. Two items were added using the same format to measure cyber bullying. For each form, four categories were created: bully, victim, bully-victim, and not involved. Multinomial logistic regressions were applied, with sociodemographic variables, parental support, and number of friends as predictors. Results: Prevalence rates of having bullied others or having been bullied at school for at least once in the last 2 months were 20.8% physically, 53.6% verbally, 51.4% socially, or 13.6% electronically. Boys were more involved in physical or verbal bullying, whereas girls were more involved in relational bullying. Boys were more likely to be cyber bullies, whereas girls were more likely to be cyber victims. African-American adolescents were involved in more bullying (physical, verbal, or cyber) but less victimization (verbal or relational). Higher parental support was associated with less involvement across all forms and classifications of bullying. Having more friends was associated with more bullying and less victimization for physical, verbal, and relational forms but was not associated with cyber bullying. Conclusions: Parental support may protect adolescents from all four forms of bullying. Friends associate differentially with traditional and cyber bullying. Results indicate that cyber bullying is a distinct nature from that of traditional bullying. (C) 2009 Society for Adolescent Medicine. All rights reserved. C1 [Wang, Jing; Iannotti, Ronald J.; Nansel, Tonja R.] NIH, Bethesda, MD 20892 USA. RP Wang, J (reprint author), NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM wangji2@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Maternal and Child Health Bureau of the Health Resources and Services Administration FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Maternal and Child Health Bureau of the Health Resources and Services Administration. NR 24 TC 401 Z9 421 U1 36 U2 201 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD OCT PY 2009 VL 45 IS 4 BP 368 EP 375 DI 10.1016/j.jadohealth.2009.03.021 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 502AM UT WOS:000270426200009 PM 19766941 ER PT J AU Metcalfe, DD Peavy, RD Gilfillan, AM AF Metcalfe, Dean D. Peavy, Richard D. Gilfillan, Alasdair M. TI Mechanisms of mast cell signaling in anaphylaxis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Anaphylaxis; mast cells; Fc is an element of RI; signal transduction ID FC-EPSILON-RI; AFFINITY IGE RECEPTOR; ALLERGIC RESPONSES; NEGATIVE REGULATION; TYROSINE KINASE; CHANNEL FUNCTION; DEFICIENT MICE; FYN KINASE; LYN KINASE; ACTIVATION AB The recent development of a consensus definition and proposed diagnostic criteria for anaphylaxis offers promise for research efforts and a better understanding of the epidemiology and pathogenesis of this enigmatic and life-threatening disease. This review examines basic principles and recent research advances in the mechanisms of mast cell signaling believed to underlie anaphylaxis. The unfolding complexity of mast cell signaling suggests that the system is sensitive to regulation by any of several individual signaling pathways and intermediates and that complementary pathways regulate mast cell activation by amplified signals. The signaling events underlying anaphylactic reactions have largely been identified through experiments in genetically modified mice and supported by biochemical studies of mast cells derived from these mice. These studies have revealed that signaling pathways exist to both upregulate and downregulate mast cell responses. In this review we will thus describe the key molecular players in these pathways in the context of anaphylaxis. (J Allergy Clin Immunol 2009;124:639-46.) C1 [Metcalfe, Dean D.; Peavy, Richard D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), Bldg 10-11C207,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM dmetcalfe@niaid.nih.gov FU Merck Co., Inc.; National Institute of Allergy anti Infectious Diseases, National Institutes of Health FX Supported by the Intramural Research Program of the National Institute of Allergy anti Infectious Diseases, National Institutes of Health. NR 71 TC 92 Z9 94 U1 2 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2009 VL 124 IS 4 BP 639 EP 646 DI 10.1016/j.jaci.2009.08.035 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 506UV UT WOS:000270802800002 PM 19815110 ER PT J AU Plaut, M Sawyer, RT Fenton, MJ AF Plaut, Marshall Sawyer, Richard T. Fenton, Matthew J. TI Summary of the 2008 National Institute of Allergy and Infectious Diseases-US Food and Drug Administration Workshop on Food Allergy Clinical Trial Design SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Food allergy; clinical trials; clinical trial design; oral food challenge; precautions; prevention; treatment; tolerance; desensitization ID COWS MILK ALLERGY; ORAL TOLERANCE INDUCTION; 1ST 3 YEARS; PEANUT ALLERGY; EGG ALLERGY; SUBLINGUAL IMMUNOTHERAPY; NATURAL-HISTORY; DOUBLE-BLIND; CHILDREN; SENSITIZATION AB This article summarizes the proceedings of a 2008 Workshop on Food Allergy Clinical Trials Design co-organized by the National Institute of Allergy and Infectious Diseases and the US Food and Drug Administration. The use of food allergens both as therapy and for oral food challenges is associated with a risk of anaphylaxis. Investigators are strongly encouraged to address regulatory considerations by discussing proposed studies with the US Food and Drug Administration. Food allergen administration through the oral or sublingual routes might be less risky than through the subcutaneous route, but this hypothesis has not been proved, and subjects with food allergy might still be at high risk of allergic reactions to such allergen administration. Two distinct mechanisms might lead to beneficial clinical outcomes: desensitization (reversible when food allergen therapy is stopped) and tolerance (persistent benefit even after allergen therapy is stopped). There are important clinical distinctions between desensitization and tolerance. The efficacy of a therapy for food allergy can be evaluated by assessing changes in the dose response to double-blind, placebo-controlled oral food challenges before and after therapy and also by assessing changes in the number of allergic episodes during a longitudinal natural history/exposure study; both approaches have strengths and limitations. (,J Allergy Clin Immunol 2009;124:671-78.) C1 [Plaut, Marshall; Sawyer, Richard T.; Fenton, Matthew J.] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. RP Plaut, M (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr,Room 3069, Bethesda, MD 20892 USA. EM mplaut@niaid.nih.gov NR 45 TC 14 Z9 14 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2009 VL 124 IS 4 BP 671 EP 678 DI 10.1016/j.jaci.2009.05.027 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 506UV UT WOS:000270802800007 PM 19560803 ER PT J AU Salo, PM Zeldin, DC AF Salo, Paeivi M. Zeldin, Darryl C. TI Does exposure to cats and dogs decrease the risk of allergic sensitization and disease? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material DE Cats; dogs; allergic sensitization; domestic pets ID FEL D 1; ASTHMA; PETS; ENVIRONMENT; PREVALENCE; CHILDHOOD; CHILDREN; CENTERS; CD14; IGE C1 [Salo, Paeivi M.; Zeldin, Darryl C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Room A222, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov FU Intramural NIH HHS [Z01 ES025041-11]; NIEHS NIH HHS [Z01 ES025041] NR 18 TC 2 Z9 2 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2009 VL 124 IS 4 BP 751 EP 752 DI 10.1016/j.jaci.2009.08.012 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 506UV UT WOS:000270802800020 PM 19815117 ER PT J AU Komarow, HD Hu, ZH Brittain, E Uzzaman, A Gaskins, D Metcalfe, DD AF Komarow, Hirsh D. Hu, Zonghui Brittain, Erica Uzzaman, Ashraf Gaskins, Donna Metcalfe, Dean D. TI Serum tryptase levels in atopic and nonatopic children SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID ANAPHYLAXIS; DEFICIENCY C1 [Komarow, Hirsh D.; Uzzaman, Ashraf; Gaskins, Donna; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Hu, Zonghui; Brittain, Erica] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Komarow, HD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM komarowh@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000951-06, NIH0010049406, Z01 AI000951-03] NR 8 TC 22 Z9 22 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2009 VL 124 IS 4 BP 845 EP 848 DI 10.1016/j.jaci.2009.06.040 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 506UV UT WOS:000270802800034 PM 19665778 ER PT J AU Cohen, SG Mazzullo, JC AF Cohen, Sheldon G. Mazzullo, Joy C. TI The allergy archives: Pioneers and milestones Discovering anaphylaxis: Elucidation of a shocking phenomenon SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article C1 [Cohen, Sheldon G.; Mazzullo, Joy C.] NIAID, Natl Lib Med, NIH, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, Natl Lib Med, NIH, 8600 Rockville Pike,Bldg 38,Room 1E21, Bethesda, MD 20892 USA. EM scohen@niaid.nih.gov NR 14 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2009 VL 124 IS 4 BP 866 EP 869 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 506UV UT WOS:000270802800046 PM 19830893 ER PT J AU Abraham, TT Barnes, AJ Lowe, RH Spargo, EAK Milman, G Pirnay, SO Gorelick, DA Goodwin, RS Huestis, MA AF Abraham, Tsadik T. Barnes, Allan J. Lowe, Ross H. Spargo, Erin A. Kolbrich Milman, Garry Pirnay, Stephane O. Gorelick, David A. Goodwin, Robert S. Huestis, Marilyn A. TI Urinary MDMA, MDA, HMMA, and HMA Excretion Following Controlled MDMA Administration to Humans SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID CHROMATOGRAPHY-MASS SPECTROMETRY; GAS-CHROMATOGRAPHY; 3,4-METHYLENEDIOXYMETHAMPHETAMINE ECSTASY; METABOLITES; PHARMACOKINETICS; PLASMA; AMPHETAMINE; PH; QUANTIFICATION; PHARMACOLOGY C1 [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Spargo, Erin A. Kolbrich] SW Inst Forens Sci, Dallas, TX 75235 USA. [Pirnay, Stephane O.] Univ Paris 05, Fac Pharm, INSERM, U705, F-75010 Paris, France. [Gorelick, David A.] NIDA, Off Sci Director, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program; National Institutes of Health; National Institute on Drug Abuse (NIDA/IRP) FX This research was supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse (NIDA/IRP). The authors wish to thank Janeen Nichels, John Etter, Kathleen Demuth, and David Darwin for assistance with study procedures. NR 30 TC 21 Z9 21 U1 1 U2 4 PU PRESTON PUBL INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2009 VL 33 IS 8 BP 439 EP 446 PG 8 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 502ZN UT WOS:000270500000006 PM 19874650 ER PT J AU Karschner, EL Schwilke, EW Lowe, RH Darwin, WD Herning, RI Cadet, JL Huestis, MA AF Karschner, Erin L. Schwilke, Eugene W. Lowe, Ross H. Darwin, W. David Herning, Ronald I. Cadet, Jean Lud Huestis, Marilyn A. TI Implications of Plasma Delta(9)-Tetrahydrocannabinol, 11-Hydroxy-THC, and 11-nor-9-Carboxy-THC Concentrations in Chronic Cannabis Smokers SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID FIELD SOBRIETY TESTS; MARIJUANA USE; DELTA-9-TETRAHYDROCANNABINOL THC; BLOOD CANNABINOIDS; HALF-LIFE; USERS; METABOLISM; SMOKING; THCCOOH; TIME C1 [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Suite 200,251 Bayview Blvd,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse; National Institutes of Health FX The authors would like to thank Allan J. Barnes for data analysis support and Kathleen Demuth, Janeen Nichels, and John Etter for clinical research assistance. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 44 TC 36 Z9 37 U1 3 U2 16 PU PRESTON PUBL INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2009 VL 33 IS 8 BP 469 EP 477 PG 9 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 502ZN UT WOS:000270500000010 PM 19874654 ER PT J AU Demner-Fushman, D Chapman, WW McDonald, CJ AF Demner-Fushman, Dina Chapman, Wendy W. McDonald, Clement J. TI What can natural language processing do for clinical decision support? SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Review DE Natural language processing; Decision support techniques; Clinical decision support systems; Review ID PART-OF-SPEECH; ELECTRONIC MEDICAL-RECORD; NAMED-ENTITY RECOGNITION; PATIENT SAFETY RESEARCH; BIOMEDICAL LITERATURE; INFORMATION; DOCUMENTS; TEXT; PERFORMANCE; EXTRACTION AB Computerized clinical decision support (CDS) aims to aid decision making of health care providers and the public by providing easily accessible health-related information at the point and time it is needed. natural language processing (NLP) is instrumental in using free-text information to drive CDS, representing clinical knowledge and CDS interventions in standardized formats, and leveraging clinical narrative. The early innovative NLP research of clinical narrative was followed by a period of stable research conducted at the major clinical centers and a shift of mainstream interest to biomedical NLP. This review primarily focuses on the recently renewed interest in development of fundamental NLP methods and advances in the NLP systems for CDS. The current solutions to challenges posed by distinct sublanguages, intended user groups, and support goals are discussed. Published by Elsevier Inc. C1 [Demner-Fushman, Dina; McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, Commun Engn Branch, US Natl Lib Med, Bethesda, MD 20894 USA. [Chapman, Wendy W.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA 15260 USA. RP Demner-Fushman, D (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, Commun Engn Branch, US Natl Lib Med, Bldg 38A,Room 10S-1020,8600 Rockville Pike MSC-38, Bethesda, MD 20894 USA. EM ddemner@mail.nih.gov OI Chapman, Wendy/0000-0001-8702-4483 FU National Library of Medicine, National Institutes of Health FX This work was partially supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. We also thank Kevin Bretonnel Cohen for inspiration and valuable comments, and the anonymous reviewers for the detailed analysis and helpful comments. NR 132 TC 110 Z9 116 U1 3 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2009 VL 42 IS 5 BP 760 EP 772 DI 10.1016/j.jbi.2009.08.007 PG 13 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 507QV UT WOS:000270870500002 PM 19683066 ER PT J AU Fiszman, M Demner-Fushman, D Kilicoglu, H Rindflesch, TC AF Fiszman, Marcelo Demner-Fushman, Dina Kilicoglu, Halil Rindflesch, Thomas C. TI Automatic summarization of MEDLINE citations for evidence-based medical treatment: A topic-oriented evaluation SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Natural language processing; Semantic processing; Automatic summarization; Evidence-based medicine; Knowledge representation; Artificial intelligence; Evaluation ID CLINICAL QUESTIONS; BIOMEDICAL TEXT; RETRIEVAL; KNOWLEDGE; FRAMEWORK; QUALITY; SYSTEM AB As the number of electronic biomedical textual resources increases, it becomes harder for physicians to find useful answers at the point of care. Information retrieval applications provide access to databases; however, little research has been done on using automatic summarization to help navigate the documents returned by these systems. After presenting a semantic abstraction automatic summarization system for MEDLINE citations, we concentrate on evaluating its ability to identify useful drug interventions for 53 diseases. The evaluation methodology uses existing sources of evidence-based medicine as surrogates for a physician-annotated reference standard. Mean average precision (MAP) and a clinical usefulness score developed for this study were computed as performance metrics. The automatic summarization system significantly outperformed the baseline in both metrics. The MAP gain was 0.17 (p < 0.01) and the increase in the overall score of clinical usefulness was 0.39 (p < 0.05). Published by Elsevier Inc. C1 [Fiszman, Marcelo; Demner-Fushman, Dina; Kilicoglu, Halil; Rindflesch, Thomas C.] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Kilicoglu, Halil] Concordia Univ, Dept Comp Sci & Software Engn, Montreal, PQ, Canada. RP Fiszman, M (reprint author), NIH, Natl Lib Med, 8600 Rockville Pike,Bldg 38A,Rm B1N-28J, Bethesda, MD 20894 USA. EM fiszmanm@mail.nih.gov FU National Institutes of Health; National Library of Medicine FX We would like to thank Charles Sneiderman and Jimmy Lin for valuable discussions about the evaluation methodology and available resources. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 45 TC 19 Z9 22 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2009 VL 42 IS 5 BP 801 EP 813 DI 10.1016/j.jbi.2008.10.002 PG 13 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 507QV UT WOS:000270870500006 PM 19022398 ER PT J AU Neveol, A Shooshan, SE Humphrey, SM Mork, JG Aronson, AR AF Neveol, Aurelie Shooshan, Sonya E. Humphrey, Susanne M. Mork, James G. Aronson, Alan R. TI A recent advance in the automatic indexing of the biomedical literature SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Abstracting and Indexing as Topic/methods/statistics & numerical data; Artificial Intelligence; Dictionaries, Medical; Evaluation Studies as Topic; MEDLINE; Medical Subject Headings; Natural Language Processing ID TEXT CATEGORIZATION; DOCUMENTS; ARTICLES; KEYWORDS; MEDLINE AB The volume of biomedical literature has experienced explosive growth in recent years. This is reflected in the corresponding increase in the size of MEDLINE(R), the largest bibliographic database of biomedical citations. Indexers at the US National Library of Medicine (NLM) need efficient tools to help them accommodate the ensuing workload. After reviewing issues in the automatic assignment of Medical Subject Headings (MeSH(R) terms) to biomedical text, we focus more specifically on the new subheading attachment feature for NLM's Medical Text Indexer (MTI). Natural Language Processing, statistical, and machine learning methods of producing automatic MeSH main heading/subheading pair recommendations were assessed independently and combined. The best combination achieves 48% precision and 30% recall. After validation by NLM indexers, a suitable combination of the methods presented in this paper was integrated into MTI as a subheading attachment feature producing MeSH indexing recommendations compliant with current state-of-the-art indexing practice. (C) 2008 Elsevier Inc. All rights reserved. C1 [Neveol, Aurelie; Shooshan, Sonya E.; Humphrey, Susanne M.; Mork, James G.; Aronson, Alan R.] NIH, US Natl Lib Med, Bethesda, MD 20894 USA. RP Neveol, A (reprint author), NIH, US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM neveola@nlm.nih.gov; sonya@nlm.nih.gov; humphrey@nlm.nih.gov; mork@nlm.nih.gov; alan@nlm.nih.gov FU NIH; National Library of Medicine; Oak Ridge Institute for Science and Education FX This work was supported in part by the Intramural Research Program of the NIH, National Library of Medicine and by an appointment of A. Neveol to the NLM Research Participation Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education. The authors thank James Marcetich and Joe Thomas of NLM's Indexing Section for their interest and feedback on this work. The authors also acknowledge Willie J. Rogers for his technical help with implementing and running the JDI method. NR 24 TC 27 Z9 27 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2009 VL 42 IS 5 BP 814 EP 823 DI 10.1016/j.jbi.2008.12.007 PG 10 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 507QV UT WOS:000270870500007 PM 19166973 ER PT J AU Lu, ZY Wilbur, WJ AF Lu, Zhiyong Wilbur, W. John TI Improving accuracy for identifying related PubMed queries by an integrated approach SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE PubMed distance; Related query; PubMed query log; Session segmentation; Lexical similarity; Contextual similarity ID ENDOPLASMIC-RETICULUM; SEARCH ENGINE; LOGS; COPII AB PubMed is the most widely used tool for searching biomedical literature online. As with many other online search tools, a user often types a series of multiple related queries before retrieving satisfactory results to fulfill a single information need. Meanwhile, it is also a common phenomenon to see a user type queries on unrelated topics in a single session. In order to study PubMed users' search strategies, it is necessary to be able to automatically separate unrelated queries and group together related queries. Here, we report a novel approach combining both lexical and contextual analyses for segmenting PubMed query sessions and identifying related queries and compare its performance with the previous approach based solely on concept mapping. We experimented with our integrated approach on sample data consisting of 1539 pairs of consecutive user queries in 351 user sessions. The prediction results of 1396 pairs agreed with the gold-standard annotations, achieving an overall accuracy of 90.7%. This demonstrates that our approach is significantly better than the previously published method. By applying this approach to a one day query log of PubMed, we found that a significant proportion of information needs involved more than one PubMed query, and that most of the consecutive queries for the same information need are lexically related. Finally, the proposed PubMed distance is shown to be an accurate and meaningful measure for determining the contextual similarity between biological terms. The integrated approach can play a critical role in handling real-world PubMed query log data as is demonstrated in our experiments. Published by Elsevier Inc. C1 [Lu, Zhiyong; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM luzh@ncbi.nlm.nih.gov FU NIH; National Library of Medicine FX The authors thank Jorge R. Herskovic and Elmer V. Bernstam for their previous work that motivated this study and their kindness for providing the test data and results used in their work for us to compare with. We are grateful to Larry Hunter for bringing the Google distance metric to our attention and Kevin B. Cohen for his critical review of this manuscript. We also thank Bill Baumgartner for proofreading this manuscript. This research was funded by the Intramural Research Program of the NIH, National Library of Medicine. NR 22 TC 6 Z9 6 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 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2009 VL 42 IS 5 SI SI BP 831 EP 838 DI 10.1016/j.jbi.2008.12.006 PG 8 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 507QV UT WOS:000270870500009 PM 19162232 ER PT J AU Smith, LH Wilbur, WJ AF Smith, Larry H. Wilbur, W. John TI The value of parsing as feature generation for gene mention recognition SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Natural language processing; Named entity recognition; Biological text; Gene mention recognition; Parsers; Machine learning; Support vector machines ID TEXT AB We measured the extent to which information surrounding a base noun phrase reflects the presence of a gene name, and evaluated seven different parsers in their ability to provide information for that purpose. Using the GENETAG corpus as a gold standard, we performed machine learning to recognize from its context when a base noun phrase contained a gene name. Starting with the best lexical features, we assessed the gain of adding dependency or dependency-like relations from a full sentence parse. Features derived from parsers improved performance in this partial gene mention recognition task by a small but statistically significant amount. There were virtually no differences between parsers in these experiments. Published by Elsevier Inc. C1 [Smith, Larry H.; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. RP Smith, LH (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Room 6S614-N,Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM lsmith@ncbi.nlm.nih.gov; wilbur@ncbi.nlm.nih.gov FU NIH; NLM; NCBI FX We thank Dr. D. Comeau and Dr. L. Tanabe for their contributions in annotation. This research was supported by the Intramural Research Program of the NIH, NLM, and NCBI. NR 42 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2009 VL 42 IS 5 BP 895 EP 904 DI 10.1016/j.jbi.2009.03.011 PG 10 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 507QV UT WOS:000270870500015 PM 19345281 ER PT J AU Norton, JT Titus, SA Dexter, D Austin, CP Zheng, W Huang, S AF Norton, John T. Titus, Steven A. Dexter, Dwayne Austin, Christopher P. Zheng, Wei Huang, Sui TI Automated High-Content Screening for Compounds That Disassemble the Perinucleolar Compartment SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE high-content screening; nucleus; cancer; perinucleolar compartment; small molecules ID POLYMERASE-III TRANSCRIPTS; TRACT-BINDING-PROTEIN; RNA; PREVALENCE AB All solid malignancies share characteristic traits, including unlimited cellular proliferation, evasion of immune regulation, and the propensity to metastasize. The authors have previously described that a subnuclear structure, the perinucleolar compartment (PNC), is associated with the metastatic phenotype in solid tumor cancer cells. The percentage of cancer cells that contain PNCs (PNC prevalence) is indicative of the malignancy of a tumor both in vitro and in vivo, and thus PNC prevalence is a marker that reflects metastatic capability in a population of tumor cells. Although the function of the PNC remains to be determined, the PNC is highly enriched with small RNAs and RNA binding proteins. The initial chemical biology studies using a set of anticancer drugs that disassemble PNCs revealed a direct association of the structure with DNA. Therefore, PNC prevalence reduction as a phenotypic marker can be used to identify compounds that target cellular processes required for PNC maintenance and hence used to elucidate the nature of the PNC function. Here the authors report the development of an automated high-content screening assay that is capable of detecting PNC prevalence in prostate cancer cells (PC-3M) stably expressing a green fluorescent protein (GFP)-fusion protein that localizes to the PNC. The assay was optimized using known PNC-reducing drugs and non-PNC-reducing cytotoxic drugs. After optimization, the fidelity of the assay was probed with a collection of 8284 compounds and was shown to be robust and capable of detecting known and novel PNC-reducing compounds, making it the first reported high-content phenotypic screen for small changes in nuclear structure. (Journal of Biomolecular Screening 2009:1045-1053) C1 [Norton, John T.; Huang, Sui] Northwestern Univ, Feinberg Sch Med Cell & Mol Biol, Chicago, IL 60611 USA. [Titus, Steven A.; Austin, Christopher P.; Zheng, Wei] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Dexter, Dwayne] GE Healthcare, Piscataway, NJ USA. RP Huang, S (reprint author), Northwestern Univ, Feinberg Sch Med Cell & Mol Biol, 303 E Chicago Ave, Chicago, IL 60611 USA. EM s-huang2@northwestern.edu RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural NIH HHS [NIH0012490817]; PHS HHS [NIH0012490817] NR 15 TC 6 Z9 7 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD OCT PY 2009 VL 14 IS 9 BP 1045 EP 1053 DI 10.1177/1087057109343120 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 514LL UT WOS:000271396100002 PM 19762548 ER PT J AU Boden, BP Breit, I Sheehan, FT AF Boden, Barry P. Breit, Ilan Sheehan, Frances T. TI Tibiofemoral Alignment: Contributing Factors to Noncontact Anterior Cruciate Ligament Injury SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID DEFICIENT STIFLE JOINT; VIDEO ANALYSIS; TIBIAL SLOPE; KNEE; MECHANISMS; TRANSLATION; STABILITY; RUPTURE; BIOMECHANICS; ASSOCIATION AB Background: The mechanisms of noncontact anterior cruciate ligament injury remain undefined. The purpose of this study was to identify the tibiofemoral alignment in the lateral compartment of the knee for three variations of a one-limb landing in noncontact sports activities: the safe, provocative, and exaggerated provocative positions. These positions were chosen on the basis of a previous study that measured the average joint angles of the limb at the point of ground contact for athletes who landed without injury (safe) and those who sustained an anterior cruciate ligament injury (provocative). It was hypothesized that, in the provocative positions, altered tibiofemoral alignment predisposes the knee to possible subluxation, potentially leading to an anterior cruciate ligament injury. Methods: Magnetic resonance images were acquired for a single knee in twenty-five noninjured athletes for the three landing positions. The angle between the posterior tibial slope and the femur along with three distances (from the tibiofemoral point of contact to [1] the femoral sulcus point, [2] the posterior tibial point, and [3] the most anterior point of the circular posterior aspect of the condyle) were measured for each acquisition. Results: The tibial slope relative to the femur was directed significantly more inferior to superior in the provocative and exaggerated positions than in the safe landing position. Similarly, as the limb transitioned from the safe to the provocative positions, the tibiofemoral joint contact point was significantly closer to the femoral sulcus point and to the most anterior point of the circular posterior portion of the lateral femoral condyle. Conclusions: As the limb moves toward the provocative landing position, the anatomical alignment based on slope and contact characteristics places the knee at possible risk for noncontact anterior cruciate ligament injury. An enhanced understanding of the mechanism of anterior cruciate ligament injury may lead to improved preventative strategies. C1 [Boden, Barry P.] Orthopaed Ctr, Rockville, MD 20850 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIH, Funct & Appl Biomechan Lab, Bethesda, MD 20892 USA. RP Boden, BP (reprint author), Orthopaed Ctr, 9711 Med Ctr Dr,Suite 201, Rockville, MD 20850 USA. EM bboden@starpower.net RI sheehan, frances/B-6962-2009 NR 34 TC 27 Z9 32 U1 3 U2 12 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD OCT PY 2009 VL 91A IS 10 BP 2381 EP 2389 DI 10.2106/JBJS.H.01721 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 503FV UT WOS:000270519700010 PM 19797573 ER PT J AU Giallauria, F Lucci, R D'Agostino, M Vitelli, A Maresca, L Mancini, M Aurino, M Del Forno, D Giannuzzi, P Vigorito, C AF Giallauria, Francesco Lucci, Rosa D'Agostino, Mariantonietta Vitelli, Alessandra Maresca, Luigi Mancini, Maria Aurino, Mario Del Forno, Domenico Giannuzzi, Pantaleo Vigorito, Carlo TI Two-year multicomprehensive secondary prevention program: favorable effects on cardiovascular functional capacity and coronary risk profile after acute myocardial infarction SO JOURNAL OF CARDIOVASCULAR MEDICINE LA English DT Article DE cardiac rehabilitation; cardiopulmonary exercise testing; exercise training; lipid profile; long-term multi-comprehensive cardiac rehabilitation; multi-comprehensive approach; myocardial infarction; oxygen consumption; secondary prevention ID RANDOMIZED CONTROLLED-TRIAL; HEART-RATE RECOVERY; BODY-MASS INDEX; CARDIAC REHABILITATION; ARTERY-DISEASE; PHYSICAL-ACTIVITY; EUROPEAN-SOCIETY; CLINICAL-TRIAL; BLOOD-LIPIDS; TASK-FORCE AB Background Cardiac rehabilitation includes interventions aimed at facilitating physical, psychological and emotional recovery following the acute phase of myocardial infarction (AMI). To date, optimal cardiac rehabilitation program duration and frequency of patient contact has yet to be identified. Objective The present study was performed to evaluate the effects of two different strategies of secondary prevention (2 years, multifactorial continued educational and behavioral intervention versus usual care) implemented into a cardiac rehabilitation setting on several cardiovascular endpoints indicating cardiovascular functional exercise capacity and coronary risk profile in patients with recent AMI. Methods This was a prospective randomized study including 52 postinfarction patients. Initially, all patients were enrolled in a 3-month outpatient cardiac rehabilitation program. Thereafter, they were randomly subdivided into two groups (I = intervention group; C = control group), each composed of 26 patients, and followed for 24 months. Results At the end of the 3-month outpatient cardiac rehabilitation program, both groups showed a significant (P<0.05) improvement in cardiopulmonary parameters (maximal oxygen consumption, maximal workload) and in cardiovascular risk profile (BMI, lipid profile). During the 24-month study period, group I showed stabilization or even improvement (P<0.05) of both cardiopulmonary parameters and cardiovascular risk profile, whereas group C patients showed a deterioration or significant impairment (P<0.05) of the same parameters. Clinical events occurred in 27% of patients in the control group (n = 7) and in 11% in the training group (n = 3) (P< 0.05). Conclusion Long-term, multifactorial educational and behavioral intervention maintained for 2 years in a multicomprehensive cardiac rehabilitation setting represents a valid strategy for improving long-term cardiovascular functional capacity and cardiovascular risk profile in postinfarction patients. J Cardiovasc Med 10:772-780 (C) 2009 Italian Federation of Cardiology. C1 [Giallauria, Francesco; Lucci, Rosa; D'Agostino, Mariantonietta; Vitelli, Alessandra; Maresca, Luigi; Mancini, Maria; Aurino, Mario; Del Forno, Domenico; Vigorito, Carlo] Univ Naples Federico 2, Cardiac Rehabil Unit, Dept Clin Med Cardiovasc & Immunol Sci, I-80131 Naples, Italy. [Giallauria, Francesco] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Giannuzzi, Pantaleo] Med Ctr Rehabil, IRCCS, Salvatore Maugeri Fdn, Div Cardiol, Veruno, Italy. RP Giallauria, F (reprint author), Univ Naples Federico 2, Cardiac Rehabil Unit, Dept Clin Med Cardiovasc & Immunol Sci, Via Pansini5, I-80131 Naples, Italy. EM giallauria@libero.it RI Giallauria, Francesco/B-5681-2013; Giannuzzi, Pantaleo/K-2797-2016 OI Giallauria, Francesco/0000-0003-4119-9397; Giannuzzi, Pantaleo/0000-0002-2313-9115 FU University of Naples "Federico II"; NIH, National Institute on Aging FX This research is supported by University of Naples "Federico II" and in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 44 TC 15 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1558-2027 J9 J CARDIOVASC MED JI J. Cardiovasc. Med. PD OCT PY 2009 VL 10 IS 10 BP 772 EP 780 DI 10.2459/JCM.0b013e32832d55fe PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 497GN UT WOS:000270046400006 PM 19531961 ER PT J AU Heymann, JAW Hinshaw, JE AF Heymann, Juergen A. W. Hinshaw, Jenny E. TI Dynamins at a glance SO JOURNAL OF CELL SCIENCE LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAIN; MARIE-TOOTH DISEASE; MITOCHONDRIAL MORPHOLOGY; MEMBRANE FISSION; CENTRONUCLEAR MYOPATHY; PEROXISOMAL FISSION; ACTIN CYTOSKELETON; ALZHEIMERS-DISEASE; CRYSTAL-STRUCTURE; PLASMA-MEMBRANE C1 [Heymann, Juergen A. W.; Hinshaw, Jenny E.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Heymann, JAW (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM heymannj@mail.nih.gov FU NIDDK; National Institutes of Health FX The laboratory is supported by the intramural research program of the NIDDK, National Institutes of Health. Deposited in PMC for release after 12 months. NR 59 TC 45 Z9 46 U1 0 U2 5 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 OCT PY 2009 VL 122 IS 19 BP 3427 EP 3431 DI 10.1242/jcs.051714 PG 5 WC Cell Biology SC Cell Biology GA 494TK UT WOS:000269839900001 PM 19759282 ER PT J AU Boheler, KR AF Boheler, Kenneth R. TI Stem Cell Pluripotency: A Cellular Trait That Depends on Transcription Factors, Chromatin State and a Checkpoint Deficient Cell Cycle SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID NANOG GENE-EXPRESSION; EMBRYONIC STEM; B-MYB; SELF-RENEWAL; EPIGENETIC REGULATION; ES CELLS; DEVELOPMENTAL REGULATORS; NUCLEAR ARCHITECTURE; FORCED EXPRESSION; HUMAN FIBROBLASTS AB Embryonic stem (ES) and induced pluripotent stem (iPS) cells self-renew and are pluripotent. Differentiation of these cells can yield over 200 somatic cell types, making pluripotent cells an obvious source for regenerative medicine. Before the potential of these cells can be maximally harnessed for clinical applications, it will be necessary to understand the processes that maintain pluripotentiality and signal differentiation. Currently, three unique molecular properties distinguish pluripotent stem cells from somatic cells. These include a unique transcriptional hierarchy that sustains the pluripotent state during the process of self-renewal; a poised epigenetic state that maintains chromatin in a form ready for rapid cell fate decisions; and a cell cycle characterized by an extremely short gap I (G 1) phase and the near absence of normal somatic cell checkpoint controls. Recently, B-MYB (MYBL2) was implicated in the gene regulation of two pluripotency factors and normal cell cycle progression. In this article, the three pluripotency properties and the potential role of B-Myb to regulate these processes will be discussed. J. Cell. Physiol. 221: 10-17, 2009. (C) 2009 Wiley-Liss, Inc. C1 NIA, NIH, GRC, LCS, Baltimore, MD 21224 USA. RP Boheler, KR (reprint author), NIA, NIH, GRC, LCS, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bohelerk@grc.nia.nih.gov FU Research Program of the NIH; National Institute on Aging FX This research was supported entirely by the Research Program of the NIH, National Institute on Aging. NR 95 TC 43 Z9 44 U1 2 U2 24 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD OCT PY 2009 VL 221 IS 1 BP 10 EP 17 DI 10.1002/jcp.21866 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 491IZ UT WOS:000269573400003 PM 19562686 ER PT J AU Benton, G George, J Kleinman, HK Arnaoutova, IP AF Benton, G. George, J. Kleinman, H. K. Arnaoutova, I. P. TI Advancing Science and Technology Via 3D Culture on Basement Membrane Matrix SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID ENDOTHELIAL-CELL INVASION; EXTRACELLULAR-MATRIX; IN-VITRO; GENE-EXPRESSION; TUMOR-CELLS; BRANCHING MORPHOGENESIS; ACINAR DIFFERENTIATION; TISSUE MORPHOGENESIS; CHEMOINVASION ASSAY; BIOLOGICAL-ACTIVITY AB Many cells in tissues are in contact with a highly specialized extracellular matrix, termed the basement membrane. Basement membranes have certain common components, including collagen IV, laminins, heparan sulfate proteoglycans, and growth factors which have a wide variety of biological activities. Extracts of basement membrane-rich tissue have yielded material suitable for studying cell-basement membrane interactions. Cells cultured in a 3D basement membrane matrix allow the in vitro modeling of cell behavior, including differentiation, apoptosis, steps in capillary formation, cancer growth, invasion, etc. It has also led to the development of widely used assays for invasion and angiogenesis and more recently for tumor cell dormancy. Importantly, stem cell culture in 3D basement membrane matrices has provided important advances that allow for expansion of these cells in feeder layer-free cultures and for studying their differentiation. 3D basement membrane culture has allowed the molecular dissection of pathways and genes important in differentiation, aided in the identification of progenitor cells, and led to the development of tissue constructs which may be models for regenerative medicine. This review will outline how this technology has led to important research assays and findings that have advanced our understanding of tissue development and disease and aided in the preclinical development of various therapeutics. J. Cell. Physiol. 221: 18-25, 2009. (C) Published 2009 Wiley-Liss, Inc.(dagger) C1 [Kleinman, H. K.] NIDCR, NIH, Bethesda, MD 20892 USA. [Benton, G.; George, J.; Arnaoutova, I. P.] Trevigen Inc, Gaithersburg, MD USA. [Benton, G.] Georgetown Univ, Washington, DC USA. RP Kleinman, HK (reprint author), NIDCR, NIH, 30-402,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov OI Benton, Gabriel/0000-0003-4244-5764 NR 53 TC 55 Z9 56 U1 0 U2 27 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD OCT PY 2009 VL 221 IS 1 BP 18 EP 25 DI 10.1002/jcp.21832 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 491IZ UT WOS:000269573400004 PM 19492404 ER PT J AU Aid, S Silva, AC Candelario-Jalil, E Choi, SH Rosenberg, GA Bosetti, F AF Aid, S. Silva, A. C. Candelario-Jalil, E. Choi, S. -H. Rosenberg, G. A. Bosetti, F. TI Cyclooxygenase-1 and 2 differently modulate lipopolysaccharide-induced blood-brain barrier disruption via a matrix metalloproteinase mechanism SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Aid, S.; Choi, S. -H.; Bosetti, F.] NIA, BPMS, NIH, Bethesda, MD 20892 USA. [Silva, A. C.] NINDS, Cerebral Microcirculat Unit, NIH, Bethesda, MD 20892 USA. [Candelario-Jalil, E.; Rosenberg, G. A.] Univ New Mexico, Dept Neurol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S479 EP S479 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900584 ER PT J AU Bishu, S Schmidt, K Unterman, A Zametkin, A Channing, M Liu, ZH Qin, M Kammerer, W Herscovitch, P Quezado, Z Smith, CB AF Bishu, S. Schmidt, K. Unterman, A. Zametkin, A. Channing, M. Liu, Z. -H. Qin, M. Kammerer, W. Herscovitch, P. Quezado, Z. Smith, C. Beebe TI Propofol anesthesia alters tissue clearance of leucine but not regional rates of cerebral protein synthesis SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Bishu, S.; Schmidt, K.; Unterman, A.; Zametkin, A.; Liu, Z. -H.; Qin, M.; Smith, C. Beebe] NIMH, Sect Neuroadaptat & Prot Metab, Bethesda, MD 20892 USA. [Channing, M.; Herscovitch, P.] NIH, PET Dept, Bethesda, MD 20892 USA. [Kammerer, W.; Quezado, Z.] NIH, Dept Anesthesia, Bethesda, MD 20892 USA. RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S11 EP S11 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900012 ER PT J AU Fujimura, Y Yasuno, F Farris, A Liow, JS Geraci, M Drevets, W Pine, D Ghose, S Lerner, A Hargreaves, R Bruns, D Morse, C Pike, V Innis, R AF Fujimura, Y. Yasuno, F. Farris, A. Liow, J. -S. Geraci, M. Drevets, W. Pine, D. Ghose, S. Lerner, A. Hargreaves, R. Bruns, D. Morse, C. Pike, V. Innis, R. TI Decreased neurokinin(1) (substance P) receptor binding in patients with panic disorder: positron emission tomographic study with [F-18]SPA-RQ SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Fujimura, Y.; Yasuno, F.; Farris, A.; Liow, J. -S.; Lerner, A.; Morse, C.; Pike, V.; Innis, R.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Geraci, M.; Drevets, W.; Pine, D.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Ghose, S.] UT SW Med Ctr, Dept Psychiat, Dallas, TX USA. [Hargreaves, R.; Bruns, D.] Merck Res Labs, West Point, PA USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S585 EP S586 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900719 ER PT J AU Fujimura, Y Zoghbi, S Simeon, F Taku, A Victor, P Innis, R Fujita, M AF Fujimura, Y. Zoghbi, S. Simeon, F. Taku, A. Victor, P. Innis, R. Fujita, M. TI Quantification of peripheral benzodiazepine receptors in human brain with F-18-PBR06 SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Fujimura, Y.; Zoghbi, S.; Simeon, F.; Taku, A.; Victor, P.; Innis, R.; Fujita, M.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S360 EP S360 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900434 ER PT J AU Fujita, M Zoghbi, S Zarate, C Mallinger, A Hong, J Ozaki, H Pike, V Innis, R Drevets, W AF Fujita, M. Zoghbi, S. Zarate, C. Mallinger, A. Hong, J. Ozaki, H. Pike, V. Innis, R. Drevets, W. TI Changes of brain phosphodiesterase 4 in major depression SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Fujita, M.; Zoghbi, S.; Hong, J.; Ozaki, H.; Pike, V.; Innis, R.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Zarate, C.; Mallinger, A.] NIMH, Mood & Anxiety Disorders Res Unit, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S582 EP S582 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900715 ER PT J AU Henning, E Martin, A Warach, S Latour, L AF Henning, E. Martin, A. Warach, S. Latour, L. TI Flair of early BBB disruption in acute experimental stroke SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Henning, E.; Martin, A.; Warach, S.; Latour, L.] NINDS, Stroke Diagnost & Therapeut Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S482 EP S482 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900588 ER PT J AU Hirano, Y Liu, J Stefanovic, B Silva, A AF Hirano, Y. Liu, J. Stefanovic, B. Silva, A. TI Spatiotemporal investigation of the bold and CBV response to brief somatosensory stimulation in awake marmosets SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Hirano, Y.; Liu, J.; Silva, A.] NINDS, CMU LFMI, NIH, Bethesda, MD 20892 USA. [Stefanovic, B.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S603 EP S604 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900739 ER PT J AU Honda, M Sanchez-Lemus, E Saavedra, JM AF Honda, M. Sanchez-Lemus, E. Saavedra, J. M. TI Clarification of the anti-stress effects of angiotensin II AT1 receptor blockers and their mechanisms of action SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism ID ISOLATION STRESS; DECREASES; PITUITARY C1 [Honda, M.; Sanchez-Lemus, E.; Saavedra, J. M.] NIMH, Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S425 EP S426 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900514 ER PT J AU Itoh, T Abe, K Inoue, O Hong, J Pike, VW Innis, RB Fujita, M AF Itoh, T. Abe, K. Inoue, O. Hong, J. Pike, V. W. Innis, R. B. Fujita, M. TI The effect of cAMP dependent protein kinase activator and inhibitor on [C-11]rolipram binding to phosphodiesterase 4 in conscious rats SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Itoh, T.; Hong, J.; Pike, V. W.; Innis, R. B.; Fujita, M.] NIMH, Bethesda, MD 20892 USA. [Itoh, T.; Abe, K.] Shionogi & Co Ltd, Osaka, Japan. [Abe, K.; Inoue, O.] Osaka Univ, Grad Sch Med, Osaka, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S13 EP S14 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900015 ER PT J AU Kannan, S Saadani-Makki, F Dai, H Chakraborthy, P Muzik, O Romero, R Chugani, D AF Kannan, S. Saadani-Makki, F. Dai, H. Chakraborthy, P. Muzik, O. Romero, R. Chugani, D. TI Brain tryptophan metabolism using small animal pet in a neonatal rabbit model of maternal inflammation induced cerebral palsy SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Kannan, S.; Saadani-Makki, F.; Dai, H.; Chakraborthy, P.; Muzik, O.; Chugani, D.] Wayne State Univ, Detroit, MI USA. [Romero, R.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S97 EP S98 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900107 ER PT J AU Kocharyan, A Stefanovic, B Silva, AC AF Kocharyan, A. Stefanovic, B. Silva, A. C. TI Neuronal PGE(2) is involved in cerebral blood flow response to somatosensory stimulation in chloralose anesthetized rats SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Kocharyan, A.; Silva, A. C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Stefanovic, B.] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Stefanovic, B.] Univ Toronto, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S191 EP S192 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900227 ER PT J AU Kreisl, WC Fujimura, Y Kimura, N Hong, JS Morse, CL Zoghbi, SS Gladding, RL Pike, VW Fujita, M Innis, RB AF Kreisl, W. C. Fujimura, Y. Kimura, N. Hong, J. S. Morse, C. L. Zoghbi, S. S. Gladding, R. L. Pike, V. W. Fujita, M. Innis, R. B. TI Identification of human 'non-binders' and measurement of specific binding with [C-11](R)-PK 11195: implications for PET imaging of brain inflammation SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism ID RADIOLIGAND C1 [Kreisl, W. C.; Fujimura, Y.; Kimura, N.; Hong, J. S.; Morse, C. L.; Zoghbi, S. S.; Gladding, R. L.; Pike, V. W.; Fujita, M.; Innis, R. B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S70 EP S70 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900077 ER PT J AU Leoni, R Paiva, FF de Araujo, DB Silva, AC AF Leoni, R. Paiva, F. F. de Araujo, D. B. Silva, A. C. TI Reduced cerebrovascular reactivity to CO2 induced by hypertension and age: an arterial spin labeling study in rats SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism ID CEREBRAL BLOOD-FLOW C1 [Leoni, R.; Paiva, F. F.; Silva, A. C.] NINDS, Cerebral Microcirculat Unit, NIH, Bethesda, MD 20892 USA. [Leoni, R.; de Araujo, D. B.] Univ Sao Paulo, Dept Math & Phys, BR-14049 Ribeirao Preto, Brazil. RI Paiva, Fernando/C-1429-2012; Leoni, Renata/J-3182-2012; Araujo, Draulio/I-6038-2012 OI Paiva, Fernando/0000-0002-8989-9707; Leoni, Renata/0000-0002-4568-0746; Araujo, Draulio/0000-0002-6934-2485 NR 5 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S132 EP S133 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900151 ER PT J AU Liu, J Bock, N Kocharyan, A Hirano, Y Silva, A AF Liu, J. Bock, N. Kocharyan, A. Hirano, Y. Silva, A. TI Structural MRI-measured T-1 map reflects functional topography in primary somatosensory cortex of a non-human primate SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Liu, J.; Bock, N.; Kocharyan, A.; Hirano, Y.; Silva, A.] NINDS, CMU LFMI, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S602 EP S603 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900738 ER PT J AU Mazzetto-Betti, KC Leoni, RF Pontes-Neto, OM Santos, AC Silva, AC De Araujo, DB AF Mazzetto-Betti, K. C. Leoni, R. F. Pontes-Neto, O. M. Santos, A. C. Silva, A. C. De Araujo, D. B. TI Mapping the hemodynamic response function in the primary auditory cortex under normo- and hypercapnia SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Mazzetto-Betti, K. C.; Pontes-Neto, O. M.; Santos, A. C.; De Araujo, D. B.] Univ Sao Paulo, Dept Neurol Psychiat & Med Psycol, FMRP, BR-14049 Ribeirao Preto, Brazil. [Leoni, R. F.; De Araujo, D. B.] Univ Sao Paulo, Dept Math & Phys, FFCLRP, BR-14049 Ribeirao Preto, Brazil. [Leoni, R. F.; Silva, A. C.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. RI Pontes-Neto, Octavio/G-4294-2012; Leoni, Renata/J-3182-2012; Araujo, Draulio/I-6038-2012 OI Pontes-Neto, Octavio/0000-0003-0317-843X; Leoni, Renata/0000-0002-4568-0746; Araujo, Draulio/0000-0002-6934-2485 NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S569 EP S570 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900701 ER PT J AU Miller, DS Wang, X AF Miller, D. S. Wang, X. TI Upregulation of blood-brain barrier drug efflux pumps by the constitutive-androstane receptor (CAR, NR1I3): a xenobiotic-activated nuclear receptor SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism ID P-GLYCOPROTEIN C1 [Miller, D. S.; Wang, X.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S82 EP S82 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900090 ER PT J AU Ozaki, H Zoghbi, S Hong, J Pike, V Innis, R Fujita, M AF Ozaki, H. Zoghbi, S. Hong, J. Pike, V. Innis, R. Fujita, M. TI Protoporphyrin IX interaction with peripheral type benzodiazepine receptor in rats SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Ozaki, H.; Zoghbi, S.; Hong, J.; Pike, V.; Innis, R.; Fujita, M.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S365 EP S365 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900440 ER PT J AU Palumbo, S Toscano, CD Silva, A Bosetti, F AF Palumbo, S. Toscano, C. D. Silva, A. Bosetti, F. TI Brain arachidonic acid metabolic pathway is altered during cuprizone-induced demyelination SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism ID REMYELINATION C1 [Palumbo, S.; Bosetti, F.] NIA, BPMS, NIH, Bethesda, MD 20892 USA. [Toscano, C. D.] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Div Neurol Prod,Off Drug Evaluat 1, Silver Spring, MD USA. [Silva, A.] NINDS, NIH, Bethesda, MO USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S281 EP S282 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900342 ER PT J AU Piknova, B Schechter, AN Silva, AC AF Piknova, B. Schechter, A. N. Silva, A. C. TI Exogenously administered nitric oxide does not recover the attenuation of the CBF response to somatosensory stimulation after nNOS inhibition SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Piknova, B.; Schechter, A. N.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Silva, A. C.] NINDS, Cerebral Microcirculat Unit, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S133 EP S134 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900152 ER PT J AU Seneca, N Zoghbi, SS Liow, JS Kreisl, W Herscovitch, P Jenko, K Gladding, RL Taku, A Pike, VW Innis, RB AF Seneca, N. Zoghbi, S. S. Liow, J. -S. Kreisl, W. Herscovitch, P. Jenko, K. Gladding, R. L. Taku, A. Pike, V. W. Innis, R. B. TI Human brain imaging and radiation dosimetry of [C-11]-N-desmethyl-loperamide, a positron emission tomographic radiotracer to measure the function of P-glycoprotein SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Seneca, N.] F Hoffmann La Roche Ltd, Clin Res & Exploratory Dev, Basl, Switzerland. [Seneca, N.; Zoghbi, S. S.; Liow, J. -S.; Kreisl, W.; Jenko, K.; Gladding, R. L.; Taku, A.; Pike, V. W.; Innis, R. B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Herscovitch, P.] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S480 EP S481 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900586 ER PT J AU Simonyan, K Herscovitch, P AF Simonyan, K. Herscovitch, P. TI Striatal dopaminergic function during speech production SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Simonyan, K.] NINDS, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. [Herscovitch, P.] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S587 EP S588 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900721 ER PT J AU Sojkova, J Zhou, Y Kraut, M Brasic, J Ferrucci, L Wong, D Resnick, S AF Sojkova, J. Zhou, Y. Kraut, M. Brasic, J. Ferrucci, L. Wong, D. Resnick, S. TI Spatial patterns of longitudinal changes in amyloid deposition in nondemented older adults SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Sojkova, J.; Ferrucci, L.] NIA, NIH, Baltimore, MD 21224 USA. [Sojkova, J.; Zhou, Y.; Kraut, M.; Brasic, J.; Wong, D.; Resnick, S.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. RI Brasic, James/B-3503-2008 OI Brasic, James/0000-0002-3948-4853 NR 0 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 BP S44 EP S44 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900050 ER PT J AU Terry, G Liow, JS Zoghbi, S Hirvonen, J Farris, A Lerner, A Tauscher, J Schaus, J Phebus, L Felder, C Morse, C Hong, J Halldin, C Pike, V Innis, R AF Terry, G. Liow, J. -S. Zoghbi, S. Hirvonen, J. Farris, A. Lerner, A. Tauscher, J. Schaus, J. Phebus, L. Felder, C. Morse, C. Hong, J. Halldin, C. Pike, V. Innis, R. TI Imaging and quantitation of cannabinoid CB1 receptors in healthy human brain using the inverse agonist radioligand [C-11]MePPEP SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Terry, G.; Liow, J. -S.; Zoghbi, S.; Hirvonen, J.; Farris, A.; Lerner, A.; Morse, C.; Hong, J.; Pike, V.; Innis, R.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Terry, G.; Halldin, C.] Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Stockholm, Sweden. [Tauscher, J.; Schaus, J.; Phebus, L.; Felder, C.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S364 EP S364 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900439 ER PT J AU Tomasi, G Bertoldo, A Bishu, S Unterman, A Smith, CB Schmidt, K AF Tomasi, G. Bertoldo, A. Bishu, S. Unterman, A. Smith, C. Beebe Schmidt, K. TI Voxel-based quantification of L-[1-C-11] leucine kinetics for determination of regional rates of cerebral protein synthesis SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism ID TISSUE AMINO-ACIDS; PET C1 [Tomasi, G.] Yale Univ, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Bertoldo, A.] Univ Padua, Dept Informat Engn, Padua, Italy. [Bishu, S.; Unterman, A.; Smith, C. Beebe; Schmidt, K.] NIMH, Sect Neuroadaptat & Prot Metab, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S312 EP S312 PG 1 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900381 ER PT J AU Veronese, M Bertoldo, A Bishu, S Unterman, A Tomasi, G Smith, CB Schmidt, KC AF Veronese, M. Bertoldo, A. Bishu, S. Unterman, A. Tomasi, G. Smith, C. B. Schmidt, K. C. TI A new spectral analysis method for measuring regional rates of cerebral protein synthesis in L-[1-C-11]leucine PET studies SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Meeting Abstract CT 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET CY JUN 29-JUL 03, 2009 CL Chicago, IL SP Int Soc Cerebral Blood Flow & Metabolism C1 [Veronese, M.; Bertoldo, A.] Univ Padua, Dept Informat Engn, Padua, Italy. [Bishu, S.; Unterman, A.; Smith, C. B.; Schmidt, K. C.] NIMH, Sect Neuroadaptat & Prot Metab, Bethesda, MD 20892 USA. [Tomasi, G.] Yale Univ, Dept Diagnost Radiol, New Haven, CT 06510 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD OCT PY 2009 VL 29 SU S1 BP S318 EP S319 PG 2 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 500UB UT WOS:000270329900388 ER PT J AU Dror, O Schneidman-Duhovny, D Inbar, Y Nussinov, R Wolfson, HJ AF Dror, Oranit Schneidman-Duhovny, Dina Inbar, Yuval Nussinov, Ruth Wolfson, Haim J. TI Novel Approach for Efficient Pharmacophore-Based Virtual Screening: Method and Applications SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID DRUG DESIGN; MOLECULAR DOCKING; IDENTIFICATION; SUPERPOSITION; 3D; ALGORITHM; SEARCH; SUBSTRUCTURES; RECEPTORS; DATABASES AB Virtual screening is emerging as a productive and cost-effective technology in rational drug design for the identification of novel lead compounds. An important model for virtual screening is the pharmacophore. Pharmacophore is the spatial configuration of essential features that enable a ligand molecule to interact with a specific target receptor. In the absence of a known receptor structure, a pharmacophore can be identified from a set of ligands that have been observed to interact with the target receptor. Here, we present a novel computational method for pharmacophore detection and virtual screening. The pharmacophore detection module is able to (i) align multiple flexible ligands in a deterministic manner without exhaustive enumeration of the conformational space, (ii) detect subsets of input ligands that may bind to different binding sites or have different binding modes, (iii) address cases where the input ligands have different affinities by defining weighted pharmacophores based on the number of ligands that share them, and (iv) automatically select the most appropriate pharmacophore candidates for virtual screening. The algorithm is highly efficient, allowing a fast exploration of the chemical space by virtual screening of huge compound databases. The performance of PharmaGist was successfully evaluated on a commonly used data set of G-Protein Coupled Receptor alpha]A. Additionally,a large-scale evaluation using the DUD (directory of useful decoys) data set was performed. DUD contains 2950 active ligands for 40 different receptors, with 36 decoy compounds for each active ligand. PharmaGist enrichment rates are comparable with other state-of-the-art tools for virtual screening. C1 [Dror, Oranit; Schneidman-Duhovny, Dina; Inbar, Yuval; Wolfson, Haim J.] Tel Aviv Univ, Blavatnik Sch Comp Sci, Raymond Fac Exact Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] Tel Aviv Univ, Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Blavatnik Sch Comp Sci, Raymond Fac Exact Sci, IL-69978 Tel Aviv, Israel. EM wolfson@tau.ac.il RI Wolfson, Haim/A-1837-2011 FU Intramural NIH HHS [Z01 BC010442-06]; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [1UC1AI067231, UC1 AI067231] NR 52 TC 44 Z9 44 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD OCT PY 2009 VL 49 IS 10 BP 2333 EP 2343 DI 10.1021/ci900263d PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 509JJ UT WOS:000271011500017 PM 19803502 ER PT J AU Kratochvil, CJ May, DE Silva, SG Madaan, V Puumala, SE Curry, JF Walkup, J Kepley, H Vitiello, B March, JS AF Kratochvil, Christopher J. May, Diane E. Silva, Susan G. Madaan, Vishal Puumala, Susan E. Curry, John F. Walkup, John Kepley, Hayden Vitiello, Benedetto March, John S. TI Treatment Response in Depressed Adolescents With and Without Co-Morbid Attention-Deficit/Hyperactivity Disorder in the Treatment for Adolescents with Depression Study SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; SEROTONIN REUPTAKE INHIBITORS; COGNITIVE-BEHAVIORAL THERAPY; MAJOR DEPRESSION; CASE SERIES; CHILDREN; COMORBIDITY; FLUOXETINE; ADHD; SAFETY AB Objective: In the Treatment for Adolescents with Depression Study (TADS), fluoxetine (FLX) and the combination of fluoxetine with cognitive-behavioral therapy (COMB) had superior improvement trajectories compared to pill placebo (PBO), whereas cognitive-behavioral therapy (CBT) was not significantly different from PBO. Because attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) frequently co-exist, we examined whether ADHD moderated these outcomes in TADS. Method: A total of 439 adolescents with MDD, 12-17 years old, were randomized to FLX, CBT, COMB, or PBO. Random coefficients regression models examined depression improvement in 377 depressed youths without ADHD and 62 with ADHD, including 20 who were treated with a psychostimulant. Results: Within the ADHD group, the improvement trajectories of the three active treatments were similar, all with rates of improvement greater than PBO. For those without ADHD, only COMB had a rate of improvement that was superior to PBO. Conclusions: Co-morbid ADHD moderated treatment of MDD. CBT alone or FLX alone may offer benefits similar to COMB in the treatment of MDD in youths with co-morbid MDD and ADHD, whereas monotherapy may not match the benefits of COMB for those without ADHD. The ADHD subgroup analysis presented in this paper is exploratory in nature because of the small number of youths with ADHD in the sample. C1 [Kratochvil, Christopher J.; May, Diane E.; Madaan, Vishal; Puumala, Susan E.] Univ Nebraska Med Ctr, Dept Psychiat, Omaha, NE USA. [Silva, Susan G.; Curry, John F.; March, John S.] Duke Univ, Med Ctr, Durham, NC USA. [Walkup, John] Johns Hopkins Univ, Baltimore, MD USA. [Kepley, Hayden] Univ N Carolina, Wilmington, NC 28401 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Kratochvil, CJ (reprint author), 985581 Nebraska Med Ctr, Omaha, NE 68198 USA. EM ckratoch@unmc.edu FU National Institute of Mental Health to Duke University Medical Center [N01 MH80008] FX TADS was supported by contract N01 MH80008 from the National Institute of Mental Health to Duke University Medical Center (John S. March, Principal Investigator). Eli Lilly provided fluoxetine and matching placebo under an independent educational grant to Duke University. Eli Lilly had no role in the design or implementation of this study and did not participate in the analysis of the data or in authoring this manuscript. The opinions and assertions contained in this publication are the private views of the authors and are not to be construed as official or as reflecting the views of the National Institute of Mental Health, the National Institutes of Health, or the Department of Health and Human Services. NR 34 TC 15 Z9 15 U1 2 U2 7 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD OCT PY 2009 VL 19 IS 5 BP 519 EP 527 DI 10.1089/cap.2008.0143 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 514KC UT WOS:000271392100006 PM 19877976 ER PT J AU Mueller, SC Temple, V Cornwell, B Grillon, C Pine, DS Ernst, M AF Mueller, Sven C. Temple, Veronica Cornwell, Brian Grillon, Christian Pine, Daniel S. Ernst, Monique TI Impaired spatial navigation in pediatric anxiety SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Pediatric; anxiety; hippocampus; water maze; spatial navigation ID MORRIS WATER MAZE; SEX-DIFFERENCES; DEPRESSIVE-DISORDERS; HIPPOCAMPAL-LESIONS; SOCIAL PHOBIA; CHILDREN; MEMORY; ADOLESCENTS; INDIVIDUALS; PERFORMANCE AB Background: Previous theories implicate hippocampal dysfunction in anxiety disorders. Most of the data supporting these theories stem from animal research, particularly lesion studies. The generalization of findings from rodent models to human function is hampered by fundamental inter-species differences. The present work uses a task of spatial orientation, which is known to rely on hippocampal function. Deficits in spatial navigation in anxious children suggest that the hippocampal network involved in spatial orientation is also implicated in anxiety disorders. Methods: Thirty-four treatment-naive children with an anxiety disorder (mean 11.00 years +/- 2.54) are compared to 35 healthy age- and IQ-matched healthy children (mean 11.95 years +/- 2.36) on a virtual, computer-based equivalent of the Morris Water Maze task. Results: Results indicate that children with anxiety disorder exhibit overall impaired performance relative to the comparison group. Anxious children made more heading direction errors and had worse accuracy in completing trials relative to controls. Conclusions: The results present novel evidence that spatial orientation deficits occur in pediatric anxiety. C1 [Mueller, Sven C.; Temple, Veronica; Cornwell, Brian; Grillon, Christian; Pine, Daniel S.; Ernst, Monique] NIMH, MAP, NIH, Bethesda, MD 20892 USA. RP Mueller, SC (reprint author), NIMH, MAP, NIH, 15K N Dr, Bethesda, MD 20892 USA. EM msven@mail.nih.gov FU Intramural Research Programme of the NIMH; NIH FX This research was supported, in part, by the Intramural Research Programme of the NIMH, NIH. We would like to thank the three anonymous reviewers for their helpful comments in improving this manuscript. NR 52 TC 13 Z9 13 U1 6 U2 12 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD OCT PY 2009 VL 50 IS 10 BP 1227 EP 1234 DI 10.1111/j.1469-7610.2009.02112.x PG 8 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 496MH UT WOS:000269977800005 PM 19594834 ER PT J AU de Castro, A Concheiro, M Shakleya, DM Huestis, MA AF de Castro, Ana Concheiro, Marta Shakleya, Diaa M. Huestis, Marilyn A. TI Development and validation of a liquid chromatography mass spectrometry assay for the simultaneous quantification of methadone, cocaine, opiates and metabolites in human umbilical cord SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Methadone; Cocaine; Opiates; Umbilical cord; LCMS; In utero ID DRUG-DEPENDENT MOTHERS; FETAL EXPOSURE; AMNIOTIC-FLUID; ILLICIT DRUGS; BIRTH-WEIGHT; MECONIUM; ABUSE; INFANTS; TISSUE; PREGNANCY AB A liquid chromatography mass spectrometric selected reaction monitoring mode (SRM) method for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine (BE), 6-acetylmorphine, morphine and codeine quantification in human umbilical cord was developed and fully validated. Analytes were extracted from homogenized tissue (1 g) by solid phase extraction. Linearity was 2.5-500 ng/g, except for methadone (10-2000 ng/g). Method imprecision was <12.7%CV with analytical recovery 85.9-112.7%, extraction efficiency >59.2%, matrix effect 4.5-39.5%, process efficiency 48.6-92.6% and stability >84.6%. Analysis of an umbilical cord following controlled methadone administration and illicit drug use contained in ng/g, 40.3 morphine, 3.6 codeine, 442 BE, 186 methadone and 45.9 EDDP. Published by Elsevier B.V. C1 [de Castro, Ana; Concheiro, Marta; Shakleya, Diaa M.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [de Castro, Ana] Univ Santiago Compostela, Inst Legal Med, Forens Toxicol Serv, Santiago De Compostela 15782, Spain. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Biomed Res Ctr, NIH, 251 Bayview Blvd Suite 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI DE CASTRO, ANA/M-5159-2015 OI DE CASTRO, ANA/0000-0002-9832-012X FU National Institutes of Health; Intramural Research Program of the National Institute on Drug Abuse; Direccion Xeral de Investigacion, Desenvolvemento a Innovacion (Conselleria de Innovacion a Industria), Galicia, Spain FX The authors would like to thank Dr. Askin, March and Ruan from the Department of Pathology, Johns Hopkins Bayview Medical Center, for providing us with anonymous human blank umbilical cord tissue for the development of this method. This research was supported by the National Institutes of Health, Intramural Research Program of the National Institute on Drug Abuse, and from Direccion Xeral de Investigacion, Desenvolvemento a Innovacion (Conselleria de Innovacion a Industria), Galicia, Spain. NR 35 TC 15 Z9 15 U1 2 U2 9 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 OCT 1 PY 2009 VL 877 IS 27 BP 3065 EP 3071 DI 10.1016/j.jchromb.2009.07.028 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 499SS UT WOS:000270246400019 PM 19656745 ER PT J AU Munzer, T Harman, SM Sorkin, JD Blackman, MR AF Muenzer, Thomas Harman, S. Mitchell Sorkin, John D. Blackman, Marc R. TI Growth Hormone and Sex Steroid Effects on Serum Glucose, Insulin, and Lipid Concentrations in Healthy Older Women and Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; IMPROVES BODY-COMPOSITION; PLACEBO-CONTROLLED TRIAL; ESTROGEN PLUS PROGESTIN; CORONARY-HEART-DISEASE; GH-DEFICIENT ADULTS; MIDDLE-AGED MEN; REPLACEMENT THERAPY; POSTMENOPAUSAL WOMEN; ELDERLY-WOMEN AB Context: With aging, GH, IGF-I, and sex steroid concentrations and glucose tolerance decrease, and body fat and serum lipids increase. Objective: The aim of the study was to assess GH and/or sex steroid administration effects on serum glucose, insulin, insulin sensitivity, and lipids in older individuals. Design: A double-masked, 2 x 2 factorial, placebo-controlled, double-dummy design was used for the study. Intervention: GH and/or sex steroid [transdermal estradiol plus oral medroxyprogesterone acetate in women (HRT); testosterone enanthate (T) in men] were administered for 6 months. Participants: Healthy, community-dwelling women (n = 57) and men (n = 74) ages 65-88 yr (mean, 72 yr) participated in the study. Main Outcome Measures: We measured serum glucose, insulin, and insulin sensitivity [quantitative insulin sensitivity check index (QUICKI) and insulin sensitivity index (ISI)] before and during an oral glucose tolerance test and lipid profiles. Results: In women, GH did not alter oral glucose tolerance test 120 min or 2-h area under the curve (AUC) glucose values, but it increased 120 min insulin and AUC insulin. There were no significant effects of HRT or GH + HRT. ISI and QUICKI decreased after GH. In men, GH increased 120 min and AUC glucose and insulin AUC. GH + T increased 120 min glucose and glucose and insulin AUCs. T alone did not affect glucose or insulin. ISI decreased after GH and GH + T, whereas QUICKI decreased after GH. GH in women and men and GH + T in men decreased QUICKI by 4 wk. In women, HRT decreased total cholesterol and low-density lipoprotein (LDL)-cholesterol, and GH decreased LDL-cholesterol. In men, total cholesterol decreased after T and GH + T. LDL-cholesterol decreased after GH and GH + T. GH increased serum triglycerides. Conclusions: GH administration to healthy older individuals for 6 months increased insulin resistance with moderately beneficial effects on lipids. (J Clin Endocrinol Metab 94: 3833-3841, 2009) C1 [Blackman, Marc R.] Vet Affairs Med Ctr, Res Serv, Washington, DC 20422 USA. [Muenzer, Thomas; Harman, S. Mitchell; Blackman, Marc R.] NIA, Endocrine Sect, Clin Invest Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Sorkin, John D.] NIA, Metab Sect, Clin Invest Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Muenzer, Thomas] Geriatr Klin, CH-9000 St Gallen, Switzerland. [Harman, S. Mitchell] Kronos Longev Res Inst, Phoenix, AZ 85016 USA. [Sorkin, John D.; Blackman, Marc R.] Ctr Geriatr Res Educ & Clin, Baltimore Vet Affairs Med Ctr, Dept Vet Affairs, Baltimore, MD 21201 USA. [Sorkin, John D.] Univ Maryland, Sch Med, Claude D Pepper Older Amer Independence Ctr, Baltimore, MD 21201 USA. [Blackman, Marc R.] Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD 21218 USA. RP Blackman, MR (reprint author), VA Med Ctr, Res Serv 151, 50 Irving St NW, Washington, DC 20422 USA. EM marc.blackman@va.gov FU National Institute on Aging (NIA); National Center for Research Resources, National Institutes of Health (Bethesda, MD) [RO-1 AG11005, MO-1-RR-02719]; Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatrics Research, Education, and Clinical Center; Claude D. Pepper Older Americans Independence Center [P60-AG-12583]; National Institutes of Health; Robert Bosch Foundation, Stuttgart, Germany FX This work was supported by the Intramural Research Program of the National Institute on Aging (NIA); National Institutes of Health Research Grant RO-1 AG11005 (to M. R. B.) and General Clinical Research Center Grant MO-1-RR-02719, from the National Center for Research Resources, National Institutes of Health (Bethesda, MD); Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatrics Research, Education, and Clinical Center; Claude D. Pepper Older Americans Independence Center Grant P60-AG-12583 at the University of Maryland; and the Research Service, Washington, D. C., Veterans Affairs Medical Center. T. M. was supported in part by the Fogarty International Fellowship Program of the National Institutes of Health. T. M. now receives grant support from the Robert Bosch Foundation, Stuttgart, Germany. NR 60 TC 16 Z9 17 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2009 VL 94 IS 10 BP 3833 EP 3841 DI 10.1210/jc.2009-1275 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 503IE UT WOS:000270526500028 PM 19602554 ER PT J AU Baid, SK Rubino, D Sinaii, N Ramsey, S Frank, A Nieman, LK AF Baid, Smita K. Rubino, Domenica Sinaii, Ninet Ramsey, Sheila Frank, Arthur Nieman, Lynnette K. TI Specificity of Screening Tests for Cushing's Syndrome in an Overweight and Obese Population SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TANDEM MASS-SPECTROMETRY; DEXAMETHASONE-SUPPRESSION TEST; SALIVARY CORTISOL-LEVELS; URINARY FREE CORTISOL; DIAGNOSTIC-TESTS; HYPERCORTISOLISM AB Context: Recent reports suggest a higher prevalence (1-5%) of Cushing's syndrome in certain patient populations with features of the disorder (e. g., diabetes), but the prevalence in the overweight and obese population is not known. Objective: The aim of the study was to evaluate the diagnostic performance of screening tests for Cushing's syndrome in overweight and obese subjects with at least two other features of the disorder. Design and Setting: We conducted a cross-sectional prospective study. Subjects and Methods: A total of 369 subjects (73% female) completed two or three tests: a 24-h urine cortisol, and/or late-night salivary cortisol, and/or 1 mg dexamethasone suppression test (DST). If any result was abnormal [based on laboratory reference range or cortisol after DST >= 1.8 mu g/dl (50 nmol/liter)], tests were repeated and/or a dexamethasone-CRH test was performed. Subjects with abnormal DST results and a low dexamethasone level were asked to repeat the test with 2 mg of dexamethasone. Results: In addition to obesity, subjects had a mean of five to six features of Cushing's syndrome. None was found to have Cushing's syndrome. Test specificities to exclude Cushing's syndrome for subjects who completed three tests were: urine cortisol, 96% [95% confidence interval (CI), 93-98%]; DST, 90% (95% CI, 87-93%); salivary cortisol, 84% by RIA (95% CI, 79-89%) and 92% by liquid chromatography-tandem mass spectrometry (95% CI, 88-95%). The combined specificity (both tests normal) for all combinations of two tests was 84 to 90%, with overlapping CIs. Conclusion: These data do not support widespread screening of overweight and obese subjects for Cushing's syndrome; test results for such patients may be falsely abnormal. (J Clin Endocrinol Metab 94: 3857-3864, 2009) C1 [Baid, Smita K.; Nieman, Lynnette K.] Eunice Kennedy Shriver NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Rubino, Domenica; Ramsey, Sheila; Frank, Arthur] George Washington Univ, Weight Management Program, Washington, DC 20037 USA. [Rubino, Domenica; Ramsey, Sheila] Washington Ctr Weight Management & Res, Arlington, VA 22201 USA. [Sinaii, Ninet] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Clin Res Ctr, Bldg 10,1 E,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM NiemanL@nih.gov FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Development FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, The Eunice Kennedy Shriver National Institute of Child Health and Development. NR 20 TC 43 Z9 47 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2009 VL 94 IS 10 BP 3857 EP 3864 DI 10.1210/jc.2008-2766 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 503IE UT WOS:000270526500031 PM 19602562 ER PT J AU Robinson-White, AJ Bossis, I Hsiao, HP Nesterova, M Leitner, WW Stratakis, CA AF Robinson-White, Audrey J. Bossis, Ioannis Hsiao, Hui-Pin Nesterova, Maria Leitner, Wolfgang W. Stratakis, Constantine A. TI 8-Cl-Adenosine Inhibits Proliferation and Causes Apoptosis in B-Lymphocytes via Protein Kinase A-Dependent and Independent Effects: Implications for Treatment of Carney Complex-Associated Tumors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SPOTTY SKIN PIGMENTATION; ALPHA REGULATORY SUBUNIT; MULTIPLE-MYELOMA CELLS; NUCLEOSIDE TRANSPORTERS; ENDOCRINE OVERACTIVITY; S-ADENOSYLHOMOCYSTEINE; ACTIVE METABOLITE; GROWTH-INHIBITION; DOWN-REGULATION; LEUKEMIA-CELLS AB Context: Carney complex, a multiple neoplasia syndrome, characterized primarily by spotty skin pigmentation and a variety of endocrine and other tumors, is caused by mutations in PRKAR1A, the gene that codes for the RI alpha subunit of protein kinase A (PKA). PKA controls cell proliferation in many cell types. The cAMP analogue 8-Cl-adenosine (8-Cl-ADO) is thought to inhibit cancer cell proliferation. Objective: The objective of the study was to study the antiproliferative effects of 8-Cl-ADO on growth and proliferation in B-lymphocytes of Carney complex patients that have PKA defects and to determine whether 8-CL-ADO could be used as a therapeutic agent in the treatment of Carney complex-associated tumors. Design: We used a multiparametric approach (i.e. growth and proliferation assays, PKA, and PKA subunit assays, cAMP and (3)H-cAMP binding assays, and apoptosis assays) to understand the growth and proliferative effects of 8-Cl-ADO on human B-lymphocytes. Results: 8-Cl-ADO inhibited proliferation, mainly through its intracellular transport and metabolism, which induced apoptosis. PKA activity, cAMP levels, and (3)H-cAMP binding were increased or decreased, respectively, by 8-Cl-ADO, whereas PKA subunit levels were differentially affected. 8-Cl-ADO also inhibited proliferation induced by G protein-coupled receptors for isoproterenol and adenosine, as well as proliferation induced by tyrosine kinase receptors. Conclusions: 8-Cl-ADO in addition to unambiguously inhibiting proliferation and inducing apoptosis in a PKA-independent manner also has PKA-dependent effects that are unmasked by a mutant PRKAR1A. Thus, 8-Cl-ADO could serve as a therapeutic agent in patients with Carney complex-related tumors. (J Clin Endocrinol Metab 94: 4061-4069, 2009) C1 [Robinson-White, Audrey J.; Hsiao, Hui-Pin; Nesterova, Maria; Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Natl Inst Hlth, Bethesda, MD 20892 USA. [Leitner, Wolfgang W.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Bossis, Ioannis] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Hsiao, Hui-Pin] Kaohsiung Med Univ, Dept Pediat, Kaohsiung Municipal Hsiao Kang Hosp, Kaohsiung 807, Taiwan. RP Robinson-White, AJ (reprint author), NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Natl Inst Hlth, Bldg 10,Room 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM robinsoa@mail.nih.gov RI Hsiao, Hui-Pin/B-3892-2010; Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 FU National Institutes of Health, National Institute of Child Health and Human Development intramural project [Z01-HD-000642-04] FX This work was supported by the National Institutes of Health, National Institute of Child Health and Human Development intramural project Z01-HD-000642-04 ( to C. A. S.). NR 40 TC 3 Z9 4 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2009 VL 94 IS 10 BP 4061 EP 4069 DI 10.1210/jc.2009-0759 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 503IE UT WOS:000270526500058 PM 19773399 ER PT J AU Berger, VW AF Berger, Vance William TI Valid, adaptive, data-driven comparisons of binary end points SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Letter C1 [Berger, Vance William] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance William] Univ Maryland Baltimore Cty, Bethesda, MD USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Bethesda, MD 20892 USA. EM vb78c@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 3 TC 2 Z9 2 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD OCT PY 2009 VL 62 IS 10 BP 1112 EP 1112 DI 10.1016/j.jclinepi.2009.04.009 PG 1 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 499UB UT WOS:000270250500016 PM 19699055 ER PT J AU Weir, MR Yeh, F Silverman, A Devereux, RB Galloway, JM Henderson, JA Howard, WJ Russell, M Wilson, C Ratner, R Sorkin, J Umans, JG Fleg, JL Stylianou, M Lee, E Howard, BV AF Weir, Matthew R. Yeh, Fawn Silverman, Angela Devereux, Richard B. Galloway, James M. Henderson, Jeffrey A. Howard, William J. Russell, Marie Wilson, Charlton Ratner, Robert Sorkin, John Umans, Jason G. Fleg, Jerome L. Stylianou, Mario Lee, Elisa Howard, Barbara V. TI Safety and Feasibility of Achieving Lower Systolic Blood Pressure Goals in Persons With Type 2 Diabetes: The SANDS Trial SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID CORONARY-HEART-DISEASE; RANDOMIZED-TRIAL; AMERICAN-INDIANS; LOWER TARGETS; CHOLESTEROL; ATHEROSCLEROSIS; COMMITTEE AB The Stop Atherosclerosis in Native Diabetics Study (SANDS) was a randomized open-label clinical trial in type 2 diabetics designed to examine the effects of intensive reduction of blood pressure, aggressive vs standard goals (< 115/75 mm Hg vs < 130/80 mm Hg), and low-density lipoprotein (LDL) cholesterol on the composite outcome of change in carotid intimal-medial thickness and cardiovascular events. The study demonstrated that in conjunction with a lower LDL cholesterol target of 70 mg/dL, aggressive systolic blood pressure-lowering resulted in a reduction in carotid intimal-medial thickness and left ventricular mass without measurable differences in cardiovascular events. The blood pressure treatment algorithm included renin-angiotensin system blockade, with other agents added if necessary. The authors conclude that both standard and more aggressive systolic blood pressure reduction can be achieved with excellent safety and good tolerability in patients with type 2 diabetes mellitus. C1 [Weir, Matthew R.] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. [Yeh, Fawn; Lee, Elisa] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Silverman, Angela; Howard, William J.; Ratner, Robert; Umans, Jason G.; Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD USA. [Devereux, Richard B.] Weill Cornell Med Coll, New York, NY USA. [Galloway, James M.] Univ Arizona, Hlth Sci Ctr, Tucson, AZ USA. [Henderson, Jeffrey A.] Black Hills Ctr Amer Indian Hlth, Rapid City, SD USA. [Russell, Marie; Wilson, Charlton] Phoenix Indian Med Ctr, Phoenix, AZ USA. [Fleg, Jerome L.; Stylianou, Mario] NHLBI, Bethesda, MD 20892 USA. RP Weir, MR (reprint author), Univ Maryland, Sch Med, Div Nephrol, 22 S Greene St,Room N3W143, Baltimore, MD 21201 USA. EM mweir@medicine.umaryland.edu FU First Horizon Pharmacy (Triglide); Merck and Co (Cozaar/Hyzaar); Pfizer, Inc (Lipitor) FX We thank the Indian Health Services facilities, SANDS participants, and participating tribal communities for extraordinary cooperation and involvement without which this study would not have been possible. We also acknowledge the valuable contributions of the following SANDS study staff: Tauqeer Ali, PhD; Collen Begay; Stephanie Big Crow; Verna Cable; Damon Davis, RN; Joanne Detwiler, PA-C; Lynne Dobrovolny, PA; Verdell Kanuho; Tanya Molina; Missy Oines; Maria Ramos, PA-C; Corinne Wills, CNP; and Jackie Yotter, RN, for coordination of study centers and Tia A. Paul, University of Maryland School of Medicine, Baltimore, MD, for editing the manuscript. We also gratefully acknowledge donations of pharmacologic agents by First Horizon Pharmacy (Triglide); Merck and Co (Cozaar/Hyzaar); and Pfizer, Inc (Lipitor), and we thank Dr John Lachin for providing advice on statistical methods. NR 16 TC 10 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD OCT PY 2009 VL 11 IS 10 BP 540 EP 548 DI 10.1111/j.1751-7176.2009.00121.x PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 504BP UT WOS:000270588700003 PM 19817934 ER PT J AU Nabel, EG AF Nabel, Elizabeth G. TI Linking biomedical research to health care SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article C1 NHLBI, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM directornhlbi@mail.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 2858 EP 2858 DI 10.1172/JCI41035 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100012 PM 20069715 ER PT J AU Doi, K Leelahavanichkul, A Yuen, PST Star, RA AF Doi, Kent Leelahavanichkul, Asada Yuen, Peter S. T. Star, Robert A. TI Animal models of sepsis and sepsis-induced kidney injury SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID ACUTE-RENAL-FAILURE; TUMOR-NECROSIS-FACTOR; TOLL-LIKE RECEPTORS; PERITUBULAR CAPILLARY DYSFUNCTION; CRITICALLY-ILL PATIENTS; IN-VIVO EXPRESSION; SEPTIC SHOCK; CECAL LIGATION; BLOOD-FLOW; POLYMICROBIAL SEPSIS AB Sepsis is characterized by a severe inflammatory response to infection, and its complications, including acute kidney injury, can be fatal. Animal models that correctly mimic human disease are extremely valuable because they hasten the development of clinically useful therapeutics. Too often, however, animal models do not properly mimic human disease. In this Review, we outline a bedside-to-bench-to-bedside approach that has resulted in improved animal models for the study of sepsis - a complex disease for which preventive and therapeutic strategies are unfortunately lacking. We also highlight a few of the promising avenues for therapeutic advances and biomarkers for sepsis and sepsis-induced acute kidney injury. Finally, we review how the study of drug targets and biomarkers are affected by and in turn have influenced these evolving animal models. C1 [Yuen, Peter S. T.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. [Doi, Kent] Univ Tokyo, Dept Nephrol & Endocrinol, Tokyo, Japan. [Leelahavanichkul, Asada] Chulalongkorn Univ, Dept Med, Div Nephrol, Bangkok, Thailand. RP Yuen, PST (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, 10 Ctr Dr,Room 3N108, Bethesda, MD 20892 USA. EM py@nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU Intramural Research Program of the NIH; NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. We apologize to all the authors whose. work we could not cover due to space limitations. NR 126 TC 197 Z9 207 U1 6 U2 29 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 2868 EP 2878 DI 10.1172/JCI39421 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100019 PM 19805915 ER PT J AU Gress, RE Deeks, SG AF Gress, Ronald E. Deeks, Steven G. TI Reduced thymus activity and infection prematurely age the immune system SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID T-CELL SUBSETS; REPERTOIRE; RISK; THYMOPOIESIS; ACTIVATION; EXPANSION; ADULTS; LIFE AB The aging process affects all aspects of the immune system, particularly the T cells. The immune system in older individuals is often characterized by lower T cell numbers, lower naive/memory T cell ratios, and lower T cell diversity. Most measures of inflammation increase with age. Why this happens, and why there is so much person-to-person variability in these changes, is not known. In this issue of the JCI, Sauce and colleagues show that removal of the thymus during infancy results in premature onset of many of these age-associated changes to the immune system (see the related article beginning on page 3070). The effect of thymectomy was particularly notable in those individuals who acquired CMV infection. Data from this study, as well as data from other observational settings, suggest that reduced thymic function and persistent viral infections combine to accelerate a decline in immunologic function. C1 [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Deeks, SG (reprint author), Univ Calif San Francisco, Ward 84,Bldg 80,995 Potero Ave, San Francisco, CA 94143 USA. EM sdeeks@php.ucsf.edu NR 20 TC 13 Z9 16 U1 1 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 2884 EP 2887 DI 10.1172/JCI40855 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100022 PM 19770512 ER PT J AU Snow, AL Marsh, RA Krummey, SM Roehrs, P Young, LR Zhang, KJ van Hoff, J Dhar, D Nichols, KE Filipovich, AH Su, HC Bleesing, JJ Lenardo, MJ AF Snow, Andrew L. Marsh, Rebecca A. Krummey, Scott M. Roehrs, Philip Young, Lisa R. Zhang, Kejian van Hoff, Jack Dhar, Deepali Nichols, Kim E. Filipovich, Alexandra H. Su, Helen C. Bleesing, Jack J. Lenardo, Michael J. TI Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HUMORAL IMMUNE-RESPONSES; MICE DEFICIENT; ENCODING GENE; XLP SYNDROME; SH2 DOMAIN; ACTIVATION; RECEPTOR; DEATH; SLAM; LYMPHOCYTES AB X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency that leads to an extreme, usually fatal increase in the number of lymphocytes upon infection with EBV. It is most commonly defined molecularly by loss of expression of SLAM-associated protein (SAP). Despite this, there is little understanding of how SAP deficiency causes lymphocytosis following EBV infection. Here we show that T cells from individuals with XLP are specifically resistant to apoptosis mediated by TCR restimulation, a process that normally constrains T cell expansion during immune responses. Expression of SAP and the SLAM family receptor NK, T, and B cell antigen (NTB-A) were required for TCR-induced upregulation of key pro-apoptotic molecules and subsequent apoptosis. Further, SAP/NTB-A signaling augmented the strength of the proximal TCR signal to achieve the threshold required for restimulation-induced cell death (RICD). Strikingly, TCR ligation in activated T cells triggered increased recruitment of SAP to NTB-A, dissociation of the phosphatase SHP-1, and colocalization of NTB-A with CD aggregates. In contrast, NTB-A and SHP-1 contributed to RICD resistance in XLP T cells. Our results reveal what we believe to be novel roles for NTB-A and SAP in regulating T cell homeostasis through apoptosis and provide mechanistic insight into the pathogenesis of lymphoproliferative disease in XLP. C1 [Snow, Andrew L.; Krummey, Scott M.; Dhar, Deepali; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zhang, Kejian] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH USA. [Young, Lisa R.] Cincinnati Childrens Hosp, Med Ctr, Div Pulm Med, Cincinnati, OH USA. [Marsh, Rebecca A.; Roehrs, Philip; Filipovich, Alexandra H.; Bleesing, Jack J.] Cincinnati Childrens Hosp, Med Ctr, Div Bone Marrow Transplantat Immune Deficiency, Cincinnati, OH USA. [van Hoff, Jack] Dartmouth Hitchcock Med Ctr, Dept Hematol Oncol, Lebanon, NH 03766 USA. [Nichols, Kim E.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Su, Helen C.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), Bldg 10,Rm 11N311,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lenardo@nih.gov RI Su, Helen/H-9541-2015; OI Su, Helen/0000-0002-5582-9110; Snow, Andrew/0000-0002-8728-6691 FU NIH; National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences FX We thank the patients and their families, as well as Lewis Silverman at Dana Farber Cancer Institute for providing blood samples on XLP PtS. We also thank Juraj Kabat for help with confocal microscopy analysis and Pamela Schwartzberg for critical reading of the manuscript. We acknowledge the clinical laboratory testing performed by the Cincinnati Children's Hospital Diagnostic Immunology Laboratory as well as care for the patients provided by the bone marrow transplant physicians, nurses, and staff at Cincinnati Children's Hospital. This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. A.L. Snow was supported by a Pharmacology Research Associate Training Program Fellowship from the National Institute of General Medical Sciences. NR 45 TC 68 Z9 71 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 2976 EP 2989 DI 10.1172/JCI39518 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100032 PM 19759517 ER PT J AU Li, JH Chou, CL Li, B Gavrilova, O Eisner, C Schnermann, J Anderson, SA Deng, CX Knepper, MA Wess, J AF Li, Jian Hua Chou, Chung-Lin Li, Bo Gavrilova, Oksana Eisner, Christoph Schnermann, Juergen Anderson, Stasia A. Deng, Chu-Xia Knepper, Mark A. Wess, Juergen TI A selective EP4 PGE(2) receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MEDULLARY COLLECTING DUCT; RAT-KIDNEY; WATER PERMEABILITY; PROSTAGLANDIN E-2; KNOCKOUT MICE; VASOPRESSIN; AQUAPORIN-2; GENE; MUTATIONS; PATHOGENESIS AB X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present, no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE(2) receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology. These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of the newly generated V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI. C1 [Wess, Juergen] NIDDK, Bioorgan Chem Lab, Mol Signaling Sect, NIH, Bethesda, MD 20892 USA. [Chou, Chung-Lin; Knepper, Mark A.] NIDDK, Kidney & Electrolyte Metab Lab, NHLBI, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Facil, NIH, Bethesda, MD 20892 USA. [Eisner, Christoph; Schnermann, Juergen] NIDDK, Renal Funct & Injury Sect, NIH, Bethesda, MD 20892 USA. [Anderson, Stasia A.] NIDDK, Anim MRI Imaging Core, NHLBI, NIH, Bethesda, MD 20892 USA. [Deng, Chu-Xia] NIDDK, Mammalian Genet Sect, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Bioorgan Chem Lab, Mol Signaling Sect, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Li, Jianhua/B-7671-2011 OI Li, Jianhua/0000-0002-5744-3182 FU National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK); National Heart, Lung, and Blood Institute (NHLBI) [ZO1-HL-001285] FX This research was supported by the Intramural Research Program budgets of the National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI) (project number ZO1-HL-001285). We thank Brenda Klaunberg and Vivian Diaz (In Vivo NMR Center, National Institute of Neurological Disorders and Stroke) for their help with the blood pressure measurements, Shawn Kozlov (NHLBI) for analyzing urine and serum samples, and Cuiling Li and Yinghong Cui (NIDDK) for expert technical assistance. NR 49 TC 50 Z9 52 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 3115 EP 3126 DI 10.1172/JCI39680 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100044 PM 19729836 ER PT J AU Mandinova, A Kolev, V Neel, V Hu, B Stonely, W Lieb, J Wu, XW Colli, C Han, R Pazin, M Ostano, P Dummer, R Brissette, JL Dotto, GP AF Mandinova, Anna Kolev, Vihren Neel, Victor Hu, Bing Stonely, Wesley Lieb, Jocelyn Wu, Xunwei Colli, Claudia Han, Rong Pazin, Mike Ostano, Paola Dummer, Reinhard Brissette, Janice L. Dotto, G. Paolo TI A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GROWTH-FACTOR RECEPTOR; EPITHELIAL TERMINAL DIFFERENTIATION; SEBORRHEIC KERATOSES; C-JUN; MULTIPLE-MYELOMA; FGFR3 MUTATIONS; NUDE GENE; EPIDERMAL-GROWTH; EXPRESSION; PROTEIN AB Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus, we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype. C1 [Hu, Bing; Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Neel, Victor; Dotto, G. Paolo] MGH, Dept Dermatol, Boston, MA USA. [Mandinova, Anna; Kolev, Vihren; Stonely, Wesley; Lieb, Jocelyn; Wu, Xunwei; Colli, Claudia; Han, Rong; Brissette, Janice L.; Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Pazin, Mike] NIA, NIH, Baltimore, MD 21224 USA. [Ostano, Paola] Fondo Edo Tempia, Lab Canc Pharmacogenom, Biella, Italy. [Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. RP Dotto, GP (reprint author), Univ Lausanne, Dept Biochem, Chemin Boveresses 155, CH-1066 Epalinges, Switzerland. EM gian-paolo.dotto@unil.ch OI Han, Rong/0000-0002-5766-8277; Pazin, Michael/0000-0002-7561-3640 FU NIH [AR39190, AR054856, AR04S284, CA16038, CA73796]; Swiss National Foundation; European Union [LSHB-CT-2005-019067]; Cutaneous Biology Research Center through the MGH/Shiseido Co. Ltd. Agreement FX We thank W. Austen for human skin material, D. Prowse for the FOXN1-ER retrovirus, D. Ornitz for FGFR3 constructs, and V. Rajashekara for skillful technical help. This work was supported by NIH grants AR39190, AR054856, AR04S284, CA16038, and CA73796; by the Swiss National Foundation; by a grant from the European Union (Epistem, Sixth Framework Program, LSHB-CT-2005-019067); and in part by the Cutaneous Biology Research Center through the MGH/Shiseido Co. Ltd. Agreement. NR 61 TC 33 Z9 33 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 3127 EP 3137 DI 10.1172/JCI38543 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100045 PM 19729838 ER PT J AU Iwasawa, M Miyazaki, T Nagase, Y Akiyama, T Kadono, Y Nakamura, M Oshima, Y Yasui, T Matsumoto, T Nakamura, T Kato, S Hennighausen, L Nakamura, K Tanaka, S AF Iwasawa, Mitsuyasu Miyazaki, Tsuyoshi Nagase, Yuichi Akiyama, Toru Kadono, Yuho Nakamura, Masaki Oshima, Yasushi Yasui, Tetsuro Matsumoto, Takumi Nakamura, Takashi Kato, Shigeaki Hennighausen, Lothar Nakamura, Kozo Tanaka, Sakae TI The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CELL-DEATH; C-SRC; ENDOPLASMIC-RETICULUM; CONDITIONAL DELETION; NUCLEAR-ENVELOPE; IN-VIVO; APOPTOSIS; FAMILY; RECEPTOR; EXPRESSION AB The B cell lymphoma 2 (Bcl-2) family member Bcl-xL has a well-characterized antiapoptotic function in lymphoid cells. However, its functions in other cells - including osteoclasts, which are of hematopoietic origin and other cellular processes remain unknown. Here we report an unexpected function of Bcl-xL in attenuating the bone-resorbing activity of osteoclasts in mice. To investigate the role of Bcl-xL in osteoclasts, we generated mice with osteoclast-specific conditional deletion of Bcl-x (referred to herein as Bcl-x cKO mice) by mating Bcl-x(fl/fl) mice with mice in which the gene encoding the Cre recombinase has been knocked into the cathepsin K locus and specifically expressed in mature osteoclasts. Although the Bcl-x cKO mice grew normally with no apparent morphological abnormalities, they developed substantial osteopenia at 1 year of age, which was caused by increased bone resorption. Bcl-x deficiency increased the bone-resorbing activity of osteoclasts despite their high susceptibility to apoptosis, whereas Bcl-xL overexpression produced the opposite effect. In addition, Bcl-x cKO osteoclasts displayed increased c-Src activity, which was linked to increased levels of vitronectin and fibronectin expression. These results suggest that Bcl-xL attenuates osteoclastic bone-resorbing activity through the decreased production of ECM proteins, such as vitronectin and fibronectin, and thus provide evidence for what we believe to be a novel cellular function of Bcl-xL. C1 [Tanaka, Sakae] Univ Tokyo, Fac Med, Dept Orthopaed Surg, Bunkyo Ku, Tokyo 1130033, Japan. [Miyazaki, Tsuyoshi] Tokyo Metropolitan Geriatr Hosp, Dept Geriatr Med, Tokyo 173, Japan. [Miyazaki, Tsuyoshi] Inst Gerontol, Tokyo, Japan. [Nakamura, Takashi; Kato, Shigeaki] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo, Japan. [Hennighausen, Lothar] NIH, Lab Genet & Physiol, Bethesda, MD 20892 USA. RP Tanaka, S (reprint author), Univ Tokyo, Fac Med, Dept Orthopaed Surg, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM TANAKAS-ORT@h.u-tokyo.ac.jp OI Akiyama, Toru/0000-0001-9493-4768 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Labor, and Welfare of Japan; National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX The authors thank R. Yamaguchi (Department of Orthopaedic Surgery, University of Tokyo) for providing expert technical assistance. ABT-737 was provided by Abbott Laboratories. This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by Health Science research grants from the Ministry of Health, Labor, and Welfare of Japan to S. Tanaka. The research of L. Hennighausen was funded through the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Pacific Edit reviewed the manuscript prior to submission. NR 41 TC 18 Z9 21 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 3149 EP 3159 DI 10.1172/JCI39819 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100047 PM 19759519 ER PT J AU Chang, SW Biswas, K Martin, BK Stauffer, S Sharan, SK AF Chang, Suhwan Biswas, Kajal Martin, Betty K. Stauffer, Stacey Sharan, Shyam K. TI Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BREAST-CANCER SUSCEPTIBILITY; EARLY-ONSET BREAST; OVARIAN-CANCER; EMBRYONIC LETHALITY; MISSENSE MUTATIONS; GERMLINE MUTATIONS; SEQUENCE VARIANTS; GENE BRCA1; IN-VIVO; PHOSPHORYLATION AB To date, inheritance of a mutant BRCA1 or BRCA2 gene is the best-established indicator of an increased risk of developing breast cancer. Sequence analysis of these genes is being used to identify BRCA1/2 mutation carriers, though these efforts are hampered by the high frequency of variants of unknown clinical significance (VUSs). Functional evaluation of such variants has been restricted due to lack of a physiologically relevant assay. In this study we developed a functional assay using mouse ES cells to study variants of BRCA1. We introduced BAC clones with human wild-type BRCA1 or variants into Brca1-null ES cells and confirmed that only wild-type and a known neutral variant rescued cell lethality. The same neutral variant was also able to rescue embryogenesis in Brca1-null mice. A test of several BRCT domain mutants revealed all to be deleterious, including a VUS. Furthermore, we used this assay to determine the effects of BRCA1 variants on cell cycle regulation, differentiation, and genomic stability. Importantly, we discovered that ES cells rescued by S1497A BRCA1 exhibited significant hypersensitivity after gamma-irradiation. Our results demonstrate that this ES cell-based assay is a powerful and reliable method for analyzing the functional impact of BRCA1 variants, which we believe could be used to determine which patients may require preventative treatments. C1 [Chang, Suhwan; Biswas, Kajal; Stauffer, Stacey; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Martin, Betty K.] NCI, SAIC Frederick, Ft Detrick, MD 21702 USA. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560,Room 32-31C,1050 Boyles St, Ft Detrick, MD 21702 USA. EM sharans@mail.nih.gov FU Center for Cancer Research, NCI, NIH FX We thank J. Acharya, I. Daar, K. Reilly, and L. Tessarollo for helpful discussions and critical review of the manuscript. We also thank Kyung-Ae Kim and Susan Lynn North for technical assistance; Deborah Swing, Yongping Yang, Prajakta Varadkar, and Lionel Feigenbaum for help with BAC transgenic mice; Sandra Burkett for cytogenetic analysis; Allen Kane, Jiro Wada, and Richard Frederickson (NCI-Frederick Publications Department) for illustracions; Serguei Kozlov for help with in vitro ES cell differentiation; and Diana Haines for histolopathological analysis. The research was sponsored by the Center for Cancer Research, NCI, NIH. NR 47 TC 41 Z9 41 U1 0 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2009 VL 119 IS 10 BP 3160 EP 3171 DI 10.1172/JCI39836 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 503HA UT WOS:000270523100048 PM 19770520 ER PT J AU Howard, WJ Russell, M Fleg, JL Mete, M Ali, T Devereux, RB Galloway, JM Otvos, JD Ratner, RE Roman, MJ Silverman, A Umans, JG Weissman, NJ Wilson, C Howard, BV AF Howard, Wm. James Russell, Marie Fleg, Jerome L. Mete, Mihriye Ali, Tauqeer Devereux, Richard B. Galloway, James M. Otvos, James D. Ratner, Robert E. Roman, Mary J. Silverman, Angela Umans, Jason G. Weissman, Neil J. Wilson, Charlton Howard, Barbara V. TI Prevention of atherosclerosis with low-density lipoprotein cholesterol lowering-lipoprotein changes and interactions: the SANDS study SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE Atherosclerosis; Cardiovascular disease; Carotid arteries; Cholesterol; Lipoproteins ID CORONARY-HEART-DISEASE; METAANALYSIS; EFFICACY; TRIALS; RISK AB BACKGROUND: Lowering low-density lipoprotein cholesterol (LDL-C) with statins reduces atherosclerosis. LDL and high-density lipoprotein (HDL) are commonly measured by their cholesterol content, but non-HDL cholesterol, LDL particle number (LDL-P), or total apolipoprotein B (apoB) may be better predictors of cardiovascular risk. Few studies have examined the relationship arnong lipoprotein levels and composition before and after interventions to lower LDL-C and non-HDL-C. OBJECTIVE: We sought to measure changes in carotid artery intimal media thickness (CIMT) and lipid concentration and composition during 36 months of statin therapy. METHODS: Analyses were conducted on 418 diabetic individuals, with complete data and no previous cardiovascular events, who were randomized to aggressive (AG) versus standard treatment for LDL-C, non-HDL-C, and systolic blood pressure as part of the Stop Atherosclerosis in Native Diabetics Study (SANDS). RESULTS: The AG group achieved average LDL-C and non-HDL-C of 71 mg/dL and 100 mg/dL and a decrease in CIMT. No significant interactions were observed between treatment effect and initial levels of LDL-C, non-HDL-C, HDL-C, triglycerides, apoB, or LDL-P. Decreases in LDL-C (P < .005) and non-HDL-C (P < .001) were independently correlated with CIMT regression in the AG group. Changes in apoB and LDL-P demonstrated borderline correlations with CIMT regression (P = .07 and P = .09). CONCLUSIONS: In diabetic adults with no previous cardiovascular events, treatment to current targets for lipids and systolic blood pressure reduces atherosclerosis progression and when more aggressive targets are met, atherosclerosis regresses. The aggressive targets for LDL-C and non-HDL-C appeared to be the main determinants of CIMT regression and were more predictive of this outcome than changes in LDL-P or apoB. (C) 2009 National Lipid Association. All rights reserved. C1 [Howard, Wm. James] Washington Hosp Ctr, Lipid Clin, Washington, DC 20010 USA. [Howard, Wm. James] Washington Hosp Ctr, Consultat Serv, Washington, DC 20010 USA. [Russell, Marie; Wilson, Charlton] Phoenix Indian Med Ctr, Phoenix, AZ USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Mete, Mihriye; Ratner, Robert E.; Silverman, Angela; Umans, Jason G.; Weissman, Neil J.; Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD USA. [Ali, Tauqeer] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Devereux, Richard B.; Roman, Mary J.] Weill Cornell Med Coll, New York, NY USA. [Galloway, James M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Otvos, James D.] LipoSci Inc, Raleigh, NC USA. RP Howard, WJ (reprint author), Washington Hosp Ctr, Lipid Clin, Rm 6A-126,110 Irving St NW, Washington, DC 20010 USA. EM wm.james.howard@medstar.net FU NHLBI NIH HHS [U01 HL067031, U01 HL067031-01A1] NR 17 TC 15 Z9 15 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD OCT PY 2009 VL 3 IS 5 BP 322 EP 331 DI 10.1016/j.jacl.2009.09.001 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 511LF UT WOS:000271165900004 PM 20161568 ER PT J AU Hickey, PW Sutton, DA Fothergill, AW Rinaldi, MG Wickes, BL Schmidt, HJ Walsh, TJ AF Hickey, Patrick W. Sutton, Deanna A. Fothergill, Annette W. Rinaldi, Michael G. Wickes, Brian L. Schmidt, Howard J. Walsh, Thomas J. TI Trichosporon mycotoxinivorans, a Novel Respiratory Pathogen in Patients with Cystic Fibrosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; OF-THE-LITERATURE; AMPHOTERICIN-B; PULLULANS INFECTION; GENUS TRICHOSPORON; EMERGING PATHOGEN; IDENTIFICATION; LOUBIERI; BEIGELII; THERAPY AB This report describes the molecular epidemiology, in vitro susceptibility, colonial and microscopic morphologies, and biochemical features of Trichosporon mycotoxinivorans, a newly recognized pathogen that appears to have a propensity for patients with cystic fibrosis. The index patient died with histologically documented Trichosporon pneumonia complicating cystic fibrosis. This is also the first report of disease caused by a Trichosporon species in a nontransplant patient with cystic fibrosis. As T. mycotoxinivorans has not previously been recognized as a respiratory pathogen, the significance of its recovery from sputum samples was not initially appreciated. Genetic analysis of archived clinical samples found three additional cases of T. mycotoxinivorans infection which had previously been identified as other members of the genus. An additional isolate of T. mycotoxinivorans was identified from a clinical sample on initial testing. Three of these four cases were also patients with cystic fibrosis. All isolates had MICs at 48 h of amphotericin B of >= 1 mu g/ml and of echinocandins of >= 16 mu g/ml, but they displayed various susceptibilities to the triazoles. In summary, Trichosporon mycotoxinivorans is a newly recognized human pathogen that is associated with cystic fibrosis. C1 [Hickey, Patrick W.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Hickey, Patrick W.] Walter Reed Army Med Ctr, Div Pediat Infect Dis, Washington, DC 20307 USA. [Schmidt, Howard J.] Walter Reed Army Med Ctr, Div Pediat Pulmonol, Washington, DC 20307 USA. [Sutton, Deanna A.; Fothergill, Annette W.; Rinaldi, Michael G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, Fungus Testing Lab, San Antonio, TX 78229 USA. [Wickes, Brian L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol, San Antonio, TX 78229 USA. [Schmidt, Howard J.] Virginia Commonwealth Univ, Div Pediat Pulmonol, Richmond, VA USA. [Walsh, Thomas J.] NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. RP Hickey, PW (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM phickey@usuhs.mil FU U. S. Army Medical Research and Materiel Command, Office of Congressionally Directed Medical Research Programs [PR054228]; National Cancer Institute FX B. L. W. is supported by grant PR054228 from the U. S. Army Medical Research and Materiel Command, Office of Congressionally Directed Medical Research Programs. This work was supported in part by the intramural research program of the National Cancer Institute. NR 34 TC 30 Z9 30 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2009 VL 47 IS 10 BP 3091 EP 3097 DI 10.1128/JCM.00460-09 PG 7 WC Microbiology SC Microbiology GA 501BC UT WOS:000270351700003 PM 19656976 ER PT J AU Pfaller, MA Diekema, DJ Ghannoum, MA Rex, JH Alexander, BD Andes, D Brown, SD Chaturvedi, V Espinel-Ingroff, A Fowler, CL Johnson, EM Knapp, CC Motyl, MR Ostrosky-Zeichner, L Sheehan, DJ Walsh, TJ AF Pfaller, M. A. Diekema, D. J. Ghannoum, M. A. Rex, J. H. Alexander, B. D. Andes, D. Brown, S. D. Chaturvedi, V. Espinel-Ingroff, A. Fowler, C. L. Johnson, E. M. Knapp, C. C. Motyl, M. R. Ostrosky-Zeichner, L. Sheehan, D. J. Walsh, T. J. CA Clinical Lab Stand Inst Antifungal TI Wild-Type MIC Distribution and Epidemiological Cutoff Values for Aspergillus fumigatus and Three Triazoles as Determined by the Clinical and Laboratory Standards Institute Broth Microdilution Methods SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CELL TRANSPLANT RECIPIENTS; 14-ALPHA-STEROL DEMETHYLASE CYP51A; INVASIVE ASPERGILLOSIS; CROSS-RESISTANCE; IN-VITRO; ITRACONAZOLE RESISTANCE; REDUCED SUSCEPTIBILITY; AZOLE RESISTANCE; AMPHOTERICIN-B; RISK-FACTORS AB Antifungal susceptibility testing of Aspergillus species has been standardized by both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Recent studies suggest the emergence of strains of Aspergillus fumigatus with acquired resistance to azoles. The mechanisms of resistance involve mutations in the cyp51A (sterol demethylase) gene, and patterns of azole cross-resistance have been linked to specific mutations. Studies using the EUCAST broth microdilution (BMD) method have defined wild-type (WT) MIC distributions, epidemiological cutoff values (ECVs), and cross-resistance among the azoles. We tested a collection of 637 clinical isolates of A. fumigatus for which itraconazole MICs were <= 2 mu g/ml against posaconazole and voriconazole using the CLSI BMD method. An ECV of <= 1 mu g/ml encompassed the WT population of A. fumigatus for itraconazole and voriconazole, whereas an ECV of <= 0.25 mu g/ml was established for posaconazole. Our results demonstrate that the WT distribution and ECVs for A. fumigatus and the mold-active triazoles were the same when determined by the CLSI or the EUCAST BMD method. A collection of 43 isolates for which itraconazole MICs fell outside of the ECV were used to assess cross-resistance. Cross-resistance between itraconazole and posaconazole was seen for 53.5% of the isolates, whereas cross-resistance between itraconazole and voriconazole was apparent in only 7% of the isolates. The establishment of the WT MIC distribution and ECVs for the azoles and A. fumigatus will be useful in resistance surveillance and is an important step toward the development of clinical breakpoints. C1 [Pfaller, M. A.; Diekema, D. J.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [Pfaller, M. A.] Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. [Ghannoum, M. A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Rex, J. H.] AstraZeneca, Macclesfield, Cheshire, England. [Alexander, B. D.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Andes, D.] Univ Wisconsin, Madison, WI 53792 USA. [Brown, S. D.] Inst Clin Microbiol, Wilsonville, OR 97070 USA. [Chaturvedi, V.] New York State Dept Hlth, Albany, NY 12201 USA. [Espinel-Ingroff, A.] Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. [Fowler, C. L.] BioMerieux Inc, Durham, NC 27712 USA. [Johnson, E. M.] HPA Ctr Infect, Bristol, Avon, England. [Knapp, C. C.] Trek Diagnost Syst, Cleveland, OH 44131 USA. [Motyl, M. R.] Merck & Co Inc, Rahway, NJ 07065 USA. [Ostrosky-Zeichner, L.] Univ Texas Houston, Sch Med, Houston, TX 77030 USA. [Sheehan, D. J.] Pfizer Inc, New York, NY 10017 USA. [Walsh, T. J.] NCI, Bethesda, MD 20892 USA. RP Pfaller, MA (reprint author), Univ Iowa, Coll Med, Dept Pathol, Div Microbiol, C606 GH, Iowa City, IA 52242 USA. EM michael-pfaller@uiowa.edu OI Diekema, Daniel/0000-0003-1273-0724 FU Pfizer Pharmaceuticals; Schering- Plough Research Institute FX This study was supported in part by research and educational grants from Pfizer Pharmaceuticals and the Schering- Plough Research Institute. NR 50 TC 72 Z9 76 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2009 VL 47 IS 10 BP 3142 EP 3146 DI 10.1128/JCM.00940-09 PG 5 WC Microbiology SC Microbiology GA 501BC UT WOS:000270351700010 PM 19692559 ER PT J AU Baddley, JW Marr, KA Andes, DR Walsh, TJ Kauffman, CA Kontoyiannis, DP Ito, JI Balajee, SA Pappas, PG Moser, SA AF Baddley, John W. Marr, Kieren A. Andes, David R. Walsh, Thomas J. Kauffman, Carol A. Kontoyiannis, Dimitrios P. Ito, James I. Balajee, S. Arunmozhi Pappas, Peter G. Moser, Stephen A. TI Patterns of Susceptibility of Aspergillus Isolates Recovered from Patients Enrolled in the Transplant-Associated Infection Surveillance Network SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID AMPHOTERICIN-B; IN-VITRO; INVASIVE ASPERGILLOSIS; CROSS-RESISTANCE; AZOLE RESISTANCE; FUMIGATUS; ITRACONAZOLE; VORICONAZOLE; TERREUS; RAVUCONAZOLE AB We analyzed antifungal susceptibilities of 274 clinical Aspergillus isolates from transplant recipients with proven or probable invasive aspergillosis collected as part of the Transplant-Associated Infection Surveillance Network (TRANSNET) and examined the relationship between MIC and mortality at 6 or 12 weeks. Antifungal susceptibility testing was performed by the Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth dilution method for amphotericin B (AMB), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), and ravuconazole (RAV). The isolate collection included 181 Aspergillus fumigatus, 28 Aspergillus niger, 27 Aspergillus flavus, 22 Aspergillus terreus, seven Aspergillus versicolor, five Aspergillus calidoustus, and two Aspergillus nidulans isolates and two isolates identified as Aspergillus spp. Triazole susceptibilities were <= 4 mu g/ml for most isolates (POS, 97.6%; ITR, 96.3%; VOR, 95.9%; RAV, 93.5%). The triazoles were not active against the five A. calidoustus isolates, for which MICs were >= 4 mu g/ml. AMB inhibited 93.3% of isolates at an MIC of 1 mu g/ml. The exception was A. terreus, for which 15 (68%) of 22 isolates had MICs of >1 mu g/ml. One of 181 isolates of A. fumigatus showed resistance (MIC > 4 mu g/ml) to two of three azoles tested. Although there appeared to be a correlation of higher VOR MICs with increased mortality at 6 weeks, the relationship was not statistically significant (R(2) = 0.61; P = 0.065). Significant relationships of in vitro MIC to all-cause mortality at 6 and 12 weeks for VOR or AMB were not found. C1 [Baddley, John W.; Pappas, Peter G.] Univ Alabama, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Infect Dis Sect, Dept Med, Birmingham, AL USA. [Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Andes, David R.] Univ Wisconsin, Dept Med, Div Infect Dis, Madison, WI USA. [Walsh, Thomas J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Kauffman, Carol A.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Kauffman, Carol A.] Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Dept Med, Houston, TX 77030 USA. [Ito, James I.] City Hope Natl Med Ctr, Dept Med, Div Infect Dis, Duarte, CA 91010 USA. [Balajee, S. Arunmozhi] Ctr Dis Control & Prevent, Div Mycot Dis, Atlanta, GA USA. [Moser, Stephen A.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. RP Baddley, JW (reprint author), Univ Alabama, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 Tinsley Harrison Tower, Birmingham, AL 35294 USA. EM jbaddley@uab.edu RI Moser, Stephen/A-1168-2008 FU NIH [K23AI064613] FX J.W.B. is sponsored in part by NIH grant K23AI064613. NR 30 TC 86 Z9 88 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2009 VL 47 IS 10 BP 3271 EP 3275 DI 10.1128/JCM.00854-09 PG 5 WC Microbiology SC Microbiology GA 501BC UT WOS:000270351700029 PM 19692558 ER PT J AU Castle, PE Sadorra, M Lau, T Aldrich, C Garcia, FAR Kornegay, J AF Castle, Philip E. Sadorra, Mark Lau, Tiffany Aldrich, Carrie Garcia, Francisco A. R. Kornegay, Janet TI Evaluation of a Prototype Real-Time PCR Assay for Carcinogenic Human Papillomavirus (HPV) Detection and Simultaneous HPV Genotype 16 (HPV16) and HPV18 Genotyping SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; LINEAR-ARRAY; SCREENING-TESTS; CANCER; DNA; WOMEN; PRECANCER; RISK; CYTOLOGY; HYBRID-CAPTURE-2 AB Results from a prototype real-time PCR assay that separately detected human papillomavirus genotype 16 (HPV16), HPV18, and 12 other carcinogenic HPV genotypes in aggregate (cobas 4800 HPV test) and results from a PCR assay that detects 37 HPV genotypes individually (Linear Array) were compared using a convenience sample of cervical specimens (n = 531). The percentage of total agreement between the two assays was 94.7% (95% confidence interval, 92.5 to 96.5%). The Linear Array test was more likely than cobas 4800 HPV test to test positive for the 12 other carcinogenic HPV genotypes among women without evidence of cervical disease (P = 0.004). C1 [Castle, Philip E.] NCI, Div Canc Epidemiol, DHHS, NIH, Bethesda, MD 20892 USA. [Sadorra, Mark; Lau, Tiffany; Aldrich, Carrie; Kornegay, Janet] Roche Mol Syst, Alameda, CA USA. [Garcia, Francisco A. R.] Univ Arizona, Hlth Sci Ctr, Tucson, AZ USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5030,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU NIH/NCI FX This work was supported in part by the intramural research program of the NIH/NCI. NR 27 TC 29 Z9 33 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2009 VL 47 IS 10 BP 3344 EP 3347 DI 10.1128/JCM.00725-09 PG 4 WC Microbiology SC Microbiology GA 501BC UT WOS:000270351700043 PM 19675214 ER PT J AU Gianni, L Norton, L Wolmark, N Suter, TM Bonadonna, G Hortobagyi, GN AF Gianni, Luca Norton, Larry Wolmark, Norman Suter, Thomas M. Bonadonna, Gianni Hortobagyi, Gabriel N. TI Role of Anthracyclines in the Treatment of Early Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID TOPOISOMERASE-II-ALPHA; DOXORUBICIN PLUS CYCLOPHOSPHAMIDE; TRIAL COMPARING DOXORUBICIN; DENSE SEQUENTIAL CHEMOTHERAPY; MAMMARY EPITHELIAL-CELLS; SURGICAL ADJUVANT BREAST; CONGESTIVE HEART-FAILURE; LEUKEMIA GROUP-B; NCIC CTG MA.5; RANDOMIZED-TRIAL AB Purpose To review data relating to anthracyclines in the adjuvant treatment of early breast cancer. Design This is a report from a seminar in which the future of anthracyclines in the adjuvant treatment of breast cancer was considered. In particular, the question of whether anthracyclines should now be discarded and replaced by taxanes was addressed. Results Accumulating data from large randomized trials indicate that genetic markers may have a role in predicting sensitivity to cytotoxic drugs. However, no reliable, validated test is available for predicting sensitivity to anthracyclines in particular. Topoisomerase II alpha amplification and/or deletion, especially in conjunction with human epidermal growth factor receptor-2 amplification, has been proposed to fulfill this role but more data are needed. Currently, only one published trial has shown that a taxane-based regimen may be superior to an anthracycline-based regimen, but several trials indicate that combinations including both anthracyclines and taxanes may be better still. Further studies aimed at optimizing anthracyclines and taxanes in combination, and integrating biologic agents, seem to be the way forward. There is no validated test that can determine whether anthracyclines can be of greater benefit than other agents for individual patients. Conclusion Anthracyclines have been extensively tested in clinical trials spanning several decades; currently, there are insufficient data to recommend replacing them in the adjuvant treatment of breast cancer. C1 [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. Fdn Michelangelo, Milan, Italy. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Swiss Cardiovasc Ctr, Bern, Switzerland. RP Hortobagyi, GN (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Holcombe Blvd,Unit 1354, Houston, TX 77030 USA. EM ghortoba@mdanderson.org OI Norton, Larry/0000-0003-3701-9250 NR 100 TC 52 Z9 53 U1 1 U2 8 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 OCT 1 PY 2009 VL 27 IS 28 BP 4798 EP 4808 DI 10.1200/JCO.2008.21.4791 PG 11 WC Oncology SC Oncology GA 500LS UT WOS:000270304100027 PM 19687331 ER PT J AU Murty, VP Sambataro, F Das, S Tan, HY Callicott, JH Goldberg, TE Meyer-Lindenberg, A Weinberger, DR Mattay, VS AF Murty, Vishnu P. Sambataro, Fabio Das, Saumitra Tan, Hao-Yang Callicott, Joseph H. Goldberg, Terry E. Meyer-Lindenberg, Andreas Weinberger, Daniel R. Mattay, Venkata S. TI Age-related Alterations in Simple Declarative Memory and the Effect of Negative Stimulus Valence SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; EVENT-RELATED FMRI; EMOTIONAL MEMORY; FUNCTIONAL CONNECTIVITY; RECOGNITION MEMORY; EPISODIC RETRIEVAL; ALZHEIMERS-DISEASE; NEURAL MECHANISMS; WORKING-MEMORY; OLDER-ADULTS AB Healthy aging has been shown to modulate the neural circuitry underlying simple declarative memory; however, the functional impact of negative stimulus valence on these changes has not been fully investigated. Using BOLD fMRI, we explored the effects of aging on behavioral performance, neural activity, and functional coupling during the encoding and retrieval of novel aversive and neutral scenes. Behaviorally, there was a main effect of valence with better recognition performance for aversive greater than neutral stimuli in both age groups. There was also a main effect of age with better recognition performance in younger participants compared to older participants. At the imaging level, there was a main effect of valence with increased activity in the medial-temporal lobe ( amygdala and hippocampus) during both encoding and retrieval of aversive relative to neutral stimuli. There was also a main effect of age with older participants showing decreased engagement of medial-temporal lobe structures and increased engagement of prefrontal structures during both encoding and retrieval sessions. Interestingly, older participants presented with relatively decreased amygdalar-hippocampal coupling and increased amygdalar prefrontal coupling when compared to younger participants. Furthermore, older participants showed increased activation in prefrontal cortices and decreased activation in the amygdala when contrasting the retrieval of aversive and neutral scenes. These results suggest that although normal aging is associated with a decline in declarative memory with alterations in the neural activity and connectivity of brain regions underlying simple declarative memory, memory for aversive stimuli is relatively better preserved than for neutral stimuli, possibly through greater compensatory prefrontal cortical activity. C1 [Mattay, Venkata S.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Goldberg, Terry E.] Hillside Zucker Hosp, Glen Oaks, NJ USA. [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. RP Mattay, VS (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. EM vsm@mail.nih.gov RI Sambataro, Fabio/E-3426-2010; Callicott, Joseph/C-9102-2009; Meyer-Lindenberg, Andreas/H-1076-2011 OI Sambataro, Fabio/0000-0003-2102-416X; Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Intramural NIH HHS [Z01 MH002734-12] NR 57 TC 35 Z9 35 U1 2 U2 5 PU M I T PRESS PI CAMBRIDGE PA 238 MAIN STREET, STE 500, CAMBRIDGE, MA 02142-1046 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD OCT PY 2009 VL 21 IS 10 BP 1920 EP 1933 DI 10.1162/jocn.2009.21130 PG 14 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 505ZK UT WOS:000270741100006 PM 18823239 ER PT J AU Carroll, KM Martino, S Ball, SA Nich, C Frankforter, T Anez, LM Paris, M Suarez-Morales, L Szapocznik, J Miller, WR Rosa, C Matthews, J Farentinos, C AF Carroll, Kathleen M. Martino, Steve Ball, Samuel A. Nich, Charla Frankforter, Tami Anez, Luis M. Paris, Manuel Suarez-Morales, Lourdes Szapocznik, Jose Miller, William R. Rosa, Carmen Matthews, Julie Farentinos, Chris TI A Multisite Randomized Effectiveness Trial of Motivational Enhancement Therapy for Spanish-Speaking Substance Users SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE motivational interviewing; randomized clinical trials; Spanish-speaking; drug dependence ID DRUG-ABUSE; ETHNIC-MINORITIES; DISPARITIES; HISPANICS; SERVICES; ISSUES AB Hispanic individuals are underrepresented in clinical and research populations and are often excluded from clinical trials in the United States. Hence, there are few data on the effectiveness of most empirically validated therapies for Hispanic substance users. The authors conducted a multisite randomized trial comparing the effectiveness of 3 individual sessions of motivational enhancement therapy with that of 3 individual sessions of counseling as usual on treatment retention and frequency of substance use; all assessment and treatment sessions were conducted in Spanish among 405 individuals seeking treatment for any type of current substance use. Treatment exposure was good, with 66% of participants completing all 3 protocol sessions. Although both interventions resulted in reductions in substance use during the 4-week therapy phase, there were no significant Treatment Condition X Time interactions nor Site X Treatment Condition interactions. Results suggest that the individual treatments delivered in Spanish were both attractive to and effective with this heterogeneous group of Hispanic adults, but the differential effectiveness of motivational enhancement therapy may be limited to those whose primary substance use problem is alcohol and may be fairly modest in magnitude. C1 [Carroll, Kathleen M.] Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06519 USA. [Suarez-Morales, Lourdes; Szapocznik, Jose] Univ Miami, Dept Psychiat & Behav Studies, Coral Gables, FL 33124 USA. [Miller, William R.] Univ New Mexico, Dept Psychiat & Psychol, Albuquerque, NM 87131 USA. [Rosa, Carmen] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Matthews, Julie] Adv Behav Hlth, Middletown, CT USA. [Farentinos, Chris] Changepoint Inc, Portland, OR USA. RP Carroll, KM (reprint author), Yale Univ, Sch Med, Dept Psychiat, 950 Campbell Ave,151D, West Haven, CT 06519 USA. EM kathleen.carroll@yale.edu OI Carroll, Kathleen/0000-0003-3263-3374 FU NIDA NIH HHS [U10 DA015833, K05 DA000457, K05 DA000457-08, K05 DA000457-09, K05 DA000457-10, U10 DA013035, U10 DA013035-01A1, U10 DA013036, U10 DA013036-04, U10 DA013038, U10 DA013038-01, U10 DA013716, U10 DA013716-02, U10 DA013720, U10 DA013720-01, U10 DA015833-01, U10 DA13035, U10 DA13036, U10 DA13038, U10 DA13716, U10 DA13720] NR 17 TC 55 Z9 56 U1 0 U2 8 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD OCT PY 2009 VL 77 IS 5 BP 993 EP 999 DI 10.1037/a0016489 PG 7 WC Psychology, Clinical SC Psychology GA 503TX UT WOS:000270564400019 PM 19803579 ER PT J AU Valenti, G Ferrucci, L Lauretani, F Ceresini, G Bandinelli, S Luci, M Ceda, G Maggio, M Schwartz, RS AF Valenti, G. Ferrucci, L. Lauretani, F. Ceresini, G. Bandinelli, S. Luci, M. Ceda, G. Maggio, M. Schwartz, R. S. TI Dehydroepiandrosterone sulfate and cognitive function in the elderly: The InCHIANTI Study SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Article DE Cognitive function; DHEAS; elderly ID MINI-MENTAL-STATE; DECLARATIVE MEMORY; OLDER MEN; CORTISOL; DHEA; MICE; WOMEN; RECEPTOR; STRESS; AGE AB DHEA and its sulfate derivative (DHEAS) decline with age. The decline in DHEAS levels has been associated with many physiological impairments in older persons including cognitive dysfunction. However, data regarding the possible relationship between DHEAS and cognition are scant. We investigated whether DHEAS levels are associated with presence and development of lower cognitive function measured by the Mini Mental State Examination (MMSE) in older men and women. One thousand and thirty-four residents aged >= 65 yr of the InCHIANTI Study with data available on DHEAS and MMSE were randomly selected. MMSE was administered at baseline and 3 yr later. Among these, 841 completed a 3-yr follow-up. Parsimonious models obtained by backward selection from initial fully-adjusted models were used to identify independent factors associated with MMSE and DHEAS. The final analysis was performed in 755 participants (410 men and 345 women) with MMSE score >= 21. A significant age-related decline of both DHEAS levels (p<0.001) and MMSE score (p<0.001) was found over the 3-yr follow-up. At enrolment, DHEAS was significantly and positively associated with MMSE score, independently of age and other potential confounders (beta +/- SE 0.003 +/- 0.001, p<0.005). Low baseline DHEAS levels were predictive of larger decline of MMSE and this relationship was significant after adjusting for covariates (beta +/- SE -0.004 +/- 0.002, p<0.03). Our data show a significant and positive association between DHEAS and cognitive function, assessed by MMSE test. Low DHEAS levels predict accelerated decline in MMSE score during the 3-yr follow-up period. (J. Endocrinol. Invest. 32: 766-772, 2009) (C) 2009, Editrice Kurtis C1 [Valenti, G.; Ceresini, G.; Luci, M.; Ceda, G.; Maggio, M.] Univ Parma, Dept Internal Med & Med Sci, Sect Geriatr, I-43100 Parma, Italy. [Ferrucci, L.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Lauretani, F.] Univ Hosp Parma, Geriatr Rehabil Dept, Parma, Italy. [Bandinelli, S.] AUSL 10 Florence, Geriatr Unit, Florence, Italy. [Schwartz, R. S.] Univ Colorado, Div Geriatr Med, Denver, CO 80202 USA. RP Valenti, G (reprint author), Azienda Osped Univ, Clin Geriatr, Via Gramsci 14, I-43100 Parma, Italy. EM giorgiovalenti@libero.it RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health [ICS 110.1/RS97.71]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821 336] FX The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336) and by the Intramural Research Program of the U.S. National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336). NR 52 TC 17 Z9 17 U1 0 U2 3 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD OCT PY 2009 VL 32 IS 9 BP 766 EP 772 DI 10.3275/6438 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 537RX UT WOS:000273132600009 PM 19620821 ER PT J AU Ganiban, JM Ulbricht, JA Spotts, EL Lichtenstein, P Reiss, D Hansson, K Neiderhiser, JA AF Ganiban, Jody M. Ulbricht, Jennifer A. Spotts, Erica L. Lichtenstein, Paul Reiss, David Hansson, Kjell Neiderhiser, Jenae A. TI Understanding the Role of Personality in Explaining Associations Between Marital Quality and Parenting SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article DE marriage; parenting; personality; twins ID GENETIC-ANALYSIS; ENVIRONMENTAL-INFLUENCES; TEMPERAMENT; SATISFACTION; CONFLICT; ADJUSTMENT; STABILITY; FAMILIES; BEHAVIOR; MODEL AB Analyses assessed the degrees to which personality accounts for associations between marital quality and parenting and mediates genetic contributions to these relationships. Participants included 318 male and 544 female same-sex twin pairs from the Twin and Offspring Study in Sweden. All twins completed self-report measures of marital quality and personality (anxiousness, aggression, sociability). Composite measures of parent negativity and warmth were derived from the twins' and their adolescent children's ratings of the twins' disciplinary styles and the emotional tone of the parent-child relationship. Observational ratings of marital quality and parenting were also obtained for a subset of twins. Personality characteristics explained 33% to 42% of the covariance between reported marital quality and parenting and 26% to 28% of the covariance between observed marital quality and parenting. For both sets of analyses, personality accounted for more than half of the genetic contributions to covariance between marital quality and parenting. Results indicate that personality significantly contributes to associations between marital quality and parenting and that personality is an important path through which genetic factors contribute to family relationships. C1 [Ganiban, Jody M.; Ulbricht, Jennifer A.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Spotts, Erica L.] NIA, Behav & Social Res Program, Bethesda, MD 20892 USA. [Lichtenstein, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Reiss, David] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Hansson, Kjell] Lund Univ, Sch Social Work, Lund, Sweden. [Neiderhiser, Jenae A.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. RP Ganiban, JM (reprint author), George Washington Univ, Dept Psychol, 2121 1st St NW, Washington, DC 20052 USA. EM ganiban@gwu.edu OI lichtenstein, paul/0000-0003-3037-5287 FU NIMH NIH HHS [R01MH54601, R01 MH054610-04, R01 MH054610] NR 67 TC 13 Z9 13 U1 2 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD OCT PY 2009 VL 23 IS 5 BP 646 EP 660 DI 10.1037/a0016091 PG 15 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 506SL UT WOS:000270796200004 PM 19803601 ER PT J AU Lee, YC Cook, M Bhatia, S Chow, WH Goto, H Lin, JT Li, YQ Rhee, PL Sharma, P Sung, JJ Wong, J Wu, JCY Ho, KY AF Lee, Y. C. Cook, M. Bhatia, S. Chow, W. H. Goto, H. Lin, J. T. Li, Y. Q. Rhee, P. L. Sharma, P. Sung, J. J. Wong, J. Wu, J. C. Y. Ho, K. Y. CA ASIAN BARRETT'S CONSORTIUM TI Inter-observer agreement in the diagnosis of endoscopically suspected Barrett's esophagus: an Asian multinational study SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Meeting Abstract C1 [Lee, Y. C.; Lin, J. T.] Natl Taiwan Univ, Dept Internal Med, Taipei, Taiwan. [Cook, M.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chow, W. H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Goto, H.] Nagoya Univ, Dept Gastroenterol, Grad Sch Med, Nagoya, Aichi 4648601, Japan. [Lin, J. T.] I Shou Univ, Kaohsiung Cty, Taiwan. [Lin, J. T.] E DA Hosp, Dept Internal Med, Kaohsiung Cty, Taiwan. [Li, Y. Q.] Shandong Univ, Dept Gastroenterol, Qilu Hosp, Jinan, Peoples R China. [Rhee, P. L.] Sungkyunkwan Univ, Dept Med, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Sharma, P.] Univ Kansas, Sch Med, Div Gastroenterol & Hepatol, Lawrence, KS 66045 USA. [Sung, J. J.; Wu, J. C. Y.] Chinese Univ Hong Kong, Dept Med & Therapeut, Prince Wales Hosp, Hong Kong, Hong Kong, Peoples R China. [Sung, J. J.; Wu, J. C. Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore. RI Wu, Justin/N-6916-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD OCT PY 2009 VL 24 BP A121 EP A121 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 497QI UT WOS:000270075200321 ER PT J AU Rastgou, M Habibi, MK Izadpanah, K Masenga, V Milne, RG Wolf, YI Koonin, EV Turina, M AF Rastgou, M. Habibi, M. K. Izadpanah, K. Masenga, V. Milne, R. G. Wolf, Y. I. Koonin, E. V. Turina, M. TI Molecular characterization of the plant virus genus Ourmiavirus and evidence of inter-kingdom reassortment of viral genome segments as its possible route of origin SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID DOUBLE-STRANDED RNAS; MOVEMENT PROTEINS; MAXIMUM-LIKELIHOOD; MELON-VIRUS; EVOLUTION; DISEASE; CHERRY; RANUNCULUS; ALGORITHM; SEQUENCE AB Ourmia melon virus (OuMV), Epirus cherry virus (EpCV) and Cassava virus C (CsVC) are three species placed in the genus Ourmiavirus. We cloned and sequenced their RNA genomes. The sizes of the three genomic RNAs of OuMV, the type member of the genus, were 2814, 1064 and 974 nt and each had one open reading frame. RNA1 potentially encoded a 97.5 kDa protein carrying the GDD motif typical of RNA-dependent RNA polymerases (RdRps). The putative RdRps of ourmiaviruses are distantly related to known viral RdRps, with the closest similarity and phylogenetic affinity observed with fungal viruses of the genus Narnaviridae. RNA2 encoded a 31.6 kDa. protein which, expressed in bacteria as a His-tag fusion protein and in plants through agroinfiltration, reacted specifically with antibodies made against tubular structures found in the cytoplasm. The ORF2 product is significantly similar to movement proteins of the genus Tombusviridae, and phylogenetic analysis supported this evolutionary relationship. The product of OuMV ORF3 is a 23.8 kDa protein. This protein was also expressed in bacteria and plants, and reacted specifically with antisera. against the OuMV coat protein. The sequence of the ORF3 protein showed limited but significant similarity to capsid proteins of several plant and animal viruses, although phylogenetic analysis failed to reveal its most likely origin. Taken together, these results indicate that ourmiaviruses comprise a unique group of plant viruses that might have evolved by reassortment of genomic segments of RNA viruses infecting hosts belonging to different eukaryotic kingdoms, in particular, fungi and plants. C1 [Masenga, V.; Milne, R. G.; Turina, M.] CNR, Ist Virol Vegetale, I-10135 Turin, Italy. [Wolf, Y. I.; Koonin, E. V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Rastgou, M.; Habibi, M. K.] Univ Tehran, Dept Plant Protect, Fac Hort Sci & Plant Protect, Coll Agr & Nat Resources, Karaj, Iran. [Rastgou, M.] Urmia Univ, Dept Plant Protect, Coll Agr, Orumiyeh, Iran. [Izadpanah, K.] Shiraz Univ, Plant Virol Res Ctr, Shiraz, Iran. RP Turina, M (reprint author), CNR, Ist Virol Vegetale, Str Cacce 73, I-10135 Turin, Italy. EM m.turina@ivv.cnr.it RI Turina, Massimo/B-7550-2015 OI Turina, Massimo/0000-0002-9659-9470 FU Iran Ministry of Science, Research and Technology FX We thank Maud Swanson (formerly Aiton), Scottish Crop Research Institute, for kindly providing isolates of CsVC, and Caterina Perrone for skilful technical assistance in the greenhouse. M. R. was recipient of a scholarship from the Iran Ministry of Science, Research and Technology, as part of her PhD project. NR 51 TC 29 Z9 33 U1 1 U2 10 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD OCT PY 2009 VL 90 BP 2525 EP 2535 DI 10.1099/vir.0.013086-0 PG 11 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 502ZL UT WOS:000270499700026 PM 19535502 ER PT J AU Hossain, MM Chowdhury, NA Shirin, M Saha, SK Miller-Bell, M Edwards, D Aranda, J Coffey, P Darmstadt, GL AF Hossain, M. Monir Chowdhury, Nazma A. Shirin, Mahfuza Saha, Samir K. Miller-Bell, Mary Edwards, David Aranda, Jacob Coffey, Patricia Darmstadt, Gary L. TI Simplified Dosing of Gentamicin for Treatment of Sepsis in Bangladeshi Neonates SO JOURNAL OF HEALTH POPULATION AND NUTRITION LA English DT Article DE Aminoglycoside; Antibiotics; Gentamicin; Infection; Newborns; Observational studies; Pharmacokinetics; Prospective studies; Sepsis; Bangladesh ID ANTIBACTERIAL ACTIVITY; DEVELOPING-COUNTRIES; RURAL BANGLADESH; CONTROLLED-TRIAL; PHARMACOKINETICS; INFANTS; AMINOGLYCOSIDES; STRATEGIES; INFECTION; TOXICITY AB Extended-interval dosing of gentamicin has several advantages over conventional multiple-daily dosing for the treatment of sepsis. The study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24- or 48-hour intervals, according to weight category, and to develop a simplified protocol for use in peripheral healthcare settings in developing countries. This prospective observational study was conducted among 59 neonates admitted to the Special Care Nursery at Dhaka Shishu Hospital, Bangladesh, with suspected sepsis and treated with antibiotics, including gentamicin. Intravenous dosing of gentamicin according to weight category was: 10 mg every 48 hours if the infant weighed < 2,000 g (n=23), 10 mg every 24 hours if the infant weighed 2,000-2,249 g (n=12), or 13.5 mg every 24 hours if the infant weighed 2,500-3,000 g (n=24). Peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined. The mean +/- standard deviation peak concentration of gentamicin was 12.3 +/- 3.7 mu g/mL in infants weighing < 2,000 g, 9.6 +/- 3.1 mu g/mL in infants 2,000-2,249 g, and 10.0 +/- 3.4 mu g/mL in infants 2,500-3,000 g. Initial peak concentration of gentamicin was > 12 mu g/mL in 28.8% and initial trough concentration was > 2 mu g/mL in 6.8% of the subjects. No signs of nephrotoxicity or ototoxicity were detected. Favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis. C1 [Hossain, M. Monir; Chowdhury, Nazma A.; Shirin, Mahfuza] Dhaka Shishu Childrens Hosp, Bangladesh Inst Child Hlth, Dept Neonatol, Dhaka 1207, Bangladesh. [Saha, Samir K.] Dhaka Shishu Childrens Hosp, Bangladesh Inst Child Hlth, Dept Microbiol, Dhaka 1207, Bangladesh. [Miller-Bell, Mary] Duke Univ, Dept Pharmacol, Durham, NC USA. [Edwards, David] Wayne State Univ, Dept Pharm Practice, Detroit, MI USA. [Edwards, David; Aranda, Jacob] Wayne State Univ, Childrens Hosp Michigan, NIH, NICHD,Pediat Pharmacol Res Unit Network, Detroit, MI USA. [Coffey, Patricia] PATH, Seattle, WA USA. [Darmstadt, Gary L.] Johns Hopkins Univ, Bloomberg Sch Med, Dept Int Hlth, Int Ctr Advancing Neonatal Hlth, Baltimore, MD 21205 USA. RP Darmstadt, GL (reprint author), Johns Hopkins Univ, Bloomberg Sch Med, Dept Int Hlth E8153, Int Ctr Advancing Neonatal Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. EM gdarmsta@jhsph.edu FU Bill & Melinda Gates Foundation; United States Agency for International Development (USAID) [GPH-A-0001-00005] FX This study was supported by Save the Children-USA through a grant from the Bill & Melinda Gates Foundation and by PATH. PATH's contribution to this study was made possible through support provided by the Office of Health, United States Agency for International Development (USAID) under the HealthTech Cooperative Agreement No. GPH-A-0001-00005. The opinions expressed herein are those of the authors and do not necessarily reflect the views of USAID. The authors thank Additional Professor Vinod Paul of All-India Institute of Medical Sciences, Delhi, for serving on the Data and Safety Monitoring Board. The authors also thankfully acknowledge Dr. Shaheen Akter and Dr. Manifa Afreen of Dhaka Shishu Hospital for their technical assistance. NR 29 TC 8 Z9 8 U1 1 U2 2 PU ICDDR B PI DHAKA PA MOHAKHALI, 1212 DHAKA, BANGLADESH SN 1606-0997 EI 2072-1315 J9 J HEALTH POPUL NUTR JI J. Heatlh Popul. Nutr. PD OCT PY 2009 VL 27 IS 5 BP 640 EP 645 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 514LF UT WOS:000271395500006 PM 19902799 ER PT J AU Maximova, OA Faucette, LJ Ward, JM Murphy, BR Pletnev, AG AF Maximova, Olga A. Faucette, Lawrence J. Ward, Jerrold M. Murphy, Brian R. Pletnev, Alexander G. TI Cellular Inflammatory Response to Flaviviruses in the Central Nervous System of a Primate Host SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE flaviviruses; non-human primates; central nervous system; cellular inflammatory response; immunohistochemistry; digital whole-tissue section slides; computerized morphometric analysis ID WEST-NILE-VIRUS; TICK-BORNE ENCEPHALITIS; JAPANESE ENCEPHALITIS; INTERFERON-GAMMA; IMMUNE-RESPONSES; T-CELLS; INFECTION; BRAIN; NEUROVIRULENCE; PROTECTION AB Flaviviruses such as tick-borne encephalitis virus, Japanese encephalitis virus, West Nile virus, and St. Louis encephalitis virus are important neurotropic human pathogens, typically causing a devastating and often fatal neuroinfection. Flaviviruses induce neuroinflammation with typical features of viral encephalitides, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. Development of safe and effective live-virus vaccines against neurotropic flavivirus infections demands a detailed knowledge of their neuropathogenesis in a primate host that is evolutionarily close to humans. Here, we used computerized morphometric analysis to quantitatively assess the cellular inflammatory responses in the central nervous system (CNS) of rhesus monkeys infected with three antigenically divergent attenuated flaviviruses. The kinetics, spatial pattern, and magnitude of microglial activation, trafficking of T and B cells, and changes in T cell subsets within the CNS define unique phenotypic signatures for each of the three viruses. Our results provide a benchmark for investigation of cellular inflammatory responses induced by attenuated flaviviruses in the CNS of primate hosts and provide insight into the neuropathogenesis of flavivirus encephalitis that might guide the development of safe and effective live-virus vaccines. (J Histochem Cytochem 57:973-989, 2009) C1 [Maximova, Olga A.; Murphy, Brian R.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Faucette, Lawrence J.; Ward, Jerrold M.] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Maximova, OA (reprint author), NIAID, Infect Dis Lab, NIH, 33 N Dr,Room 3W10A,MSC 3203, Bethesda, MD 20892 USA. EM maximovao@niaid.nih.gov; apletnev@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by funds provided by the National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research Program. NR 37 TC 10 Z9 11 U1 0 U2 3 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD OCT PY 2009 VL 57 IS 10 BP 973 EP 989 DI 10.1369/jhc.2009.954180 PG 17 WC Cell Biology SC Cell Biology GA 499TT UT WOS:000270249500008 PM 19581627 ER PT J AU Liu, XP Zuo, YM Zhang, WN Yang, DG Xiong, CY Zhang, XZ AF Liu, Xiuping Zuo, Yumei Zhang, Weina Yang, Deguang Xiong, Changyun Zhang, Xiaozhou TI Expression of Interleukin-15 and Its Receptor on the Surface of Stimulated Human Umbilical Vein Endothelial Cells SO JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY-MEDICAL SCIENCES LA English DT Article DE endothelial cells; interleukin-15; interleukin-15 receptor; cytokines ID IL-15/IL-15R-ALPHA INTRACELLULAR TRAFFICKING; ALPHA-CHAIN; IL-2 RECEPTOR; HUMAN-DISEASE; KILLER-CELLS; GAMMA-CHAIN; TNF-ALPHA; IN-VITRO; IL-15R-ALPHA; APOPTOSIS AB Human interleukin-15 (hIL-15) is an important cytokine to activate endothelial cells and can be regulated by many other cytokines. The aim of this study is to examine the ability of interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) to induce the production of human interleukin-15 (hIL-15) and IL-15 receptor (IL-15R alpha) by human umbilical vein endothelial cells (HUVECs). The data are summarized as follows: 1. Northern blot revealed that IL-15 mRNA was up-regulated by IFN-gamma and TNF-alpha. 2. Intracellular IL-15 protein was visualized by fluorescence microscopy, whereas the expression of IL-15 on the surface of HUVECs was detected by fluorescence activated cell sorting (FACS), and no detectable IL-15 in the medium was verified by ELISA. 3. IL-15R alpha was detected on the surface of HUVECs by FACS after IFN-gamma and TNF-alpha stimulation, whereas Western blotting revealed that the elevated expression on surface IL-15R alpha was not due to the increased protein expression. The conclusion demonstrated from our results is that IFN-gamma and TNF-alpha play an important role in regulating the expression of IL-15 and IL-15R alpha on the surface of HUVECs. C1 [Zhang, Xiaozhou] Huazhong Univ Sci & Technol, Xianggan Med Coll Hosp, Xiaogan 432000, Peoples R China. [Liu, Xiuping] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Wuhan 430074, Peoples R China. [Liu, Xiuping] Hubei Vocat & Tech Coll, Xiaogan 432000, Peoples R China. [Zuo, Yumei] Third Mil Med Univ, Dept Cardiol, Southwest Hosp, Chongqing 400038, Peoples R China. [Zhang, Weina] Huazhong Univ Sci & Technol, Minist Educ,Minist Hlth, Inst Organ Transplantat,Tongji Med Coll, Tongji Hosp,Key Lab Organ Transplantat, Wuhan 430030, Peoples R China. [Yang, Deguang] NE Agr Univ, Coll Agr, Harbin 150030, Peoples R China. [Xiong, Changyun] NCI, Mol Targets Dev Program, NIH, Frederick, MD 21702 USA. RP Zhang, XZ (reprint author), Huazhong Univ Sci & Technol, Xianggan Med Coll Hosp, Xiaogan 432000, Peoples R China. EM Liuxiuping2006@gmail.com FU NIH of USA [HL42550] FX This project was supported by NIH grant HL42550 of USA. NR 35 TC 2 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1672-0733 J9 J HUAZHONG U SCI-MED JI J. Huazhong Univ. Sci. Tech.-Med. PD OCT PY 2009 VL 29 IS 5 BP 527 EP 534 DI 10.1007/s11596-009-0501-x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 505HA UT WOS:000270681700001 PM 19821081 ER PT J AU Peter, I Kelley-Hedgepeth, A Huggins, GS Housman, DE Mendelsohn, ME Vita, JA Vasan, RS Levy, D Benjamin, EJ Mitchell, GF AF Peter, I. Kelley-Hedgepeth, A. Huggins, G. S. Housman, D. E. Mendelsohn, M. E. Vita, J. A. Vasan, R. S. Levy, D. Benjamin, E. J. Mitchell, G. F. TI Association between arterial stiffness and variations in oestrogen-related genes SO JOURNAL OF HUMAN HYPERTENSION LA English DT Article DE arterial stiffness; tonometry; oestrogen receptor; polymorphism ID RECEPTOR-ALPHA GENE; CORONARY-HEART-DISEASE; PREMATURE OVARIAN FAILURE; FLOW-MEDIATED DILATION; LEFT-VENTRICULAR MASS; SMOOTH-MUSCLE-CELLS; WAVE REFLECTION; NITRIC-OXIDE; POSTMENOPAUSAL WOMEN; ENDOTHELIAL FUNCTION AB Increased arterial stiffness and wave reflection have been identified as cardiovascular disease risk factors. In light of significant sex differences and the moderate heritability of vascular function measures, we hypothesized that variation in the genes coding for oestrogen receptors alpha (ESR1) and beta (ESR2) and aromatase (CYP19A1) is associated with aortic stiffness and pressure wave reflection as measured by non-invasive arterial tonometry. In all, 1261 unrelated Framingham Offspring Study participants who attended the seventh examination cycle (mean age 62 +/- 10 years, 52% women) and had arterial tonometry and genotyping data were included in the study. Analysis of covariance was used to assess the association of polymorphisms with forward wave amplitude, augmented pressure, augmentation index (AI), carotid-femoral pulse wave velocity and mean arterial pressure with adjustment for potential confounders. In the sex-pooled analysis, those homozygous for the minor allele at any of four ESR1 variants that were in strong linkage disequilibrium ((TA)(n), rs2077647, rs2234693 and rs9340799) had on an average 18% higher augmented pressure and 16% greater AI compared with carriers of one or two major alleles (P = 0.0002-0.01). A similar magnitude of association was detected in those homozygous for the common allele at two ESR2 single-nucleotide polymorphisms (P = 0.007-0.02). Our results are consistent with the hypothesis that variation in ESR1 and ESR2, but not CYP19A1, is associated with an increased wave reflection that may contribute to associations between these variants and adverse clinical events demonstrated earlier. Our findings will need to be replicated in additional cohorts. Journal of Human Hypertension (2009) 23, 636-644; doi:10.1038/jhh.2009.1; published online 5 February 2009 C1 [Peter, I.] NYU, Dept Genet & Genom Sci, Mt Sinai Sch Med, New York, NY 10029 USA. [Kelley-Hedgepeth, A.; Huggins, G. S.; Mendelsohn, M. E.] Tufts Med Ctr, Dept Med, Mol Cardiol Res Inst, Boston, MA USA. [Housman, D. E.] MIT, Dept Biol, Cambridge, MA USA. [Vita, J. A.; Vasan, R. S.; Levy, D.; Benjamin, E. J.] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [Vita, J. A.; Vasan, R. S.; Benjamin, E. J.] Boston Univ, Sch Med, Dept Prevent Med & Cardiol, Boston, MA 02118 USA. [Levy, D.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Benjamin, E. J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Mitchell, G. F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Peter, I (reprint author), NYU, Dept Genet & Genom Sci, Mt Sinai Sch Med, 1425 Madison Ave, New York, NY 10029 USA. EM inga.peter@mssm.edu OI Vita, Joseph/0000-0001-5607-1797; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [P01 HL077378, P01 HL077378-02, P01 HL077378-05, T32 HL069770, T32 HL069770-05] NR 46 TC 18 Z9 18 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD OCT PY 2009 VL 23 IS 10 BP 636 EP 644 DI 10.1038/jhh.2009.1 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 495DU UT WOS:000269871500002 PM 19194457 ER PT J AU Duffield, RM Snelling, RR Fales, HM Blum, MS AF Duffield, Richard M. Snelling, Roy R. Fales, Henry M. Blum, Murray S. TI Mandibular Gland Chemistry of Two Nearctic Species of Camponotus (Colobopsis) (Hymenoptera: Formicidae) SO JOURNAL OF HYMENOPTERA RESEARCH LA English DT Article ID ALARM-DEFENCE SYSTEM; CARPENTER ANTS; TRAIL PHEROMONE; WEAVER ANT; IDENTIFICATION; CONSTITUENTS; SECRETION; MELLEIN AB The chemistry of the mandibular gland secretions of three Nearctic species of carpenter ants of the subgenus Colobopsis was studied. No volatile compound was detected in worker mandibular secretions of C. itnpressus and C. etiolates. Worker secretions of C. mississippiensis were dominated by 2,6-dimethyl-5-heptene-1-ol and citronellol. Male head extracts of C. impressus and C. mississippiensis exhibited these two compounds and an additional volatile which was identified as mellein. Citronellol constituted 50% of the volatile components in each of these species. C1 [Duffield, Richard M.] Howard Univ, Dept Biol, Washington, DC 20059 USA. [Snelling, Roy R.] Nat Hist Museum Los Angeles Cty, Entomol Sect, Los Angeles, CA 90007 USA. [Fales, Henry M.] NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. [Blum, Murray S.] Univ Georgia, Dept Entomol, Athens, GA 30602 USA. RP Duffield, RM (reprint author), Howard Univ, Dept Biol, Washington, DC 20059 USA. EM rduffield@howard.edu NR 31 TC 1 Z9 1 U1 1 U2 6 PU PENSOFT PUBL PI SOFIA PA GEO MILEV STR 13A, SOFIA, 1111, BULGARIA SN 1070-9428 EI 1314-2607 J9 J HYMENOPT RES JI J. Hymenopt. Res. PD OCT PY 2009 VL 18 IS 2 BP 140 EP 144 PG 5 WC Entomology SC Entomology GA 700WR UT WOS:000285775500004 ER PT J AU Lev, A Dimberu, P Das, SR Maynard, JC Nicchitta, CV Bennink, JR Yewde, JW AF Lev, Avital Dimberu, Peniel Das, Suman R. Maynard, Jason C. Nicchitta, Christopher V. Bennink, Jack R. Yewde, Jonathan W. TI Efficient Cross-Priming of Antiviral CD8(+) T Cells by Antigen Donor Cells Is GRP94 Independent SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEAT-SHOCK PROTEINS; CLASS-I MOLECULES; ENDOPLASMIC-RETICULUM; MAJOR HISTOCOMPATIBILITY; CYTOSOLIC PEPTIDES; SCAVENGER RECEPTOR; PRESENTING CELLS; GP96; INNATE; VIVO AB Cross-priming, the activation of naive CD8(+) T cells by dendritic cells presenting Ags synthesized by other cells, is believed to play an important role in the generation of antiviral and antitumor responses. The molecular mechanism(s) underlying cross-priming remain poorly defined and highly controversial. GRP94 (gp96), an abundant endoplasmic reticulum chaperone with innate immune-activating capacity, has been widely reported to play a major role in cross-priming. In this study, we show that cells whose expression of GRP94 is silenced via transient or stable transfection with GRP94-directed small interfering RNAs demonstrate no reduction in their abilities to generate class I peptide complexes in cultured cells or to prime antiviral CD8(+) T cell responses in vivo. In demonstrating the dispensability of GRP94, our finding points to the importance of alternative mechanisms for generation of class I peptide complexes from endogenous and exogenous Ags and immunogens. The Journal of Immunology, 2009, 183: 4205-4210. C1 [Yewde, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Maynard, Jason C.; Nicchitta, Christopher V.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Yewde, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 33, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012; Das, Suman/C-8760-2009 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health [CA 104392] FX J.R.B. and J.W.Y. are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. C.V.N. is supported by Grant CA 104392 from the National Institutes of Health. NR 42 TC 9 Z9 11 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2009 VL 183 IS 7 BP 4205 EP 4210 DI 10.4049/jimmunol.0901828 PG 6 WC Immunology SC Immunology GA 503GU UT WOS:000270522500012 PM 19752220 ER PT J AU Ishizuka, J Grebe, K Shenderov, E Peters, B Chen, QY Peng, Y Wang, LL Dong, T Pasquetto, V Oseroff, C Sidney, J Hickman, H Cerundolo, V Sette, A Bennink, JR McMichael, A Yewdell, JW AF Ishizuka, Jeffrey Grebe, Kristie Shenderov, Eugene Peters, Bjoern Chen, Qiongyu Peng, YanChun Wang, Lili Dong, Tao Pasquetto, Valerie Oseroff, Carla Sidney, John Hickman, Heather Cerundolo, Vincenzo Sette, Alessandro Bennink, Jack R. McMichael, Andrew Yewdell, Jonathan W. TI Quantitating T Cell Cross-Reactivity for Unrelated Peptide Antigens SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSGENIC MICE; INFLUENZA NUCLEOPROTEIN; REPERTOIRE DIVERSITY; HIGH-AFFINITY; RESPONSES; RECEPTOR; LYMPHOCYTES; VIRUS; CYTOMEGALOVIRUS; SPECIFICITY AB Quantitating the frequency of T cell cross-reactivity to unrelated peptides is essential to understanding T cell responses in infectious and autoimmune diseases. Here we used 15 mouse or human CD8(+) T cell clones (11 antiviral, 4 anti-self) in conjunction with a large library of defined synthetic peptides to examine nearly 30,000 TCR-peptide MHC class I interactions for cross-reactions. We identified a single cross-reaction consisting of an anti-self TCR recognizing a poxvirus peptide at relatively low sensitivity. We failed to identify any cross-reactions between the synthetic peptides in the panel and polyclonal. CD8(+) T cells raised to viral or alloantigens. These findings provide the best estimate to date of the frequency of T cell cross-reactivity to unrelated peptides (similar to 1/30,000), explaining why cross-reactions between unrelated pathogens are infrequently encountered and providing a critical parameter for understanding the scope of self-tolerance. The Journal of Immunology, 2009, 183: 4337-4345. C1 [Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Ishizuka, Jeffrey; Shenderov, Eugene; Chen, Qiongyu; Peng, YanChun; Wang, Lili; Dong, Tao; Cerundolo, Vincenzo; McMichael, Andrew] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DU, England. [Peters, Bjoern; Pasquetto, Valerie; Oseroff, Carla; Sidney, John; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Room 2E13C1,Bldg 33,33 North Dr, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012; OI Cerundolo, Vincenzo/0000-0003-0040-3793 FU Intramural Research, National Institute of Allergy and Infectious Diseases; Medical Research Council Human Immunology Unit; Cancer Research UK [C399/A2291] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (to J.R.B. and J.W.Y.), by the Medical Research Council Human Immunology Unit (to T.D. and A.M.), and by Cancer Research UK (Grant C399/A2291) (to V.C.). NR 38 TC 28 Z9 28 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2009 VL 183 IS 7 BP 4337 EP 4345 DI 10.4049/jimmunol.0901607 PG 9 WC Immunology SC Immunology GA 503GU UT WOS:000270522500026 PM 19734234 ER PT J AU Chen, Q Davidson, TS Huter, EN Shevach, EM AF Chen, Qian Davidson, Todd S. Huter, Eva N. Shevach, Ethan M. TI Engagement of TLR2 Does not Reverse the Suppressor Function of Mouse Regulatory T Cells, but Promotes Their Survival SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; IMMUNE-RESPONSES; CUTTING EDGE; IN-VITRO; EXPRESSION; TRANSCRIPTION; LYMPHOCYTES; FOXP3; IL-2; VIVO AB TLRs are a class of conserved pattern recognition receptors that are used by cells of the innate immune system. Recent studies have demonstrated the expression of TLRs on both human and mouse T cells raising the possibility that TLRs play a direct role in adaptive immunity. TLR2 is activated primarily by bacterial wall components including peptidoglycan and lipoproteins. Several studies have shown that mouse regulatory T (Treg) cells express TLR2 and claimed that engagement of TLR2 by synthetic ligands reversed their suppressive function. In contrary, enhancement of Treg function was observed following engagement of TLR2 on human Treg. We have reexamined the expression and function of TLR2 on mouse Treg purified from Foxp3-GFP knock-in mice. TLR2 ligation by TLR2 agonist, the synthetic bacterial lipoprotein Pam3CSK4, enhanced the proliferative responses of both conventional T cells and Treg in response to TLR stimulation in the absence of APC. Treatment of Foxp(3+) Treg with Pam3CSK4 did not alter their suppressive function in vitro or in vivo and did not reduce their level of Foxp3 expression. An additional effect of TLR2 stimulation of Treg was induction of Bcl-x(L) resulting in enhanced survival in vitro. Treatment of mice with the TLR2 agonist enhanced the Ag-driven proliferation of Treg in vivo, but did not abolish their ability to suppress the development of experimental autoimmune encephalomyelitis. Development of methods to selectively stimulate TLR2 on Treg may lead to a novel approaches for the treatment of autoimmune diseases. The Journal of Immunology, 2009, 183: 4458-4466. C1 [Chen, Qian; Davidson, Todd S.; Huter, Eva N.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institutes of Health FX These studies were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 33 TC 60 Z9 64 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2009 VL 183 IS 7 BP 4458 EP 4466 DI 10.4049/jimmunol.0901465 PG 9 WC Immunology SC Immunology GA 503GU UT WOS:000270522500039 PM 19748987 ER PT J AU Crane, DD Warner, SL Bosio, CM AF Crane, Deborah D. Warner, Shayna L. Bosio, Catharine M. TI A Novel Role for Plasmin-Mediated Degradation of Opsonizing Antibody in the Evasion of Host Immunity by Virulent, but Not Attenuated, Francisella tularensis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID OUTER-MEMBRANE PROTEINS; YERSINIA-PESTIS; STREPTOCOCCUS-PNEUMONIAE; STAPHYLOCOCCUS-AUREUS; BORRELIA-BURGDORFERI; CELL ACTIVATION; FC RECEPTOR; SURFACE; INFECTION; BINDING AB Opsonization by Abs represents a critical component of the host immune response against many pathogens. The mechanisms by which virulent microbes evade this protective response are not completely understood. In disease mediated by Francisella tularensis, Ab can effectively protect against infections with attenuated strains, for example, LVS, but not virulent strains such as SchuS4. Thus, it is likely that SchuS4 has mechanisms, which are not present in INS, that allow evasion of opsonization by Ab, dampening the protective effects of these host molecules. Here we demonstrate that evasion of Ab-mediated opsonization and phagocytosis by the highly virulent SchuS4 is associated with its ability to bind the host serine protease plasmin. SchuS4, but not the closely related LVS, bound active plasmin. Plasmin bound SchuS4 degraded exogenous and opsonizing Abs, whereas LVS failed to do so. Furthermore, plasmin-mediated inhibition of Ab opsonization by SchuS4 also inhibited Ab-mediated uptake of this bacterium by macrophages. Ab-mediated uptake of uncoated and opsonized SchuS4 elicited a strong proinflammatory response in infected macrophages. However, plasmin-coated, opsonized SchuS4 poorly elicited production of these protective proinflammatory cytokines. This unique host-pathogen interplay is a novel immune evasion strategy utilized by virulent F. tularensis, and it provides one explanation for the ability of Ab to protect against attenuated, but not virulent, strains of F. tularensis. This mechanism may also represent a more common hereto unrecognized strategy by which virulent bacteria evade detection and clearance by Ig. The Journal of Immunology, 2009, 183: 4593-4600. C1 [Crane, Deborah D.; Warner, Shayna L.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Bosio, CM (reprint author), NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 36 TC 27 Z9 27 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2009 VL 183 IS 7 BP 4593 EP 4600 DI 10.4049/jimmunol.0901655 PG 8 WC Immunology SC Immunology GA 503GU UT WOS:000270522500054 PM 19752236 ER PT J AU Reddy, NM Suryanarayana, V Kalvakolanu, DV Yamamoto, M Kensler, TW Hassoun, PM Kleeberger, SR Reddy, SP AF Reddy, Narsal M. Suryanarayana, Vegiraju Kalvakolanu, Dhananjaya V. Yamamoto, Masayuki Kensler, Thomas W. Hassoun, Paul M. Kleeberger, Steven R. Reddy, Sekhar P. TI Innate Immunity against Bacterial Infection following Hyperoxia Exposure Is Impaired in NRF2-Deficient Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACUTE LUNG INJURY; VENTILATOR-ASSOCIATED PNEUMONIA; PULMONARY OXYGEN-TOXICITY; TRANSCRIPTION FACTOR NRF2; SCAVENGER RECEPTOR MARCO; 2-RELATED FACTOR-2 GENE; PSEUDOMONAS-AERUGINOSA; PROMOTER POLYMORPHISM; ALVEOLAR MACROPHAGES; OXIDATIVE STRESS AB Oxygen supplementation is used as therapy to support critically ill patients with severe respiratory impairment. Although hyperoxia has been shown to enhance the lung susceptibility to subsequent bacterial infection, the mechanisms underlying enhanced susceptibility remain enigmatic. We have reported that disruption of NF-E2-related factor 2 (Nrf2), a master transcription regulator of various stress response pathways, enhances susceptibility to hyperoxia-induced acute lung injury in mice, and have also demonstrated an association between a polymorphism in the NRF2 promoter and increased susceptibility to acute lung injury. In this study, we show that Nrf2-deficient (Nrf2(-/-)) but not wild-type (Nrf2(+/+)) mice exposed to sublethal hyperoxia succumbed to death during recovery after Pseudomonas aeruginosa infection. Nrf2-deficiency caused persistent bacterial pulmonary burden and enhanced levels of inflammatory cell infiltration as well as edema. Alveolar macrophages isolated from Nrf2(-/-) mice exposed to hyperoxia displayed persistent oxidative stress and inflammatory cytokine expression concomitant with diminished levels of antioxidant enzymes, such as Gclc, required for glutathione biosynthesis. In vitro exposure of Nrf2(-/-) macrophages to hyperoxia strongly diminished their antibacterial activity and enhanced inflammatory cytokine expression compared with Nrf2(+/+) cells. However, glutathione supplementation during hyperoxic insult restored the ability of Nrf2(-/-) cells to mount antibacterial response and suppressed cytokine expression. Thus, loss of Nrf2 impairs lung innate immunity and promotes susceptibility to bacterial infection after hyperoxia exposure, ultimately leading to death of the host. The Journal of Immunology, 2009, 183: 4601-4608. C1 [Reddy, Narsal M.; Suryanarayana, Vegiraju; Kensler, Thomas W.; Reddy, Sekhar P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Kalvakolanu, Dhananjaya V.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Yamamoto, Masayuki] Tohoku Univ, Dept Med Biochem, Sendai, Miyagi 980, Japan. [Hassoun, Paul M.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Kleeberger, Steven R.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. RP Reddy, NM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Room E7610,615 N Wolfe St, Baltimore, MD 21205 USA. EM nmachire@jhsph.edu; sreddy@jhsph.edu RI Yamamoto, Masayuki/A-4873-2010; Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NIH [HL66109, ES 11863, HL049441]; SCCOR [P50 HL073994, ES007141, CA105005, CA94076]; NIH, National Institute of Environmental Health Sciences FX This work was funded by NIH Grants HL66109 and ES 11863 (to S.P.R.), HL049441 (to P.H.), SCCOR P50 HL073994 (to S.P.R. and P.H.), ES007141 (to S.V.), CA105005 (to D.V.K.), and CA94076 (to T.W.K.) and, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (to S.RX.). NR 49 TC 31 Z9 31 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2009 VL 183 IS 7 BP 4601 EP 4608 DI 10.4049/jimmunol.0901754 PG 8 WC Immunology SC Immunology GA 503GU UT WOS:000270522500055 PM 19734219 ER PT J AU Anderson, CF Stumhofer, JS Hunter, CA Sacks, D AF Anderson, Charles F. Stumhofer, Jason S. Hunter, Christopher A. Sacks, David TI IL-27 Regulates IL-10 and IL-17 from CD4(+) Cells in Nonhealing Leishmania major Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AZAR DERMAL LEISHMANIASIS; CENTRAL-NERVOUS-SYSTEM; T-CELLS; KALA-AZAR; CUTANEOUS LEISHMANIASIS; VISCERAL LEISHMANIASIS; CYTOKINE RESPONSES; IMMUNE-RESPONSES; INTERFERON-GAMMA; CUTTING EDGE AB Control of infection caused by Leishmania major requires the development of IFN-gamma(+)CD4(+) lymphocytes for the induction of microbicidal activity in host macrophages. We recently reported on the inability of conventionally resistant C57BL/6 mice to successfully resolve infection by an isolate of L. major, despite a strong IFN-gamma response by the host. Susceptibility was caused by Ag-specific IL-10 from CD4(+) cells that were also producing IFN-gamma. In the present studies, we have explored the role for IL-27 in the regulation of IL-10 from Th1 cells in leishmaniasis. Cytokine analysis of CD4(+) cells in the lesions and draining lymph nodes of infected IL-27R-deficient (WSX-1(-/-)) mice revealed diminished IL-10 from IFN-gamma(+) CD4(+) cells, which was accompanied by a reduction in total IFN-gamma(+)CD4(+) cells and an increase in IL-4. Despite the inhibition of IL-10 from CD4(+) cells, no significant change in parasite numbers was observed, due both to the shift in the Th1/Th2 balance and to residual levels of IL-10. Strikingly, infected WSX-1(-/-) mice developed more severe lesions that were associated with the appearance of IL-17(+) CD4(+) cells, demonstrating a function for IL-27 in blocking the development of inappropriate Th17 cells during L. major infection. The results demonstrate the pleiotropic effects that IL-27 has on L. major-driven Th1, Th2, and Th17 development, and reinforce its function as a key regulatory cytokine that controls the balance between immunity and pathology. The Journal of Immunology, 2009, 183: 4619-4627. C1 [Anderson, Charles F.; Sacks, David] NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Stumhofer, Jason S.; Hunter, Christopher A.] Univ Penn, Dept Pathobiol, Sch Vet Med, Philadelphia, PA 19104 USA. RP Sacks, D (reprint author), NIAID, NIH, Parasit Dis Lab, Bldg 4,Room 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. EM dsacks@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [142334, D43 TW007127] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and in part by National Institutes of Health Grants At 142334 and D43 TW007127. NR 43 TC 73 Z9 77 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 OCT 1 PY 2009 VL 183 IS 7 BP 4619 EP 4627 DI 10.4049/jimmunol.0804024 PG 9 WC Immunology SC Immunology GA 503GU UT WOS:000270522500057 PM 19748991 ER PT J AU Tsuno, T Mejido, J Zhao, TM Schmeisser, H Morrow, A Zoon, KC AF Tsuno, Takaya Mejido, Josef Zhao, Tongmao Schmeisser, Hana Morrow, Angel Zoon, Kathryn C. TI IRF9 is a Key Factor for Eliciting the Antiproliferative Activity of IFN-alpha SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE IFN-alpha; JAK-STAT pathway; antiproliferative activity; IRF9; TRAIL ID INTERFERON-ALPHA; MELANOMA-CELLS; SIGNAL TRANSDUCER; START SITES; HUMAN GENES; FACTOR-I; EXPRESSION; TRAIL; APOPTOSIS; ACTIVATION AB A number of tumors are still resistant to the antiproliferative activity of human interferon (IFN)-alpha. The Janus kinases/Signal Transducers and Activators of Transcription (JAK-STAT) pathway plays an important role in initial IFN signaling. To enhance the antiproliferative activity of IFN-alpha, it is important to elucidate which factors in the JAK-STAT pathway play a key role in eliciting this activity. In human ovarian adenocarcinoma OVCAR3 cells sensitive to both IFN-alpha and IFN-gamma, only IFN regulatory factor 9 (IRF9)-RNA interference (RNAi) completely inhibited the antiproliferative activity of IFN-alpha among the intracellular JAK-STAT pathway factors. Conversely, Stat1-RNAi did not inhibit the antiproliferative activity of IFN-alpha, whereas it partially inhibited that of IFN-gamma. As a cell death pathway, it is reported that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis through TRAIL-receptor (R) 1 and TRAIL-R2. In IFN-alpha-treated OVCAR3 cells, IRF9-RNAi inhibited transcription of TRAIL whereas Stat1-RNAi did not, suggesting that the transcription of TRAIL induced by IFN-alpha predominantly required IRF9. Furthermore, IFN-stimulated response element-like motifs of TRAIL bound to IFIN-stimulated gene factor 3 (ISGF3) complex after IFN-alpha treatment. Subsequently, TRAIL-R2-RNAi inhibited both antiproliferative activities of IFN-alpha and TRAIL, suggesting that TRAIL-R2 mediated both IFN-alpha and TRAIL signals to elicit their antiproliferative activities. Finally, IRF9 overexpression facilitated IFN-alpha-induced apoptosis in T98G (human glioblastoma multiforme) cells, which were resistant to IFN-alpha. Thus, this study suggests that IRF9 is the key factor for eliciting the antiproliferative activity of IFN-alpha and TRAIL may be one of the potential mediators. C1 [Zoon, Kathryn C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, Div Intramural Res, NIH, Bldg 33,Rm 2N09G 2,33 N Dr, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000944-04, Z99 AI999999] NR 43 TC 26 Z9 26 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2009 VL 32 IS 8 BP 803 EP 816 PG 14 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 500RF UT WOS:000270321100004 PM 19752753 ER PT J AU Zielinski, R Lyakhov, I Jacobs, A Chertov, O Kramer-Marek, G Francella, N Stephen, A Fisher, R Blumenthal, R Capala, J AF Zielinski, Rafal Lyakhov, Ilya Jacobs, Amy Chertov, Oleg Kramer-Marek, Gabriela Francella, Nicholas Stephen, Andrew Fisher, Robert Blumenthal, Robert Capala, Jacek TI Affitoxin-A Novel Recombinant, HER2-specific, Anticancer Agent for Targeted Therapy of HER2-positive Tumors SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE Affibody molecule; HER2; breast cancer; targeted therapy; Pseudomonas exotoxin A ID METASTATIC BREAST-CANCER; IMPROVED ANTIGEN-BINDING; DISULFIDE-STABILIZED FV; PSEUDOMONAS EXOTOXIN-A; ANTITUMOR-ACTIVITY; IN-VITRO; FUSION PROTEIN; MONOCLONAL-ANTIBODY; AFFIBODY MOLECULES; CARCINOMA-CELLS AB Expression of the human epidermal growth factor receptor 2 (HER2) is amplified in 25% to 30% of breast cancers and has been associated with an unfavorable prognosis. Here we report the construction, purification, and characterization of Affitoxin-a novel class of HER2-specific cytotoxic molecules combining HER2-specific Affibody molecule as a targeting moiety and PE38KDEL, which is a truncated version of Pseudomonas exotoxin A, as a cell killing agent. It is highly soluble and does not require additional refolding, oxidation, or reduction steps (luring its purification. Using surface plasmon resonance technology and competitive binding assays, we have shown that Affitoxin binds specifically to HER2 with nanomolar affinity. We have also observed a high correlation between HER2 expression and retention of Affitoxin bound to the cell surface. Affitoxin binding and internalization is followed by Pseudomonas exotoxin A activity domain-mediated ADP-ribosylation of translation elongation factor 2 and, consequently, inhibition of protein synthesis as shown by protein expression analysis of HER2-positive cells treated with Affitoxin. Measured IC(50) value for HER2-negative cells MDA-MB468 (65 +/- 2.63 pM) was more than 20 times higher than the value for low HER2 level-expressing MCF7 cells (2.56 +/- 0.1 pM), and almost 3 orders of magnitude higher for its HER2-overexpressing derivative MCF7/HER2 (62.7 +/- 5.9fM). These studies suggest that Affitoxin is an attractive PE38-based candidate for treatment of HER2-positive tumors. C1 [Zielinski, Rafal; Jacobs, Amy; Kramer-Marek, Gabriela; Francella, Nicholas; Blumenthal, Robert; Capala, Jacek] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lyakhov, Ilya; Chertov, Oleg; Stephen, Andrew; Fisher, Robert] SAIC Frederick Inc, NCI Frederick, Frederick, MD USA. [Jacobs, Amy] SUNY Buffalo, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. RP Capala, J (reprint author), NCI, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room B3B69D, Bethesda, MD 20892 USA. EM capalaj@mail.nih.gov FU Center for Cancer Research; National Cancer Institute; Breast Cancer Research Stamp Fund; National Institutes of Health [N01-CO-12400, N01-CO-12401] FX Funded in part with Federal funds from the National Cancer Institute and National Institutes of Health under contracts N01-CO-12400 and N01-CO-12401, respectively. NR 50 TC 32 Z9 32 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2009 VL 32 IS 8 BP 817 EP 825 PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 500RF UT WOS:000270321100005 PM 19752752 ER PT J AU Smith, FO Klapper, JA Wunderlich, JR Rosenberg, SA Dudley, ME AF Smith, Franz O. Klapper, Jacob A. Wunderlich, John R. Rosenberg, Steven A. Dudley, Mark E. TI Impact of a Recombinant Fowlpox Vaccine on the Efficacy of Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes in a Patient With Metastatic Melanoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE recombinant fowlpox vaccine; gp100: 209-217 (210M); metastatic melanoma; adoptive cell therapy; tumor infiltrating lymphocytes ID ANTIGEN-4 BLOCKADE; T-CELLS; AUTOIMMUNITY; IMMUNOTHERAPY; REGRESSION; CANCER; SELF; CTL AB A patient with metastatic melanoma who had progressive disease after prior surgical resections, high dose interleukin-2. and anti-cytotoxic T lymphocyte antigen-4 antibody received sequential treatments with autologous tumor infiltrating lymphocytes that recognized the gp100 melanocyte differentiation antigen. Although no clinical response was seen when cells were administered alone, an objective clinical response to therapy was seen with tumor infiltrating lymphocytes administered together with a highly immunogenic fowlpox vaccine expressing a gp100: 209-217 (210M) epitope. Persistence of the transferred antigen-specific lymphocytes in the peripheral blood was observed only after adoptive cell therapy plus administration of vaccine. Cell proliferation in vitro was further stimulated by additional vaccine and interleukin-2. The patient has an ongoing partial response at 10 months after the last treatment. C1 [Smith, Franz O.; Klapper, Jacob A.; Wunderlich, John R.; Rosenberg, Steven A.; Dudley, Mark E.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Dudley, ME (reprint author), NCI, Surg Branch, NIH, CRC 3-5752,10 Ctr Dr, Bethesda, MD 20892 USA. EM Mark_Dudley@nih.gov NR 13 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2009 VL 32 IS 8 BP 870 EP 874 PG 5 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 500RF UT WOS:000270321100010 PM 19752747 ER PT J AU Goff, SL Robbins, PF El-Gamil, M Rosenberg, SA AF Goff, Stephanie L. Robbins, Paul F. El-Gamil, Mona Rosenberg, Steven A. TI No Correlation Between Clinical Response to CTLA-4 Blockade and Presence of NY-ESO-1 Antibody in Patients With Metastatic Melanoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Letter ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; CANCER; REGRESSION; HYPOPHYSITIS C1 [Goff, Stephanie L.; Robbins, Paul F.; El-Gamil, Mona; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Goff, SL (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 8 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2009 VL 32 IS 8 BP 884 EP 885 PG 2 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 500RF UT WOS:000270321100012 PM 19752745 ER PT J AU Morens, DM Folkers, GK Fauci, AS AF Morens, David M. Folkers, Gregory K. Fauci, Anthony S. TI What Is a Pandemic? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID INFLUENZA C1 [Morens, David M.; Folkers, Gregory K.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM dmorens@niaid.nih.gov NR 27 TC 13 Z9 14 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2009 VL 200 IS 7 BP 1018 EP 1021 DI 10.1086/644537 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 490CN UT WOS:000269475000002 PM 19712039 ER PT J AU Nair, N Moss, WJ Scott, S Mugala, N Ndhlovu, ZM Lilo, K Ryon, JJ Monze, M Quinn, TC Cousens, S Cutts, F Griffin, DE AF Nair, Nitya Moss, William J. Scott, Susana Mugala, Nanthalile Ndhlovu, Zaza M. Lilo, Kareem Ryon, Judith J. Monze, Mwaka Quinn, Thomas C. Cousens, Simon Cutts, Felicity Griffin, Diane E. TI HIV-1 Infection in Zambian Children Impairs the Development and Avidity Maturation of Measles Virus-Specific Immunoglobulin G after Vaccination and Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID REDUCTION NEUTRALIZATION TEST; B-CELLS; CELLULAR RECEPTOR; UNINFECTED CHILDREN; THIOCYANATE ELUTION; ANTIBODY-AFFINITY; CD46; IMMUNOGENICITY; PROTEIN; ELISA AB Background. Endemic transmission of measles continues in many countries that have a high human immunodeficiency virus (HIV) burden. The effects that HIV infection has on immune responses to measles and to measles vaccine can impact measles elimination efforts. Assays to measure antibody include the enzyme immunoassay (EIA), which measures immunoglobulin G (IgG) to all measles virus (MV) proteins, and the plaque reduction neutralization (PRN) assay, which measures antibody to the hemagglutinin and correlates with protection. Antibody avidity may affect neutralizing capacity. Methods. HIV-infected and HIV-uninfected Zambian children were studied after measles vaccination (n = 44) or MV infection (n = 57). Laboratory or wild-type MV strains were used to infect Vero or Vero/signaling lymphocyte-activation molecule (SLAM) cells in PRN assays. IgG to MV was measured by EIA, and avidity was determined by ammonium thiocyanate dissociation. Results. HIV infection impaired EIA IgG responses after vaccination and measles but not PRN responses measured using laboratory-adapted MV. Avidity was lower among HIV-infected children 3 months after vaccination and 1 and 3 months after measles. Neutralization of wild-type MV infection of Vero/SLAM cells correlated with IgG avidity. Conclusion. Lower antibody quality and quantity in HIV-infected children after measles vaccination raise challenges for assuring the long- term protection of these children. Antibody quality in children receiving antiretroviral therapy requires assessment. C1 [Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Nair, Nitya; Moss, William J.; Ndhlovu, Zaza M.; Lilo, Kareem; Ryon, Judith J.; Griffin, Diane E.] Johns Hopkins Univ, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Moss, William J.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Scott, Susana; Cousens, Simon; Cutts, Felicity] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Monze, Mwaka] Univ Teaching Hosp, Virol Lab, Lusaka, Zambia. [Mugala, Nanthalile] Univ Teaching Hosp, Hlth Serv & Syst Program, Lusaka, Zambia. RP Griffin, DE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, 615 N Wolfe St,Rm E5132, Baltimore, MD 21205 USA. EM dgriffin@jhsph.edu RI Nair, Nitya/D-2651-2017 OI Nair, Nitya/0000-0002-9524-9313 FU Intramural NIH HHS [ZIA AI000361-28]; NIAID NIH HHS [AI23047, R01 AI023047]; Wellcome Trust [GR059114MA] NR 45 TC 33 Z9 33 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2009 VL 200 IS 7 BP 1031 EP 1038 DI 10.1086/605648 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 490CN UT WOS:000269475000004 PM 19702505 ER PT J AU An, P Johnson, R Phair, J Kirk, GD Yu, XF Donfield, S Buchbinder, S Goedert, JJ Winkler, CA AF An, Ping Johnson, Randall Phair, John Kirk, Gregory D. Yu, Xiao-Fang Donfield, Sharyne Buchbinder, Susan Goedert, James J. Winkler, Cheryl A. TI APOBEC3B Deletion and Risk of HIV-1 Acquisition SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 58th Annual Meeting of the American-Society-of-Human-Genetics CY NOV 11-15, 2008 CL Philadelphia, PA SP Amer Soc Human Genet ID VIF; STRATIFICATION; REPLICATION; INFECTION; GENE; AIDS AB The human APOBEC3 family of cytidine deaminases provides intrinsic immunity to retroviral infection. A naturally occurring 29.5-kb deletion removes the entire APOBEC3B gene. We examined the impact of the APOBEC3B gene deletion in >4000 individuals from 5 human immunodeficiency virus type 1 (HIV-1) natural history cohorts. The hemizygous genotype had no effect on either acquisition of HIV-1 infection or progression to AIDS. However, the homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition (odds ratio, 7.37; P = .024), progression to AIDS (relative hazard, 4.01; P = .03) and viral set point (P = .04). These findings suggest that the loss of APOPBEC3B may increase host susceptibility to HIV-1 acquisition and progression to AIDS and warrant further study. C1 [Winkler, Cheryl A.] NCI, Lab Genom Div, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. [Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Yu, Xiao-Fang] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Bethesda, MD 20892 USA. [Phair, John] Northwestern Univ, Chicago, IL 60611 USA. [Donfield, Sharyne] Rho, Chapel Hill, NC USA. [Buchbinder, Susan] San Francisco Dept Publ Hlth, San Francisco, CA USA. RP Winkler, CA (reprint author), NCI, Lab Genom Div, SAIC Frederick, FCRDC, Bldg 560, Frederick, MD 21702 USA. EM winkler@ncifcrf.gov RI Johnson, Randall/B-1517-2014 OI Johnson, Randall/0000-0001-7754-0847 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [Z01 BC010297-11, ZIA BC010297-15, ZIA BC010297-13, Z01 BC010798-01, Z01 BC010297-10, ZIA BC010297-12, Z01 BC010798-02, Z99 CA999999, ZIA BC010297-14]; NCI NIH HHS [N02CP55504, HHSN261200800001E]; NIDA NIH HHS [R56 DA004334, R01 DA004334, R01-DA04334]; PHS HHS [R01-12586] NR 15 TC 34 Z9 35 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2009 VL 200 IS 7 BP 1054 EP 1058 DI 10.1086/605644 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 490CN UT WOS:000269475000007 PM 19698078 ER PT J AU Weinberg, A Zhang, JH Oxman, MN Johnson, GR Hayward, AR Caulfield, MJ Irwin, MR Clair, J Smith, JG Stanley, H Marchese, RD Harbecke, R Williams, HM Chan, ISF Arbeit, RD Gershon, AA Schodel, F Morrison, VA Kauffman, CA Straus, SE Schmader, KE Davis, LE Levin, MJ AF Weinberg, Adriana Zhang, Jane H. Oxman, Michael N. Johnson, Gary R. Hayward, Anthony R. Caulfield, Michael J. Irwin, Michael R. Clair, James Smith, Jeffrey G. Stanley, Harold Marchese, Rocio D. Harbecke, Ruth Williams, Heather M. Chan, Ivan S. F. Arbeit, Robert D. Gershon, Anne A. Schoedel, Florian Morrison, Vicki A. Kauffman, Carol A. Straus, Steve E. Schmader, Kenneth E. Davis, Larry E. Levin, Myron J. CA US Dept Vet Affairs TI Varicella-Zoster Virus-Specific Immune Responses to Herpes Zoster in Elderly Participants in a Trial of a Clinically Effective Zoster Vaccine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID POSTHERPETIC NEURALGIA; OLDER-ADULTS; LONG-TERM; INFECTION; PAIN; PERSISTENCE; VALIDATION; PREVENTION; RECIPIENTS; SHIPMENT AB Background. The objectives of this study were to evaluate the association between varicella-zoster virus (VZV) specific humoral and cell-mediated immunity (CMI) to herpes zoster (HZ) and protection against HZ morbidity and to compare immune responses to HZ and zoster vaccine. Methods. In 981 elderly persons who developed HZ during a zoster vaccine efficacy trial (321 vaccinees and 660 placebo recipients) and 1362 without HZ (682 vaccinees and 680 placebo recipients), CMI was measured by VZV responder cell frequency and interferon-gamma enzyme-linked immunospot, and antibodies were measured by VZV enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA). Results. Robust VZV CMI at HZ onset correlated with reduced HZ morbidity, whereas VZV gpELISA titers did not. Three weeks after HZ onset, gpELISA titers were highest in those with more severe HZ and were slightly increased in placebo recipients (compared with zoster vaccine recipients) and in older individuals. VZV CMI responses to HZ were similar in zoster vaccine and placebo recipients and were not affected by demographic characteristics or antiviral therapy, except for responder cell frequency at HZ onset, which decreased with age. When responses to zoster vaccine and HZ could be compared, VZV CMI values were similar, but antibody titers were lower. Conclusions. Higher VZV CMI at HZ onset was associated with reduced HZ severity and less postherpetic neuralgia. Higher antibody titers were associated with increased HZ severity and occurrence of postherpetic neuralgia. HZ and zoster vaccine generated comparable VZV CMI. C1 [Zhang, Jane H.; Johnson, Gary R.] VA Connecticut Healthcare Syst, W Haven Cooperat Studies Program, Coordinating Ctr, West Haven, CT USA. [Weinberg, Adriana; Levin, Myron J.] Univ Colorado Denver, West Haven, CT USA. [Oxman, Michael N.; Stanley, Harold; Harbecke, Ruth; Williams, Heather M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Oxman, Michael N.; Stanley, Harold; Harbecke, Ruth; Williams, Heather M.] VA San Diego Healthcare Syst, San Diego, CA USA. [Irwin, Michael R.] Univ Calif Los Angeles, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA USA. [Hayward, Anthony R.; Straus, Steve E.] NIH, Bethesda, MD 20892 USA. [Caulfield, Michael J.; Clair, James; Smith, Jeffrey G.; Marchese, Rocio D.; Chan, Ivan S. F.; Schoedel, Florian] Merck Res Labs, West Point, PA USA. [Arbeit, Robert D.] Tufts Univ, Boston, MA 02111 USA. [Gershon, Anne A.] Columbia Univ, New York, NY USA. [Morrison, Vicki A.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Morrison, Vicki A.] Vet Adm Med Ctr, Minneapolis, MN 55417 USA. [Kauffman, Carol A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Kauffman, Carol A.] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Schmader, Kenneth E.] Durham VA Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC USA. [Schmader, Kenneth E.] Duke Univ, Med Ctr, Durham, NC USA. [Davis, Larry E.] VA Med Ctr, Albuquerque, NM USA. RP Weinberg, A (reprint author), Res Complex 2,Mail Stop 8604,12700 E 19th Ave, Aurora, CO 80045 USA. EM Adriana.Weinberg@ucdenver.edu RI Irwin, Michael/H-4870-2013 OI Irwin, Michael/0000-0002-1502-8431 FU West Haven Cooperative Studies Program Coordinating Center FX Laboratory assistance for the RCF assay was provided at the San Diego site by P. Jordan and at the Denver site by L. Enomoto, G. Pott, E. Ponnuraj, D. Thrasher, and M. Borakove. Clinical assistance was provided at the San Diego site by P. McCook, D. Beck, J. Guatelli, P. Brooks, and A. Kendall; at the Denver site by N. Lang and D. Barber; and at Merck by M. E. Thompson, R. Rutledge, and N. Bundick. Data management and analysis support at West Haven Cooperative Studies Program Coordinating Center was provided by K. Dellert. Statistical assistance at Merck was provided by W. W. B. Wang, J. Xu, J. Heyse, and H. Matthews. Clinical administration at Merck was provided by F. S., J. Sadoff, S. Manoff, C. J. White, and R. Vessey. Laboratory assistance at Merck was provided by R. Kaufhold, M. Wooters, J. Field, H. Joseph for ELISPOT and by O. Hammond, P. Stump, M. Norris, M. Santo, C. Moyer, M. Constanzer, and J. Kessler for gpELISA. NR 29 TC 109 Z9 114 U1 0 U2 9 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2009 VL 200 IS 7 BP 1068 EP 1077 DI 10.1086/605611 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 490CN UT WOS:000269475000009 PM 19712037 ER PT J AU Hoshino, Y Pesnicak, L Dowdell, KC Burbelo, PD Knipe, DM Straus, SE Cohen, JI AF Hoshino, Yo Pesnicak, Lesley Dowdell, Kennichi C. Burbelo, Peter D. Knipe, David M. Straus, Stephen E. Cohen, Jeffrey I. TI Protection from Herpes Simplex Virus (HSV)-2 Infection with Replication-Defective HSV-2 or Glycoprotein D2 Vaccines in HSV-1-Seropositive and HSV-1-Seronegative Guinea Pigs SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the American-Society-for-Virology CY JUL 12-18, 2008 CL Ithaca, NY SP Amer Soc Virol ID GENITAL HERPES; RECOMBINANT GLYCOPROTEIN; TYPE-2; IMMUNOGENICITY; VACCINATION; EFFICACY; WOMEN; MEN AB Background. A herpes simplex virus (HSV)-2 candidate vaccine consisting of glycoprotein D (gD2) in alum and monophosphoryl lipid A (MPL) reduced genital herpes disease in HSV-1-seronegative women but not in men or HSV-1-seropositive women. Methods. To determine the effect of HSV-1 serostatus on effectiveness of different vaccines, we tested gD2 in alum/MPL, gD2 in Freund's adjuvant, and dl5-29 (a replication-defective HSV-2 mutant) in HSV-1-seropositive or HSV-1-seronegative guinea pigs. Results. In HSV-1-seronegative animals, dl5-29 induced the highest titers of neutralizing antibody, and after vaginal challenge with wild-type virus, dl5-29 resulted in lower rates of vaginal shedding, lower levels of HSV DNA in ganglia, and a trend for less acute and recurrent genital herpes, compared with the gD2 vaccines. In HSV-1-seropositive animals, all 3 vaccines induced similar titers of neutralizing antibodies and showed similar levels of protection against acute and recurrent genital herpes after vaginal challenge with wild-type virus, but dl5-29 reduced vaginal shedding after challenge more than did the gD2 vaccines. Conclusions. dl5-29 Is an effective vaccine in both HSV-1-seropositive and HSV-1- seronegative guinea pigs and was superior to gD2 vaccines in reducing virus shedding after challenge in both groups of animals. dl5-29 Might reduce transmission of HSV-2. C1 [Hoshino, Yo; Pesnicak, Lesley; Dowdell, Kennichi C.; Straus, Stephen E.; Cohen, Jeffrey I.] NIAID, Med Virol Sect, LCID, Bethesda, MD 20892 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Knipe, David M.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, LCID, Bldg 10,Rm 11N234,10 Ctr Dr, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999, Z99 DE999999, Z01 AI000548-20]; NCRR NIH HHS [P51 RR000168]; NIAID NIH HHS [AI057552, R56 AI057552, R01 AI057552] NR 20 TC 38 Z9 42 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2009 VL 200 IS 7 BP 1088 EP 1095 DI 10.1086/605645 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 490CN UT WOS:000269475000011 PM 19702506 ER PT J AU Madhavarao, CN Arun, P Anikster, Y Mog, SR Staretz-Chacham, O Moffett, JR Grunberg, NE Gahl, WA Namboodiri, AMA AF Madhavarao, C. N. Arun, P. Anikster, Y. Mog, S. R. Staretz-Chacham, O. Moffett, J. R. Grunberg, N. E. Gahl, W. A. Namboodiri, A. M. A. TI Glyceryl triacetate for Canavan disease: A low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID N-ACETYLASPARTIC ACIDURIA; CENTRAL-NERVOUS-SYSTEM; MAGNETIC-RESONANCE-SPECTROSCOPY; MYELIN LIPID-SYNTHESIS; ACETYL-L-ASPARTATE; ASPARTOACYLASE DEFICIENCY; CHAIN TRIGLYCERIDES; BRAIN; ACETATE; ACETYLASPARTYLGLUTAMATE AB Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (similar to 90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted. C1 [Madhavarao, C. N.; Arun, P.; Moffett, J. R.; Namboodiri, A. M. A.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Program Neurosci, Bethesda, MD 20814 USA. [Madhavarao, C. N.; Arun, P.; Moffett, J. R.; Namboodiri, A. M. A.] Uniformed Serv Univ Hlth Sci, Program Mol & Cell Biol, Bethesda, MD 20814 USA. [Anikster, Y.] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Anikster, Y.] Safra Children Hosp, Metab Dis Unit, Sheba Med Ctr, Tel Hashomer, Israel. [Mog, S. R.] AFRRI, Div Comparat Pathol, Bethesda, MD USA. [Staretz-Chacham, O.; Gahl, W. A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Grunberg, N. E.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Program Neurosci, Bethesda, MD 20814 USA. RP Namboodiri, AMA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Program Neurosci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM anamboodiri@usuhs.mil FU Rosalind Poss Rosen Clinical Research Training Fellowship; American Academy of Neurology Foundation; St Paul; Canavan Foundation, New York; Jacob's Cure Foundation; NTSAD; Boston; Samueli Institute; NIH [NS039387] FX C. N. Madhavarao was supported by the Rosalind Poss Rosen Clinical Research Training Fellowship sponsored by the American Academy of Neurology Foundation, St Paul, MN and Canavan Foundation, New York, NY. The study was supported by Jacob's Cure Foundation, NTSAD, Boston, Samueli Institute and NIH R56 grant NS039387 for A. M. A. Namboodiri. GTA for the clinical trials was provided gratis by Cognis Oleo Chemicals, Germany. The authors thank the National Bio Resource Project for the Rat, Kyoto University, Kyoto, Japan, for providing breeding pairs of tremor rats. NR 39 TC 17 Z9 17 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD OCT PY 2009 VL 32 IS 5 BP 640 EP 650 DI 10.1007/s10545-009-1155-3 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 509AC UT WOS:000270982100006 PM 19685155 ER PT J AU Dacosta, RS Tang, Y Kalliomaki, T Reilly, RM Weersink, R Elford, AR Marcon, NE Wilson, BC AF Dacosta, Ralph S. Tang, Ying Kalliomaki, Tuula Reilly, Raymond M. Weersink, Robert Elford, Alisha R. Marcon, Norman E. Wilson, Brian C. TI IN VIVO NEAR-INFRARED FLUORESCENCE IMAGING OF HUMAN COLON ADENOCARCINOMA BY SPECIFIC IMMUNOTARGETING OF A TUMOR-ASSOCIATED MUCIN SO JOURNAL OF INNOVATIVE OPTICAL HEALTH SCIENCES LA English DT Article DE Autofluorescence imaging; endoscopy; colon adenocarcinoma; TAG72; CC49; mucin; monoclonal antibody; conjugate; confocal fluorescence microscopy AB Background and Aims: Accurate endoscopic detection of premalignant lesions and early cancers in the colon is essential for cure, since prognosis is closely related to lesion size and stage. Although it has great clinical potential, autofluorescence endoscopy has limited tumor-to-normal tissue image contrast for detecting small preneoplastic lesions. We have developed a molecularly specific, near-infrared fluorescent monoclonal antibody (CC49) bioconjugate which targets tumor-associated glycoprotein 72 (TAG72), as a contrast agent to improve fluorescence-based endoscopy of colon cancer. Methods: The fluorescent anti-TAG72 conjugate was evaluated in vitro and in vivo in athymic nude mice bearing human colon adenocarcinoma (LS174T) subcutaneous tumors. Autofluorescence, a fluorescent but irrelevant antibody and the free fluorescent dye served as controls. Fluorescent agents were injected intravenously, and in vivo whole body fluorescence imaging was performed at various time points to determine pharmacokinetics, followed by ex vivo tissue analysis by confocal fluorescence microscopy and histology. Results: Fluorescence microscopy and histology confirmed specific LS174T cell membrane targeting of labeled CC49 in vitro and ex vivo. In vivo fluorescence imaging demonstrated significant tumor-to-normal tissue contrast enhancement with labeled-CC49 at three hours post injection, with maximum contrast after 48 h. Accumulation of tumor fluorescence demonstrated that modification of CC49 antibodies did not alter their specific tumor-localizing properties, and was antibody-dependent since controls did not produce detectable tumor fluorescence. Conclusions: These results show proof-of-principle that our near-infrared fluorescent-antibody probe targeting a tumor-associated mucin detects colonic tumors at the molecular level in real time, and offer a basis for future improvement of image contrast during clinical fluorescence endoscopy. C1 [Dacosta, Ralph S.] Ontario Canc Inst, Div Biophys & Bioimaging, Toronto, ON M5G 2M9, Canada. [Kalliomaki, Tuula; Wilson, Brian C.] Univ Toronto, Dept Med Biophys, Princess Margaret Hosp, Ontario Canc Inst,Univ Hlth Network, Toronto, ON, Canada. [Tang, Ying] NCI, NIH, Radiat Oncol Branch, Bethesda, MD USA. [Reilly, Raymond M.] Toronto Gen Hosp, Div Clin Invest & Human Physiol, Res Inst, Toronto, ON, Canada. [Reilly, Raymond M.] Univ Toronto, Leslie Dan Fac Pharm Toronto, Toronto, ON, Canada. [Weersink, Robert] Univ Hlth Network, Lab Appl Biophoton, Toronto, ON, Canada. [Elford, Alisha R.] Ontario Canc Inst, Campbell Family Inst Breast Canc Res, Univ Hlth Network, Dept Med Biophys & Immunol, Toronto, ON M5G 2M9, Canada. [Marcon, Norman E.] St Michaels Hosp, Ctr Therapeut Endoscopy & Endoscop Oncol, Toronto, ON M5B 1W8, Canada. RP Dacosta, RS (reprint author), Ontario Canc Inst, Div Biophys & Bioimaging, 610 Univ Toronto, Toronto, ON M5G 2M9, Canada. EM rdacosta@uhnres.utoronto.ca FU Ontario Research and Development Challenge Fund (ORDCF) FX This work was supported by the Ontario Research and Development Challenge Fund (ORDCF). The authors wish to thank Anoja Giles, Bob Kuba, Annie Lin and Kelvin Ho for their technical assistance. NR 74 TC 3 Z9 3 U1 0 U2 2 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 1793-5458 J9 J INNOV OPT HEAL SCI JI J. Innov. Opt. Health Sci. PD OCT PY 2009 VL 2 IS 4 BP 407 EP 422 DI 10.1142/S1793545809000759 PG 16 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA V27YC UT WOS:000208647500009 ER PT J AU Lee, NR Wallace, GL Weddle, CR Liverpool, M Clasen, LS Blumenthal, J Lenroot, RK Giedd, JN AF Lee, N. R. Wallace, G. L. Weddle, C. R. Liverpool, M. Clasen, L. S. Blumenthal, J. Lenroot, R. K. Giedd, J. N. TI Executive function profiles of males and females with an additional X chromosome SO JOURNAL OF INTELLECTUAL DISABILITY RESEARCH LA English DT Meeting Abstract DE sex chromosome variation; executive function; CANTAB; BRIEF C1 [Lee, N. R.; Wallace, G. L.; Weddle, C. R.; Liverpool, M.; Clasen, L. S.; Blumenthal, J.; Lenroot, R. K.; Giedd, J. N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RI Lee, Nancy Raitano/F-2565-2011; Giedd, Jay/A-3080-2008; 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 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0964-2633 J9 J INTELL DISABIL RES JI J. Intell. Disabil. Res. PD OCT PY 2009 VL 53 BP 836 EP 836 PG 1 WC Education, Special; Genetics & Heredity; Clinical Neurology; Psychiatry; Rehabilitation SC Education & Educational Research; Genetics & Heredity; Neurosciences & Neurology; Psychiatry; Rehabilitation GA 499AO UT WOS:000270189000022 ER PT J AU Scharschmidt, TC List, K Grice, EA Szabo, R Renaud, G Lee, CCR Wolfsberg, TG Bugge, TH Segre, JA AF Scharschmidt, Tiffany C. List, Karin Grice, Elizabeth A. Szabo, Roman Renaud, Gabriel Lee, Chyi-Chia R. Wolfsberg, Tyra G. Bugge, Thomas H. Segre, Julia A. CA NISC Comparative Sequencing Progra TI Matriptase-Deficient Mice Exhibit Ichthyotic Skin with a Selective Shift in Skin Microbiota SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID EPIDERMAL DIFFERENTIATION COMPLEX; AUTOSOMAL RECESSIVE ICHTHYOSIS; ATOPIC-DERMATITIS; ANTIMICROBIAL PEPTIDES; BARRIER FUNCTION; STRATUM-CORNEUM; BACTERIAL BIOTA; DIVERSITY; ENVIRONMENT; ECOLOGY AB Suppressor of tumorigenicity 14 (St14) encodes matriptase, a serine protease, which regulates processing of profilaggrin to filaggin in vivo. Here, we report that transgenic mice with 1% of wild-type St14 levels (St14(hypo/-)) display aberrant processing of profilaggrin and model human ichthyotic skin phenotypes. Scaling of the skin appears at 1 week of age with underlying epidermal acanthosis and orthohyperkeratosis as well as a CD4+ T-cell dermal infiltrate. Upregulation of antimicrobial peptides occurs when challenged by exposure to the postnatal environment. Direct genomic sequencing of bacterial 16S rRNA genes to query microbial diversity identifies a significant shift in both phylogeny and community structure between St14(hypo/-) mice and control littermates. St14(hypo/-) mice have a selective shift in resident skin microbiota with a decrease of the dominant genus of skin bacteria, Pseudomonas and an accompanying increase of Corynebacterium and Streptococcus. St14(hypo/-) mice provide early evidence that the cutaneous microbiome can be specifically altered by genetic state, which may play an important role in modulating skin disease. C1 [Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Scharschmidt, Tiffany C.] Univ Calif, San Francisco Sch Med, HHMI, NIH,Res Scholars Program, Bethesda, MD USA. [List, Karin; Szabo, Roman; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [NISC Comparative Sequencing Progra] NIH, Intramural Sequencing Ctr, Rockville, MD USA. [Lee, Chyi-Chia R.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Room 4A26, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov RI Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Scharschmidt, Tiffany/0000-0001-5517-089X; Grice, Elizabeth/0000-0003-3939-2200 FU NHGRI; NIDCR; Department of Defense [DAMD-17-02-1-0693] FX This work was supported by the NHGRI and NIDCR Research Programs and by a grant from the Department of Defense (DAMD-17-02-1-0693) to Thomas Bugge. All studies were appropriately reviewed by an NIH Animal Care and Use Committee. We thank Cherry Yang for genotyping, Dr Maria Turner for assisting with histological interpretation, Drs Pamela Schwartzberg and Jennifer Cannons for sharing immunologic expertise, Martha Kirby and Stacie Anderson for FACs analysis, Dr Peter Elias for intellectual discussions on skin barrier analysis and the CRTH2 antibody, Histoserv Inc. for immunohistochemistry services, Alice Young, Robert Blakesly and Gerard Bouffard from NISC for their sequencing expertise and services, Julia Fekecs for assistance with figures, and Drs Christina Herrick and Heidi Kong for reviewing the article. We also thank members of the lab for their underlying contributions. NR 45 TC 29 Z9 31 U1 0 U2 16 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 OCT PY 2009 VL 129 IS 10 BP 2435 EP 2442 DI 10.1038/jid.2009.104 PG 8 WC Dermatology SC Dermatology GA 498SL UT WOS:000270163300019 PM 19387477 ER PT J AU Subleski, JJ Ortaldo, JR AF Subleski, Jeff J. Ortaldo, John R. TI NKT cells: to suppress or not to suppress, that is the question SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material DE human NKT cells; suppression; APC ID KILLER T-CELLS; NATURAL-KILLER; IMMUNOSURVEILLANCE; KRN7000 C1 [Subleski, Jeff J.; Ortaldo, John R.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Ortaldo, JR (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, 560 Chandler St, Frederick, MD 21702 USA. EM ortaldo@mail.ncifcrf.gov NR 11 TC 1 Z9 1 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2009 VL 86 IS 4 BP 751 EP 752 DI 10.1189/jlb.0309118 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 501FS UT WOS:000270366500002 PM 19797301 ER PT J AU Piao, W Song, C Chen, HY Diaz, MAQ Wahl, LM Fitzgerald, KA Li, LW Medvedev, AE AF Piao, Wenji Song, Chang Chen, Haiyan Diaz, Marco A. Quevedo Wahl, Larry M. Fitzgerald, Katherine A. Li, Liwu Medvedev, Andrei E. TI Endotoxin tolerance dysregulates MyD88-and Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE lipopolysaccharide; signal transduction; suppression/anergy; cell activation; monocytes/macrophages ID NF-KAPPA-B; TOLL-LIKE RECEPTORS; NECROSIS-FACTOR-ALPHA; CUTTING EDGE; GENE-EXPRESSION; TRANSCRIPTION FACTORS; BACTERIAL FLAGELLIN; IMMUNE-RESPONSES; EPITHELIAL-CELLS; INNATE IMMUNITY AB Endotoxin tolerance reprograms cell responses to LPS by repressing expression of proinflammatory cytokines, while not inhibiting production of anti-inflammatory cytokines and antimicrobial effectors. Molecular mechanisms of induction and maintenance of endotoxin tolerance are incompletely understood, particularly with regard to the impact of endotoxin tolerization on signalosome assembly, activation of adaptor-kinase modules, and expression of negative regulators of TLR signaling in human cells. In this study, we examined LPS-mediated activation of MyD88-dependent and Toll-IL-1R-containing adaptor inducing IFN-beta (TRIF)-dependent pathways emanating from TLR4 and expression of negative regulators of TLR signaling in control and endotoxin-tolerant human monocytes. Endotoxin tolerization suppressed LPS-inducible TLR4-TRIF and TRIF-TANK binding kinase (TBK) 1 associations, induction of TBK1 kinase activity, activation of IFN regulatory factor (IRF)-3, and expression of RANTES and IFN-beta. Tolerance-mediated dysregulation of the TLR4-TRIF-TBK1 signaling module was accompanied by increased levels of suppressor of I kappa B kinase-epsilon (SIKE) and sterile alpha and Armadillo motif-containing molecule (SARM). LPS-tolerant cells showed increased expression of negative regulators Toll-interacting protein (Tollip), suppressor of cytokine signaling (SOCS)-1, IL-1R-associated kinase-M, and SHIP-1, which correlated with reduced p38 phosphorylation, I kappa B-alpha degradation, and inhibited expression of TNF-alpha, IL-6, and IL-8. To examine functional consequences of increased expression of Tollip in LPS-tolerized cells, we overexpressed Tollip in 293/ TLR4/MD-2 transfectants and observed blunted LPS-inducible activation of NF-kappa B and RANTES, while TNF-alpha responses were not affected. These data demonstrate dysregulation of TLR4-triggered MyD88-and TRIF-dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes. J. Leukoc. Biol. 86: 863-875; 2009. C1 [Piao, Wenji; Song, Chang; Chen, Haiyan; Diaz, Marco A. Quevedo; Medvedev, Andrei E.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Wahl, Larry M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA USA. [Li, Liwu] Virginia Tech, Dept Biol, Blacksburg, VA USA. RP Medvedev, AE (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, 660 W Redwood St,Howard Hall Bldg,Rm HH 324, Baltimore, MD 21201 USA. EM amedvedev@som.umaryland.edu OI Li, Liwu/0000-0001-8870-5299 FU National Institutes of Health RO1 [AI-059524, AI067497, AI64414] FX This work was supported by National Institutes of Health RO1 grants AI-059524 (A. E. M.), AI067497 (K. A. F.), and AI64414 (L. L.). NR 75 TC 69 Z9 70 U1 1 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2009 VL 86 IS 4 BP 863 EP 875 DI 10.1189/jlb.0309189 PG 13 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 501FS UT WOS:000270366500014 PM 19656901 ER PT J AU Hu, K Doucleff, M Clore, GM AF Hu, Kaifeng Doucleff, Michaeleen Clore, G. Marius TI Using multiple quantum coherence to increase the N-15 resolution in a three-dimensional TROSY HNCO experiment for accurate PRE and RDC measurements SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE TROSY HNCO; High resolution; RDC; PRE ID RESIDUAL DIPOLAR COUPLINGS; PARAMAGNETIC RELAXATION ENHANCEMENT; SMALL ALPHA/BETA PROTEIN; CORRELATED MOTIONS; MOLECULAR-DYNAMICS; ORDER PARAMETERS; PULSE SEQUENCES; NMR STRUCTURES; BACKBONE; COMPLEXES AB We present a new version of the 3D TROSY HNCO pulse scheme, referred to as HR-TROSY HNCO, with comparable resolution in the N-15 dimension to a 2D H-1-N-15 HSQC experiment. In the conventional 3D TROSY HNCO, the constant time period (1/2J(NC) similar to 32 ms) severely limits the maximum resolution in the N-15 dimension. In the HR-TROSY HNCO experiment presented here, both constant time periods (similar to 32 ms each) for coherence forward and backward transfer between N-15 and C-13' are utilized to double the N-15 evolution time. This leads to a dramatic enhancement in peak separation along the N-15 dimension, making the HR-TROSY HNCO an ideal pulse scheme for accurate paramagnetic relaxation enhancement and residual dipolar coupling measurements. Published by Elsevier Inc. C1 [Hu, Kaifeng; Doucleff, Michaeleen; Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU NIDDK, National Institutes of Health; Office of the Director of the National Institutes of Health FX This work was supported by the intramural program of NIDDK, National Institutes of Health, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health (to G. M. C.). NR 37 TC 10 Z9 10 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 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD OCT PY 2009 VL 200 IS 2 BP 173 EP 177 DI 10.1016/j.jmr.2009.06.019 PG 5 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 526AW UT WOS:000272260900001 PM 19615926 ER PT J AU Shemesh, N Ozarslan, E Bar-Shir, A Basser, PJ Cohen, Y AF Shemesh, Noam Oezarslan, Evren Bar-Shir, Amnon Basser, Peter J. Cohen, Yoram TI Observation of restricted diffusion in the presence of a free diffusion compartment: Single- and double-PFG experiments SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Double-pulsed gradient spin echo; PGSE; Double PGSE; d-PGSE; Diffusion; White matter phantom; Crossing fibers; Low-q; Pulsed field gradients; PFG; NMR; Fast; Slow diffusing ID Q-SPACE DIFFUSION; MAGNETIC-RESONANCE-SPECTROSCOPY; RELAXATION-TIME NMR; GRADIENT WAVE-FORMS; SPIN-ECHO ANALYSIS; FIELD-GRADIENT; STRUCTURAL INFORMATION; EXPERIMENTAL PARAMETERS; WATER DIFFUSION; SPHERICAL PORES AB Theoretical and experimental studies of restricted diffusion have been conducted for decades using single pulsed field gradient (s-PFG) diffusion experiments. In homogenous samples, the diffusion-diffraction phenomenon arising from a single population of diffusing species has been observed experimentally and predicted theoretically. In this study, we introduce a composite bi-compartmental model which superposes restricted diffusion in microcapillaries with free diffusion in an unconfined compartment, leading to fast and slow diffusing components in the NMR signal decay. Although simplified (no exchange), the superposed diffusion modes in this model may exhibit features seen in more complex porous materials and biological tissues. We find that at low q-values the freely diffusing component masks the restricted diffusion component, and that prolongation of the diffusion time shifts the transition from free to restricted profiles to lower q-values. The effect of increasing the volume fraction of freely diffusing water was also studied; we find that the transition in the signal decay from the free mode to the restricted mode occurs at higher q-values when the volume fraction of the freely diffusing water is increased. These findings were then applied to a phantom consisting of crossing fibers, which demonstrated the same qualitative trends in the signal decay. The angular d-PGSE experiment, which has been recently shown to be able to measure small compartmental dimensions even at low q-values, revealed that microscopic anisotropy is lost at low q-values where the fast diffusing component is prominent. Our findings may be of importance in studying realistic systems which exhibit compartmentation. (C) 2009 Elsevier Inc. All rights reserved. C1 [Shemesh, Noam; Bar-Shir, Amnon; Cohen, Yoram] Tel Aviv Univ, Sch Chem, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. [Oezarslan, Evren; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD USA. RP Cohen, Y (reprint author), Tel Aviv Univ, Sch Chem, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. EM ycohen@post.tau.ac.il RI Ozarslan, Evren/B-4858-2013; Basser, Peter/H-5477-2011; OI Ozarslan, Evren/0000-0003-0859-1311; Shemesh, Noam/0000-0001-6681-5876 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX P.J.B and E.O. were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 62 TC 28 Z9 28 U1 2 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD OCT PY 2009 VL 200 IS 2 BP 214 EP 225 DI 10.1016/j.jmr.2009.07.005 PG 12 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 526AW UT WOS:000272260900006 PM 19656697 ER PT J AU Vogel-Claussen, J Skrok, J Dombroski, D Shea, SM Shapiro, EP Bohlman, M Lorenz, CH Lima, JAC Bluemke, DA AF Vogel-Claussen, Jens Skrok, Jan Dombroski, David Shea, Steven M. Shapiro, Edward P. Bohlman, Mark Lorenz, Christine H. Lima, Joao A. C. Bluemke, David A. TI Comprehensive Adenosine Stress Perfusion MRI Defines the Etiology of Chest Pain in the Emergency Room: Comparison With Nuclear Stress Test SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE adenosine stress perfusion cardiac MRI; emergency room; chest pain; microvascular disease ID CORONARY-ARTERY-DISEASE; CARDIAC MAGNETIC-RESONANCE; EMISSION-COMPUTED-TOMOGRAPHY; CONTRAST-ENHANCED MRI; SMALL VESSEL DISEASE; MYOCARDIAL-PERFUSION; PROGNOSTIC VALUE; MICROVASCULAR DYSFUNCTION; SYNDROME-X; ANGIOGRAPHY AB Purpose: To compare standard of care nuclear SPECT imaging with cardiac magnetic resonance imaging (MRI) for emergency room (ER) patients with chest pain and intermediate probability for coronary artery disease. Materials and Methods: Thirty-one patients with chest pain, negative electrocardiogram (ECG), and negative cardiac enzymes who underwent cardiac single photon emission tomography (SPECT) within 24 h of ER admission were enrolled. Patients underwent a comprehensive cardiac MRI exam including gated cine imaging, adenosine stress and rest perfusion imaging and delayed enhancement imaging. Patients were followed for 14 +/- 4.7 months. Results: Of 27 patients, 8 (30%) showed subendocardial hypoperfusion on MRI that was not detected on SPECT. These patients had a higher rate of diabetes (P = 0.01) and hypertension (P = 0.01) and a lower global myocardial perfusion reserve (P = 0.01) compared with patients with a normal cardiac MRI (n = 10). Patients with subendocardial hypoperfusion had more risk factors for cardiovascular disease (mean 4.4) compared with patients with a normal MRI (mean 2.5; P = 0.005). During the follow-up period. patients with subendocardial hypoperfusion on stress MRI were more likely to return to the ER with chest pain compared with patients who had a normal cardiac MRI (P = 0.02). Four patients did not finish the MR exam due to claustrophobia. Conclusion: In patients with chest pain, diabetes and hypertension, cardiac stress perfusion MRI identified diffuse subendocardial hypoperfusion defects in the ER setting not seen on cardiac SPECT, which is suspected to reflect microvascular disease. C1 [Vogel-Claussen, Jens; Skrok, Jan; Dombroski, David; Bohlman, Mark; Lima, Joao A. C.; Bluemke, David A.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, Baltimore, MD 21287 USA. [Shapiro, Edward P.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Cardiol, Sch Med, Baltimore, MD 21287 USA. [Shea, Steven M.; Lorenz, Christine H.] Siemens Corp Res Inc, Imaging & Visualizat, Princeton, NJ USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Vogel-Claussen, J (reprint author), Johns Hopkins Univ, Dept Radiol, Nelson Basement MRI 143,600 N Wolfe St, Baltimore, MD 21287 USA. EM jclauss1@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Siemens Medical Solutions. Inc. [JHU-2006-MR-27-01] FX Contract grant sponsor: Siemens Medical Solutions. Inc.; Contract grant number: numbers; Contract grant number: JHU-2006-MR-27-01. NR 32 TC 14 Z9 14 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD OCT PY 2009 VL 30 IS 4 BP 753 EP 762 DI 10.1002/jmri.21899 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 503GY UT WOS:000270522900008 PM 19787721 ER PT J AU Leppert, IR Almli, CR McKinstry, RC Mulkern, RV Pierpaoli, C Rivkin, MJ Pike, GB AF Leppert, Ilana R. Almli, C. Robert McKinstry, Robert C. Mulkern, Robert V. Pierpaoli, Carlo Rivkin, Micheal J. Pike, G. Bruce CA Brain Dev Cooperative Grp TI T2 Relaxometry of Maturing Brains Response SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Letter C1 [Leppert, Ilana R.; Pike, G. Bruce] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Almli, C. Robert] Washington Univ, Sch Med, Dept Neurol, Dev Neuropsychobiol Lab,Program Neurosci, St Louis, MO 63110 USA. [Almli, C. Robert] Washington Univ, Sch Med, Dept Psychol, Dev Neuropsychobiol Lab,Program Neurosci, St Louis, MO 63110 USA. [Almli, C. Robert] Washington Univ, Sch Med, Program Occupat Therapy, St Louis, MO 63110 USA. [McKinstry, Robert C.] Washington Univ, Med Ctr, St Louis Childrens Hosp, St Louis, MO 63110 USA. [McKinstry, Robert C.] Washington Univ, Med Ctr, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Mulkern, Robert V.] Harvard Univ, Childrens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Pierpaoli, Carlo] NICHHD, NIH, Bethesda, MD 20892 USA. [Rivkin, Micheal J.] Harvard Univ, Childrens Hosp, Sch Med, Dept Neurol Psychiat & Radiol, Boston, MA 02115 USA. RP Leppert, IR (reprint author), McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. EM ilana@bic.nmi.mcgill.ca RI Pierpaoli, Carlo/E-1672-2011; Pike, Bruce/K-5562-2014 OI Pike, Bruce/0000-0001-8924-683X NR 2 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD OCT PY 2009 VL 30 IS 4 BP 912 EP 912 DI 10.1002/jmri.21928 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 503GY UT WOS:000270522900032 ER PT J AU Miller, FG AF Miller, F. G. TI Death and organ donation: back to the future SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID BRAIN-DEATH AB The practice of transplantation of vital organs from "brain-dead'' donors is in a state of theoretical disarray. Although the law and prevailing medical ethics treat patients diagnosed as having irreversible total brain failure as dead, scholars have increasingly challenged the established rationale for regarding these patients as dead. To understand the ethical situation that we now face, it is helpful to revisit the writings of the philosopher Hans Jonas, who forcefully challenged the emerging effort to redefine death in the late 1960s. C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU Intramural Research Program of the Clinical Center; National Institutes of Health. FX This research was supported by the Intramural Research Program of the Clinical Center, National Institutes of Health. NR 27 TC 10 Z9 10 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD OCT PY 2009 VL 35 IS 10 BP 616 EP 620 DI 10.1136/jme.2009.030627 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 501FL UT WOS:000270365400009 PM 19793942 ER PT J AU Chou, WYS Hunt, YM Beckjord, EB Moser, RP Hesse, BW AF Chou, Wen-ying Sylvia Hunt, Yvonne M. Beckjord, Ellen Burke Moser, Richard P. Hesse, Bradford W. TI Social Media Use in the United States: Implications for Health Communication SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Internet; social media; social networking; demography; population surveillance; eHealth, new technologies; health communication ID NATIONAL TRENDS SURVEY; SUPPORT GROUPS; INFORMATION; INTERNET; PARTICIPATION; HINTS; CARE AB Background: Given the rapid changes in the communication landscape brought about by participative Internet use and social media, it is important to develop a better understanding of these technologies and their impact on health communication. The first step in this effort is to identify the characteristics of current social media users. Up-to-date reporting of current social media use will help monitor the growth of social media and inform health promotion/communication efforts aiming to effectively utilize social media. Objective: The purpose of the study is to identify the sociodemographic and health-related factors associated with current adult social media users in the United States. Methods: Data came from the 2007 iteration of the Health Information National Trends Study (HINTS, N = 7674). HINTS is a nationally representative cross-sectional survey on health-related communication trends and practices. Survey respondents who reported having accessed the Internet (N = 5078) were asked whether, over the past year, they had (1) participated in an online support group, (2) written in a blog, (3) visited a social networking site. Bivariate and multivariate logistic regression analyses were conducted to identify predictors of each type of social media use. Results: Approximately 69% of US adults reported having access to the Internet in 2007. Among Internet users, 5% participated in an online support group, 7% reported blogging, and 23% used a social networking site. Multivariate analysis found that younger age was the only significant predictor of blogging and social networking site participation; a statistically significant linear relationship was observed, with younger categories reporting more frequent Use. Younger age, poorer subjective health, and a personal cancer experience predicted support group participation. In general, social media are penetrating the US population independent of education, race/ethnicity, or health care access. Conclusions: Recent growth of social media is not uniformly distributed across age groups; therefore, health communication programs utilizing social media must first consider the age of the targeted population to help ensure that messages reach the intended audience. While racial/ethnic and health status-related disparities exist in Internet access, among those with Internet access, these characteristics do not affect social media use. This finding suggests that the new technologies, represented by social media, may be changing the communication pattern throughout the United States. C1 [Chou, Wen-ying Sylvia] NCI, Hlth Commun & Informat Res Branch, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Beckjord, Ellen Burke] RAND Corp, Pittsburgh, PA USA. [Moser, Richard P.] NCI, Behav Res Program, Bethesda, MD 20892 USA. RP Chou, WYS (reprint author), NCI, Hlth Commun & Informat Res Branch, Canc Prevent Fellowship Program, 6130 Execut Blvd EPN,4051A, Bethesda, MD 20892 USA. EM chouws@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU National Cancer Institute, National Institutes of Health FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health. NR 29 TC 220 Z9 221 U1 25 U2 164 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD OCT-DEC PY 2009 VL 11 IS 4 AR e48 DI 10.2196/jmir.1249 PG 12 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 556YW UT WOS:000274633000009 PM 19945947 ER PT J AU Kader, M Bixler, S Roederer, M Veazey, R Mattapallil, JJ AF Kader, M. Bixler, S. Roederer, M. Veazey, R. Mattapallil, J. J. TI CD4 T cell subsets in the mucosa are CD28+Ki-67-HLA-DR-CD69+but show differential infection based on alpha 4 beta 7 receptor expression during acute SIV infection SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 26th Annual Symposium on Non-Human Primate Models for AIDS CY DEC 09-12, 2008 CL San Juan, PR SP Wisconsin Natl Primate Res Ctr, Caribbean Primate Res Ctr, Natl Inst Hlth, Natl Inst Allergies & Infect Dis, Off AIDS Res DE acute; CD4; Gut; HIV; IL-17; IL-21; IL-23; immunodeficiency; intestine; mucosa; simian; SIV; TGF beta ID SIMIAN IMMUNODEFICIENCY VIRUS; GASTROINTESTINAL-TRACT; TGF-BETA; ANTIRETROVIRAL THERAPY; VIRAL REPLICATION; RHESUS MACAQUES; LYMPHOID-TISSUE; DEPLETION; GUT; LYMPHOCYTES AB Background CD4 T cell depletion in the mucosa has been well documented during acute HIV and SIV infections. The demonstration the HIV/SIVcan use the alpha 4 beta 7 receptor for viral entry suggests that these viruses selectively target CD4 T cells in the mucosa that express high levels of alpha 4 beta 7 receptor. Methods Mucosal samples obtained from SIV infected rhesus macaques during the early phase of infection were used for immunophenotypic analysis. CD4 T cell subsets were sorted based on the expression of beta 7 and CD95 to quantify the level of SIV infection in different subsets of CD4 T cells. Changes in IL-17, IL-21, IL-23 and TGF beta mRNA expression was determined using Taqman PCR. Results CD4 T cells in the mucosa were found to harbor two major population of cells; -25% of CD4 T cells expressed the alpha 4+beta 7hi phenotype, whereas the rest of the 75% expressed an alpha 4+beta 7int phenotype. Both the subsets were predominantly CD28+Ki-67-HLA-DR- but CD69+, and expressed detectable levels of CCR5 on their surface. Interestingly, however, alpha 4+beta 7hiCD4 T cells were found to harbor more SIV than the alpha 4+beta 7int subsets at day 10 pi. Early infection was associated with a dramatic increase in the expression of IL-17, and IL-17 promoting cytokines IL-21, IL-23, and TGF beta that stayed high even after the loss of mucosal CD4 T cells. Conclusions Our results suggest that the differential expression of the alpha 4 beta 7 receptor contributes to the differences in the extent of infection in CD4 T cell subsets in the mucosa. Early infection is associated dysregulation of the IL-17 network in mucosal tissues involves other non-Th-17 cells that likely contributes to the pro-inflammatory environment in the mucosa during acute stages of SIV infection. C1 [Mattapallil, J. J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Roederer, M.] Tulane Natl Reg Primate Ctr, Covington, LA USA. [Veazey, R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Mattapallil, JJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Room B4098, Bethesda, MD 20814 USA. EM jmattapallil@usuhs.mil FU NIAID NIH HHS [K22 AI071812-02, K22AI07812, K22 AI071812-01, K22 AI071812]; NIDCR NIH HHS [R21 DE018339-02, R21 DE018339, R21 DE018339-01, R21DE018339, R21 DE018339-02S1] NR 30 TC 17 Z9 17 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2009 VL 38 BP 24 EP 31 DI 10.1111/j.1600-0684.2009.00372.x PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 508BJ UT WOS:000270901500005 PM 19863675 ER PT J AU Kader, M Bixler, S Piatak, M Lifson, J Mattapallil, JJ AF Kader, M. Bixler, S. Piatak, M. Lifson, J. Mattapallil, J. J. TI Anti-retroviral therapy fails to restore the severe Th-17: Tc-17 imbalance observed in peripheral blood during simian immunodeficiency virus infection SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 26th Annual Symposium on Non-Human Primate Models for AIDS CY DEC 09-12, 2008 CL San Juan, PR SP Wisconsin Natl Primate Res Ctr, Caribbean Primate Res Ctr, Natl Inst Hlth, Natl Inst Allergies & Infect Dis, Off AIDS Res DE ART; CD4; FTC; Gut; HIV; immunodeficiency; intestine; mucosa; PMPA; simian; SIV ID T-CELL DEPLETION; PLASMA VIRAL LOAD; LYMPHOID-TISSUE; HIV-1 INFECTION; GASTROINTESTINAL-TRACT; SIV INFECTION; TH17 CELLS; GUT; MEMORY; AIDS AB Background Human immuno deficiency virus and simian immunodeficiency virus infections are characterized by a severe loss of Th-17 cells (IL-17+CD4+ T cells) that has been associated with disease progression and systemic dissemination of bacterial infections. Anti-retroviral therapy (ART) has led to repopulation of CD4+ T cells in peripheral tissues with little sustainable repopulation in mucosal tissues. Given the central importance of Th-17 cells in mucosal homeostasis, it is not known if the failure of ART to permanently repopulate mucosal tissues is associated with a failure to restore Th-17 cells that are lost during infection. Methods Dynamics of alpha 4+beta 7hi CD4+ T cells in peripheral blood of SIV infected rhesus macaques were evaluated and compared to animals that were treated with ART. The frequency of Th-17 and Tc-17 cells was determined following infection and after therapy. Relative expression of IL-21, IL-23, and TGF beta was determined using Taqman PCR. Results Treatment of SIV infected rhesus macaques with anti-retroviral therapy was associated with a substantial repopulation of mucosal homing alpha 4+beta 7hiCD4+ T cells in peripheral blood. This repopulation, however, was not accompanied by a restoration of Th-17 responses. Interestingly, SIV infection was associated with an increase in Tc-17 responses (IL-17+CD8+ T cells) suggesting to a skewing in the ratio of Th-17: Tc-17 cells from a predominantly Th-17 phenotype to a predominantly Tc-17 phenotype. Surprisingly, Tc-17 responses remained high during the course of therapy suggesting that ART failed to correct the imbalance in Th-17 : Tc-17 responses induced following SIV infection. Conclusions ART was associated with substantial repopulation of alpha 4+beta 7hi CD4+ T cells in peripheral blood with little or no rebound of Th-17 cells. On the other hand, repopulation of alpha 4+beta 7hi CD4+ T cells was accompanied by persistence of high levels of Tc-17 cells in peripheral blood. The dysregulation of Th-17 and Tc-17 responses likely plays a role in disease progression. C1 [Mattapallil, J. J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Piatak, M.; Lifson, J.] NCI, SAIC, Frederick, MD 21701 USA. RP Mattapallil, JJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Room B4098, Bethesda, MD 20814 USA. EM jmattapallil@usuhs.mil FU NIAID NIH HHS [K22AI07812, K22 AI071812-02, K22 AI071812, K22 AI071812-01]; NIDCR NIH HHS [R21DE018339, R21 DE018339, R21 DE018339-01, R21 DE018339-02, R21 DE018339-02S1] NR 31 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2009 VL 38 BP 32 EP 38 DI 10.1111/j.1600-0684.2009.00373.x PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 508BJ UT WOS:000270901500006 PM 19863676 ER PT J AU Vinogradova, TM Lakatta, EG AF Vinogradova, Tatiana M. Lakatta, Edward G. TI Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE Sinoatrial nodal cells; Local Ca2+ release; Ryanodine receptor; Ionic channels; Beta-adrenergic receptor stimulation; Phosphodiesterase ID RABBIT SINOATRIAL NODE; SUSTAINED INWARD CURRENT; PROTEIN-KINASE-A; RECTIFIER POTASSIUM CURRENT; BETA-ADRENERGIC STIMULATION; NA+-CA2+ EXCHANGE CURRENT; SPONTANEOUS BEATING RATE; ACTIVATED CURRENT IF; CAT RIGHT ATRIUM; SARCOPLASMIC-RETICULUM AB Decades of intensive research of primary cardiac pacemaker, the sinoatrial node, have established potential roles of specific membrane channels in the generation of the diastolic depolarization, the major mechanism allowing sinoatrial node cells to generate spontaneous beating. During the last three decades, multiple studies made either in the isolated sinoatrial node or sinoatrial node cells have demonstrated a pivotal role of Ca2+ and, specifically Ca2+ release from sarcoplasmic reticulum, for spontaneous beating of cardiac pacemaker. Recently, spontaneous, rhythmic local subsarcolemmal Ca2+ releases from ryanodine receptors during late half of the diastolic depolarization have been implicated as a vital factor in the generation of sinoatrial node cell spontaneous. ring. Local Ca2+ releases are driven by a unique combination of high basal cAMP production by adenylyl cyclases, high basal cAMP degradation by phosphodiesterases and a high level of cAMP-mediated PKA-dependent phosphorylation. These local Ca2+ releases activate an inward Na+-Ca2+ exchange current which accelerates the terminal diastolic depolarization rate and, thus, controls the spontaneous pacemaker. ring. Both the basal primary pacemaker beating rate and its modulation via beta-adrenergic receptor stimulation appear to be critically dependent upon intact RyR function and local subsarcolemmal sarcoplasmic reticulum generated Ca2+ releases. This review aspires to integrate the traditional viewpoint that has emphasized the supremacy of the ensemble of surface membrane ion channels in spontaneous. ring of the primary cardiac pacemaker, and these novel perspectives of cAMP-mediated PKA-dependent Ca2+ cycling in regulation of the heart pacemaker clock, both in the basal state and during beta-adrenergic receptor stimulation. (C) 2009 Published by Elsevier Inc. C1 [Vinogradova, Tatiana M.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health FX This work is supported, in part, by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 168 TC 33 Z9 34 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD OCT PY 2009 VL 47 IS 4 BP 456 EP 474 DI 10.1016/j.yjmcc.2009.06.014 PG 19 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 526AX UT WOS:000272261000006 PM 19573534 ER PT J AU Crawford, JR Santi, MR Cornelison, R Sallinen, SL Haapasalo, H MacDonald, TJ AF Crawford, John R. Santi, Maria Rita Cornelison, Robbie Sallinen, Satu-Leena Haapasalo, Hannu MacDonald, Tobey J. TI Detection of human herpesvirus-6 in adult central nervous system tumors: predominance of early and late viral antigens in glial tumors SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Human herpesvirus-6; Brain tumor; Tissue microarray; HHV-6 ID MULTIPLE-SCLEROSIS PATIENTS; STEM-CELL TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; HUMAN CYTOMEGALOVIRUS; BRAIN-TUMORS; INTEGRATED HUMAN-HERPESVIRUS-6; CLINICAL-FEATURES; GENOMIC SEQUENCES; HUMAN ASTROCYTES; 6 DNA AB The purpose is to determine the incidence of active and latent human herpesvirus-6 (HHV-6) infection in a large cohort of adult primary and recurrent CNS tumors. We screened a tissue microarray (TMA) containing more than 200 adult primary and recurrent CNS tumors with known clinical information for the presence of HHV-6 DNA by in situ hybridization (ISH) and protein by immunohistochemistry (IHC). One hundred six of 224 (47%) CNS tumors were positive for HHV-6 U57 Major Capsid Protein (MCP) gene by ISH compared to 0/25 non tumor control brain (P = 0.001). Fourteen of 30 (47%) tumors were HHV-6 MCP positive by nested PCR compared to 0/25 non-tumor brain controls (P = 0.001), revealing HHV-6 Variant A in 6 of 14 samples. HHV-6A/B early (p41) and late (gp116/64/54) antigens were detected by IHC in 66 of 277 (24%) (P = 0.003) and 84 of 282 (35%) (P = 0.002) tumors, respectively, suggesting active infection. HHV-6 p41 (P = 0.645) and gp116/64/54 (P = 0.198) antigen detection was independent of recurrent disease. Glial tumors were 3 times more positive by IHC compared to non glial tumors for both HHV-6 gp116/64/54 (P = 0.0002) and HHV-6 p41 (P = 0.004). Kaplan Meier survival analysis showed no effect of HHV-6 gp116/64/54 (P = 0.852) or HHV-6 p41 (P = 0.817) antigen detection on survival. HHV-6 early and late antigens are detected in adult primary and recurrent CNS tumors more frequently in glial tumors. We hypothesize that the glial-tropic features of HHV-6 may play an important modifying role in tumor biology that warrants further investigation. C1 [Crawford, John R.] Univ Calif San Diego, Dept Neurol, La Jolla, CA 92093 USA. [Haapasalo, Hannu] Tampere Univ Hosp, Dept Pathol, Tampere 33521, Finland. [Sallinen, Satu-Leena] Tampere Univ Hosp, Genet Outpatient Clin, Dept Pediat, Tampere 33521, Finland. [Cornelison, Robbie] NCI, Mol Genet Sect, Bethesda, MD 20892 USA. [Crawford, John R.] George Washington Univ, Dept Neurol, Washington, DC 20010 USA. [Santi, Maria Rita] George Washington Univ, Dept Pathol, Washington, DC 20010 USA. [MacDonald, Tobey J.] George Washington Univ, Dept Hematol Oncol, Washington, DC 20010 USA. [Crawford, John R.; Santi, Maria Rita; MacDonald, Tobey J.] George Washington Univ, Childrens Natl Med Ctr, Brain Tumor Inst, Washington, DC 20010 USA. RP Crawford, JR (reprint author), Univ Calif San Diego, Dept Neurol, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM jrcrawford@ucsd.edu RI MacDonald, Tobey/D-4554-2013 FU National Institutes of Health Neurological Sciences Academic Development Award (NSADA) [K12NS052159-01A] FX The authors would like to thank Dr. Juha Kononen for gifting the adult tissue microarray and Dr. Elisabeth Rushing (Armed Forces Institute of Pathology, Washington DC) for providing the adult non tumor control tissue. We thank Dr. Steven Jacobson (National Institute of Neurological Disorders and Stroke) for providing positive control HHV-6 encephalitis material and infected cell lysate. This work was supported by the National Institutes of Health Neurological Sciences Academic Development Award (NSADA) K12NS052159-01A. NR 50 TC 12 Z9 15 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD OCT PY 2009 VL 95 IS 1 BP 49 EP 60 DI 10.1007/s11060-009-9908-2 PG 12 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 495IO UT WOS:000269884600006 PM 19424665 ER PT J AU Sanchez-Ortiz, E Hahm, BK Armstrong, DL Rossie, S AF Sanchez-Ortiz, Efrain Hahm, Byoung Kwon Armstrong, David L. Rossie, Sandra TI Protein phosphatase 5 protects neurons against amyloid-beta toxicity SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; amyloid-beta; neuroprotection; oxidative stress; protein phosphatase 5 ID STAUROSPORINE-INDUCED APOPTOSIS; CULTURED CORTICAL-NEURONS; RAT HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; CELL-DEATH; TRANSGENIC MICE; A-BETA; NEURODEGENERATIVE DISEASES AB Amyloid-beta (A beta) is thought to promote neuronal cell loss in Alzheimer's disease, in part through the generation of reactive oxygen species (ROS) and subsequent activation of mitogen-activated protein kinase (MAPK) pathways. Protein phosphatase 5 (PP5) is a ubiquitously expressed serine/threonine phosphatase which has been implicated in several cell stress response pathways and shown to inactivate MAPK pathways through key dephosphorylation events. Therefore, we examined whether PP5 protects dissociated embryonic rat cortical neurons in vitro from cell death evoked by A beta. As predicted, neurons in which PP5 expression was decreased by small-interfering RNA treatment were more susceptible to A beta toxicity. In contrast, over-expression of PP5, but not the inactive mutant, PP5(H304Q), prevented MAPK phosphorylation and neurotoxicity induced by A beta. PP5 also prevented cell death caused by direct treatment with H(2)O(2), but did not prevent A beta-induced production of ROS. Thus, the neuroprotective effect of PP5 requires its phosphatase activity and lies downstream of A beta-induced generation of ROS. In summary, our data indicate that PP5 plays a pivotal neuroprotective role against cell death induced by A beta and oxidative stress. Consequently, PP5 might be an effective therapeutic target in Alzheimer's disease and other neurodegenerative disorders in which oxidative stress is implicated. C1 [Sanchez-Ortiz, Efrain; Hahm, Byoung Kwon; Rossie, Sandra] Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USA. [Sanchez-Ortiz, Efrain; Hahm, Byoung Kwon; Rossie, Sandra] Purdue Univ, Purdue Canc Ctr, W Lafayette, IN 47907 USA. [Armstrong, David L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Rossie, S (reprint author), Purdue Univ, Dept Biochem, 175 S Univ St, W Lafayette, IN 47907 USA. EM rossie@purdue.edu FU NIH [NS031221]; Indiana University-Indiana Alzheimer Disease Center (NIH) [P30 AG010133]; NIH Intramural Research Program [Z01-ES080043]; Roy J. Carver Foundation FX This study was supported by NIH grant NS031221 (SR), Indiana University-Indiana Alzheimer Disease Center (NIH) grant P30 AG010133 (SR), and the NIH Intramural Research Program at National Institute of Environmental Health Sciences through Grant Z01-ES080043 (DLA). PP5 adenovirus constructs were prepared at the Gene Transfer Vector Core at the University of Iowa, supported in part by the NIH and the Roy J. Carver Foundation. NR 69 TC 13 Z9 13 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2009 VL 111 IS 2 BP 391 EP 402 DI 10.1111/j.1471-4159.2009.06337.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 498OY UT WOS:000270152600010 PM 19686245 ER PT J AU Cao, DH Kevala, K Kim, J Moon, HS Jun, SB Lovinger, D Kim, HY AF Cao, Dehua Kevala, Karl Kim, Jeffrey Moon, Hyun-Seuk Jun, Sang Beom Lovinger, David Kim, Hee-Yong TI Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE docosahexaenoic acid; hippocampal development; long-term potentiation; neurite growth; synaptic function; synaptogenesis ID POLYUNSATURATED FATTY-ACIDS; RETINOID-X-RECEPTOR; LONG-TERM POTENTIATION; CA3 NMDA RECEPTORS; SYNAPSIN-I; NEURITE OUTGROWTH; NERVOUS-SYSTEM; AMPA RECEPTORS; RAT-BRAIN; LIGAND AB Docosahexaenoic acid (DHA, 22:6n-3), the major polyunsaturated fatty acid accumulated in the brain during development, has been implicated in learning and memory, but underlying cellular mechanisms are not clearly understood. Here, we demonstrate that DHA significantly affects hippocampal neuronal development and synaptic function in developing hippocampi. In embryonic neuronal cultures, DHA supplementation uniquely promoted neurite growth, synapsin puncta formation and synaptic protein expression, particularly synapsins and glutamate receptors. In DHA-supplemented neurons, spontaneous synaptic activity was significantly increased, mostly because of enhanced glutamatergic synaptic activity. Conversely, hippocampal neurons from DHA-depleted fetuses showed inhibited neurite growth and synaptogenesis. Furthermore, n-3 fatty acid deprivation during development resulted in marked decreases of synapsins and glutamate receptor subunits in the hippocampi of 18-day-old pups with concomitant impairment of long-term potentiation, a cellular mechanism underlying learning and memory. While levels of synapsins and NMDA receptor subunit NR2A were decreased in most hippocampal regions, NR2A expression was particularly reduced in CA3, suggesting possible role of DHA in CA3-NMDA receptor-dependent learning and memory processes. The DHA-induced neurite growth, synaptogenesis, synapsin, and glutamate receptor expression, and glutamatergic synaptic function may represent important cellular aspects supporting the hippocampus-related cognitive function improved by DHA. C1 [Cao, Dehua; Kevala, Karl; Kim, Jeffrey; Moon, Hyun-Seuk; Kim, Hee-Yong] NIAAA, Mol Signalling Lab, DICBR, NIH, Bethesda, MD 20892 USA. [Jun, Sang Beom; Lovinger, David] NIAAA, Lab Integrat Neurosci, DICBR, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Mol Signalling Lab, DICBR, NIH, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov RI Moon, Hyun-Seuk/G-8576-2015 OI Moon, Hyun-Seuk/0000-0002-5216-2090 FU NIAAA, NIH FX This research was supported by the Intramural Research Program of the NIAAA, NIH. NR 52 TC 120 Z9 124 U1 0 U2 15 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2009 VL 111 IS 2 BP 510 EP 521 DI 10.1111/j.1471-4159.2009.06335.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 498OY UT WOS:000270152600020 PM 19682204 ER PT J AU Zhuang, P Hallett, M Zhang, X Li, J Zhang, Y Li, Y AF Zhuang, P. Hallett, M. Zhang, X. Li, J. Zhang, Y. Li, Y. TI Neuronal activity in the globus pallidus internus in patients with tics SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID DEEP BRAIN-STIMULATION; BASAL GANGLIA; TOURETTES-SYNDROME; SUBTHALAMIC NUCLEUS; PARKINSONS-DISEASE; SQUIRREL-MONKEY; MOTOR CONTROL; MOVEMENT; DISORDERS; PALLIDOTOMY AB Objective: To explore the role of neuronal activity in the globus pallidus internus (GPi) in the generation of tic movements. Methods: 8 patients with Tourette's syndrome with medically intractable tics who underwent a unilateral pallidotomy for severe tics were studied. They ranged in age from 17 to 24 years; disease duration was 7 19 years. Microelectrode recording was performed in the GPi. The electromyogram (EMG) was simultaneously recorded in muscle groups appropriate for the patient's tics. The relationship between neuronal firing pattern and the EMG was studied. Results: 232 neurons were recorded during tics from eight trajectories. Of these neurons, in addition to decreased neuronal firing rate and irregular firing pattern, 105 (45%) were tic related showing either a burst of activity or a pause in ongoing tonic activity. They could be synchronous (n = 75), earlier than EMG onset (n = 27) or following EMG onset (n = 3). The GPi neuronal bursts preceded EMG onset with decreased (n = 6) or increased activity (n = 21). The initial change in neural activity occurred about 50 ms to 2 s before the EMG onset. Conclusions: Although the data are descriptive and preliminary, the tic related neuronal activity observed in GPi appears to indicate that the basal ganglia motor circuit is involved in tic movements. The early neuronal activity seen in GPi may reflect premonitory sensations that precede a tic. C1 [Zhuang, P.; Zhang, X.; Li, J.; Zhang, Y.; Li, Y.] Capital Med Univ, Xuanwu Hosp, Beijing Inst Funct Neurosurg, Key Lab Neurodegenerat Dis,Minist Educ, Beijing, Peoples R China. [Hallett, M.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD USA. RP Li, Y (reprint author), 45 Changchun St, Beijing 100053, Peoples R China. EM lyj8828@vip.sina.com FU NSFC [30370473, 30770746]; NSFB [7042027]; NIH FX This study was supported by grants NSFC (30370473, 30770746) and NSFB (7042027) and supported in part by the Intramural Program of the NIH. NR 37 TC 21 Z9 22 U1 0 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD OCT PY 2009 VL 80 IS 10 BP 1075 EP 1081 DI 10.1136/jnnp.2008.161869 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 496BI UT WOS:000269942600006 PM 19279028 ER PT J AU Davis, CD Milner, JA AF Davis, Cindy D. Milner, Jofm A. TI Gastrointestinal microflora, food components and colon cancer prevention SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Review DE Prebiotics; Probiotics; Microbiota; Colon cancer ID ABERRANT CRYPT FOCI; ESTROGEN-RECEPTOR-ALPHA; INTESTINAL TUMOR-FORMATION; GUT BACTERIAL METABOLISM; CONJUGATED LINOLEIC-ACID; URINARY EQUOL EXCRETION; RED WINE POLYPHENOLS; INULIN-TYPE FRUCTANS; IN-VITRO; BIFIDOBACTERIUM-LONGUM AB Evidence that the intestinal microbiota is intrinsically linked with overall health, including cancer risk, is emerging. Moreover, its composition is not fixed but can be influenced by several dietary components. Dietary modifiers, including the consumption of live bacteria (probiotics) and indigestible or limited digestible food constituents such as oligosaccharides (prebiotics) and polyphenols or both (synbiotics), are recognized modifiers of the numbers and types of microbes and have been reported to reduce colon cancer risk experimentally. Microorganisms also have the ability to generate bioactive compounds from food components. Examples include equol from isoflavones, enterodiol and enterolactone from lignans and urolithins from ellagic acid, which have also been demonstrated to retard experimentally induced cancers. The gastrointestinal microbiota. can also influence both sides of the energy balance equation, namely, as a factor influencing energy utilization from the diet and as a factor that influences host genes that regulate energy expenditure and storage. Because of the link between obesity and cancer incidence and mortality, this complex complexion deserves greater attention. Overall, a dynamic interrelationship exists between the intestinal microbiota and colon cancer risk, which can be modified by dietary components and eating behaviors. Published by Elsevier Inc. C1 [Davis, Cindy D.] NCI, Nutr Sci Res Grp, Canc Prevent Div, Rockville, MD 20892 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, Rockville, MD 20892 USA. EM davisci@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 106 TC 129 Z9 136 U1 10 U2 77 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD OCT PY 2009 VL 20 IS 10 BP 743 EP 752 DI 10.1016/j.jnutbio.2009.06.001 PG 10 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 502EY UT WOS:000270439400001 PM 19716282 ER PT J AU Ponnamperuma, RM King, KE Elsir, T Glick, AB Wahl, GM Nister, M Weinberg, WC AF Ponnamperuma, Roshini M. King, Kathryn E. Elsir, Tamador Glick, Adam B. Wahl, Geoffrey M. Nister, Monica Weinberg, Wendy C. TI The transcriptional regulatory function of p53 is essential for suppression of mouse skin carcinogenesis and can be dissociated from effects on TGF-beta-mediated growth regulation SO JOURNAL OF PATHOLOGY LA English DT Article DE p53; squamous cell carcinoma; epidermis; senescence; tumour suppression; TGF-beta; transactivation ID MUTANT P53; HOMOLOGOUS RECOMBINATION; MALIGNANT PROGRESSION; APOPTOTIC ACTIVITY; TUMOR-DEVELOPMENT; GENE DOSAGE; IN-VIVO; TRANSACTIVATION; DEFICIENT; KERATINOCYTES AB Transcriptional regulation by p53 is critical for p53-mediated tumour suppression; however, p53-mediated transactivation has been dissociated from p53-mediated biological processes including apoptosis, DNA repair, and differentiation. We compared the effects of a mutant allele, p53(QS-val135), containing a double mutation in the amino-terminus abrogating transactivation activity and a modification at amino acid 135 partially affecting DNA binding, to complete loss of p53. We applied in vitro endpoints correlated with epithelial tumourigenesis and an in vivo assay of tumour phenotype to assess whether loss of p53-mediated transcriptional regulation underlies the malignant phenotype of p53(-/-)/v-ras(Ha)-overexpressing keratinocytes. Transactivation deficiency of p53(QS-val135) was confirmed by reporter gene assays in fibroblasts and differentiating keratinocytes. Ras oncogene-induced senescence was lost in both p53(QS-val135/QS-val135) and p53(-/-) keratinocytes. Similarly, p53(QS-val135/QS-val135), like p53(-/-), cooperated with v-ras(Ha) to enhance malignant conversion. The tumours arising in p53(QS-val135/QS-val135) keratinocytes displayed strong nuclear p53 expression; thus, the p53(QS-val135) allele was maintained and the deficient transactivation function of the expressed p53QS mutant protein was supported by absence of p21(waf1) in these tumours. The p53(QS-val135) allele did not confer a dominant-negative phenotype, as p53(+/QS-val135) keratinocytes senesced normally in response to v-ras(Ha) expression and formed benign tumours. While p53(-/-) keratinocytes displayed diminished response to TGF-beta, p53(QS-val135/QS-val135) and p53(+/+) keratinocytes responded equivalently, indicating that the requirement for p53 in maximizing TGF-beta-mediated growth regulation is independent of its transactivation domain and that the ability of keratinocytes to respond to TGF-beta is insufficient to suppress the malignant phenotype in this model. Furthermore, TGF-beta enhances p53QS-induced activation of a dual p53-TGF-beta responsive reporter in a keratinocyte cell line. These findings support an essential role for p53-mediated transcriptional regulation in suppressing malignancies arising from ras-induced skin tumours, consistent with previous findings in spontaneous carcinogenesis in other organs, and highlight the potential importance of senescence for tumour suppression in vivo. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Weinberg, Wendy C.] US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Elsir, Tamador; Nister, Monica] Karolinska Inst, Stockholm, Sweden. [Glick, Adam B.] Penn State Univ, University Pk, PA 16802 USA. [Wahl, Geoffrey M.] Salk Inst Biol Studies, La Jolla, CA 92037 USA. RP Weinberg, WC (reprint author), US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 29 Lincoln Dr,NIH Bldg 29B,Room 3NN04, Bethesda, MD 20892 USA. EM wendy.weinberg@fda.hhs.gov FU FDA Intramural Funds [Z01 BO 04006-06 LIMB]; Swedish Cancer Foundation; Karolinska Institutet; Karolinska University Hospital; Cancer Society in Stockholm; Erik and Edith Fernstrom Foundation for Medical Research FX We wish to acknowledge Michelle Beeche for her assistance in establishing the p53QS-val135 colony, Dr Kinnimulki Vijayachandra for help with the in vitro senescence assay, Dr Anna Eriksson for advice regarding the immunohistochemical analyses, and Dr Stefano Piccolo for providing the Mix.2 plasmid. We are deeply indebted to Dr Ulrike Lichti for her advice and guidance in setting up the grafting model. This work was supported by FDA Intramural Funds for project Z01 BO 04006-06 LIMB (WCW, RMP, KEK), the Swedish Cancer Foundation (MN), Karolinska Institutet (MN, TE), Karolinska University Hospital (MN), the Cancer Society in Stockholm (MN), and the Erik and Edith Fernstrom Foundation for Medical Research (MN, TE). Tissue analysis was partly performed at the KI/Karolinska University Hospital-supported core facility for mouse tissue analysis. NR 42 TC 3 Z9 3 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD OCT PY 2009 VL 219 IS 2 BP 263 EP 274 DI 10.1002/path.2600 PG 12 WC Oncology; Pathology SC Oncology; Pathology GA 501YZ UT WOS:000270421900013 PM 19718706 ER PT J AU Goldenberg, AJ Hull, SC Botkin, JR Wilfond, BS AF Goldenberg, Aaron J. Hull, Sara Chandros Botkin, Jeffrey R. Wilfond, Benjamin S. TI Pediatric Biobanks: Approaching Informed Consent for Continuing Research After Children Grow Up SO JOURNAL OF PEDIATRICS LA English DT Article ID GENETIC RESEARCH; CHILDHOOD-CANCER; ETHICAL-ISSUES; TISSUE SAMPLES; POPULATION; ATTITUDES; DONATION; RESOURCE; STORAGE; COHORT AB Objective Proposals for pediatric biobanks have prompted questions of whether parental permission is sufficient to continue to use biological samples and data after the children become adults. The objective of this study was to examine adults' attitudes about continued research with their pediatric samples/data, particularly when they could not be located to provide consent. Study design Telephone interviews were conducted with 1186 patients from 5 academic medical centers by using a hypothetical scenario. Results Most respondents, 799 (67%), would not be concerned about the use of their sample/data after they reached adulthood. Those respondents who were concerned were more likely to be more private about their medical records, less trusting of medical researchers, or African-American. A total of 543 respondents (46%) believed their consent should be obtained to continue using their sample/data for research. Of these, 407 respondents (75%) would be at least moderately willing to give consent, when asked. Of the 1186 respondents, 310 (26%) would not want researchers to use their sample/data when they could not be located to ask for consent. Conclusion The data are consistent with the normative view that when feasible, adults should be asked for consent for continued research on their data collected during childhood, but it is generally acceptable to continue to conduct research when adults cannot be located. Further public engagement may help determine how best to balance the potential social value of continued research using pediatric samples/data and the expectations for explicit consent expressed by a minority of respondents that may reflect concerns about privacy and trust. (J Pediatr 2009;155:578-83). C1 [Goldenberg, Aaron J.] Case Western Reserve Univ, Dept Bioeth, Cleveland, OH 44106 USA. [Goldenberg, Aaron J.] Case Western Reserve Univ, Ctr Genet Res Eth & Law, Cleveland, OH 44106 USA. [Hull, Sara Chandros] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Hull, Sara Chandros] NIH, Off Clin Director, NHGRI, Bethesda, MD 20892 USA. [Botkin, Jeffrey R.] Univ Utah, Salt Lake City, UT USA. [Wilfond, Benjamin S.] Seattle Childrens Hosp, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Wilfond, Benjamin S.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. RP Wilfond, BS (reprint author), Metropolitan Pk W,M-S MPW 8-2,1100 Olive Way,Room, Seattle, WA 98101 USA. EM benjamin.wilfond@seattlechildrens.org FU National Human Genome Research Institute; National Institutes of Health [IH P50HG003390] FX The study was supported by National Human Genome Research Institute (S.H and B.W.). J.B. received support for the recruitment of subjects. A. G. was supported by the National Institutes of Health (IH P50HG003390, The Center for Genetic Research Ethics and Law). No statement in this article should be construed as an official position of the National Human Genome Research Institute, National Institutes of Health, or Department of Health and Human Services. The authors declare no conflicts of interest. NR 32 TC 37 Z9 37 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2009 VL 155 IS 4 BP 578 EP 583 DI 10.1016/j.jpeds.2009.04.034 PG 6 WC Pediatrics SC Pediatrics GA 502YT UT WOS:000270497800028 PM 19595370 ER PT J AU Ohashi, N Nomura, W Kato, M Narumi, T Lewin, NE Blumberg, PM Tamamura, H AF Ohashi, Nami Nomura, Wataru Kato, Mai Narumi, Tetsuo Lewin, Nancy E. Blumberg, Peter M. Tamamura, Hirokazu TI Synthesis of protein kinase C delta C1b domain by native chemical ligation methodology and characterization of its folding and ligand binding SO JOURNAL OF PEPTIDE SCIENCE LA English DT Article DE protein kinase C; native chemical ligation; C1b domain; ligand binding ID CONFORMATIONALLY CONSTRAINED ANALOGS; PHORBOL ESTER BINDING; DAG-LACTONES; PK-C; COMPLEX; DIACYLGLYCEROL; ACTIVATION; APOPTOSIS; PEPTIDE; SITE AB The C1b domain of protein kinase C delta (PKC delta), a potent receptor for ligands such as diacylglycerol and phorbol esters, was synthesized by utilizing native chemical ligation. With this synthetic strategy, the domain was efficiently constructed and shown to have high affinity ligand binding and correct folding. The C1b domain has been utilized for the development of novel ligands for the control of phosphorylation by PKC family members. This strategy will pave the way for the efficient construction of C1b domains modified with fluorescent dyes, biotin, etc. Copyright (C) 2009 European Peptide Society and John Wiley & Sons, Ltd. C1 [Ohashi, Nami; Nomura, Wataru; Kato, Mai; Narumi, Tetsuo; Tamamura, Hirokazu] Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Chiyoda Ku, Tokyo 1010062, Japan. [Lewin, Nancy E.; Blumberg, Peter M.] Natl Canc Inst, Lab Canc Biol & Genet, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nomura, W (reprint author), Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Chiyoda Ku, 2-3-10 Kandasurugadai, Tokyo 1010062, Japan. EM nomura.mr@tmd.ac.jp; tamamura.mr@tmd.ac.jp RI Nomura, Wataru/F-5812-2015 FU Ministry of Education, Culture, Sports, Science, and Technology, Japan; Ministry of Health, Labour, and Welfare; National Institutes of Health, Center for Cancer Research, National Cancer Institute FX This work was supported in part by a Grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and of the Ministry of Health, Labour, and Welfare. It was also supported in part by the Intramural Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. The authors thank Professor Kazunari Akiyoshi, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, for his assistance in the CD experiments. NR 22 TC 3 Z9 3 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1075-2617 J9 J PEPT SCI JI J. Pept. Sci. PD OCT PY 2009 VL 15 IS 10 BP 642 EP 646 DI 10.1002/psc.1161 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 498VO UT WOS:000270173500004 PM 19672879 ER PT J AU Lockenhoff, CE Ironson, GH O'Cleirigh, C Costa, PT AF Loeckenhoff, Corinna E. Ironson, Gail H. O'Cleirigh, Conall Costa, Paul T., Jr. TI Five-Factor Model Personality Traits, Spirituality/Religiousness, and Mental Health Among People Living With HIV SO JOURNAL OF PERSONALITY LA English DT Article ID QUALITY-OF-LIFE; PSYCHOLOGICAL ADJUSTMENT; RELIGION; SPIRITUALITY; METAANALYSIS; WOMEN; STRATEGIES; MEDIATION; ATTITUDES; DISTRESS AB We examined the association between five-factor personality domains and facets and spirituality/religiousness as well as their joint association with mental health in a diverse sample of people living with HIV (n=112, age range 18-66). Spirituality/religiousness showed stronger associations with Conscientiousness, Openness, and Agreeableness than with Neuroticism and Extraversion. Both personality traits and spirituality/religiousness were significantly linked to mental health, even after controlling for individual differences in demographic measures and disease status. Personality traits explained unique variance in mental health above spirituality and religiousness. Further, aspects of spirituality and religiousness were found to mediate some of the links between personality and mental health in this patient sample. These findings suggest that underlying personality traits contribute to the beneficial effects of spirituality/religiousness among vulnerable populations. C1 [Loeckenhoff, Corinna E.; Costa, Paul T., Jr.] NIA, Bethesda, MD 20892 USA. [Ironson, Gail H.] Univ Miami, Coral Gables, FL 33124 USA. [O'Cleirigh, Conall] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Fenway Inst, Cambridge, MA 02138 USA. RP Lockenhoff, CE (reprint author), Cornell Univ, Dept Human Dev, MVR G27-35, Ithaca, NY 14853 USA. EM CEL72@cornell.edu OI Costa, Paul/0000-0003-4375-1712; Loeckenhoff, Corinna/0000-0003-1605-1323 FU Intramural NIH HHS [NIH0011894836, Z01 AG000184-19]; NIMH NIH HHS [R01 MH066697, R01MH066697, R01MH53791] NR 62 TC 16 Z9 17 U1 0 U2 12 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3506 J9 J PERS JI J. Pers. PD OCT PY 2009 VL 77 IS 5 BP 1411 EP 1436 DI 10.1111/j.1467-6494.2009.00587.x PG 26 WC Psychology, Social SC Psychology GA 490LS UT WOS:000269503000007 PM 19686457 ER PT J AU Ahmet, I Morrell, C Lakatta, EG Talan, MI AF Ahmet, Ismail Morrell, Chris Lakatta, Edward G. Talan, Mark I. TI Therapeutic Efficacy of a Combination of a beta 1-Adrenoreceptor (AR) Blocker and beta 2-AR Agonist in a Rat Model of Postmyocardial Infarction Dilated Heart Failure Exceeds That of a beta 1-AR Blocker plus Angiotensin-Converting Enzyme Inhibitor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; LEFT-VENTRICULAR DYSFUNCTION; ISCHEMIC CARDIOMYOPATHY; CLINICAL-IMPLICATIONS; CARDIAC MYOCYTES; ACE-INHIBITORS; SURVIVAL; MORTALITY; TRIAL; ENALAPRIL AB We had proposed previously a novel combination of beta 2-adrenoreceptor (AR) agonist and beta 1-AR blocker that in the rat model of postmyocardial infarction (MI) dilated cardiomyopathy exceeds the therapeutic effectiveness of either monotherapy. In the present study, we compared that treatment with a combination of beta 1-AR blocker and angiotensin-converting enzyme inhibitor (ACEi), a current standard chronic heart failure (CHF) therapy. Two weeks after coronary artery ligation, rats were divided into groups of similar average MI size, measured by echocardiography, and the following 12-month treatments were initiated: fenoterol (250 mu g/kg/day), a beta 2-AR agonist, plus metoprolol (100 mg/kg/day), a beta 1-AR blocker (beta 1-beta 2+); metoprolol plus enalapril (20 mg/kg/day), an ACEi (beta 1-ACEi); and a combination of all three drugs (beta 1-beta 2+ACEi). These treatment groups were compared with each other and with nontreated (nT) and sham groups. The 12-month mortality was significantly reduced in all treatment groups (44% in beta 1-beta 2+, 56% in beta 1-beta 2+ACEi, 59% in beta 1-ACEi versus 81% in nT). Bimonthly echocardiography revealed significant attenuation of the left ventricular (LV) chamber remodeling, LV functional deterioration, and MI expansion in all three treatment groups, but effects were significantly more pronounced when treatment included a beta 2-AR agonist. The results indicated that a combination of beta 1-AR blocker and beta 2-AR agonist is equipotent to a combination of beta 1-AR blocker and ACEi in the treatment of CHF in rats, with the respect to mortality, and exceeds the latter with respect to cardiac remodeling and MI expansion. Thus, this novel therapeutic regimen for CHF warrants detailed clinical investigation. C1 [Talan, Mark I.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Talan, MI (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM talanm@grc.nia.nih.gov FU National Institutes of Health National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute on Aging. NR 40 TC 22 Z9 23 U1 1 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2009 VL 331 IS 1 BP 178 EP 185 DI 10.1124/jpet.109.157107 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 497SE UT WOS:000270081500019 PM 19587314 ER PT J AU Gonzalez, N Nakagawa, T Mantey, SA Sancho, V Uehara, H Katsuno, T Jensen, RT AF Gonzalez, Nieves Nakagawa, Tomoo Mantey, Samuel A. Sancho, Veronica Uehara, Hirotsugu Katsuno, Tatsuro Jensen, Robert T. TI Molecular Basis for the Selectivity of the Mammalian Bombesin Peptide, Neuromedin B, for Its Receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GASTRIN-RELEASING-PEPTIDE; 2ND EXTRACELLULAR LOOP; HIGH-AFFINITY BINDING; AGONIST-BINDING; AMINO-ACIDS; SPECIES SELECTIVITY; ANTAGONIST-BINDING; SUBTYPES; CHOLECYSTOKININ; IDENTIFICATION AB The mammalian bombesin (Bn) peptides, neuromedin B (NMB) and gastrin-releasing peptide (GRP), have widespread actions in many tissues, and their effects are mediated by two closely related G-protein-coupled receptors, the NMBR and GRPR. Little is known about the structural determinants of NMBR selectivity for NMB, in contrast to GRP selectivity for the GRPR, which has been extensively studied. To provide insight, chimeric NMBR-GRPR loss-of-affinity and gain-of-affinity mutants were made, as well as NH(2)-terminally truncated NMBR and point mutants using site-directed mutagenesis. Receptors were expressed in Balb-3T3-cells or CHOP cells, and affinities were determined. NMB had 115-fold greater affinity for NMBR than GRPR. Receptor-chimeric studies showed that NMBR selectivity for NMB was primarily determined by differences in the third extracellular (EC3) regions of GRPR-NMBR and adjacent upper-transmembrane-5 (TM5) region. In this region, 24 NMB gain-of-affinity GRPR mutants or NMBR loss-of-affinity point/combination mutants were made. Three gain-of-affinity mutant GRPRs [[A198I] (EC3), [H202Q] (EC3), [S215I] (upper TM5)] had increased NMB affinity (2.4-21-fold), and these results were confirmed with NMBR loss-of-affinity mutants [I199A, Q203H, I215S-NMBR]. The combination mutant [A198I, S215]GRPR had the greatest effect causing a complete NMB gain-of-affinity. The importance of differences at position 199NMBR or 203NMBR was studied by substituting amino acids with various properties. Our results show that NMBR selectivity for NMB is due to differences in the EC3 of NMBR-GRPR and the adjacent upper-TM5 region. Within these regions, isoleucines in NMBR [position 199 ( EC3)] (instead of A198GRPR) and in 215NMBR (TM5) ( instead of S214GRPR), as well as Q203NMBR (instead of H202GRPR) are responsible for high NMB-affinity/selectivity of NMBR. The effect at position 199 is primarily due to differences in hydrophobicity of the substitution, whereas steric factors and charge of the substitution at position 203 were important determinants of NMB selectivity. C1 [Gonzalez, Nieves; Nakagawa, Tomoo; Mantey, Samuel A.; Sancho, Veronica; Uehara, Hirotsugu; Katsuno, Tatsuro; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Nakagawa, Tomoo; Uehara, Hirotsugu; Katsuno, Tatsuro] Chiba Univ, Grad Sch Med, Dept Clin Cell Biol, Div Gastroenterol, Chiba, Japan. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov RI Gonzalez, Nieves/N-2199-2014 OI Gonzalez, Nieves/0000-0002-1551-2872 FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. NR 44 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2009 VL 331 IS 1 BP 265 EP 276 DI 10.1124/jpet.109.154245 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 497SE UT WOS:000270081500028 PM 19628633 ER PT J AU Gorman, GS Coward, L Kerstner-Wood, C Freeman, L Hebert, CD Kapetanovic, IM AF Gorman, Gregory S. Coward, Lori Kerstner-Wood, Corenna Freeman, Lea Hebert, Charles D. Kapetanovic, Izet M. TI In-vitro and in-vivo metabolic studies of the candidate chemopreventative pentamethylchromanol using liquid chromatography/tandem mass spectrometry SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE CYP450; drug metabolism; liquid chromatography/tandem mass spectrometry; pentamethylchromanol ID HUMAN LIVER; VITAMIN-E; UDP-GLUCURONOSYLTRANSFERASES; GLUCURONIDATION; EXPRESSION; HORMONE; DRUGS AB Objectives This study focuses on the in-vitro metabolic profiles of pentamethylchromanol in human, rat, dog and non-human primates, and characterizes the associated metabolic kinetics and specific human isozymes responsible for metabolism. Additional investigations compare in-vitro data with in-vivo metabolic data from rats and dogs. Methods In-vitro metabolites were generated from commercially available microsomes, S9 fractions and cytochrome P450 isozymes. Reaction mixtures were analysed using liquid chromatography/tandem mass spectrometry for metabolite identification, stability, phenotyping and kinetic profiles. Plasma samples were collected from 28-day toxicology studies in rats and dogs, and analysed using the same methodology as for the identification of in-vitro metabolites. Key findings Samples from in-vitro experiments produced a total of eight identified metabolites while five were observed in the in-vivo samples. Kinetic analysis of metabolites in human microsomes generated Michaelis constants (K(M)) ranging from 10.9 to 104.9 mu m. Pentamethylchromanol metabolic stability varied by species and multiple isozymes were identified for the observed biotransformation pathways. Pentamethylchromanol is susceptible to multiple metabolic pathways and differential metabolic stability, which is species dependent. Conclusions In-vitro metabolism was not a strong predictor of in-vivo metabolism for the samples assays but showed glucuronidation and sulfation as common biotransformation pathways. C1 [Gorman, Gregory S.; Coward, Lori; Kerstner-Wood, Corenna; Freeman, Lea; Hebert, Charles D.] So Res Inst, Toxicol & Bioanalyt Sci Dept, Birmingham, AL 35205 USA. [Kapetanovic, Izet M.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Gorman, GS (reprint author), So Res Inst, Toxicol & Bioanalyt Sci Dept, 2000 9th Ave S, Birmingham, AL 35205 USA. EM gorman@southernresearch.org FU National Cancer Institute [N01-CN-43307] FX This work was funded by the National Cancer Institute under contract N01-CN-43307. NR 20 TC 2 Z9 2 U1 0 U2 1 PU PHARMACEUTICAL PRESS-ROYAL PHARMACEUTICAL SOC GREAT BRITIAN PI LONDON PA 1 LAMBETH HIGH ST, LONDON SE1 7JN, ENGLAND SN 0022-3573 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD OCT PY 2009 VL 61 IS 10 BP 1309 EP 1318 DI 10.1211/jpp/61.10.0006 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 507RX UT WOS:000270873400006 PM 19814862 ER PT J AU Fishelovitch, D Shaik, S Wolfson, HJ Nussinov, R AF Fishelovitch, Dan Shaik, Sason Wolfson, Haim J. Nussinov, Ruth TI Theoretical Characterization of Substrate Access/Exit Channels in the Human Cytochrome P450 3A4 Enzyme: Involvement of Phenylalanine Residues in the Gating Mechanism SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID STEERED MOLECULAR-DYNAMICS; BURIED ACTIVE-SITE; POSSIBLE PATHWAY(S); MEMBRANE-BINDING; PRODUCTS EXIT; FORCE-FIELD; P450CAM; RESOLUTION; PROTEINS; HYDROXYLATION AB The human cytochrome P450 3A4 mono-oxygenates similar to 50% of all drugs. Its substrates/products enter/leave the active site by access/exit channels. Here, we perform steered molecular dynamics simulations, pulling the products temazepam and testosterone-6 beta OH out of the P450 3A4 enzyme in order to identify the preferred substrate/product pathways and their gating mechanism. We locate six different egress pathways of products from the active site with different exit preferences for the two products and find that there is more than just one access/exit channel in CYP3A4. The so-called solvent channel manifests the largest opening for both tested products, thereby identifying this channel as a putative substrate channel. Most channels consist of one or two pi-stacked pherylalanine residues that serve as gate keepers. The oxidized drug breaks the hydrophobic interactions of the gating residues and forms mainly hydrophobic contacts with the gate. We argue that product exit preferences in P450s are regulated by protein-substrate specificity. C1 [Nussinov, Ruth] NCI, CCRNB, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Fishelovitch, Dan; Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Lise Meitner Minerva Ctr Computat Quantum Chem, IL-91904 Jerusalem, Israel. [Wolfson, Haim J.] Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, CCRNB, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Bldg 469,Rm 149, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov FU National Cancer Institute; National Institutes of Health [N01-CO-12400]; ISF [53/09] 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 No. N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Dept. 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 National Institutes of Health, National Cancer Institute, Center for Cancer Research. The research of S.S. at the H.U. was supported by all ISF grant 53/09. This study utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http:// biowulf.nih.gov). NR 57 TC 59 Z9 60 U1 2 U2 11 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 OCT 1 PY 2009 VL 113 IS 39 BP 13018 EP 13025 DI 10.1021/jp810386z PG 8 WC Chemistry, Physical SC Chemistry GA 496ST UT WOS:000269999400024 PM 19728720 ER PT J AU Boja, ES Phillips, D French, SA Harris, RA Balaban, RS AF Boja, Emily S. Phillips, Darci French, Stephanie A. Harris, Robert A. Balaban, Robert S. TI Quantitative Mitochondrial Phosphoproteomics Using iTRAQ on an LTQ-Orbitrap with High Energy Collision Dissociation SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Quantitative Phosphoproteomics; iTRAQ; HCD; LTO-Orbitrap; Mitochondria ID PYRUVATE-DEHYDROGENASE; PROTEIN-PHOSPHORYLATION; MASS-SPECTROMETRY; BOVINE KIDNEY; RAT-HEART; CALCIUM; KINASE; COMPLEX; SITES; BRAIN AB With the use of iTRAQ labeling and mass spectrometry on an LTQ-Orbitrap with HCD capability, we assessed relative changes in protein phosphorylation in the mitochondria upon physiological perturbation. As a reference reaction, we monitored the well-characterized regulation of pyruvate dehydrogenase (PDH) activity via phosphorylation/dephosphorylation by pyruvate dehydrogenase kinase/pyruvate dehydrogenase phosphatase in response to dichloroacetate, de-energization and Ca(2+). Relative quantification of phosphopeptides of PDH-E1 alpha subunit from porcine heart revealed dephosphorylation at three serine sites (Ser231, Ser292 and Ser299). Dephosphorylation at Ser292 (i.e., the inhibitory site) with DCA correlated with an activation of PDH activity as previously reported, consistent with our deenergization data. Calcium also dephosphorylated (i.e., activated) PDH, thus, confirming calcium activation of PDP. With this approach, we successfully monitored other phosphorylation sites of mitochondrial proteins including adenine nucleotide translocase, malate dehydrogenase and mitochondrial creatine kinase. Among them, four proteins exhibited phosphorylation changes with these physiological stimuli: (1) BCKDH-E1 alpha subunit increased phosphorylation at Ser337 with DCA and deenergization; (2) apoptosis-inducing factor phosphorylation was elevated at Ser345 with calcium; (3) ATP synthase F1 complex alpha subunit and (4) mitofilin dephosphorylated at Ser65 and Ser264 upon deenergization. This screening validated the iTRAQ/HCD technology as a method for functional quantitation of mitochondrial protein phosphorylation as well as providing insight into the regulation of mitochondria via phosphorylation. C1 [Phillips, Darci; French, Stephanie A.; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Boja, Emily S.] NHLBI, Prote Core Facil, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Harris, Robert A.] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, 10 Ctr Dr,Room B1D416, Bethesda, MD 20892 USA. EM rsb@nih.gov FU Intramural Funding of the Division of Intramural Research; NHLBI; NIH; DHHS FX This work was supported by the Intramural Funding of the Division of Intramural Research, NHLBI, NIH, DHHS. Supporting NR 40 TC 64 Z9 67 U1 2 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD OCT PY 2009 VL 8 IS 10 BP 4665 EP 4675 DI 10.1021/pr900387b PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 501BM UT WOS:000270353900024 PM 19694452 ER PT J AU Bingham, CO Pohl, C Woodworth, TG Hewlett, SE May, JE Rahman, MU Witter, JP Furst, DE Strand, CV Boers, M Alten, RE AF Bingham, Clifton O., III Pohl, Christoph Woodworth, Tasia G. Hewlett, Sarah E. May, James E. Rahman, Mahboob U. Witter, James P. Furst, Daniel E. Strand, C. Vibeke Boers, Maarten Alten, Rieke E. TI Developing a Standardized Definition for Disease "Flare" in Rheumatoid Arthritis (OMERACT 9 Special Interest Group) SO JOURNAL OF RHEUMATOLOGY LA English DT Article; Proceedings Paper CT 9th International Consensus Conference on Outcome Measures in Rheumatology Clinical Trails (OMERACT 9) CY MAY 27-31, 2008 CL Kananaskis, CANADA DE RHEUMATOID ARTHRITIS; FLARE; WORSENING; DISEASE ACTIVITY; PATIENT PERSPECTIVE; OUTCOME MEASURES ID PATIENT PERSPECTIVE; CLINICAL-TRIALS; DOSE TITRATION; DOUBLE-BLIND; INFLIXIMAB; METHOTREXATE; THERAPY; ETANERCEPT; WITHDRAWAL; OUTCOMES AB Objective. Traditional outcome measures in randomized controlled trials (RCT) include well-established response criteria its well as ACR EULAR responses using Disease Activity Score 44 (DAS44)/DAS28 to assess improvement; however, a measure to assess worsening of disease has yet to be developed. This special interest group (SIG) was established to develop an evidence-based, consensus-driven standard definition of "flare" in rheumatoid arthritis (RA). Methods. At OMERACT 8, the need fora standardized definition of RA flare was recognized; interested individuals developed a proposal to form a SIG. A literature review was performed to identify publications and abstracts with flare definitions applied in RA, JIA, and lupus RCT as well as concerning patient perspectives on disease worsening. A SIG was held at OMERACT 9 with breakout sessions for patients and investigators. Results. The RA flare SIG was attended by about 120 participants, including 11 patients. Patients and investigators held separate breakout sessions to discuss various aspects of disease worsening. The following consensus was obtained at OMERACT 9: it working definition of flare should indicate worsening of disease activity (88%), persistence, and duration its critical elements (77%), and consideration of change or increase in therapy (74%). Conclusion. A working definition of RA flare was developed based on these votes: flare is any worsening of disease activity that would, if persistent, in most cases lead to initiation or change of therapy; and a flare represents it cluster of symptoms of sufficient duration and intensity to require initiation, change, or increase in therapy. Using this working definition, evaluation of candidate domains will be conducted via Delphi exercise and further informed by patient focus groups. Validation of candidate definitions in appropriate RCT will be required. (First Release August 15 2009; J Rheumatol 2009:36:2335-41; doi: 10.3899/jrheum.090369) C1 Charite, Schlosspk Klin, D-13353 Berlin, Germany. Roche Prod Ltd, Welwyn Garden City AL7 3AY, Herts, England. Univ Calif Los Angeles, Los Angeles, CA USA. Univ W England, Bristol BS16 1QY, Avon, England. Univ Penn, Philadelphia, PA 19104 USA. Centocor Inc, Philadelphia, PA USA. NIAMS, NIH, Bethesda, MD USA. Stanford Univ, Portola Valley, CA USA. Vrije Univ Amsterdam, Amsterdam, Netherlands. RP Bingham, CO (reprint author), Johns Hopkins Univ, Div Rheumatol, 5200 Eastern Ave,Mason Lord Ctr Tower,Room 404, Baltimore, MD 21224 USA. EM Clifton.bingham@jhmi.edu NR 38 TC 47 Z9 47 U1 0 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD OCT PY 2009 VL 36 IS 10 BP 2335 EP 2341 DI 10.3899/jrheum.090369 PG 7 WC Rheumatology SC Rheumatology GA 505KB UT WOS:000270691200034 PM 19684147 ER PT J AU Shumway, S Wetherby, AM AF Shumway, Stacy Wetherby, Amy M. TI Communicative Acts of Children With Autism Spectrum Disorders in the Second Year of Life SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE autism; ASD; social communication; joint attention; early identification ID PERVASIVE DEVELOPMENTAL DISORDERS; JOINT ATTENTION; EARLY RECOGNITION; HOME VIDEOTAPES; YOUNG-CHILDREN; FOLLOW-UP; INFANTS; AGE; INSTRUMENT; STABILITY AB Purpose: To examine the communicative profiles of children with autism spectrum disorders (ASD) in the second year of life. Method: Communicative acts were examined in 125 children 18 to 24 months of age: 50 later diagnosed with ASD; 25 with developmental delays (DD); and 50 with typical development (TD). Precise measures of rate, functions, and means of communication were obtained through systematic observation of videotaped behavior samples from the Communication and Symbolic Behavior Scales Developmental Profile (A. Wetherby & B. Prizant, 2002). Results: Children with ASD communicated at a significantly lower rate than children with DD and TD. The ASD group used a significantly lower proportion of acts for joint attention and a significantly lower proportion of deictic gestures with a reliance on more primitive gestures compared with the DD and TD groups. Children with ASD who did communicate for joint attention were as likely as other children to coordinate vocalizations, eye gaze, and gestures. Rate of communicative acts and joint attention were the strongest predictors of verbal outcome at age 3. Conclusion: By 18 to 24 months of age, children later diagnosed with ASD showed a unique profile of communication, with core deficits in communication rate, joint attention, and communicative gestures. C1 [Shumway, Stacy] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Wetherby, Amy M.] Florida State Univ, Tallahassee, FL 32306 USA. RP Shumway, S (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr,MSC 1255,Bldg 10,Room 4N208, Bethesda, MD 20892 USA. EM shumways@mail.nih.gov OI Manwaring, Stacy/0000-0002-0835-9398 FU NIDCD NIH HHS [R01 DC007462-03, R01 DC007462, 1R01 DC007462] NR 56 TC 42 Z9 45 U1 2 U2 25 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 EI 1558-9102 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD OCT 1 PY 2009 VL 52 IS 5 BP 1139 EP 1156 DI 10.1044/1092-4388(2009/07-0280) PG 18 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 498KX UT WOS:000270140100003 PM 19635941 ER PT J AU Shriberg, LD Lohmeier, HL Campbell, TF Dollaghan, CA Green, JR Moore, CA AF Shriberg, Lawrence D. Lohmeier, Heather L. Campbell, Thomas F. Dollaghan, Christine A. Green, Jordan R. Moore, Christopher A. TI A Nonword Repetition Task for Speakers With Misarticulations: The Syllable Repetition Task (SRT) SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Review DE assessment; genetics; memory; speech disorders; endophenotype ID NON-WORD REPETITION; DEVELOPMENTAL PHONOLOGICAL DISORDERS; SPEECH-SOUND DISORDER; LANGUAGE IMPAIRMENT; WORKING-MEMORY; 4-YEAR-OLD CHILDREN; PHONOTACTIC PROBABILITY; KINDERGARTEN-CHILDREN; RECEPTIVE VOCABULARY; PRESCHOOL-CHILDREN AB Purpose: Conceptual and methodological confounds occur when non(sense) word repetition tasks are administered to speakers who do not have the target speech sounds in their phonetic inventories or who habitually misarticulate targeted speech sounds. In this article, the authors (a) describe a nonword repetition task, the Syllable Repetiton Task (SRT), that eliminates this confound and (b) report findings from 3 validity studies. Method: Ninety-five preschool children with speech delay and 63 with typical speech completed an assessment battery that included the Nonword Repetition Task (NRT; C. Dollaghan & T. F. Campbell, 1998) and the SRT. SRT stimuli include only 4 of the earliest occurring consonants and 1 early occurring vowel. Results: Study 1 findings indicated that the SRT eliminated the speech confound in nonword testing with speakers who misarticulate. Study 2 findings indicated that the accuracy of the SRT to identify expressive language impairment was comparable to findings for the NRT. Study 3 findings illustrated the SRT's potential to interrogate speech processing constraints underlying poor nonword repetition accuracy. Results supported both memorial and auditory-perceptual encoding constraints underlying nonword repetition errors in children with speech-language impairment. Conclusion: The SRT appears to be a psychometrically stable and substantively informative nonword repetition task for emerging genetic research and other research with speakers who misarticulate. C1 [Shriberg, Lawrence D.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Campbell, Thomas F.; Dollaghan, Christine A.] Univ Texas Dallas, Dallas, TX 75230 USA. [Green, Jordan R.] Univ Nebraska, Lincoln, NE 68583 USA. [Moore, Christopher A.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RP Shriberg, LD (reprint author), Univ Wisconsin, Waisman Ctr, Room 439,1500 Highland Ave, Madison, WI 53705 USA. EM shriberg@waisman.wisc.edu RI Green, Jordan/A-7159-2008 OI Green, Jordan/0000-0002-1464-1373 FU NCRR NIH HHS [M01 RR000084, M01 RR00084]; NICHD NIH HHS [HD03352, P30 HD003352]; NIDCD NIH HHS [R01 DC000822-13, DC00496, DC00822, R01 DC000496, R01 DC000496-07, R01 DC000496-21, R01 DC000822] NR 114 TC 34 Z9 34 U1 4 U2 13 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD OCT 1 PY 2009 VL 52 IS 5 BP 1189 EP 1212 DI 10.1044/1092-4388(2009/08-0047) PG 24 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 498KX UT WOS:000270140100006 PM 19635944 ER PT J AU Lahiri, P Li, Y AF Lahiri, P. Li, Yan TI A new alternative to the standard F test for clustered data SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Clustered data; Intra-cluster correlation; Standard F test; Generalized least square test; Fuller-Battese transformation ID VARIANCE AB The data collection process and the inherent population structure are the main causes for clustered data. The observations in a given duster are correlated, and the magnitude of such correlation is often measured by the intra-cluster correlation coefficient. The intra-cluster correlation can lead to an inflated size of the standard F test in a linear model. In this paper. we propose a solution to this problem. Unlike previous adjustments, our method does not require estimation of the intra-class correlation, which is problematic especially when the number of clusters is small. Our simulation results show that the new method outperforms the existing methods. (C) 2009 Elsevier B.V. All rights reserved. C1 [Lahiri, P.] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Li, Yan] NCI, Biostat Branch, Rockville, MD 20852 USA. [Li, Yan] Univ Texas Arlington, Dept Math, Arlington, TX 76019 USA. RP Lahiri, P (reprint author), Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. EM plahiri@survey.umd.edu; lisherry@mail.nih.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD OCT 1 PY 2009 VL 139 IS 10 BP 3430 EP 3441 DI 10.1016/j.jspi.2009.03.019 PG 12 WC Statistics & Probability SC Mathematics GA 480AL UT WOS:000268703700004 ER PT J AU Tian, L Vexler, A Yan, L Schisterman, EF AF Tian, Lili Vexler, Albert Yan, Li Schisterman, Enrique F. TI Confidence interval estimation of the difference between paired AUCs based on combined biomarkers SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Receiver operating characteristic (ROC) curve; Optimal linear combinations; Generalized pivot; Generalized test variable ID GENERALIZED VARIABLE METHOD; ROC CURVES; LINEAR-COMBINATIONS; DIAGNOSTIC MARKERS; NORMAL-POPULATIONS; AREAS; INFERENCES; TESTS; DISTRIBUTIONS; VALUES AB In many diagnostic studies, multiple diagnostic tests are performed on each subject or multiple disease markers are available. Commonly, the information should be combined to improve the diagnostic accuracy. We consider the problem of comparing the discriminatory abilities between two groups of biomarkers. Specifically, this article focuses on confidence interval estimation of the difference between paired AUCs based on optimally combined markers under the assumption of multivariate normality. Simulation studies demonstrate that the proposed generalized variable approach provides confidence intervals with satisfying coverage probabilities at finite sample sizes. The proposed method can also easily provide P-values for hypothesis testing. Application to analysis of a subset of data from a study on coronary heart disease illustrates the utility of the method in practice. (C) 2009 Elsevier B.V. All rights reserved. C1 [Tian, Lili; Vexler, Albert; Yan, Li] SUNY Buffalo, Dept Biostat, Buffalo, NY 14214 USA. [Schisterman, Enrique F.] NICHD, Div Epidemiol Stat & Prevent, NIH, Bethesda, MD USA. RP Tian, L (reprint author), SUNY Buffalo, Dept Biostat, 249 Farber Hall,3435 Main St,Bldg 26, Buffalo, NY 14214 USA. EM ltian@buffalo.edu OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [Z01 HD008761-05] NR 28 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 EI 1873-1171 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD OCT 1 PY 2009 VL 139 IS 10 BP 3725 EP 3732 DI 10.1016/j.jspi.2009.05.001 PG 8 WC Statistics & Probability SC Mathematics GA 480AL UT WOS:000268703700032 PM 19946609 ER PT J AU Rodriguez, D Cheung, MC Housri, N Quinones-Hinojosa, A Camphausen, K Koniaris, LG AF Rodriguez, Dayron Cheung, Michael C. Housri, Nadine Quinones-Hinojosa, Alfredo Camphausen, Kevin Koniaris, Leonidas G. TI Outcomes of Malignant CNS Ependymomas: An Examination of 2408 Cases Through the Surveillance, Epidemiology, and End Results (SEER) Database (1973-2005) SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT 70th Annual Meeting of the Society-of-University-Surgeons/4th Annual Academic Surgical Congress CY FEB 03-06, 2009 CL Ft Myers, FL SP Soc Univ Surg, Assoc Acad Surg DE malignancy; cancer; survival; surgery; ependymoma; radiation; outcomes; SEER ID GASTROINTESTINAL STROMAL TUMORS; CHILDRENS CANCER GROUP; INTRACRANIAL EPENDYMOMAS; SPINAL-CORD; PROGNOSTIC-FACTORS; POSTERIOR-FOSSA; BRAIN-TUMORS; POSTOPERATIVE CHEMOTHERAPY; INFRATENTORIAL EPENDYMOMAS; CRANIOSPINAL IRRADIATION AB Background. Determine the role of surgery and radiation therapy for patients with malignant CNS ependymomas. Methods. The Surveillance, Epidemiology, and End Results (SEER) database (1973-2005) was queried. Results. Overall, a total of 2408 cases of malignant ependymomas were identified. Of these, 2132 cases (88.5%) were identified as WHO grade II ependymomas and 276 cases (11.5%) as WHO grade III (anaplastic) ependymomas. The annual incidence of ependymomas was approximately 1.97 cases per million in 2005. Overall median survival for all patients was 230 mo, with a significant difference between women and men (262 mo versus196 mo, respectively) (P = 0.004). Median age at diagnosis was 37 y among females and 34 y in males. Patients who successfully underwent surgical resection had a considerably longer median survival (237 mo versus 215 mo, P < 0.001) as well as a significantly improved five-year survival (72.4% versus 52.6%, P < 0.001). Univariate analysis demonstrated that age, gender, ethnicity, primary tumor site, WHO grade and surgical resection were significant predictors of improved survival for ependymoma patients. Multivariate analysis identified that a WHO grade III tumor, male gender, patient age, intracranial tumor locations and failure to undergo surgical resection were independent predictors of poorer outcomes. Multivariate analysis of partially resection cases revealed that lack of radiation was a sign of poor prognosis (HR 1.748, P = 0.024). Conclusion. Surgical extirpation of ependymomas is associated with significantly improved patient survival. For partially resected tumors, radiation therapy provides significant survival benefit. (C) 2009 Elsevier Inc. All rights reserved. C1 [Rodriguez, Dayron; Cheung, Michael C.; Housri, Nadine; Koniaris, Leonidas G.] Univ Miami, Miller Sch Med, DeWitt Daughtry Family Dept Surg, Div Surg Oncol, Miami, FL 33136 USA. [Quinones-Hinojosa, Alfredo] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Johns Hopkins Hosp, Baltimore, MD 21205 USA. [Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Koniaris, LG (reprint author), Univ Miami, Sch Med, Alan Livingstone Chair Surg Oncol, 3550 Sylvester Comprehens Canc Ctr,1475 NW 12th A, Miami, FL 33136 USA. EM lkoniaris@med.miami.edu NR 67 TC 43 Z9 47 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD OCT PY 2009 VL 156 IS 2 BP 340 EP 351 DI 10.1016/j.jss.2009.04.024 PG 12 WC Surgery SC Surgery GA 503TW UT WOS:000270564300026 PM 19577759 ER PT J AU Brent, DA Greenhill, LL Compton, S Emslie, G Wells, K Walkup, JT Vitiello, B Bukstein, O Stanley, B Posner, K Kennard, BD Cwik, MF Wagner, A Coffey, B March, JS Riddle, M Goldstein, T Curry, J Barnett, S Capasso, L Zelazny, J Hughes, J Shen, S Gugga, SS Turner, JB AF Brent, David A. Greenhill, Laurence L. Compton, Scott Emslie, Graham Wells, Karen Walkup, John T. Vitiello, Benedetto Bukstein, Oscar Stanley, Barbara Posner, Kelly Kennard, Betsy D. Cwik, Mary F. Wagner, Ann Coffey, Barbara March, John S. Riddle, Mark Goldstein, Tina Curry, John Barnett, Shannon Capasso, Lisa Zelazny, Jamie Hughes, Jennifer Shen, Sa Gugga, S. Sonia Turner, J. Blake TI The Treatment of Adolescent Suicide Attempters Study (TASA): Predictors of Suicidal Events in an Open Treatment Trial SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE suicide attempt; depression; pharmacotherapy; psychotherapy ID BORDERLINE PERSONALITY-DISORDER; RANDOMIZED CONTROLLED-TRIAL; SSRI-RESISTANT DEPRESSION; CHILDHOOD SEXUAL-ABUSE; PSYCHIATRIC-INPATIENTS; RISK-FACTORS; SCALE; SCHIZOPHRENIA; RELIABILITY; PREVALENCE AB Objective: To identify the predictors of suicidal events and attempts in adolescent suicide attempters with depression treated in an open treatment trial. Method: Adolescents who had made a recent suicide attempt and had unipolar depression (n = 124) were either randomized (n = 22) or given a choice (n = 102) among three conditions. Two participants withdrew before treatment assignment. The remaining 124 youths received a specialized psychotherapy for suicide attempting adolescents In = 17), a medication algorithm (n = 14), or the combination (n = 93). The participants were followed up 6 months after intake with respect to rate, timing, and predictors of a suicidal event (attempt or acute suicidal ideation necessitating emergency referral). Results: The morbid risks of suicidal events and attempts on 6-month follow-up were 0.19 and 0.12, respectively, with a median time to event of 44 days. Higher self-rated depression, suicidal ideation, family income, greater number of previous suicide attempts, lower maximum lethality of previous attempt, history of sexual abuse, and lower family cohesion predicted the occurrence, and earlier time to event, with similar findings for the outcome of attempts. A slower decline in suicidal ideation was associated with the occurrence of a suicidal event. Conclusions: In this open trial, the 6-month morbid risks for suicidal events and for reattempts were lower than those in other comparable samples, suggesting that this intervention should be studied further. Important treatment targets include suicidal ideation, family cohesion, and sequelae of previous abuse. Because 40% of events occurred with 4 weeks of intake, an emphasis on safety planning and increased therapeutic contact early in treatment may be warranted. J Am. Acad. Child Adolesc. Psychiatry, 2009;48(10):987-996. C1 [Brent, David A.; Bukstein, Oscar; Goldstein, Tina; Zelazny, Jamie] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Vitiello, Benedetto; Wagner, Ann] NIMH, Bethesda, MD 20892 USA. [Greenhill, Laurence L.; Stanley, Barbara; Posner, Kelly; Capasso, Lisa; Shen, Sa; Gugga, S. Sonia; Turner, J. Blake] Columbia Univ, New York Psychiat Inst, New York, NY 10027 USA. [Emslie, Graham; Kennard, Betsy D.; Hughes, Jennifer] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Compton, Scott; Wells, Karen; March, John S.; Curry, John] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Coffey, Barbara] NYU, Ctr Child Study, New York, NY 10003 USA. [Walkup, John T.; Cwik, Mary F.; Riddle, Mark; Barnett, Shannon] Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Brent, DA (reprint author), Univ Pittsburgh, Western Psychiat Inst & Clin, 3811 OHara St,Room 311 Bellefield Towers, Pittsburgh, PA 15213 USA. EM brentda@upmc.edu RI Stanley, Barbara/J-8736-2013 FU NIMH NIH HHS [U10 MH066778-04, U10 MH066775-04, U10 MH066775-01, U10 MH066769-04, U10 MH066769-01, U10 MH066762-05, U10 MH066762-02, U10 MH066762, U10 MH066750-05, U10 MH066750-02, U10 MH066750, MH66762, U10 MH066778-01, MH66750, U10 MH066778-03, U10 MH066750-01, U10 MH066750-04, U10 MH066762-01, U10 MH066762-04, U10 MH066769-03, U10 MH066775-03, U10 MH066769-02, MH66769, MH66775, MH66778, U10 MH066750-03, U10 MH066762-02S1, U10 MH066762-03, U10 MH066769, U10 MH066769-05, U10 MH066775, U10 MH066775-02, U10 MH066775-05, U10 MH066778, U10 MH066778-02, U10 MH066778-05] NR 38 TC 72 Z9 72 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2009 VL 48 IS 10 BP 987 EP 996 DI 10.1097/CHI.0b013e3181b5dbe4 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 499DH UT WOS:000270196600005 PM 19730274 ER PT J AU Vtiello, B Brent, DA Greenhill, LL Emslie, G Wells, K Walkup, JT Stanley, B Bukstein, O Kennard, BD Compton, S Coffey, B Cwik, MF Posner, K Wagner, A March, JS Riddle, M Goldstein, T Curry, J Capasso, L Mayes, T Shen, S Gugga, SS Turner, JB Barnett, S Zelazny, J AF Vtiello, Benedetto Brent, David A. Greenhill, Laurence L. Emslie, Graham Wells, Karen Walkup, John T. Stanley, Barbara Bukstein, Oscar Kennard, Betsy D. Compton, Scott Coffey, Barbara Cwik, Mary F. Posner, Kelly Wagner, Ann March, John S. Riddle, Mark Goldstein, Tina Curry, John Capasso, Lisa Mayes, Taryn Shen, Sa Gugga, S. Sonia Turner, J. Blake Barnett, Shannon Zelazny, Jamie TI Depressive Symptoms and Clinical Status During the Treatment of Adolescent Suicide Attempters (TASA) Study SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE adolescents; suicide; depression; treatment ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; CHILDREN; SCALE; TADS; OUTCOMES; METAANALYSIS; RELIABILITY; REMISSION; IDEATION AB Objective: To examine the course of depression during the treatment of adolescents with depression who had recently attempted suicide. Method: Adolescents (N = 124), ages 12 to 18 years, with a 90-day history of suicide attempt, a current diagnosis of depressive disorder (96.0% had major depressive disorder), and a Children's Depression Rating Scale-Revised (CDRS-R) score of 36 or higher, entered a 6-month treatment with antidepressant medication, cognitive-behavioral therapy focused on suicide prevention, or their combination (Comb), at five academic sites. Treatment assignment could be either random or chosen by study participants. Intent-to-treat, mixed effects regression models of depression and other relevant ratings were estimated. Improvement and remission rates were computed with the last observation carried forward. Results: Most patients (n = 104 or 84%) chose treatment assignment, and overall, three fourths (n = 93) received Comb. In Comb, CDRS-R declined from a baseline adjusted mean of 49.6 (SD 12.3) to 38.3 (8.0) at week 12 and to 27.0 (10.1) at week 24 (p <.0001), with a Clinical Global Impression-defined improvement rate of 58.0% at week 12 and 72.2% at week 24 and a remission (CDRS-R <= 28) rate of 32.5% at week 12 and 50.0% at week 24. The CDRS-R and the Scale for Suicidal Ideation scores were correlated at baseline (r=0.43, p <.0001) and declined in parallel. Conclusions: When vigorously treated with a combination of medication and psychotherapy, adolescents with depression who have recently attempted suicide show rates of improvement and remission of depression that seem comparable to those observed in nonsuicidal adolescents with depression. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(10):997-1004. C1 [Vtiello, Benedetto; Wagner, Ann] NIMH, Bethesda, MD 20892 USA. [Brent, David A.; Bukstein, Oscar; Goldstein, Tina; Zelazny, Jamie] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15260 USA. [Greenhill, Laurence L.; Stanley, Barbara; Posner, Kelly; Capasso, Lisa; Shen, Sa; Gugga, S. Sonia; Turner, J. Blake] Columbia Univ, New York State Psychiat Inst, New York, NY 10027 USA. [Emslie, Graham; Kennard, Betsy D.; Mayes, Taryn] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Wells, Karen; Compton, Scott; March, John S.; Curry, John] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Coffey, Barbara] NYU, Ctr Child Study, New York, NY 10003 USA. [Walkup, John T.; Cwik, Mary F.; Riddle, Mark; Barnett, Shannon] Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Vtiello, B (reprint author), NIMH, Room 7147,6001 Execut Blvd, Bethesda, MD 20892 USA. EM bvitiell@mail.nih.gov FU National Institute of Mental Health [MH66750, MH66769, MH66762, MH66775, MH66778]; NIMH FX Funded by the National Institute of Mental Health through cooperative agreement grants MH66750 (PI: KW, Duke University Medical Center), MH66769 (PI;J W, Johns Hopkins University), MH66762 (PI: L. G, New York State Psychiatric Institute), MH66775 (PI: D. B., Universiq of Pittsburgh), and MH66778 (PI: GE, Univeisity of Texas Southwestern Medical Center). Data management was funded by an NIMH contract to KAI Research, Rockville, MD. NR 26 TC 4 Z9 4 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2009 VL 48 IS 10 BP 997 EP 1004 DI 10.1097/CHI.0b013e3181b5db66 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 499DH UT WOS:000270196600006 ER PT J AU Stanley, B Brown, G Brent, DA Wells, K Poling, K Curry, J Kennard, BD Wagner, A Cwik, MF Klomek, AB Goldstein, T Vitiello, B Barnett, S Daniel, S Hughes, J AF Stanley, Barbara Brown, Gregory Brent, David A. Wells, Karen Poling, Kim Curry, John Kennard, Betsy D. Wagner, Ann Cwik, Mary F. Klomek, Anat Brunstein Goldstein, Tina Vitiello, Benedetto Barnett, Shannon Daniel, Stephanie Hughes, Jennifer TI Cognitive-Behavioral Therapy for Suicide Prevention (CBT-SP): Treatment Model, Feasibility, and Acceptability SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE suicide; psychotherapy; depression ID PARASUICIDAL BORDERLINE PATIENTS; RANDOMIZED CONTROLLED-TRIAL; DELIBERATE SELF-HARM; ADOLESCENT SUICIDE; RISK-FACTORS; INTERVENTION; ATTEMPTERS; PREVALENCE; IDEATION; CHILDREN AB Objective: To describe the elements of a manual-based cognitive-behavioral therapy for suicide prevention (CBT-SP) and to report its feasibility in preventing the recurrence of suicidal behavior in adolescents who have recently attempted suicide. Method: The CBT-SP was developed using a risk reduction and relapse prevention approach and theoretically grounded in principles of cognitive-behavioral therapy, dialectical behavioral therapy, and targeted therapies for suicidal youths with depression. The CBT-SP consists of acute and continuation phases, each lasting about 12 sessions, and includes a chain analysis of the suicidal event, safety plan development, skill building, psychoeducation, family intervention, and relapse prevention. Results: The CBT-SP was administered to 110 recent suicide attempters with depression aged 13 to 19 years (mean 15.8 years, SD 1.6) across five academic sites. Twelve or more sessions were completed by 72.4% of the sample. Conclusions: A specific intervention for adolescents at high risk for repeated suicide attempts has been developed and manual based, and further testing of its efficacy seems feasible. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(10):1005-1013. C1 [Stanley, Barbara] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [Brown, Gregory] Univ Penn, Philadelphia, PA 19104 USA. [Brent, David A.; Poling, Kim; Goldstein, Tina] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Brent, David A.; Poling, Kim; Goldstein, Tina] Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Wells, Karen; Curry, John] Duke Univ, Durham, NC 27706 USA. [Wagner, Ann; Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Kennard, Betsy D.; Hughes, Jennifer] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Cwik, Mary F.; Barnett, Shannon] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Daniel, Stephanie] Univ N Carolina, Greensboro, NC 27412 USA. RP Stanley, B (reprint author), Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York State Psychiat Inst, Unit 42 1051,Riverside Dr, New York, NY 10032 USA. EM bhs2@columbia.edu RI Stanley, Barbara/J-8736-2013 FU NIAAA NIH HHS [P20 AA015630, P20 AA015630-04]; NIMH NIH HHS [MH66775, MH66750, MH66762, MH66769, MH66778, R01 MH061017, R01 MH061017-05, U10 MH066750, U10 MH066750-04, U10 MH066762, U10 MH066762-04, U10 MH066769, U10 MH066769-04, U10 MH066775, U10 MH066775-05, U10 MH066778, U10 MH066778-04] NR 35 TC 67 Z9 68 U1 9 U2 47 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2009 VL 48 IS 10 BP 1005 EP 1013 DI 10.1097/CHI.0b013e3181b5dbfe PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 499DH UT WOS:000270196600007 PM 19730273 ER PT J AU Leachman, SA Carucci, J Kohlmann, W Banks, KC Asgari, MM Bergman, W Bianchi-Scarra, G Brentnall, T Bressac-de Paillerets, B Bruno, W Curiel-Lewandrowski, C de Snoo, FA Debniak, T Demierre, MF Elder, D Goldstein, AM Grant-Kels, J Halpern, AC Ingvar, C Kefford, RF Lang, J MacKie, RM Mann, GJ Mueller, K Newton-Bishop, J Olsson, H Peterson, GM Puig, S Rigel, D Swetter, SM Tucker, MA Yakobson, E Zitelli, JA Tsao, H AF Leachman, Sancy A. Carucci, John Kohlmann, Wendy Banks, Kimberly C. Asgari, Maryam M. Bergman, Wilma Bianchi-Scarra, Giovanna Brentnall, Teresa Bressac-de Paillerets, Brigitte Bruno, William Curiel-Lewandrowski, Clara de Snoo, Femke A. Debniak, Tadeusz Demierre, Marie-France Elder, David Goldstein, Alisa M. Grant-Kels, Jane Halpern, Allan C. Ingvar, Christian Kefford, Richard F. Lang, Julie MacKie, Rona M. Mann, Graham J. Mueller, Kurt Newton-Bishop, Julia Olsson, Hakan Peterson, Gloria M. Puig, Susana Rigel, Darrell Swetter, Susan M. Tucker, Margaret A. Yakobson, Emanuel Zitelli, John A. Tsao, Hensin TI Selection criteria for genetic assessment of patients with familial melanoma SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review DE CDKN2A; familial; genetic counseling; genetic testing; hereditary; melanoma; p16 ID GERMLINE CDKN2A MUTATIONS; MULTIPLE PRIMARY MELANOMAS; CUTANEOUS MALIGNANT-MELANOMA; ATYPICAL-MOLE SYNDROME; PANCREATIC-CARCINOMA SYNDROME; POPULATION-BASED SAMPLE; NEURAL SYSTEM TUMORS; PRONE FAMILIES; EARLY-ONSET; CDK4 MUTATIONS AB Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients Who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, We have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The Work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing. (J Am Acad Dermatol 2009;61:677-84.) C1 [Leachman, Sancy A.] Univ Utah, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Carucci, John] Cornell Univ, Weill Med Coll, Dept Dermatol, New York, NY 10021 USA. [Asgari, Maryam M.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Bergman, Wilma; de Snoo, Femke A.] Leiden Univ, Med Ctr, Dept Dermatol & Clin Genet, NL-2300 RA Leiden, Netherlands. [Bianchi-Scarra, Giovanna; Bruno, William] Univ Genoa, Dept Oncol Biol & Genet, Med Genet Serv, I-16126 Genoa, Italy. [Brentnall, Teresa] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, Serv Genet, Villejuif, France. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, CNRS, France Genomes & Canc 2939, Villejuif, France. [Curiel-Lewandrowski, Clara] Univ Arizona, Arizona Canc Ctr, Dermatol Sect, Tucson, AZ 85721 USA. [Debniak, Tadeusz] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Demierre, Marie-France] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02215 USA. [Elder, David] Hosp Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Goldstein, Alisa M.; Tucker, Margaret A.] Natl Canc Inst, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD USA. [Grant-Kels, Jane] Univ Connecticut, Ctr Hlth, Dept Dermatol, Storrs, CT 06269 USA. [Halpern, Allan C.] Mem Sloan Kettering Canc Ctr, Dermatol Serv, New York, NY 10021 USA. [Ingvar, Christian] Univ Lund Hosp, Dept Surg, Lund, Sweden. [Olsson, Hakan] Univ Lund Hosp, Dept Oncol & Canc Epidemiol, Lund, Sweden. [Kefford, Richard F.; Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Sydney, NSW 2006, Australia. [Kefford, Richard F.; Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Sydney Melanoma Unit, Sydney, NSW 2006, Australia. [Lang, Julie] Duncan Guthrie Inst Med Genet, Glasgow G3 8SJ, Lanark, Scotland. [MacKie, Rona M.] Univ Glasgow, Dept Publ Hlth, Glasgow G12 8QQ, Lanark, Scotland. [MacKie, Rona M.] Univ Glasgow, Dept Hlth Policy, Glasgow G12 8QQ, Lanark, Scotland. [MacKie, Rona M.] Univ Glasgow, Dept Med Genet, Glasgow G12 8QQ, Lanark, Scotland. [Mueller, Kurt] Gundersen Lutheran Med Ctr, Dept Dermatol, La Crosse, WI USA. [Newton-Bishop, Julia] Univ Leeds, Leeds Inst Mol Med, Div Epidemiol & Biostat, Leeds LS2 9JT, W Yorkshire, England. [Peterson, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Puig, Susana] Hosp Clin Barcelona, Melanoma Unit, Dept Dermatol, Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Puig, Susana] Ctr Invest Biobedica Red Enfermedades, Barcelona, Spain. [Rigel, Darrell] NYU, Sch Med, Dept Dermatol, New York, NY 10003 USA. [Swetter, Susan M.] Stanford Univ, Med Ctr, Dept Dermatol, Pigmented Les & Melanoma Program,Dept Vet Affairs, Stanford, CA 94305 USA. [Yakobson, Emanuel] Tel Aviv Univ, Sourasky Med Ctr, Lab Clin Biochem, Tel Aviv, Israel. [Zitelli, John A.] Univ Pittsburgh, Dept Dermatol, Pittsburgh, PA 15260 USA. [Tsao, Hensin] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Leachman, SA (reprint author), Univ Utah, Dept Dermatol, Huntsman Canc Inst, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA. EM sancy.leachman@hci.utah.edu RI Mann, Graham/G-4758-2014; Bianchi Scarra, Giovanna/G-8933-2014; Tucker, Margaret/B-4297-2015; Bruno, William/N-7477-2013; Asgari, Maryam/O-4947-2016; OI Mann, Graham/0000-0003-1301-405X; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Bruno, William/0000-0002-0337-0168; Banks, Kimberly/0000-0002-1290-3114; Newton Bishop, Julia/0000-0001-9147-6802; Puig, Susana/0000-0003-1337-9745 FU National Institute of Arthritis Musculoskeletal and Skin Diseases [K23 AR 051037]; NCI [P50 CA-93683]; RSG [MG0-112970]; NIH [R01 CA83115] FX The work of Dr Asgari is supported by the National Institute of Arthritis Musculoskeletal and Skin Diseases (K23 AR 051037). The work of Dr Tsao is supported by P50 CA-93683 (NCI), RSG MG0-112970 (American Cancer Society), NIH R01 CA83115. NR 96 TC 42 Z9 42 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2009 VL 61 IS 4 BP 677 EP 684 DI 10.1016/j.jaad.2009.03.016 PG 8 WC Dermatology SC Dermatology GA 499WU UT WOS:000270258300015 ER PT J AU Boyd, CM Ricks, M Fried, LP Guralnik, JM Xue, QL Xia, J Bandeen-Roche, K AF Boyd, Cynthia M. Ricks, Michelle Fried, Linda P. Guralnik, Jack M. Xue, Qian-Li Xia, Jin Bandeen-Roche, Karen TI Functional Decline and Recovery of Activities of Daily Living in Hospitalized, Disabled Older Women: The Women's Health and Aging Study I SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE hospitalization; activities of daily living; disability; recovery ID EMOTIONAL VITALITY; MEDICAL ILLNESSES; ELDERLY-PATIENTS; DISABILITY; INDEPENDENCE; COMMUNITY; ADULTS; FRAILTY; RISK; CARE AB OBJECTIVES To determine, in disabled, older, community-dwelling women who were hospitalized, the rates and predictors of functional decline, the probability and time course of subsequent functional recovery, and predictors of functional recovery. DESIGN Population-based observational cohort. SETTING Woman's Health and Aging Study. PARTICIPANTS A subset of the 1,002 moderately to severely disabled community-dwelling older women who were hospitalized over 3 years (N=457). MEASUREMENTS Functional decline and complete and partial recovery were defined using a 0 to 6 scale of dependencies in activities of daily living (ADLs) evaluated every 6 months over 3 years. Complete recovery was defined as returning to baseline function (function at visit immediately preceding hospitalization) after functional decline; partial recovery was defined as any improvement in the ADL scale after functional decline. Multiple logistic regression analysis was used to determine predictors of functional decline. Kaplan-Meier curves estimate the proportions recovering as a function of time since hospitalization. Discrete-time proportional hazards models regress the time-to-recovery hazards on the predictor variables. RESULTS Thirty-three percent of hospitalized women experienced functional decline at the first visit after hospitalization. Frailty, longer length of stay, and higher education were associated with functional decline. Fifty percent fully recovered over the subsequent 30 months, with 33% recovering within 6 months and an additional 14% over the following 6 months. Younger women were more likely to recover (aged 80 to 70, hazard ratio=0.39, 95% confidence interval=0.24-0.64). CONCLUSION Although most recovery of function occurs by 6 months after the first visit after a hospitalization, a substantial proportion of disabled community-dwelling women recover over the following 2 years. C1 [Boyd, Cynthia M.; Ricks, Michelle; Fried, Linda P.; Xue, Qian-Li; Xia, Jin; Bandeen-Roche, Karen] NIA, Sch Med, Ctr Aging & Hlth, Baltimore, MD 21224 USA. [Boyd, Cynthia M.; Ricks, Michelle; Fried, Linda P.; Xue, Qian-Li; Xia, Jin; Bandeen-Roche, Karen] NIA, Bloomberg Sch Publ Hlth, Ctr Aging & Hlth, Baltimore, MD 21224 USA. [Boyd, Cynthia M.; Fried, Linda P.; Xue, Qian-Li; Bandeen-Roche, Karen] NIA, Sch Med, Dept Med, Baltimore, MD 21224 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Dept Epidemiol, Baltimore, MD 21224 USA. [Bandeen-Roche, Karen] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21224 USA. RP Boyd, CM (reprint author), Johns Hopkins Univ, Div Geriatr Med & Gerontol, Sch Med, Mason F Lord Bldg,Ctr Tower,7th Floor,5200 Easter, Baltimore, MD 21224 USA. EM cboyd1@jhmi.edu FU National Institute on Aging (NIA) through the Older Americans Independence Center (OAIC); Pfizer/American Geriatrics Society Junior Faculty Scholars on Health Outcomes Award; NIANO-1AG-1-2112; OAIC [P30 AG021334]; National Institutes of Health FX Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Dr. Boyd has been supported by the National Institute on Aging (NIA) through the Older Americans Independence Center (OAIC) and received a Pfizer/American Geriatrics Society Junior Faculty Scholars on Health Outcomes Award. Drs. Qian-Li Xue, Karen Bandeen-Roche, and Linda Fried and Ms. Michelle Ricks and Jin Xia have all received funding from the NIA and the OAIC (P30 AG021334). None of the authors received corporate financial support, consultantships, speaker arrangements, company holdings, or patents related to this research and the materials described in this article. The Women's Health and Aging Study was funded by NIA Contract NO-1AG-1-2112. This work was supported, in part, by the Intramural Research Program, NIA, National Institutes of Health. NR 46 TC 45 Z9 46 U1 0 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2009 VL 57 IS 10 BP 1757 EP 1766 DI 10.1111/j.1532-5415.2009.02455.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 503PV UT WOS:000270551300003 PM 19694869 ER PT J AU Maraldi, C Harris, TB Newman, AB Kritchevsky, SB Pahor, M Koster, A Satterfield, S Ayonayon, HN Fellin, R Volpato, S AF Maraldi, Cinzia Harris, Tamara B. Newman, Anne B. Kritchevsky, Stephen B. Pahor, Marco Koster, Annemarie Satterfield, Suzanne Ayonayon, Hilsa N. Fellin, Renato Volpato, Stefano CA Hlth ABC Study TI Moderate Alcohol Intake and Risk of Functional Decline: The Health, Aging, and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE alcohol intake; functional decline; aging ID ACTIVE LIFE EXPECTANCY; CORONARY HEART-DISEASE; CARDIOVASCULAR HEALTH; PHYSICAL-ACTIVITY; OLDER-ADULTS; INFLAMMATORY MARKERS; MASS INDEX; CONSUMPTION; WOMEN; DISABILITY AB OBJECTIVES To investigate the prospective relationship between alcohol consumption and incident mobility limitation. DESIGN Cohort study. SETTING The Health Aging and Body Composition study, conducted in Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS Three thousand sixty-one adults aged 70 to 79 without mobility disability at baseline. MEASUREMENTS Incidence of mobility limitation, defined as self-report at two consecutive semiannual interviews of any difficulty walking one-quarter of a mile or climbing stairs, and incidence of mobility disability, defined as severe difficulty or inability to perform these tasks at two consecutive reports. Alcohol intake, lifestyle-related variables, diseases, and health status indicators were assessed at baseline. RESULTS During a follow-up time of 6.5 years, participants consuming moderate levels of alcohol had the lowest incidence of mobility limitation (total: 6.4 per 100 person-years (person-years); men: 6.4 per 100 person-years; women: 7.3 per 100 person-years) and mobility disability (total: 2.7 per 100 person-years; men: 2.5 per 100 person-years; women: 2.9 per 100 person-years). Adjusting for demographic characteristics, moderate alcohol intake was associated with lower risk of mobility limitation (hazard ratio (HR)=0.70, 95% confidence interval (CI)=0.55-0.89) and mobility disability (HR=0.66, 95% CI=0.45-0.95) than never or occasional consumption. Additional adjustment for lifestyle-related variables substantially reduced the strength of the associations (HR=0.85, 95% CI=0.66-1.08 and HR=0.81, 95% CI=0.56-1.18, respectively). Adjustment for diseases and health status indicators did not affect the strength of the associations, suggesting that lifestyle is most important in confounding this relationship. CONCLUSION Lifestyle-related characteristics mainly accounted for the association between moderate alcohol intake and lower risk of functional decline over time. These findings do not support a direct causal effect of alcohol intake on physical function. C1 [Maraldi, Cinzia; Fellin, Renato; Volpato, Stefano] Univ Ferrara, Sect Internal Med Gerontol & Geriatr, Dept Clin & Expt Med, I-44100 Ferrara, Italy. [Harris, Tamara B.; Koster, Annemarie] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Med, Pittsburgh, PA USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Pahor, Marco] Univ Florida, Inst Aging, Gainesville, FL USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Maraldi, C (reprint author), Univ Ferrara, Sect Internal Med Gerontol & Geriatr, Dept Clin & Expt Med, Via Savonarola 9, I-44100 Ferrara, Italy. EM mrlcnz@unife.it RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Volpato, Stefano/0000-0003-4335-6034; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging [N01-AG-6-2106, N01-AG-6-2103, N01-AG-6-2101, R01 HL72972]; National Institutes of Health FX This research was supported through National Institute on Aging Contracts N01-AG-6-2106, N01-AG-6-2103, and N01-AG-6-2101 and in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging Grant R01 HL72972. NR 41 TC 15 Z9 15 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2009 VL 57 IS 10 BP 1767 EP 1775 DI 10.1111/j.1532-5415.2009.02479.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 503PV UT WOS:000270551300004 PM 19737328 ER PT J AU Maggio, M Ceda, GP Lauretani, F Bandinelli, S Ruggiero, C Guralnik, JM Metter, EJ Ling, SM Paolisso, G Valenti, G Cappola, AR Ferrucci, L AF Maggio, Marcello Ceda, Gian Paolo Lauretani, Fulvio Bandinelli, Stefania Ruggiero, Carmelinda Guralnik, Jack M. Metter, E. Jeffrey Ling, Shari M. Paolisso, Giuseppe Valenti, Giorgio Cappola, Anne R. Ferrucci, Luigi TI Relationship Between Higher Estradiol Levels and 9-Year Mortality in Older Women: The Invecchiare in Chianti Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE estradiol; older postmenopausal women; mortality ID ENDOGENOUS SEX-HORMONES; ESTROGEN PLUS PROGESTIN; GLUCOSE-TOLERANCE STATUS; CORONARY-HEART-DISEASE; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; CARDIOVASCULAR-DISEASE; COLORECTAL-CANCER; RISK; ASSOCIATION AB OBJECTIVES To investigate the relationship between total estradiol (E2) levels and 9-year mortality in older postmenopausal women not taking hormone replacement therapy (HRT). DESIGN Population-based study of persons living in the Chianti geographic area (Tuscany, Italy). SETTING Community. PARTICIPANTS A representative sample of 509 women aged 65 and older with measures of total E2. MEASUREMENTS Serum total E2 was measured at the University of Parma using ultrasensitive radioimmunoassay (RIA). RESULTS Women who died (n=135) during 9 years of follow up were older; had higher total E2 levels; and were more likely to have evidence of stroke, hypertension, diabetes mellitus, and congestive heart failure at baseline than survivors. Higher E2 levels were associated with a greater likelihood of death (hazard ratio (HR)=1.03, 95% confidence interval (CI)=1.01-1.06), and the relationship was independent of age, waist:hip ratio, C-reactive protein, education, cognitive function, physical activity, caloric intake, smoking, and chronic disease (HR=1.08 pg/mL, 95% CI=1.03-1.13, P=.003). The excessive risk of death associated with higher total E2 was not attenuated after adjustment for total testosterone (HR=1.12, 95% CI=1.02-1.18, P <.001) and after further adjustment for insulin resistance evaluated using the homeostasis model assessment (HR=1.07, 95% CI=1.03-1.17, P <.001). Total E2 was highly predictive of death after more than 5 years (HR=1.42: CI 1.01-1.91, P=.04) and not predictive of death for less than 5 years (P=.78). CONCLUSION Higher total E2 concentration predicts mortality in older women not taking HRT. C1 [Ferrucci, Luigi] Harbor Hosp, NIA, ASTRA Unit, Longitudinal Studies Sect,, Baltimore, MD 21225 USA. [Ling, Shari M.] NIA, NIH, Clin Res Branch, Intramural Res Program, Baltimore, MD 21225 USA. [Paolisso, Giuseppe] Univ Naples 2, Unit Internal Med 6, Dept Geriatr Med & Metab Dis, Naples, Italy. [Cappola, Anne R.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Maggio, Marcello; Ceda, Gian Paolo; Valenti, Giorgio] Univ Parma, Dept Internal Med & Biomed Sci, Sect Geriatr, I-43100 Parma, Italy. [Maggio, Marcello; Ceda, Gian Paolo; Lauretani, Fulvio] Azienda Osped Univ, Geriatr Rehabil Dept, Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Florence, Italy. [Ruggiero, Carmelinda] Univ Perugia, Dept Clin & Expt Med, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21225 USA. RP Ferrucci, L (reprint author), Harbor Hosp, NIA, ASTRA Unit, Longitudinal Studies Sect,, Harbor Hosp 3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health [ICS 110.1/RS97.71]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336] FX The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336) and by the Intramural Research Program of the U.S. National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336). NR 38 TC 17 Z9 18 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2009 VL 57 IS 10 BP 1810 EP 1815 DI 10.1111/j.1532-5415.2009.02464.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 503PV UT WOS:000270551300009 PM 19737330 ER PT J AU Semba, RD Bandinelli, S Sun, K Guralnik, JM Ferrucci, L AF Semba, Richard D. Bandinelli, Stefania Sun, Kai Guralnik, Jack M. Ferrucci, Luigi TI Plasma Carboxymethyl-Lysine, an Advanced Glycation End Product, and All-Cause and Cardiovascular Disease Mortality in Older Community-Dwelling Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE advanced glycation end products; aging; all-cause mortality; cardiovascular disease mortality ID DENSITY-LIPOPROTEIN CHOLESTEROL; DIABETES-MELLITUS; OXIDATIVE STRESS; SERUM-LEVELS; RISK-FACTOR; ENDPRODUCTS; AGE; N-EPSILON-(CARBOXYMETHYL)LYSINE; ACCUMULATION; GLYCOTOXINS AB OBJECTIVES To determine whether older adults with high plasma carboxymethyl-lysine (CML), an advanced glycation end product, are at higher risk of all-cause and cardiovascular disease (CVD) mortality. DESIGN Prospective cohort study. SETTING Population-based sample of adults aged 65 and older residing in Tuscany, Italy. PARTICIPANTS One thousand thirteen adults participating in the Invecchiare in Chianti study. MEASUREMENTS Anthropometric measures, plasma CML, fasting plasma total, high-density and low-density lipoprotein cholesterol, triglycerides, glucose, creatinine. Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, cancer. Vital status measures: death certificates and causes of death according to the International Classification of Diseases. Survival methods were used to examine the relationship between plasma CML and all-cause and CVD mortality, adjusting for potential confounders. RESULTS During 6 years of follow-up, 227 (22.4%) adults died, of whom 105 died with CVD. Adults with plasma CML in the highest tertile had greater all-cause (hazard ratio (HR)=1.84, 95% confidence interval) CI)=1.30-2.60, P <.001) and CVD (HR=2.11, 95% CI=1.27-3.49, P=.003) mortality than those in the lower two tertiles after adjusting for potential confounders. In adults without diabetes mellitus, those with plasma CML in the highest tertile had greater all-cause (HR=1.68, 95% CI=1.15-2.44, P=.006) and CVD (HR=1.74, 95% CI=1.00-3.01, P=.05) mortality than those in the lower two tertiles after adjusting for potential confounders. CONCLUSION Older adults with high plasma CML are at higher risk of all-cause and CVD mortality. C1 [Semba, Richard D.; Sun, Kai] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), 550 N Broadway,Suite 700, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU National Institute on Aging (NIA) [R01 AG027012, R01 AG029148]; National Institutes of Health (NIH) FX This work was supported by National Institute on Aging (NIA) Grants R01 AG027012, R01 AG029148 and the Intramural Research Program, NIA, National Institutes of Health (NIH). NR 30 TC 42 Z9 44 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2009 VL 57 IS 10 BP 1874 EP 1880 DI 10.1111/j.1532-5415.2009.02438.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 503PV UT WOS:000270551300019 PM 19682127 ER PT J AU Park, SK Kang, D Kim, Y Yoo, KY AF Park, Sue K. Kang, Daehee Kim, Yeonju Yoo, Keun-Young TI Epidemiologic Characteristics of the Breast Cancer in Korea SO JOURNAL OF THE KOREAN MEDICAL ASSOCIATION LA Korean DT Article DE Breast cancer; Risk factors; Environment; Gene ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ATOMIC-BOMB SURVIVORS; RECEPTOR-ALPHA GENE; S-TRANSFERASE M1; BODY-MASS INDEX; LIFE-STYLE; RISK; WOMEN; POLYMORPHISMS; ASSOCIATION AB Breast cancer has been the most common cancer among Korean women since 2001 and will continue to increase for the next 20 years, at the least. Many of the established risk factors are linked to the exposure to female hormones: breast cancer risk is increased by early menarche, late menopause, nulliparity and later first full-term pregnancy, and obesity in postmenopausal women. In addition, other established risk factors such as alcohol consumption and family history of breast cancer are associated with an increased risk of breast cancer. Physical activity, breast feeding, higher number of children, and fruit and vegetable consumption seem to reduce breast cancer risk. Smoking also probably increases the risk. Both ora contraceptives in premenopausal women and hormonal replacement therapy in postmenopausal women may increase risk. Above-mentioned risk and protective factors were reported in Korean populations and the breast cancer risk by those factors is similar to that in western population. Currently, a study is being done in Korea to examine the associated risk, and population attributable risk of genetic variants in high penetrance genes including BRCA 1 and 2 and breast cancer risk among Koreans will be reported soon. Other studies conducted in Korea that investigated low penetrance genes have already been published. While the individual risk was small, there was an effect from interaction with environmental factors. Numerous Korean studies about these risk factors helped to establish a model to predict individual breast cancer risk that is utilized in the Personalized Preventive and Predictive medicine. C1 [Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Dept Prevent Med, Coll Med, Canc Res Ins,WCU, Seoul 151, South Korea. [Park, Sue K.] Seoul Natl Univ, Inst Hlth Policy & Management, Seoul 151, South Korea. [Kim, Yeonju] Natl Canc Ctr, Canc Early Detect Branch, Natl Canc Control Inst, Bethesda, MD 20892 USA. RP Park, SK (reprint author), Seoul Natl Univ, Dept Prevent Med, Coll Med, Canc Res Ins,WCU, Seoul 151, South Korea. EM suepark@snu.ac.kr; dhkang@snu.ac.kr; yeonju@ncc.re.kr; kyyoo@snu.ac.kr RI Kang, Dae Hee/E-8631-2012; Park, Sue Kyung/J-2757-2012; Kim, Yeonju/D-8948-2013 NR 58 TC 8 Z9 8 U1 2 U2 5 PU KOREAN MEDICAL ASSOC PI SEOUL PA 302-75 INCHON-1 DONG, YONGSAN-GU, SEOUL, 140-721, SOUTH KOREA SN 1975-8456 J9 J KOREAN MED ASSOC JI J. Korean Med. Assoc. PD OCT PY 2009 VL 52 IS 10 BP 937 EP 945 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 510DU UT WOS:000271069000002 ER PT J AU Hofman, KJ Kanyengo, CW Rapp, BA Kotzin, S AF Hofman, Karen J. Kanyengo, Christine W. Rapp, Barbara A. Kotzin, Sheldon TI Pubmed growth patterns and visibility of journals of Sub-Saharan African origin Response SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Letter C1 [Hofman, Karen J.] NIH, Div Int Sci Policy Planning & Evaluat, John E Fogarty Int Ctr, Bethesda, MD 20892 USA. [Kanyengo, Christine W.] Univ Zambia, Med Lib, Sch Med, Lusaka, Zambia. [Rapp, Barbara A.] NIH, Off Planning & Anal, Off Hlth Informat Programs Dev, Natl Lib Med, Bethesda, MD 20894 USA. RP Hofman, KJ (reprint author), NIH, Div Int Sci Policy Planning & Evaluat, John E Fogarty Int Ctr, 16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. EM hofmank@mail.nih.gov; ckanyengo@yahoo.com; rappb@mail.nlm.nih.gov; kotzins@mail.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2009 VL 97 IS 4 BP 243 EP 243 DI 10.3163/1536-5050.97.4.005 PG 1 WC Information Science & Library Science SC Information Science & Library Science GA 546OO UT WOS:000273820300005 ER PT J AU Dunn, K Brewer, K Marshall, JG Sollenberger, J AF Dunn, Kathel Brewer, Karen Marshall, Joanne Gard Sollenberger, Julia TI Measuring the value and impact of health sciences libraries: planning an update and replication of the Rochester Study SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID PATIENT-CARE; CLINICAL LIBRARIAN; HOSPITAL LIBRARY; DECISION-MAKING; SERVICES; SUPPORT C1 [Dunn, Kathel] Natl Lib Med, Bethesda, MD 20894 USA. [Brewer, Karen] NYU, Hlth Sci Lib, Ehrman Med Lib, New York, NY 10016 USA. [Marshall, Joanne Gard] Univ N Carolina, Sch Informat & Lib Sci, Chapel Hill, NC 27599 USA. [Sollenberger, Julia] Univ Rochester, Med Ctr, Dept Community & Prevent Med, Rochester, NY 14642 USA. [Sollenberger, Julia] Hlth Sci Lib & Technol, Rochester, NY 14642 USA. RP Dunn, K (reprint author), Natl Lib Med, Bldg 38,2N-19, Bethesda, MD 20894 USA. EM Kathel.dunn@gmail.com; Karen.brewer@med.nyu.edu; marshall@ils.unc.edu; Julia_2sollenberger@urmc.rochester.edu OI Dunn, Kathel/0000-0002-6967-130X FU NLM NIH HHS [N01-LM-6-3501] NR 23 TC 5 Z9 6 U1 3 U2 7 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2009 VL 97 IS 4 BP 308 EP 312 DI 10.3163/1536-5050.97.4.016 PG 5 WC Information Science & Library Science SC Information Science & Library Science GA 546OO UT WOS:000273820300017 PM 19851496 ER PT J AU Thorner-Bantug, E Jaszyna-Gasior, M Schroeder, JR Collins, CC Moolchan, ET AF Thorner-Bantug, Elissa Jaszyna-Gasior, Maria Schroeder, Jennifer R. Collins, Charles C. Moolchan, Eric T. TI Weight Gain, Related Concerns, and Treatment Outcomes Among Adolescent Smokers Enrolled in Cessation Treatment SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE children/adolescents; tobacco; body weight; prevention; treatment ID NICOTINE DEPENDENCE; SMOKING CESSATION; CIGARETTE-SMOKING; GENDER; GIRLS; WOMEN AB We examined associations of weight concerns and weight gain with adolescent tobacco cessation treatment and whether these effects differed by gender or ethnoracial group. Participants were 115 urban adolescents recruited for a randomized clinical trial of nicotine replacement therapy. Baseline weight gain concerns were assessed using the Eating Disorders module from the Diagnostic Interview for the Child and Adolescent DICA-IV). The average weight gain during the trial was 0.59 +/- 2.85 kg among the 43.5% of participants who completed the treatment study. As indicated by the DICA, baseline weight gain concerns were not associated with weight gain during treatment, study completion, or abstinence from smoking at 3-month posttreatment follow-up; these results did not vary by gender or ethnoracial group. Adolescents who quit smoking gained no more weight during the trial than those who smoked. C1 [Thorner-Bantug, Elissa; Jaszyna-Gasior, Maria; Schroeder, Jennifer R.; Collins, Charles C.; Moolchan, Eric T.] NIDA, Dept Hlth & Human Resources, NIH, Intramural Res Program,Biomed Res Ctr, Baltimore, MD USA. RP Moolchan, ET (reprint author), Alkermes Inc, Clin Sci, 88 Sidney St, Cambridge, MA 02139 USA. EM eric.moolchan@alkermes.com FU National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program FX This study was supported in full by funds from the National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program. NR 20 TC 6 Z9 6 U1 2 U2 4 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD OCT PY 2009 VL 101 IS 10 BP 1009 EP 1014 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 511XJ UT WOS:000271204700005 PM 19860300 ER PT J AU Ballas, SK McCarthy, WF Guo, N DeCastro, L Bellevue, R Barton, BA Waclawiw, MA AF Ballas, Samir K. McCarthy, William F. Guo, Nan DeCastro, Laura Bellevue, Rita Barton, Bruce A. Waclawiw, Myron A. CA Investigators Multictr Study Hydro TI Exposure to Hydroxyurea and Pregnancy Outcomes in Patients With Sickle Cell Anemia SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE hydroxyurea; sickle cell anemia; obstetrics/gynecology ID CHRONIC MYELOID-LEUKEMIA; DISEASE; ADULTS; COMBINATION; MANAGEMENT; RATS AB The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) was a randomized double-blind placebo-controlled trial to test whether hydroxyurea could reduce the rate of painful crises in adults who had at least 3 painful crises per year. Because hydroxyurea is known to be carcinogenic, mutagenic, and teratogenic in animals, a major inclusion criterion in MSH was the use of contraceptives both by females and males in order to avoid exposure of the fetus to hydroxyurea. Despite this precautionary measure, some women became pregnant while taking hydroxyurea or their male partners were on hydroxyurea. We followed surviving patients who were enrolled in the original MSH trial for up to 17 years postrandomization. Our findings suggest that exposure of the fetus to hydroxyurea does not cause teratogenic changes in those pregnancies that terminate in live birth whether full term or premature. This seems to be true whether the parent taking hydroxyurea was the mother or the father. The same argument seems to apply for exposure to opioids. However, it will take a much longer follow-up of many more hydroxyurea-exposed sickle cell disease subjects to establish the results conclusively. C1 [Ballas, Samir K.] Thomas Jefferson Univ, Jefferson Med Coll, Cardeza Fdn Hematol Res, Sickle Cell Ctr,Dept Med, Philadelphia, PA 19107 USA. [McCarthy, William F.; Guo, Nan; Barton, Bruce A.] Maryland Med Res Inst, Baltimore, MD USA. [DeCastro, Laura] Duke Univ, Med Ctr, Durham, NC USA. [Bellevue, Rita] New York Methodist Hosp, Brooklyn, NY USA. [Waclawiw, Myron A.] NHLBI, Bethesda, MD 20892 USA. RP Ballas, SK (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Cardeza Fdn Hematol Res, Sickle Cell Ctr,Dept Med, 1015 Walnut St, Philadelphia, PA 19107 USA. EM samir.ballas@jefferson.edu OI Barton, Bruce/0000-0001-7878-8895 FU National Heart Lung, and Blood Institute [NO1-HB-67129, UO1-HL45696] FX Funding was provided by the National Heart Lung, and Blood Institute (NO1-HB-67129 and UO1-HL45696). NR 32 TC 29 Z9 29 U1 2 U2 6 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD OCT PY 2009 VL 101 IS 10 BP 1046 EP 1051 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 511XJ UT WOS:000271204700010 PM 19860305 ER PT J AU Bell, CC AF Bell, Carl C. TI Why We Should Still Publish in JNMA More Than 25 Years Later SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Editorial Material DE National Medical Association ID ISOLATED SLEEP PARALYSIS; STRESS-RELATED DISORDERS; BLACK SUBJECTS; VICTIMIZATION; NEED; POPULATION; PREVALENCE; HEALTH C1 [Bell, Carl C.] Community Mental Hlth Council & Fdn, Chicago, IL 60617 USA. [Bell, Carl C.] Univ Illinois, Inst Juvenile Res, Chicago, IL USA. [Bell, Carl C.] NIMH, Natl Mental Hlth Advisory Council, Chicago, IL USA. RP Bell, CC (reprint author), Community Mental Hlth Council & Fdn, 8704 Constance, Chicago, IL 60617 USA. EM carlcbell@pol.net NR 31 TC 0 Z9 0 U1 0 U2 0 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD OCT PY 2009 VL 101 IS 10 BP 1067 EP 1069 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 511XJ UT WOS:000271204700014 PM 19860309 ER PT J AU Hallett, M AF Hallett, M. TI Psychogenic movement disorders SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 19th World Congress of Neurology CY OCT 24-30, 2009 CL Bangkok, THAILAND C1 [Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT PY 2009 VL 285 SU 1 BP S41 EP S41 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 529ML UT WOS:000272521300146 ER PT J AU Koroshetz, W AF Koroshetz, W. TI Imaging acute stroke: Perfusion imaging, diffusion imaging and angiographic guided endovascular procedures SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 19th World Congress of Neurology CY OCT 24-30, 2009 CL Bangkok, THAILAND C1 [Koroshetz, W.] NINDS, NIH, NINDS Off Director, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT PY 2009 VL 285 SU 1 BP S10 EP S11 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 529ML UT WOS:000272521300035 ER PT J AU Masdeu, J AF Masdeu, J. TI Imaging of dementia SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 19th World Congress of Neurology CY OCT 24-30, 2009 CL Bangkok, THAILAND C1 [Masdeu, J.] NIH, Sect Integrat Neuroimaging, Bethesda, MD 20892 USA. RI Masdeu, Joseph/B-5052-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT PY 2009 VL 285 SU 1 BP S7 EP S7 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 529ML UT WOS:000272521300023 ER PT J AU Saposnik, G Bayley, M Cheung, D Willems, J Mamdani, M Cohen, L Hall, J Dishaw, A Thorpe, K Teasell, R AF Saposnik, G. Bayley, M. Cheung, D. Willems, J. Mamdani, M. Cohen, L. Hall, J. Dishaw, A. Thorpe, K. Teasell, R. TI Virtual reality technology in stroke rehabilitation: a pilot randomized trial using Wii gaming system SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Meeting Abstract CT 19th World Congress of Neurology CY OCT 24-30, 2009 CL Bangkok, THAILAND C1 [Saposnik, G.; Cheung, D.; Willems, J.; Mamdani, M.; Hall, J.; Thorpe, K.] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Bayley, M.] Toronto Rehabil Inst, Toronto, ON, Canada. [Cohen, L.] NIH, Bethesda, MD 20892 USA. [Dishaw, A.] Toronto Grace, Toronto, ON, Canada. [Teasell, R.] Univ Western Ontario, London, ON, Canada. NR 0 TC 2 Z9 3 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT PY 2009 VL 285 SU 1 BP S76 EP S76 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 529ML UT WOS:000272521300265 ER PT J AU Yavlovich, A Singh, A Tarasov, S Capala, J Blumenthal, R Puri, A AF Yavlovich, Amichai Singh, Alok Tarasov, Sergey Capala, Jacek Blumenthal, Robert Puri, Anu TI Design of liposomes containing photopolymerizable phospholipids for triggered release of contents SO JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY LA English DT Article DE Polymerizable lipids; Lipid packing; Triggered drug release; Diacetylene phospholipids; Light-sensitive liposomes; Lipid modification; Phase separation ID POLYMERIZABLE LIPID BILAYERS; THERMOTROPIC PHASE-BEHAVIOR; PHYSICAL-PROPERTIES; ACYL CHAINS; PHOSPHATIDYLCHOLINES; MEMBRANES; MIXTURES; MONOLAYERS; VESICLES; DELIVERY AB We describe a novel class of light-triggerable liposomes prepared from a photo-polymerizable phospholipid DC(8,9)PC (1,2-bis (tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine) and DPPC (1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine). Exposure to UV (254 nm) radiation for 0-45 min at 25 A degrees C resulted in photo-polymerization of DC(8,9)PC in these liposomes and the release of an encapsulated fluorescent dye (calcein). Kinetics and extents of calcein release correlated with mol% of DC(8,9)PC in the liposomes. Photopolymerization and calcein release occurred only from DPPC/DC(8,9)PC but not from Egg PC/DC(8,9)PC liposomes. Our data indicate that phase separation and packing of polymerizable lipids in the liposome bilayer are major determinants of photo-activation and triggered contents release. C1 [Yavlovich, Amichai; Blumenthal, Robert; Puri, Anu] NCI, Membrane Struct & Funct Sect, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. [Singh, Alok] USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. [Tarasov, Sergey] NCI, Struct Biophys Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Capala, Jacek] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Puri, A (reprint author), NCI, Membrane Struct & Funct Sect, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. EM apuri@helix.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; NCI Alliance for Nanotechnology FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and NCI Alliance for Nanotechnology (Piotr Grodzinski). We would like to thank Dr. Julie M. Belanger for critical reading of the manuscript. NR 25 TC 39 Z9 39 U1 0 U2 22 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1388-6150 J9 J THERM ANAL CALORIM JI J. Therm. Anal. Calorim. PD OCT PY 2009 VL 98 IS 1 BP 97 EP 104 DI 10.1007/s10973-009-0228-8 PG 8 WC Thermodynamics; Chemistry, Analytical; Chemistry, Physical SC Thermodynamics; Chemistry GA 512WI UT WOS:000271282000013 PM 20160877 ER PT J AU Giaccone, G Rajan, A Ruijter, R Smit, E van Groeningen, C Hogendoorn, PCW AF Giaccone, Giuseppe Rajan, Arun Ruijter, Rita Smit, Egbert van Groeningen, Cees Hogendoorn, Pancras C. W. TI Imatinib Mesylate in Patients with WHO B3 Thymomas and Thymic Carcinomas SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Imatinib; KIT; Thymoma ID GASTROINTESTINAL STROMAL TUMORS; GENE-MUTATIONS; KIT; TRIAL AB Thymic malignancies are rare tumors of the mediastinum. c-KIT is highly expressed in thymic carcinomas (TC) but infrequently in thymomas. Anecdotal experience suggests activity of imatinib mesylate in TC. Patients with unresectable World Health Organization B3 thymomas or TC, performance status 0 to 2, good organ function, and measurable disease were enrolled in this study. Imatinib was administered at 600 rug PO daily. Seven patients were recruited at one institution: two World Health Organization 133 thymomas and five TC. Imatinib treatment was generally well tolerated. Two patients had stable disease and five progressed. Median survival was 4 months, and median time to progression was 2 months. c-KIT expression was found in one of four samples by immunohistochemistry. No mutations were detected in the c-KIT or PDGFRA genes in three samples analyzed. Imatinib has no major activity in this rare tumor. Given the small number of patients treated in this study, selection based on presence of c-KIT mutations might be warranted. C1 [Giaccone, Giuseppe; Rajan, Arun] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Giaccone, Giuseppe; Ruijter, Rita; van Groeningen, Cees] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Smit, Egbert] Vrije Univ Amsterdam Med Ctr, Dept Pulmonol, Amsterdam, Netherlands. [Hogendoorn, Pancras C. W.] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; Hogendoorn, Pancras/H-5859-2015 OI Giaccone, Giuseppe/0000-0002-5023-7562; Hogendoorn, Pancras/0000-0002-1513-8104 NR 16 TC 42 Z9 45 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2009 VL 4 IS 10 BP 1270 EP 1273 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 504FP UT WOS:000270601600015 PM 20197733 ER PT J AU Povsic, TJ Adams, SD Zavodni, KL Kelly, F Melton, LG Rao, SV Najjar, SS Harrington, RA Peterson, ED AF Povsic, Thomas J. Adams, Stacie D. Zavodni, Katherine L. Kelly, Francine Melton, Laura G. Rao, Sunil V. Najjar, Samer S. Harrington, Robert A. Peterson, Eric D. TI Aldehyde dehydrogenase activity allows reliable EPC enumeration in stored peripheral blood samples SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Stem cell; Endothelial progenitor cell; Atherosclerosis; Clinical trials; Cell surface marker analysis; Aldehyde dehydrogenase ID ENDOTHELIAL PROGENITOR CELLS; THERAPY; NUMBER; RISK AB Background Interest in the biology of endogenous progenitor cells (EPCs) continues to grow as evidence of their role in vascular repair mounts. EPC enumeration requires specialized laboratory techniques and is performed immediately after sample acquisition, limiting the clinical contexts in which EPC enumeration can be performed and the ability to increase sample sizes through multi-center participation. Methods We compared the numbers of EPCs enumerated in samples processed immediately after acquisition (n = 36) with EPCs enumerated in specimens stored for 24 hours or after cryopreservation of mononuclear cells (MNC) using two EPC identification strategies: cell surface marker expression (CD133/CD34) and aldehyde dehydrogenase activity (ALDH(br) cells). Results EPCs assessed in fresh samples correlated with EPCs enumerated after whole blood storage (r = 0.699 for CD133(+)CD34(+) cells, r = 0.880 for ALDH(br) cells, P < 0.005 and P < 0.0001, respectively) or mononuclear cryopreservation (r = 0.590 for CD133(+)CD34(+) cells, r = 0.894 for ALDH(br) cells, P < 0.0001 for each); however, correlation based on assessment of ALDH(br) cells was higher (P < 0.0003 for comparison of correlation coefficients). Initial results from a multi-site clinical trial suggest that EPC enumeration after mononuclear cell cryopreservation is feasible. Conclusion EPC analysis based on ALDH activity is reproducible, even after extended whole blood storage or MNC cryopreservation. C1 [Povsic, Thomas J.; Adams, Stacie D.; Zavodni, Katherine L.; Kelly, Francine] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Melton, Laura G.; Rao, Sunil V.; Harrington, Robert A.; Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Najjar, Samer S.] NIA, Baltimore, MD 21224 USA. RP Povsic, TJ (reprint author), Duke Univ, Med Ctr, Div Cardiol, Box 3126, Durham, NC 27710 USA. EM povsi001@mc.duke.edu FU National Heart, Lung, and Blood Institute [K-18 HL081419-01A1]; Society of Geriatric Cardiology Merck Geriatric Cardiology Research Award (TJP); the Duke Clinical Research Institute (TJP) FX This study was funded in part by National Heart, Lung, and Blood Institute grant K-18 HL081419-01A1 (TJP), a Society of Geriatric Cardiology Merck Geriatric Cardiology Research Award (TJP), and a grant from the Duke Clinical Research Institute (TJP). NR 13 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD OCT PY 2009 VL 28 IS 3 BP 259 EP 265 DI 10.1007/s11239-009-0306-6 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 495AD UT WOS:000269860600002 PM 19184616 ER PT J AU Koenen, KC Amstadter, AB Nugent, NR AF Koenen, Karestan C. Amstadter, Ananda B. Nugent, Nicole R. TI Gene-Environment Interaction in Posttraumatic Stress Disorder: An Update SO JOURNAL OF TRAUMATIC STRESS LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the International-Society-for-Traumatic-Stress-Studies CY NOV, 2008 CL Chicago, IL SP Int Soc Traumat Stress Studies ID SEROTONIN TRANSPORTER GENOTYPE; TRAUMA EXPOSURE; ANXIETY DISORDERS; RISK-FACTORS; VIETNAM-WAR; ADULTS; POLYMORPHISMS; ASSOCIATION; SYMPTOMS; TWIN AB The authors provide a detailed review of the extant gene-environment interaction (GxE) research in the etiology of posttraumatic stress disorder (PTSD). They begin with a discussion of why PTSD is uniquely fitting for the innovative framework of GxE methodology, followed by a review of the heritability and main effect molecular genetics studies of PTSD. Next, they discuss the six GxE investigations to date on PTSD. They end with a discussion of future directions and significance of this research, with an emphasis on the expansion of psychosocial factors that may befitting environmental variables for inclusion in this new research area. The authors posit that GxE research is vital to elucidating risk and resilience following exposure to a potentially traumatic event. C1 [Koenen, Karestan C.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Koenen, Karestan C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Amstadter, Ananda B.] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Amstadter, Ananda B.] Med Univ S Carolina, Dept Behav Sci, Charleston, SC 29425 USA. [Nugent, Nicole R.] Brown Med Sch, NIMH Inst Res Training Program, Providence, RI USA. RP Koenen, KC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 677 Huntington Ave,Kresge 613, Boston, MA 02115 USA. EM kkoenen@hsph.harvard.edu RI Koenen, Karestan/K-5402-2014 OI Koenen, Karestan/0000-0003-3293-4281 FU NIMH NIH HHS [F32 MH083469, F32 MH083469-01, K01 MH087240, K08 MH070627, K08 MH070627-06, L40 MH084279, L40 MH084279-01, MH078928, R01 MH078928, R01 MH078928-02, T32 MH078788]; PHS HHS [083469] NR 46 TC 56 Z9 58 U1 8 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 EI 1573-6598 J9 J TRAUMA STRESS JI J. Trauma Stress PD OCT PY 2009 VL 22 IS 5 BP 416 EP 426 DI 10.1002/jts.20435 PG 11 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 515SK UT WOS:000271493000010 PM 19743189 ER PT J AU Hamill, N Romero, R Hassan, SS Lee, W Myers, SA Mittal, P Kusanovic, JP Chaiworapongsa, T Vaisbuch, E Espinoza, J Gotsch, F Carletti, A Goncalves, LF Yeo, L AF Hamill, Neil Romero, Roberto Hassan, Sonia S. Lee, Wesley Myers, Stephen A. Mittal, Pooja Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Vaisbuch, Edi Espinoza, Jimmy Gotsch, Francesca Carletti, Angela Goncalves, Luis F. Yeo, Lami TI Repeatability and Reproducibility of Fetal Cardiac Ventricular Volume Calculations Using Spatiotemporal Image Correlation and Virtual Organ Computer-Aided Analysis SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE cardiac function; Contour Finder; fetal echocardiography; fetus; 4-dimensional ultrasonography; inversion mode; 3-dimensional echocardiography; ultrasonography; ventricular volume ID NORMAL HUMAN-FETUS; 4-DIMENSIONAL ULTRASOUND; BLOOD-FLOW; 3-DIMENSIONAL ULTRASOUND; INTRAUTERINE GROWTH; GESTATIONAL-AGE; STROKE VOLUME; ECHOCARDIOGRAPHY; HEART; OUTPUT AB Objective. The objective of this study was to quantify the repeatability and reproducibility of fetal cardiac ventricular volumes obtained using spatiotemporal image correlation (STIC) and Virtual Organ Computer-Aided Analysis (VOCAL; GE Healthcare, Kretztechnik, Zipf, Austria). Methods. A technique was developed to compute ventricular volumes using the subfeature Contour Finder: Trace. Twenty-five normal pregnancies were evaluated for the following: (1) to compare the coefficient of variation (CV) of ventricular volumes obtained using 15 degrees and 30 degrees rotation; (2) to compare the CV between 3 methods of quantifying ventricular volumes: (a) Manual Trace, (b) Inversion Mode, and (c) Contour Finder: Trace; and (3) to determine repeatability by calculating agreement and reliability of ventricular volumes when each STIC was measured twice by 3 observers. Reproducibility was assessed by obtaining 2 STICs from each of 44 normal pregnancies. For each STIC, 2 ventricular volume calculations were performed, and agreement and reliability were evaluated. Additionally, measurement error was examined. Results. (1) Agreement was better with 151 rotation than 30 degrees (15 degrees: 3.6%; 95% confidence interval [CI], 3.0%-4.2%; versus 30 degrees: 7.1%; 95% Cl, 5.8%-8.6%; P < .001); (2) ventricular volumes obtained with Contour Finder: Trace had better agreement than those obtained using either Inversion Mode (Contour Finder: Trace: 3.6%; 95% Cl, 3.0%-4.2%; versus Inversion Mode: 6.0%; 95% Cl, 4.9%-7.2%; P < .001) or Manual Trace (10.5%; 95% Cl, 8.7%-12.5%; P < .001); (3) ventricular volumes were repeatable with good agreement and excellent reliability for both intraobserver and interobserver measurements; and (4) ventricular volumes were reproducible with negligible differences in agreement and good reliability. In addition, bias between STIC acquisitions was minimal (<1%; mean percent difference, -0.4%; 95% limits of agreement, -5.4%-5.9%). Conclusions. Fetal echocardiography using STIC and VOCAL allows repeatable and reproducible calculation of ventricular volumes with the subfeature Contour Finder: Trace. C1 [Hamill, Neil; Romero, Roberto; Hassan, Sonia S.; Mittal, Pooja; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Vaisbuch, Edi; Espinoza, Jimmy; Gotsch, Francesca; Goncalves, Luis F.; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Hamill, Neil; Romero, Roberto; Hassan, Sonia S.; Mittal, Pooja; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Vaisbuch, Edi; Espinoza, Jimmy; Goncalves, Luis F.; Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Lee, Wesley] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Myers, Stephen A.] Case Metrohlth, Cleveland, OH USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM nichdprbchiefstaff@mail.nih.gov OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch; Division of Intramural Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health; US Department of Health and Human Services FX This research was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, US Department of Health and Human Services. NR 42 TC 18 Z9 22 U1 0 U2 3 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2009 VL 28 IS 10 BP 1301 EP 1311 PG 11 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 503KH UT WOS:000270532500004 PM 19778875 ER PT J AU Espinoza, J Romero, R Kusanovic, JP Gotsch, F Erez, O Hassan, S Yeo, L AF Espinoza, Jimmy Romero, Roberto Kusanovic, Juan Pedro Gotsch, Francesca Erez, Offer Hassan, Sonia Yeo, Lami TI Prenatal Diagnosis of Coarctation of the Aorta With the Multiplanar Display and B-Flow Imaging Using 4-Dimensional Sonography SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article ID FETAL ECHOCARDIOGRAPHY; ULTRASOUND; ULTRASONOGRAPHY; HEART AB Coarctation of the aorta is characterized by narrowing of the distal aortic arch. This obstructive lesion may reduce the blood flow in the fetal aortic arch, leading to arch hypoplasia, although in some cases this may only be clinically evident after birth. A sonographic finding described in neonates with coarctation of the aorta is the "contraductal shelf," which has been proposed to represent residual fibrous tissue derived from the ductus arteriosus. B-flow is a display modality in 4-dimensional (4D) sonography that enhances signals from weak blood reflectors from vessels, suppresses strong signals from surrounding tissues, and is angle independent. Here, we report a case of coarctation of the aorta diagnosed in utero in which B-flow imaging provided important insight into the location and nature of this aortic arch anomaly. C1 [Espinoza, Jimmy; Romero, Roberto; Kusanovic, Juan Pedro; Gotsch, Francesca; Erez, Offer; Hassan, Sonia; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Espinoza, Jimmy; Kusanovic, Juan Pedro; Erez, Offer; Hassan, Sonia; Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, US Department of Health and Human Services FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, US Department of Health and Human Services. NR 13 TC 7 Z9 9 U1 0 U2 3 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2009 VL 28 IS 10 BP 1375 EP 1378 PG 4 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 503KH UT WOS:000270532500014 PM 19778885 ER PT J AU Lee, W Comstock, CH Kazmierczak, C Wilson, J Goncalves, LF Mody, S Yeo, L Romero, R AF Lee, Wesley Comstock, Christine H. Kazmierczak, Chris Wilson, Jon Goncalves, Luis F. Mody, Swati Yeo, Lami Romero, Roberto TI Prenatal Diagnostic Challenges and Pitfalls for Schizencephaly SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article AB Schizencephaly is a developmental anomaly that causes unilateral or bilateral clefts of the cerebral hemisphere as a result of disordered neuronal migration. The clefts are lined by gray matter that can extend medially from the subarachnoid cerebrospinal fluid space into the lateral ventricle as part of a disease spectrum that includes porencephaly, Closed-lip schizencephaly (type 1) occurs when the gray matter-lined walls are in contact with each other.(1) By contrast, the open-lip variety (type 2) has separated lips with a cleft of cerebrospinal fluid that extends to the ventricles.(2) Barkovich and Kjos(3) reported that the clinical manifestations of affected infants were related to the size and location of the cleft defect. Late prenatal schizencephaly has been described. We now report a well-documented case that shows diagnostic challenges and pitfalls associated with its early diagnosis by 2- and 3-dimensional sonography and magnetic resonance imaging (MRI). C1 [Lee, Wesley; Comstock, Christine H.] Oakland Univ, William Beaumont Sch Med, Div Fetal Imaging, Dept Obstet & Gynecol, Royal Oak, MI USA. [Kazmierczak, Chris] Oakland Univ, William Beaumont Sch Med, Dept Diagnost Radiol, Royal Oak, MI USA. [Wilson, Jon] Oakland Univ, William Beaumont Sch Med, Dept Anat Pathol, Royal Oak, MI USA. [Lee, Wesley; Comstock, Christine H.; Goncalves, Luis F.; Yeo, Lami; Romero, Roberto] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Mody, Swati] Wayne State Univ, Dept Pediat Imaging, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Lee, Wesley; Goncalves, Luis F.; Yeo, Lami; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. RP Lee, W (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM wlee@beaumont.edu RI Wilson, Jon/H-5148-2012 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, US Department of Health and Human Services FX We thank the following individuals for their input regarding the potential nature of the small echogenic structure that mimicked a closed-lip schizencephalic cleft defect: James Barkovich, MD, Catherine Garel, MD, Jeffrey Golden, MD, Ana Monteagudo, MD, and Daniela Prayer MD. This research was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, US Department of Health and Human Services. NR 13 TC 5 Z9 5 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2009 VL 28 IS 10 BP 1379 EP 1384 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 503KH UT WOS:000270532500015 PM 19778886 ER PT J AU Boris, R Proano, M Linehan, WM Pinto, PA Bratslavsky, G AF Boris, Ronald Proano, Miguel Linehan, W. Marston Pinto, Peter A. Bratslavsky, Gennady TI Initial Experience With Robot Assisted Partial Nephrectomy for Multiple Renal Masses SO JOURNAL OF UROLOGY LA English DT Article DE kidney; nephrectomy; robotics; kidney neoplasms; genetic diseases ID LAPAROSCOPIC PARTIAL NEPHRECTOMY; NEPHRON-SPARING SURGERY; CELL CARCINOMA; WARM ISCHEMIA; TUMORS; OUTCOMES; KIDNEY; CRYOABLATION; FEASIBILITY; RECURRENCE AB Purpose: We evaluated the feasibility of performing robot assisted partial nephrectomy in patients with multiple renal masses and examined the results of our initial experiences. Materials and Methods: We reviewed the records of 10 patients with multiple renal masses who underwent attempted robot assisted partial nephrectomy within the last 2 years. Demographic information, and intraoperative, perioperative and renal function outcome data on these patients were reviewed. Results: A total of 24 tumors in 9 patients were removed with robot assistance. There was 1 open conversion with successful completion of partial nephrectomy. Of the patients 70% had a known hereditary renal cancer syndrome and the remainder had multifocal disease with unknown germline genetic alterations. Frozen section from the tumor bed evaluated in 5 of 10 cases was negative. One patient experienced urinary leak postoperatively, which resolved by postoperative day 9 without intervention. Of the 24 robotically resected masses 22 were malignant. Our most recent 3 patients underwent successful partial nephrectomy without hilar clamping, obviating the need for warm ischemia. Overall renal function was unchanged at most recent followup with a minimal decrease in operated kidney differential function. Conclusions: Robot assisted partial nephrectomy for multiple renal masses was feasible in our early experience. Patient selection is paramount for successful minimally invasive surgery. Robot assisted partial nephrectomy without hilar clamping, especially in the hereditary patient population in which repeat ipsilateral partial nephrectomy may be anticipated, appears promising but requires further evaluation. C1 [Boris, Ronald; Proano, Miguel; Linehan, W. Marston; Pinto, Peter A.; Bratslavsky, Gennady] NCI, Urol Oncol Branch, CRC, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bratslavsky, G (reprint author), NCI, Urol Oncol Branch, CRC, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,MSC 1107,Bldg 10,Room 2W-5942, Bethesda, MD 20892 USA. EM bratslag@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center FX Supported by the National Institutes of Health, National Cancer Institute, Center for Cancer Research Intramural Research Program. NR 22 TC 32 Z9 35 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2009 VL 182 IS 4 BP 1280 EP 1286 DI 10.1016/j.juro.2009.06.036 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 493UP UT WOS:000269764100011 PM 19683275 ER PT J AU Loeb, S Kettermann, A Carter, HB Ferrucci, L Metter, EJ Walsh, PC AF Loeb, Stacy Kettermann, Anna Carter, H. Ballentine Ferrucci, Luigi Metter, E. Jeffrey Walsh, Patrick C. TI Prostate Volume Changes Over Time: Results From the Baltimore Longitudinal Study of Aging SO JOURNAL OF UROLOGY LA English DT Article DE prostatic hyperplasia; prostate; organ size; atrophy; longitudinal studies ID HYPERPLASIA; MEN; ANTIGEN; AGE; FINASTERIDE; THERAPY; RISK; MRI AB Purpose: According to a 1944 publication by Swyer benign prostatic hyperplasia develops in some men after age 45 with further prostatic growth whereas in other men prostate size remains stable or decreases with advancing age. Although there is an abundance of literature describing prostatic enlargement in association with benign prostatic hyperplasia, less is known about the phenomenon of prostate atrophy. Materials and Methods: In the Baltimore Longitudinal Study of Aging serial pelvic magnetic resonance imaging was performed in men without prostate cancer beginning in 1993. From this population we retrospectively identified 278 men with 2 or more magnetic resonance imaging determined prostate volume measurements to examine differential growth rates in a cohort of community men over time. Results: Median age was 58 years and median prostate size was 28 cc at study entry. At a median followup of 4.3 years prostate size increased in 61.9% and remained stable or decreased in 38.1% of men. The median rate of volume change was 0.6 cc per year (range -9.9 to 62.1), corresponding to a median growth rate of 2.5% per year (range -29.2 to 176.4%). During followup 64.6% of men with an initial prostate size less than 40 cc had prostate growth compared to only 50.9% of men with an initial prostate size of 40 cc or greater. Conclusions: These results suggest that changes in prostate size are highly variable among aging men. Although benign prostatic hyperplasia is common, a considerable proportion of aging men have a stable or decreasing prostate size. Further research is needed to identify the underlying mechanism for such differences in prostate growth. C1 [Loeb, Stacy; Kettermann, Anna; Carter, H. Ballentine; Walsh, Patrick C.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Ferrucci, Luigi; Metter, E. Jeffrey] NIA, NIH, Clin Res Branch, Baltimore, MD 21224 USA. RP Loeb, S (reprint author), Johns Hopkins Brady Urol Inst, 600 N Wolfe St,Marburg 100, Baltimore, MD 21287 USA. EM stacyloeb@gmail.com OI Loeb, Stacy/0000-0003-3933-9207 FU Intramural NIH HHS [Z01 AG000015-49] NR 16 TC 23 Z9 24 U1 0 U2 0 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 OCT PY 2009 VL 182 IS 4 BP 1458 EP 1462 DI 10.1016/j.juro.2009.06.047 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 493UP UT WOS:000269764100082 PM 19683305 ER PT J AU McClenahan, SD Bok, K Neill, JD Smith, AW Rhodes, CR Sosnovtsev, SV Green, KY Romero, CH AF McClenahan, Shasta D. Bok, Karin Neill, John D. Smith, Alvin W. Rhodes, Crystal R. Sosnovtsev, Stanislav V. Green, Kim Y. Romero, Carlos H. TI A capsid gene-based real-time reverse transcription polymerase chain reaction assay for the detection of marine vesiviruses in the Caliciviridae SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Vesiviruses; Caliciviridae; Marine mammals; Real-time RT-PCR; Diagnosis ID SEA-LION-VIRUS; VESICULAR EXANTHEMA; GIRELLA-NIGRICANS; SWINE VIRUS; GASTROENTERITIS; ANTIBODIES; SEQUENCE; SEROTYPE; CATS; FISH AB A real-time reverse transcription polymerase chain reaction (rtRT-PCR) assay was developed for the identification of marine vesiviruses. The primers were designed to target a 176-nucleotide fragment within a highly conserved region of the San Miguel sea lion viruses (SMSVs) capsid gene. The assay detected viral RNA from nine marine vesivirus serotypes described previously, including two serotypes (SMSV-8 and -12) not identified with presently available molecular assays, a highly related bovine vesivirus strain (Bos-1), a mink vesivirus strain (MCV), and two novel genotypes isolated recently from Steller sea lions (SSL V810 and V1415). The real-time assay did not amplify sequences from the corresponding genomic regions of feline calicivirus (also in the genus Vesivirus) and representative members of the genus Norovirus. The rtRT-PCR assay described below may prove useful as a diagnostic tool for the detection of currently circulating, emerging and previously described marine vesiviruses in clinical samples, especially when large numbers are screened in surveillance studies of these restricted viruses. (C) 2009 Elsevier B.V. All rights reserved. C1 [McClenahan, Shasta D.; Romero, Carlos H.] Univ Florida, Dept Infect Dis & Pathol, Coll Vet Med, Gainesville, FL 32610 USA. [Neill, John D.] USDA, Natl Anim Dis Ctr, Ames, IA 50010 USA. [Smith, Alvin W.] Oregon State Univ, Lab Calicivirus Studies, Corvallis, OR 97331 USA. [Bok, Karin; Rhodes, Crystal R.; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Romero, CH (reprint author), Univ Florida, Dept Infect Dis & Pathol, Coll Vet Med, 2015 SW 16th Ave,Bldg 1017, Gainesville, FL 32610 USA. EM romeroc@vetmed.ufl.edu FU Department of Infectious Diseases and Pathology; Marine Mammal Health Program of the College of Veterinary Medicine, University of Florida; NIH; NIAID FX This research was funded by the Department of Infectious Diseases and Pathology and the Marine Mammal Health Program of the College of Veterinary Medicine, University of Florida. This research was also partially supported by the Intramural Research Program of the NIH, NIAID. NR 38 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD OCT PY 2009 VL 161 IS 1 BP 12 EP 18 DI 10.1016/j.jviromet.2009.04.026 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 484TL UT WOS:000269070300003 PM 19410604 ER PT J AU Asabe, S Wieland, SF Chattopadhyay, PK Roederer, M Engle, RE Purcell, RH Chisari, FV AF Asabe, Shinichi Wieland, Stefan F. Chattopadhyay, Pratip K. Roederer, Mario Engle, Ronald E. Purcell, Robert H. Chisari, Francis V. TI The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CD8(+) T-CELLS; LYMPHOCYTE RESPONSIVENESS; CD8-T-CELL MEMORY; RNA REPLICATION; PD-1 EXPRESSION; CD4-T-CELL HELP; HBV INFECTION; EXHAUSTION; TOLERANCE; IMMUNITY AB The impact of virus dose on the outcome of infection is poorly understood. In this study we show that, for hepatitis B virus (HBV), the size of the inoculum contributes to the kinetics of viral spread and immunological priming, which then determine the outcome of infection. Adult chimpanzees were infected with a serially diluted monoclonal HBV inoculum. Unexpectedly, despite vastly different viral kinetics, both high-dose inocula (10(10) genome equivalents [GE] per animal) and low-dose inocula (10(0) GE per animal) primed the CD4 T-cell response after logarithmic spread was detectable, allowing infection of 100% of hepatocytes and requiring prolonged immunopathology before clearance occurred. In contrast, intermediate (10(7) and 10(4) GE) inocula primed the T-cell response before detectable logarithmic spread and were abruptly terminated with minimal immunopathology before 0.1% of hepatocytes were infected. Surprisingly, a dosage of 10(1) GE primed the T-cell response after all hepatocytes were infected and caused either prolonged or persistent infection with severe immunopathology. Finally, CD4 T-cell depletion before inoculation of a normally rapidly controlled inoculum precluded T-cell priming and caused persistent infection with minimal immunopathology. These results suggest that the relationship between the kinetics of viral spread and CD4 T-cell priming determines the outcome of HBV infection. C1 [Asabe, Shinichi; Wieland, Stefan F.; Chisari, Francis V.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, Immuno Technol Sect, Immunol Lab, Vaccine Res Ctr,NIH, Bethesda, MD 20892 USA. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Chisari, FV (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, SBR-10,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM fchisari@scripps.edu RI Chattopadhyay, Pratip/B-9227-2008; Chisari, Francis/A-3086-2008; OI Chisari, Francis/0000-0002-4832-1044; Chattopadhyay, Pratip/0000-0002-5457-9666 FU National Institutes of Health (NIH) [AI20001, CA76403, N01-AI-52705, N01-AI-45180, N01-CO-56000]; Sam and Rose Stein Charitable Trust FX This study was supported by grants AI20001 and CA76403 and by contracts N01-AI-52705, N01-AI-45180 and N01-CO-56000 from the National Institutes of Health (NIH); by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, NIH; and by the Sam and Rose Stein Charitable Trust. NR 34 TC 103 Z9 112 U1 2 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2009 VL 83 IS 19 BP 9652 EP 9662 DI 10.1128/JVI.00867-09 PG 11 WC Virology SC Virology GA 491WX UT WOS:000269614300004 PM 19625407 ER PT J AU Hyde, JL Sosnovtsev, SV Green, KY Wobus, C Virgin, HW Mackenzie, JM AF Hyde, Jennifer L. Sosnovtsev, Stanislav V. Green, Kim Y. Wobus, Christiane Virgin, Herbert W. Mackenzie, Jason M. TI Mouse Norovirus Replication Is Associated with Virus-Induced Vesicle Clusters Originating from Membranes Derived from the Secretory Pathway SO JOURNAL OF VIROLOGY LA English DT Article ID MOUTH-DISEASE VIRUS; FLAVIVIRUS-INFECTED CELLS; NORWALK-LIKE VIRUSES; DOUBLE-STRANDED-RNA; ENDOPLASMIC-RETICULUM; BREFELDIN-A; SUBCELLULAR-DISTRIBUTION; VIRAL REPLICATION; GOLGI MEMBRANES; IN-VITRO AB Human noroviruses (family Caliciviridae) are the leading cause of nonbacterial gastroenteritis worldwide. Despite the prevalence of these viruses within the community, the study of human norovirus has largely been hindered due to the inability to cultivate the viruses ex vivo and the lack of a small-animal model. In 2003, the discovery of a novel murine norovirus (MNV-1) and the identification of the tropism of MNV-1 for cells of a mononuclear origin led to the establishment of the first norovirus tissue culture system. Like other positive-sense RNA viruses, MNV-1 replication is associated with host membranes, which undergo significant rearrangement during infection. We characterize here the subcellular localization of the MNV-1 open reading frame 1 proteins and viral double-stranded RNA (dsRNA). Over the course of infection, dsRNA and the MNV-1 RNA-dependent RNA polymerase (NS7) were observed to proliferate from punctate foci located in the perinuclear region. All of the MNV-1 open reading frame 1 proteins were observed to colocalize with dsRNA during the course of infection. The MNV-1 replication complex was immunolocalized to virus-induced vesicle clusters formed in the cytoplasm of infected cells. Both dsRNA and MNV-1 NS7 were observed to localize to the limiting membrane of the individual clusters by cryo-immunoelectron microscopy. We show that the MNV-1 replication complex initially associates with membranes derived from the endoplasmic reticulum, trans-Golgi apparatus, and endosomes. In addition, we show that MNV-1 replication is insensitive to the fungal metabolite brefeldin A and consistently does not appear to recruit coatomer protein complex I (COPI) or COPII component proteins during replication. These data provide preliminary insights into key aspects of replication of MNV-1, which will potentially further our understanding of the pathogenesis of noroviruses and aid in the identification of potential targets for drug development. C1 [Hyde, Jennifer L.; Mackenzie, Jason M.] La Trobe Univ, Dept Microbiol, Melbourne, Vic 3086, Australia. [Hyde, Jennifer L.] Univ Queensland, Sch Mol & Microbial Sci, Brisbane, Qld 4072, Australia. [Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Norovirus Gastroenteritis Unit, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wobus, Christiane] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Virgin, Herbert W.] Washington Univ, Sch Med, St Louis, MO 63110 USA. RP Mackenzie, JM (reprint author), La Trobe Univ, Dept Microbiol, Thomas Cherry Bldg,Kingsbury Dr, Melbourne, Vic 3086, Australia. EM j.mackenzie@latrobe.edu.au OI Mackenzie, Jason/0000-0001-6613-8350 FU National Health and Medical Research Council of Australia; National Institutes of Health [AI054483, AI065982] FX This research was supported by research grants to J. M. M. from the National Health and Medical Research Council of Australia and to J. M. M. and H. W. V. from the National Institutes of Health (grants AI054483 and AI065982). This research was also supported, in part, by the Intramural Research Program of the NIAID, National Institutes of Health (K. Y. G. and S. V. S.). NR 54 TC 49 Z9 49 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2009 VL 83 IS 19 BP 9709 EP 9719 DI 10.1128/JVI.00600-09 PG 11 WC Virology SC Virology GA 491WX UT WOS:000269614300009 PM 19587041 ER PT J AU Shiu, C Cunningham, CK Greenough, T Muresan, P Sanchez-Merino, V Carey, V Jackson, JB Ziemniak, C Fox, L Belzer, M Ray, SC Luzuriaga, K Persaud, D AF Shiu, Carlum Cunningham, Coleen K. Greenough, Thomas Muresan, Petronella Sanchez-Merino, Victor Carey, Vincent Jackson, J. Brooks Ziemniak, Carrie Fox, Lawrence Belzer, Marvin Ray, Stuart C. Luzuriaga, Katherine Persaud, Deborah CA Pediat AIDS Clinical Trials Grp P1 TI Identification of Ongoing Human Immunodeficiency Virus Type 1 (HIV-1) Replication in Residual Viremia during Recombinant HIV-1 Poxvirus Immunizations in Patients with Clinically Undetectable Viral Loads on Durable Suppressive Highly Active Antiretroviral Therapy SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; LOW-LEVEL VIREMIA; DRUG-RESISTANCE; REVERSE-TRANSCRIPTASE; COMBINATION THERAPY; LYMPHOCYTE RESPONSE; RANDOMIZED-TRIAL; EVOLUTION; ADULTS; RNA AB In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of <50 copies/ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (<6.5 copies/ml) and genotyping (five-copy sensitivity) assays. Viral evolution, consisting of new drug resistance mutations and novel amino acid changes within a relevant HLA-restricted allele (e. g., methionine, isoleucine, glutamine, or arginine for leucine at position 205 of RT), was found in 1 and 3 of 20 subjects, respectively. Sequence evolution was significantly correlated with levels of viremia of between 6.5 and <50 copies/ml (P = 0.03) and was more likely to occur within epitopes presented by relevant HLA alleles (P < 0.001). These findings suggest that ongoing virus replication contributes to low-level viremia in patients on HAART and that this ongoing replication is subject to CD8(+) T-cell selective pressures. C1 [Persaud, Deborah] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. [Cunningham, Coleen K.] Duke Univ, Med Ctr, Durham, NC USA. [Greenough, Thomas; Sanchez-Merino, Victor; Luzuriaga, Katherine] Univ Massachusetts, Worcester, MA 01605 USA. [Muresan, Petronella; Carey, Vincent] Stat & Data Anal Ctr, Boston, MA USA. [Fox, Lawrence] NIAID, NIH, Bethesda, MD 20892 USA. [Belzer, Marvin] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP Persaud, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, 200 N Wolfe St,Room 3151, Baltimore, MD 21287 USA. EM dpers@jhmi.edu RI Ray, Stuart/B-7527-2008 OI Ray, Stuart/0000-0002-1051-7260 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 A1068632]; National Center for Research Resources; National Institute of Child Health and Human Development [N01-HD-3-3345]; Pediatric AIDS Clinical Trials Group (PACTG); NIAID [R01 A155312, R01 A1062446, RO1 32391] FX We also acknowledge Linda Lambrecht from the University of Massachusetts, who performed the IFN-gamma ELISPOT assays; Roxann Ashworth from the Institute of Genetics, Johns Hopkins School of Medicine, for her independent analyses of the HIV-1 RT sequence chromatograms; and Estelle Piwowar-Manning for her contributions to the ultrasensitive viral load quantitation. We also express great appreciation to the clinical trial sites and the young adults who participated in this trial. NR 49 TC 35 Z9 35 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2009 VL 83 IS 19 BP 9731 EP 9742 DI 10.1128/JVI.00570-09 PG 12 WC Virology SC Virology GA 491WX UT WOS:000269614300011 PM 19605490 ER PT J AU Uchida, N Washington, KN Hayakawa, J Hsieh, MM Bonifacino, AC Krouse, AE Metzger, ME Donahue, RE Tisdale, JF AF Uchida, Naoya Washington, Kareem N. Hayakawa, Jun Hsieh, Matthew M. Bonifacino, Aylin C. Krouse, Allen E. Metzger, Mark E. Donahue, Robert E. Tisdale, John F. TI Development of a Human Immunodeficiency Virus Type 1-Based Lentiviral Vector That Allows Efficient Transduction of both Human and Rhesus Blood Cells SO JOURNAL OF VIROLOGY LA English DT Article ID RESTRICTS HIV-1 INFECTION; HEMATOPOIETIC STEM-CELLS; GENE-THERAPY; PERIPHERAL-BLOOD; CD34(+) CELLS; NONHUMAN-PRIMATES; SIMIAN CELLS; BONE-MARROW; BETA-GLOBIN; IN-VIVO AB Human immunodeficiency virus type 1 (HIV-1) vectors transduce rhesus blood cells poorly due to a species-specific block by TRIM5 alpha and APOBEC3G, which target HIV-1 capsid and viral infectivity factor (Vif), respectively. We sought to develop a lentiviral vector capable of transducing both human and rhesus blood cells by combining components of both HIV-1 and simian immunodeficiency virus (SIV), including SIV capsid (sCA) and SIV Vif. A chimeric HIV-1 vector including sCA (chi HIV) was superior to the conventional SIV in transducing a human blood cell line and superior to the conventional HIV-1 vector in transducing a rhesus blood cell line. Among human CD34(+) hematopoietic stem cells (HSCs), the chi HIV and HIV-1 vectors showed similar transduction efficiencies; in rhesus CD34(+) HSCs, the chi HIV vector yielded superior transduction rates. In in vivo competitive repopulation experiments with two rhesus macaques, the chi HIV vector demonstrated superior marking levels over the conventional HIV-1 vector in all blood lineages (first rhesus, 15 to 30% versus 1 to 5%; second rhesus, 7 to 15% versus 0.5 to 2%, respectively) 3 to 7 months postinfusion. In summary, we have developed an HIV-1-based lentiviral vector system that should allow comprehensive preclinical testing of HIV-1-based therapeutic vectors in the rhesus macaque model with eventual clinical application. C1 [Uchida, Naoya; Washington, Kareem N.; Hayakawa, Jun; Hsieh, Matthew M.; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bethesda, MD 20892 USA. [Uchida, Naoya] Nippon Med Sch, Div Hematol, Dept Internal Med, Tokyo 113, Japan. [Bonifacino, Aylin C.; Krouse, Allen E.; Metzger, Mark E.; Donahue, Robert E.] NHLBI, Hematol Branch, NIH, Rockville, MD USA. RP Tisdale, JF (reprint author), NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, 9000 Rockville Pike,Bldg 10 9N116, Bethesda, MD 20892 USA. EM johntis@nhlbi.nih.gov FU National Institute of Diabetes, Digestive, and Kidney Diseases; National Heart, Lung, and Blood Institute of the National Institutes of Health FX We thank Keyvan Keyvanfar and Martha Kirby for their assistance in flow cytometric analyses and the staff at 5 Research Court for their excellent care and handling of the rhesus macaques. NR 41 TC 25 Z9 25 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2009 VL 83 IS 19 BP 9854 EP 9862 DI 10.1128/JVI.00357-09 PG 9 WC Virology SC Virology GA 491WX UT WOS:000269614300021 PM 19625395 ER PT J AU Quinn, K Brindley, MA Weller, ML Kaludov, N Kondratowicz, A Hunt, CL Sinn, PL McCray, PB Stein, CS Davidson, BL Flick, R Mandell, R Staplin, W Maury, W Chiorini, JA AF Quinn, Kathrina Brindley, Melinda A. Weller, Melodie L. Kaludov, Nikola Kondratowicz, Andrew Hunt, Catherine L. Sinn, Patrick L. McCray, Paul B., Jr. Stein, Colleen S. Davidson, Beverly L. Flick, Ramon Mandell, Robert Staplin, William Maury, Wendy Chiorini, John A. TI Rho GTPases Modulate Entry of Ebola Virus and Vesicular Stomatitis Virus Pseudotyped Vectors SO JOURNAL OF VIROLOGY LA English DT Article ID DIFFICILE TOXIN-B; FOLATE RECEPTOR-ALPHA; ENVELOPE GLYCOPROTEINS; CELLULAR ENTRY; HOST-CELLS; PROTEINS; ENDOCYTOSIS; INHIBITION; BINDING; INFECTION AB To explore mechanisms of entry for Ebola virus (EBOV) glycoprotein (GP) pseudotyped virions, we used comparative gene analysis to identify genes whose expression correlated with viral transduction. Candidate genes were identified by using EBOV GP pseudotyped virions to transduce human tumor cell lines that had previously been characterized by cDNA microarray. Transduction profiles for each of these cell lines were generated, and a significant positive correlation was observed between RhoC expression and permissivity for EBOV vector transduction. This correlation was not specific for EBOV vector alone as RhoC also correlated highly with transduction of vesicular stomatitis virus GP (VSVG) pseudotyped vector. Levels of RhoC protein in EBOV and VSV permissive and nonpermissive cells were consistent with the cDNA gene array findings. Additionally, vector transduction was elevated in cells that expressed high levels of endogenous RhoC but not RhoA. RhoB and RhoC overexpression significantly increased EBOV GP and VSVG pseudotyped vector transduction but had minimal effect on human immunodeficiency virus (HIV) GP pseudotyped HIV or adeno-associated virus 2 vector entry, indicating that not all virus uptake was enhanced by expression of these molecules. RhoB and RhoC overexpression also significantly enhanced VSV infection. Similarly, overexpression of RhoC led to a significant increase in fusion of EBOV virus-like particles. Finally, ectopic expression of RhoC resulted in increased nonspecific endocytosis of fluorescent dextran and in formation of increased actin stress fibers compared to RhoA-transfected cells, suggesting that RhoC is enhancing macropinocytosis. In total, our studies implicate RhoB and RhoC in enhanced productive entry of some pseudovirions and suggest the involvement of actin-mediated macropinocytosis as a mechanism of uptake of EBOV GP and VSVG pseudotyped viral particles. C1 [Quinn, Kathrina; Weller, Melodie L.; Kaludov, Nikola; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Brindley, Melinda A.; Kondratowicz, Andrew; Hunt, Catherine L.; McCray, Paul B., Jr.; Maury, Wendy] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. [Sinn, Patrick L.; McCray, Paul B., Jr.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Stein, Colleen S.; Davidson, Beverly L.] Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Davidson, Beverly L.] Univ Iowa, Coll Med, Dept Neurol, Iowa City, IA 52242 USA. [Davidson, Beverly L.] Univ Iowa, Coll Med, Dept Physiol & Biophys, Iowa City, IA 52242 USA. [Flick, Ramon; Mandell, Robert; Staplin, William] BioProtect Syst, Ames, IA 50011 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Room 1421, Bethesda, MD 20892 USA. EM Jchiorini@dir.nidcr.nih.gov FU NIAID [064526] FX This work was supported by an Intramural NIAID biofense grant to J. A. Chiorini and an NIAID grant (064526) to Wendy Maury. NR 49 TC 37 Z9 38 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2009 VL 83 IS 19 BP 10176 EP 10186 DI 10.1128/JVI.00422-09 PG 11 WC Virology SC Virology GA 491WX UT WOS:000269614300049 PM 19625394 ER PT J AU Pinn, VW AF Pinn, Vivian W. TI Sixth Annual Interdisciplinary Women's Health Research Symposium November 17, 2009 Introduction SO JOURNAL OF WOMENS HEALTH LA English DT Editorial Material C1 NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. EM ORWH-Research@od.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD OCT PY 2009 VL 18 IS 10 BP 1487 EP 1488 DI 10.1089/jwh.2009.Ab04 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 512FJ UT WOS:000271231200001 PM 19857090 ER PT J AU Shardell, MD Alley, DE El-Kamary, SS Hicks, GE Miller, RR Magaziner, J Langenberg, P Hochberg, MC Ferrucci, L AF Shardell, Michelle D. Alley, Dawn E. El-Kamary, Samer S. Hicks, Gregory E. Miller, Ram R. Magaziner, Jay Langenberg, Patricia Hochberg, Marc C. Ferrucci, Luigi TI Sex Differences in the Relationship of Serum Carotenoid Levels with Mortality Risk among Older US Adults: The Third National Health and Nutrition Examination Survey (NHANES III) SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Shardell, Michelle D.; Alley, Dawn E.; El-Kamary, Samer S.; Miller, Ram R.; Magaziner, Jay; Langenberg, Patricia] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Hicks, Gregory E.; Hochberg, Marc C.] Univ Delaware, Dept Phys Therapy, Newark, DE 19716 USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD OCT PY 2009 VL 18 IS 10 BP 1492 EP 1492 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 512FJ UT WOS:000271231200012 ER PT J AU Hessol, NA Weber, KM Holman, S Robison, E Goparaju, L Alden, CB Kono, N Watts, DH Ameli, N AF Hessol, Nancy A. Weber, Kathleen M. Holman, Susan Robison, Esther Goparaju, Lakshmi Alden, Christine B. Kono, Naoko Watts, D. Heather Ameli, Niloufar TI Retention and Attendance of Women Enrolled in a Large Prospective Study of HIV-1 in the United States SO JOURNAL OF WOMENS HEALTH LA English DT Article ID AFRICAN-AMERICAN WOMEN; CLINICAL-TRIALS; INTERAGENCY HIV; COHORT; PARTICIPATION; INFECTION AB Objective: The objective was to assess study retention and attendance for two recruitment waves of participants in the Women's Interagency HIV Study (WIHS). Methods: The WIHS, a prospective study at six clinical centers in the United States, has experienced two phases of participant recruitment. In phase one, women were screened and enrolled at the same time, and in phase two, women were screened and enrolled at separate visits. Compliance with study follow-up was evaluated by examining semiannual study retention and visit attendance. Results: After 10 study visits, the retention rate in the original recruits (enrolled in 1994-1995) was 83% for the HIV-infected women and 69% for the HIV-uninfected women compared with 86% and 86%, respectively, in the new recruits (enrolled in 2001-2002). In logistic regression analysis of the HIV-infected women, factors associated with early (visits 2 and 3) nonattendance were temporary housing, moderate alcohol consumption, use of crack/cocaine/heroin, having a primary care provider, WIHS site of enrollment, lower CD4 cell count, and higher viral load. Among HIV-uninfected women, the factors associated with early nonattendance were recruitment into the original cohort, household income >=$12,000 per year, temporary housing, unemployment, use of crack/cocaine/heroin, and WIHS site of enrollment. Factors associated with nonattendance at later visits (7-10) among HIV-infected participants were younger age, white race, not having a primary care provider, not having health insurance, WIHS site of enrollment, higher viral load, and nonattendance at a previous visit. In HIV-uninfected participants, younger age, white race, WIHS site of enrollment, and nonattendance at a previous visit were significantly associated with nonattendance at later visits. Conclusions: Preventing early loss to follow-up resulted in better study retention early, but late loss to follow-up may require different retention strategies. C1 [Hessol, Nancy A.; Ameli, Niloufar] Univ Calif San Francisco, San Francisco, CA 94122 USA. [Weber, Kathleen M.] John H Stroger Jr Hosp Cook Cty, Core Ctr, Chicago, IL USA. [Holman, Susan] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Robison, Esther] Montefiore Med Ctr, Bronx, NY 10467 USA. [Goparaju, Lakshmi] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Alden, Christine B.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kono, Naoko] Univ So Calif, Med Ctr, Los Angeles, CA USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Hessol, NA (reprint author), Univ Calif San Francisco, 405 Irving St,2nd Floor, San Francisco, CA 94122 USA. EM Nancy.Hessol@ucsf.edu FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources [UL1 RR024131] FX We are also grateful to Dr. Peter Bacchetti for his statistical guidance of the analyses, and we thank Michael Schneider for assistance in preparing the data and for programming and Heneliaka Jones for help with manuscript preparation. NR 20 TC 22 Z9 22 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD OCT PY 2009 VL 18 IS 10 BP 1627 EP 1637 DI 10.1089/jwh.2008.1337 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 512FJ UT WOS:000271231200103 PM 19788344 ER PT J AU Fried, LP Xue, QL Cappola, AR Ferrucci, L Chaves, P Varadhan, R Guralnik, JM Leng, SX Semba, RD Walston, JD Blaum, CS Bandeen-Roche, K AF Fried, Linda P. Xue, Qian-Li Cappola, Anne R. Ferrucci, Luigi Chaves, Paulo Varadhan, Ravi Guralnik, Jack M. Leng, Sean X. Semba, Richard D. Walston, Jeremy D. Blaum, Caroline S. Bandeen-Roche, Karen TI Nonlinear Multisystem Physiological Dysregulation Associated With Frailty in Older Women: Implications for Etiology and Treatment SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Frailty etiology; Aging ID GROWTH-FACTOR-I; CARDIOVASCULAR HEALTH; MUSCLE STRENGTH; SERUM-LEVELS; IGF-I; INTERLEUKIN-6; COMPLEXITY; MORTALITY; COMMUNITY; SYSTEMS AB Frailty in older adults, defined as a constellation of signs and symptoms, is associated with abnormal levels in individual physiological systems. We tested the hypothesis that it is the critical mass of physiological systems abnormal that is associated with frailty, over and above the status of each individual system, and that the relationship is nonlinear. Using data on women aged 70-79 years from the Women's Health and Aging Studies I and II, multiple analytic approaches assessed the cross-sectional association of frailty with eight physiological measures. Abnormality in each system (anemia, inflammation, insulin-like growth factor-1, dehydroepiandrosterone-sulfate, hemoglobin A1c, micronutrients, adiposity, and fine motor speed) was significantly associated with frailty status. However, adjusting for the level of each system measure, the mean number of systems impaired significantly and nonlinearly predicted frailty. Those with three or more systems impaired were most likely to be frail, with odds of frailty increasing with number of systems at abnormal level, from odds ratios (ORs) of 4.8 to 11 to 26 for those with one to two, three to four, and five or more systems abnormal (p < .05 for all). Finally, two subgroups were identified, one with isolated or no systems abnormal and a second (in 30%) with multiple systems abnormal. The latter group was independently associated with being frail (OR = 2.6, p < .05), adjusting for confounders and chronic diseases and then controlling for individual systems. Overall, these findings indicate that the likelihood of frailty increases nonlinearly in relationship to the number of physiological systems abnormal, and the number of abnormal systems is more predictive than the individual abnormal system. These findings support theories that aggregate loss of complexity, with aging, in physiological systems is an important cause of frailty. Implications are that a threshold loss of complexity, as indicated by number of systems abnormal, may undermine homeostatic adaptive capacity, leading to the development of frailty and its associated risk for subsequent adverse outcomes. It further suggests that replacement of any one deficient system may not be sufficient to prevent or ameliorate frailty. C1 [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Xue, Qian-Li; Chaves, Paulo; Varadhan, Ravi; Leng, Sean X.; Semba, Richard D.; Walston, Jeremy D.; Bandeen-Roche, Karen] Johns Hopkins Univ, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Xue, Qian-Li; Chaves, Paulo; Varadhan, Ravi; Walston, Jeremy D.; Bandeen-Roche, Karen] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Xue, Qian-Li; Varadhan, Ravi] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Blaum, Caroline S.] Univ Michigan, Dept Internal Med, Div Geriatr Med, Ann Arbor, MI 48109 USA. [Blaum, Caroline S.] Vet Adm Hlth Ctr, Educ & Clin Ctr, Ann Arbor, MI USA. RP Fried, LP (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St,14th Floor, New York, NY 10032 USA. EM lpfried@columbia.edu FU National Institute on Aging (NIA); Older Americans Independence Center [P30 AG021334]; National Institutes of Health/NIA [R37 AG019905] FX This research was supported by the National Institute on Aging (NIA), Older Americans Independence Center, grant P30 AG021334 and National Institutes of Health/NIA grant R37 AG019905. NR 41 TC 136 Z9 137 U1 3 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2009 VL 64 IS 10 BP 1049 EP 1057 DI 10.1093/gerona/glp076 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 491VV UT WOS:000269610600005 PM 19567825 ER PT J AU Kutner, NG Muntner, P Huang, YJ Zhang, R Cohen, AJ Anderson, AH Eggers, PW AF Kutner, Nancy G. Muntner, Paul Huang, Yijian Zhang, Rebecca Cohen, Andrew J. Anderson, Amanda H. Eggers, Paul W. TI Effect of Hurricane Katrina on the mortality of dialysis patients SO KIDNEY INTERNATIONAL LA English DT Article DE dialysis; disaster; mortality; USRDS ID RELIEF TASK-FORCE; HEMODIALYSIS-PATIENTS; STRESS-DISORDER; HEALTH-CARE; DISASTER; EARTHQUAKE; ORGANIZATION; LESSONS; MARMARA AB To investigate whether Hurricane Katrina's landfall in August 2005 resulted in excess mortality, we conducted a cohort study of patients who started dialysis between January 2003 and late August 2005 and who received treatment at 94 Katrina-affected clinics in the area. Survival, regardless of patient location after the storm, was followed through February 2006. In adjusted Cox proportional hazards models, Hurricane Katrina (time-varying indicator) was not significantly associated with mortality risk for patients from regions of the Gulf Coast affected by Katrina or those from a subset of 40 New Orleans clinics. Subgroup analyses indicated no significant increased mortality risk by race, income status, or dialysis modality. Sensitivity analyses indicated no significant increased mortality risk for patients from clinics closed for 10 days or longer, patients in their first 90 days of dialysis, or patients not evacuated from the affected areas. Patients remaining in the New Orleans area may have been more vulnerable due to age and comorbidities; however, the change in their mortality risk in the month following the storm was not statistically significant. We suggest that disaster-related education for patients must be ongoing, and that each disaster may present a different set of circumstances and challenges that will require unanticipated response efforts. Kidney International ( 2009) 76, 760-766; doi: 10.1038/ki.2009.268; published online 5 August 2009 C1 [Kutner, Nancy G.] Emory Univ, Sch Med, Dept Rehabil Med, US Renal Data Syst Rehab Qual Life Special Studie, Atlanta, GA 30322 USA. [Muntner, Paul] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [Cohen, Andrew J.] Brown Univ, Warren Alpert Med Sch, Providence VA Med Ctr, Providence, RI 02912 USA. [Anderson, Amanda H.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Eggers, Paul W.] NIDDK, NIH, Bethesda, MD USA. RP Kutner, NG (reprint author), Emory Univ, Sch Med, Dept Rehabil Med, US Renal Data Syst Rehab Qual Life Special Studie, CRM-1441 Clifton Rd NE, Atlanta, GA 30322 USA. EM nkutner@emory.edu FU National Institutes of Health [HHSN267200715004C] FX This study was supported by the National Institutes of Health contract HHSN267200715004C, ADB no. N01-DK-7-5004. The interpretation and reporting of the data presented here are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government. The authors acknowledge the many helpful insights and recommendations received from manuscript reviewers and editors. A preliminary report based on a more limited data set available before 2008 was presented at the American Society of Nephrology, 4 November 2007, San Francisco, CA, USA. NR 23 TC 17 Z9 17 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD OCT PY 2009 VL 76 IS 7 BP 760 EP 766 DI 10.1038/ki.2009.268 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 494NC UT WOS:000269819100011 PM 19657326 ER PT J AU Fishbein, D Sheppard, M Hyde, C Hubal, R Newlin, D Serin, R Chrousos, G Alesci, S AF Fishbein, Diana Sheppard, Monica Hyde, Christopher Hubal, Robert Newlin, David Serin, Ralph Chrousos, George Alesci, Salvatore TI Deficits in Behavioral Inhibition Predict Treatment Engagement in Prison Inmates SO LAW AND HUMAN BEHAVIOR LA English DT Review DE Correctional treatment; Inmates; Neurocognition; Emotional regulation; Responsivity ID ANTERIOR CINGULATE CORTEX; SUBSTANCE USE DISORDERS; ABSTINENT DRUG-ABUSERS; EARLY TRAUMA INVENTORY; AGGRESSIVE-BEHAVIOR; SALIVARY CORTISOL; PREVENTIVE INTERVENTION; PSYCHOMETRIC PROPERTIES; PROACTIVE AGGRESSION; PERSONALITY-DISORDER AB Many inmates do not respond favorably to standard treatments routinely offered in prison. Executive cognitive functioning and emotional regulation may play a key role in treatment responsivity. During intake into treatment, inmates (N = 224) were evaluated for executive functioning, emotional perception, stress reactivity (salivary cortisol), IQ, psychological and behavioral traits, prior drug use, child and family background, and criminal histories and institutional behavior. Outcome measures included program completion, treatment readiness, responsivity and gain, and the Novaco Reaction to Provocation Questionnaire. Relative deficits in behavioral inhibition significantly predicted treatment outcomes, more so than background, psychological, or behavioral variables, and other neurocognitive and emotional regulatory measures. Future replications of these results have potential to improve assessment and treatment of offenders who are otherwise intractable. C1 [Fishbein, Diana; Sheppard, Monica; Hubal, Robert; Newlin, David] RTI Int, Baltimore, MD 21224 USA. [Hyde, Christopher] Bioassessments Inc, Elkton, MD 21921 USA. [Serin, Ralph] Carleton Univ, Ottawa, ON K1S 5B6, Canada. [Chrousos, George] Natl Inst Child Hlth & Dev, NIH, Bethesda, MD 20892 USA. [Alesci, Salvatore] NIMH, Bethesda, MD 20892 USA. RP Fishbein, D (reprint author), RTI Int, 6801 Eastern Ave,Suite 203, Baltimore, MD 21224 USA. EM dfishbein@rti.org NR 120 TC 17 Z9 17 U1 6 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-7307 J9 LAW HUMAN BEHAV JI Law Hum. Behav. PD OCT PY 2009 VL 33 IS 5 BP 419 EP 435 DI 10.1007/s10979-008-9163-7 PG 17 WC Law; Psychology, Social SC Government & Law; Psychology GA 503OT UT WOS:000270547700006 PM 19139980 ER PT J AU Landgren, O Weiss, BM AF Landgren, O. Weiss, B. M. TI Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis SO LEUKEMIA LA English DT Review DE MGUS; susceptibility; racial disparity; genetic; African American; immune related ID UNITED-STATES; AFRICAN-AMERICAN; FAMILIAL MYELOMA; INTERGROUPE FRANCOPHONE; SIGNIFICANCE MGUS; ADULT-POPULATION; PREVALENCE; CANCER; RISK; HISTORY AB Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant disorders in Western countries. Recent studies show that almost every multiple myeloma (MM) case is preceded by an MGUS stage. Interestingly, prevalence and incidence patterns for MGUS and MM show striking disparity patterns across ethnic/racial groups, most notably the two-to threefold increase in both these disorders in African Americans compared with Caucasians. In contrast, studies on Asian patients show lower prevalence/incidence for MGUS/MM compared with Caucasians. Familial aggregation for both MGUS and MM has been observed; the risk for MGUS or MM in family members with these disorders is increased about two-to three fold compared with the general population. Although underlying mechanisms remain unclear, there is evidence of heterogeneity among MGUS patients from different ethnic/racial groups. For example, compared with Caucasians, African- American and African MGUS patients have reportedly lower rates of immunoglobulin M (IgM) MGUS (versus IgG/IgA MGUS) and higher rates of unquantifiable immunoglobulins (Igs). This review focuses on racial disparity and familial aggregation patterns for MGUS and MM and discusses how these observations provide novel clues with regard to pathogenesis. Leukemia (2009) 23, 1691-1697; doi: 10.1038/leu. 2009.134; published online 9 July 2009 C1 [Landgren, O.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Weiss, B. M.] Walter Reed Army Med Ctr, Dept Med, Hematol Oncol Serv, Washington, DC 20307 USA. RP Landgren, O (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov FU National Cancer Institute (NCI); National Institutes of Health (NIH), Bethesda, Maryland FX This research was supported by the Intramural Research Program of the National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland. The study sponsors did not have any role in the design of the study, interpretation of the data, the writing of the paper or the decision to submit the paper for publication. We thank Dr William F Anderson, NCI/NIH for help in creating Figure 1. NR 61 TC 79 Z9 79 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD OCT PY 2009 VL 23 IS 10 BP 1691 EP 1697 DI 10.1038/leu.2009.134 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 506YX UT WOS:000270816300002 PM 19587704 ER PT J AU O'Riain, C O'Shea, DM Yang, Y Le Dieu, R Gribben, JG Summers, K Yeboah-Afari, J Bhaw-Rosun, L Fleischmann, C Mein, CA Crook, T Smith, P Kelly, G Rosenwald, A Ott, G Campo, E Rimsza, LM Smeland, EB Chan, WC Johnson, N Gascoyne, RD Reimer, S Braziel, RM Wright, GW Staudt, LM Lister, TA Fitzgibbon, J AF O'Riain, C. O'Shea, D. M. Yang, Y. Le Dieu, R. Gribben, J. G. Summers, K. Yeboah-Afari, J. Bhaw-Rosun, L. Fleischmann, C. Mein, C. A. Crook, T. Smith, P. Kelly, G. Rosenwald, A. Ott, G. Campo, E. Rimsza, L. M. Smeland, E. B. Chan, W. C. Johnson, N. Gascoyne, R. D. Reimer, S. Braziel, R. M. Wright, G. W. Staudt, L. M. Lister, T. A. Fitzgibbon, J. TI Array-based DNA methylation profiling in follicular lymphoma SO LEUKEMIA LA English DT Article DE methylation; follicular lymphoma; gene expression; polycomb; transformation ID B-CELL LYMPHOMA; NON-HODGKINS LYMPHOMAS; EMBRYONIC STEM-CELLS; COLORECTAL-CANCER; PROMOTER HYPERMETHYLATION; INSTRUCTIVE MECHANISM; UNIPARENTAL DISOMY; GENE-EXPRESSION; TRANSFORMATION; POLYCOMB AB Quantitative methylation profiling was performed using the Illumina GoldenGate Assay in untreated follicular lymphoma (FL) (164), paired pre- and post-transformation FL (20), benign haematopoietic (24) samples and purified B and T cells from two FL cases. Methylation values allowed separation of untreated FL samples from controls with one exception, based primarily on tumour-specific gains of methylation typically occurring within CpG islands. Genes that are targets for epigenetic repression in stem cells by Polycomb Repressor Complex 2 were significantly over-represented among hypermethylated genes. Methylation profiles were conserved in sequential FL and t-FL biopsies, suggesting that widespread methylation represents an early event in lymphomagenesis and may not contribute substantially to transformation. A significant (P<0.05) correlation between FL methylation values and reduced gene expression was shown for up to 28% of loci. Methylation changes occurred predominantly in B cells with variability in the amount of non-malignant tissue between samples preventing conclusive correlation with survival. This represents an important caveat in attributing prognostic relevance to methylation and future studies in cancer will optimally require purified tumour populations to address the impact of methylation on clinical outcome. Leukemia (2009) 23, 1858-1866; doi: 10.1038/leu.2009.114; published online 9 July 2009 C1 [O'Riain, C.; O'Shea, D. M.; Yang, Y.; Le Dieu, R.; Gribben, J. G.; Summers, K.; Lister, T. A.; Fitzgibbon, J.] Barts & London Queen Marys Sch Med & Dent, Ctr Med Oncol, Inst Canc, London EC1M 6BQ, England. [Yeboah-Afari, J.; Bhaw-Rosun, L.; Fleischmann, C.; Mein, C. A.] Barts & London Queen Marys Sch Med & Dent, Genome Ctr, London, England. [Crook, T.; Smith, P.] Inst Canc Res, London SW3 6JB, England. [Kelly, G.] Lincolns Inn Fields, Macrophage Lab, Lincolns Inn Fields, Canc Res UK, London WC2A 3PX, England. [Rosenwald, A.; Ott, G.] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Ott, G.] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Campo, E.] Univ Barcelona, Dept Pathol, Hosp Clin, Barcelona, Spain. [Rimsza, L. M.] Univ Arizona, Ctr Canc, Dept Pathol, Tucson, AZ USA. [Smeland, E. B.] Univ Hosp, Rikshosp, Inst Canc Res, Dept Immunol, Oslo, Norway. [Smeland, E. B.] Univ Oslo, Norwegian Radium Hosp, Ctr Canc Biomed, Fac Div, Oslo, Norway. [Chan, W. C.] Univ Nebraska, Med Ctr, Dept Pathol, Omaha, NE USA. [Johnson, N.; Gascoyne, R. D.] British Columbia Canc Res Ctr, Dept Pathol, Vancouver, BC V5Z 1L3, Canada. [Reimer, S.; Braziel, R. M.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Wright, G. W.; Staudt, L. M.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP O'Riain, C (reprint author), Barts & London Queen Marys Sch Med & Dent, Ctr Med Oncol, Inst Canc, 3rd Floor,John Vane Sci Bldg,Charterhouse Sq, London EC1M 6BQ, England. EM c.l.oriain@qmul.ac.uk OI Campo, elias/0000-0001-9850-9793 FU Cancer Research UK [MONG1E9R]; Medical Research Council Clinical Research Fellowships; Cancer Research UK; NHS [ONAG1G5R]; National Institute of Health Strategic Partnering for Evaluation of Cancer Signatures Program (SPECS) [5 U01 CA114778] FX We are grateful for the assistance of Sameena Iqbal, Andrew Davies (Institute of Cancer, London) and Susan Oliver (Oregon Health and Sciences University), for the critical review of manuscript by Emanuela Carlotti and Carolyn Owen (Institute of Cancer, London) and for helpful discussion with Attilla Lorincz (Wolfson Institute, London), Gerd Pfeifer (City of Hope, California) and Allen Yang (University of Southern California). We also thank Christy Waterfall and Mark Gibbs at Illumina UK and Illumina Technical Support staff for their assistance. CO is a Barts Cambridge Molecular Pathology Clinical Research Fellow funded by grant support from Cancer Research UK (MONG1E9R). DO and RL are in receipt of Medical Research Council Clinical Research Fellowships. This work was also supported by funding from Cancer Research UK (programme grant to Centre for Medical London NHS Trust (ONAG1G5R) and by a National Institute of Health Strategic Partnering for Evaluation of Cancer Signatures Program (SPECS) grant (5 U01 CA114778). NR 48 TC 49 Z9 49 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD OCT PY 2009 VL 23 IS 10 BP 1858 EP 1866 DI 10.1038/leu.2009.114 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 506YX UT WOS:000270816300019 PM 19587707 ER PT J AU Gasperini, P Tosato, G AF Gasperini, P. Tosato, G. TI Targeting the mammalian target of Rapamycin to inhibit VEGF and cytokines for the treatment of primary effusion lymphoma SO LEUKEMIA LA English DT Article DE PEL; rapamycin; IL-10; KSHV; drug-resistance ID ENDOTHELIAL GROWTH-FACTOR; SARCOMA-ASSOCIATED HERPESVIRUS; NITRIC-OXIDE SYNTHASE; SIGNAL-TRANSDUCTION PATHWAY; RENAL-TRANSPLANT RECIPIENTS; B-CELL LYMPHOMAS; KAPOSIS-SARCOMA; VASCULAR-PERMEABILITY; IN-VIVO; INDUCED ANGIOGENESIS AB Primary effusion lymphoma (PEL) is a fatal malignancy, which typically presents as a lymphomatous effusion that later disseminates. Rapamycin (Rapa), which targets mTOR (mammalian target of Rapa), is currently evaluated as a treatment for PEL, but the recent development of PEL in Rapa-treated post-transplant recipients questions the drug's use in PEL. Here, we used a murine model of PEL effusion that mimics the human disease to investigate the anti-PEL activity of Rapa. We found that Rapa reduces ascites accumulation and extends mouse survival. Initially, Rapa reduced PEL load compared with control mice, but most mice rapidly showed PEL progression. Levels of VEGF, which promotes vascular permeability contributing to effusion formation, were significantly reduced in ascites of Rapa-treated mice compared with controls. Expression of IL-10, the principal autocrine growth factor for PEL, was initially reduced in PEL from Rapa-treated mice but rapidly increased despite treatment. We found that the hypoxic environment of ascites and Rapa cooperate in stimulating IL-10 expression in PEL, which likely contributes to the emergence of drug resistance. These results identify Rapa an effective drug to reduce PEL effusions but illustrate the rapid development of drug resistance, which likely limits the efficacy of Rapa in PEL. Leukemia (2009) 23, 1867-1874; doi: 10.1038/leu.2009.117; published online 25 June 2009 C1 [Gasperini, P.; Tosato, G.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gasperini, P (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, 37 Convent Dr 37-4, Bethesda, MD 20892 USA. EM gasperinip@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; FIRC (Italian Foundation; Associazione Italiana per la Ricerca sul Cancro FX Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. PG supported in part by FIRC (Italian Foundation for Cancer Research). We thank Drs S Steinberg, K Ueda, R Yarchoan, S Pittaluga, D Whitby, S Sakakibara, M Segarra and P McCormick for help on aspects of this work. NR 31 TC 12 Z9 14 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD OCT PY 2009 VL 23 IS 10 BP 1867 EP 1874 DI 10.1038/leu.2009.117 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 506YX UT WOS:000270816300020 PM 19554030 ER PT J AU Kreitman, RJ Fitzgerald, DJP Pastan, I AF Kreitman, Robert J. Fitzgerald, David J. P. Pastan, Ira TI Approach to the patient after relapse of hairy cell leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE Recombinant immunotoxin; monoclonal antibody; Fv; BL22; LMB-2; HA22 ID MINIMAL RESIDUAL DISEASE; TERM-FOLLOW-UP; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; CHRONIC LYMPHOCYTIC-LEUKEMIA; NATIONAL-CANCER-INSTITUTE; RECOMBINANT IMMUNOTOXIN; ANTI-CD22 IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; CYTOTOXIC ACTIVITY; DIPHTHERIA-TOXIN AB The current hairy cell leukemia (HCL) treatment is excellent, but evidence of cure with purine analogs cladribine and pentostatin, is lacking. Significant long-term immune suppression, particularly to CD4+ T-cells, and declining complete remission rates with each course, make the identification of new therapies an important goal. The anti-CD20 monoclonal antibody (Mab) rituximab displays significant activity, and, while causing prolonged normal B-cell depletion, spares T-cells. Recombinant immunotoxins, containing an Fv fragment of a Mab fused to truncated Pseudomonas exotoxin, have shown efficacy in HCL resistant to both purine analogs and rituximab. LMB-2 targets CD25 and can induce remission providing the HCL cells are CD25+. All HCL cells display CD22. Recombinant anti-CD22 immunotoxin BL22, targeting CD22, has shown significant efficacy in phase I and II testing, and avoids prolonged suppression of both normal B- and T-cells. An improved high-affinity version of BL22, termed HA22, is currently undergoing phase I testing. C1 [Kreitman, Robert J.; Fitzgerald, David J. P.; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), 37-5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU NCI; NIH; MedImmune, LLC [BL22, HA22] FX This work is supported in part by the Intramural Research Program of the NCI, NIH, and work on BL22 and HA22 is supported in part by MedImmune, LLC. NR 66 TC 9 Z9 11 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD OCT PY 2009 VL 50 IS 1 SU 1 BP 32 EP 37 DI 10.3109/10428190903142216 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 516LL UT WOS:000271543600008 PM 19814696 ER PT J AU Bianciardi, M Fukunaga, M van Gelderen, P Horovitz, SG de Zwart, JA Shmueli, K Duyn, JH AF Bianciardi, Marta Fukunaga, Masaki van Gelderen, Peter Horovitz, Silvina G. de Zwart, Jacco A. Shmueli, Karin Duyn, Jeff H. TI Sources of functional magnetic resonance imaging signal fluctuations in the human brain at rest: a 7 T study SO MAGNETIC RESONANCE IMAGING LA English DT Article; Proceedings Paper CT International School on Magnetic Resonance and Brain Function CY MAY 18-25, 2008 CL Erice, ITALY DE Nonthermal noise; Spontaneous activity; Physiological noise; 7-T BOLD fMRI; Resting state ID BOLD SIGNAL; PHYSIOLOGICAL NOISE; FMRI; STATE; CONNECTIVITY; RESPIRATION; HYPERCAPNIA; DYNAMICS; CORTEX; SLEEP AB Signal fluctuations in functional magnetic resonance imaging (fMRI) call result from a number of sources that may have a neuronal., physiologic or instrumental origin. To determine the relative contribution of these Sources, we recorded physiological (respiration and cardiac) signals Simultaneously with fMRI in human Volunteers at rest with their eyes closed. State-of the-arty technology was used including high inagnetic field (7 T), a niultichannel detector array and high-resolution (3 mm(3)) echo-planar imaging. We investigated the relative contribution of thermal noise and other sources of variance to the observed fMRI signal fluctuations both ill the Visual cortex and in the whole brain gray matter. The following Sources of variance were evaluated separately: low-frequency drifts due to scanner instability, effects correlated with respiratory and cardiac cycles, effects clue to variability in the respiratory flow rate and cardiac rate, and other sources, tentatively attributed to spontaneous neuronal activity. We found that low-frequency drifts are the most significant source of fMRI signal fluctuations (3.0% signal change in the Visual cortex, TE=32 ills), followed by spontaneous neuronal activity (2.9%), thermal noise (2.1%), effects due to variability in physiological rates (respiration 0.9%, heartbeat 0.9%), and correlated with physiological cycles (0.6%). We Suggest the selection and use of four lagged physiological noise regressors as all effective model to explain the variance related to fluctuations in the rates of respiration volume change and cardiac pulsation. Our results also indicate that, compared to the whole brain gray matter, the visual cortex has higher sensitivity to changes in both the rate of respiration and the spontaneous resting-state activity. Under the conditions of this Study, spontaneous neuronal activity is one of the major contributors to the measured fMRI signal fluctions ions, increasing almost twofold relative to earlier experiments under similar conditions at 3 T. Published by Elsevier Inc. C1 [Bianciardi, Marta; Fukunaga, Masaki; van Gelderen, Peter; Horovitz, Silvina G.; de Zwart, Jacco A.; Shmueli, Karin; Duyn, Jeff H.] NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. RP Bianciardi, M (reprint author), NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. EM bianciardim@mail.nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013; Shmueli, Karin/B-9432-2017 OI Fukunaga, Masaki/0000-0003-1010-2644; FU Intramural NIH HHS [Z01 NS002990-08] NR 27 TC 90 Z9 90 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD OCT PY 2009 VL 27 IS 8 BP 1019 EP 1029 DI 10.1016/j.mri.2009.02.004 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 500UA UT WOS:000270329800003 PM 19375260 ER PT J AU Barnett, A AF Barnett, Alan TI Theory of Q-ball Imaging Redux: Implications for Fiber Tracking SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE q-ball imaging; fiber tracking; ODF; HARDI ID DIFFUSION TENSOR; SPIN-ECHO; FIELD-GRADIENT; HUMAN BRAIN; RESTRICTED DIFFUSION; ANGULAR RESOLUTION; MRI DATA; NMR; TISSUE; ARCHITECTURE AB Q-ball imaging is widely used to determine fiber directions for fiber tracking. In cl-ball imaging the directional dependence of water diffusion in tissue is described by Tuch's orientation distribution function (ODF); a different function, the cl-ball orientation distribution function, is measured using high angular resolution magnetic resonance diffusion imaging (HARDI). Tuch's ODF is assumed to be well approximated by the cl-ball ODF. In this study it is shown that 1) the cl-ball ODF is not a good approximation to Tuch's ODF; 2) the properties of the q-ball ODF depend strongly on q, the area of the diffusion sensitization gradients; and 3) the cl-ball ODF for a composite system is the weighted average of the cl-ball ODFs for each subsystem, but the weighting factor is the product of the percent composition and a renormalization factor. In addition, a derivation is presented of the cl-ball ODF for a system described by a Gaussian distribution and expressions are derived for both the dependence of the angular resolution on q and for the relation between the angular resolution and the signal loss. These findings might be useful in the design and interpretation of fiber-tracking experiments. Magn Reson Med 62.910-923, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Barnett, Alan] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Barnett, A (reprint author), NIH, Magnuson Clin Ctr, Bldg 10,3C213,10 Ctr Dr, Bethesda, MD 20892 USA. EM asb@nih.gov FU Intramural NIH HHS NR 30 TC 22 Z9 22 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2009 VL 62 IS 4 BP 910 EP 923 DI 10.1002/mrm.22073 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 503SA UT WOS:000270558700010 PM 19672943 ER PT J AU Qin, L van Gelderen, P Derbyshire, JA Jin, FH Lee, J de Zwart, JA Tao, Y Duyn, JH AF Qin, Lei van Gelderen, Peter Derbyshire, John Andrew Jin, Fenghua Lee, Jongho de Zwart, Jacco A. Tao, Yang Duyn, Jeff H. TI Prospective Head-Movement Correction for High-Resolution MRI Using an In-Bore Optical Tracking System SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE prospective motion correction; optical tracking; MR-compatible camera; real-time MRI; high-resolution MRI ID MOTION CORRECTION; NAVIGATOR ECHOES; FMRI; ROTATION AB In MRI of the human brain, subject motion is a major cause of magnetic resonance image quality degradation. To compensate for the effects of head motion during data acquisition, an in-bore optical motion tracking system is proposed. The system comprises two MR-compatible infrared cameras that are fixed on a holder right above and in front of the head coil. The resulting close proximity of the cameras to the object allows precise tracking of its movement. During image acquisition, the MRI scanner uses this tracking information to prospectively compensate for head motion by adjusting the gradient field direction and radio frequency (RF) phases and frequencies. Experiments performed on subjects demonstrate robust system performance with translation and rotation accuracies of 0.1 mm and 0.15 degrees, respectively. Magn Reson Med 62:924-934, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Qin, Lei; van Gelderen, Peter; Lee, Jongho; de Zwart, Jacco A.; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Qin, Lei; Jin, Fenghua; Tao, Yang] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. [Derbyshire, John Andrew] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), Natl Inst Neurol Disorders & Stroke, Adv MRI, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Rm B1D-723, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov RI Duyn, Jozef/F-2483-2010 FU Intramural NIH HHS [Z01 NS002990-08] NR 33 TC 59 Z9 59 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2009 VL 62 IS 4 BP 924 EP 934 DI 10.1002/mrm.22076 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 503SA UT WOS:000270558700011 PM 19526503 ER PT J AU Zhang, Y Li, SZ Shen, J AF Zhang, Yan Li, Shizhe Shen, Jun TI Automatic High-Order Shimming Using Parallel Columns Mapping (PACMAP) SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE high-order shimming; spherical harmonics; parallel columns; oblique plane; field map ID MAGNETIC-FIELD; ACQUISITION; BRAIN AB This work presents a new automatic high-order shimming method that maps the B(0) field using a group of parallel columns. We found that a pair of four columns in two separate slices could determine an optimal correction field comprising the spherical harmonic terms up to the third-order. The technique of multiple stimulated echoes was incorporated into the method, allowing the use of at least eight shots to accomplish field mapping. The shim currents were first determined in the logic frame by assuming that the slices were in axial planes, and then uniquely converted into the physical frame where the slices could be at any oblique angle, by using a spherical harmonics rotation transformation. This method thus works regardless of slice orientation. It was demonstrated on a 3T scanner equipped with a complete set of second-order harmonic shim coils. Both phantom and in vivo experiments showed that this newly introduced high-order shimming method is an effective and efficient way to reduce field inhomogeneity for a region of imaging slices. Magn Reson Med 62:1073-1079, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Shen, Jun] NIMH, Mol Imaging Branch, Spect Core Facil, NIH, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Spect Core Facil, NIH, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@mail.nih.gov FU Intramural NIH HHS [Z01 MH002894-01] NR 19 TC 4 Z9 4 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2009 VL 62 IS 4 BP 1073 EP 1079 DI 10.1002/mrm.22077 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 503SA UT WOS:000270558700029 PM 19645006 ER PT J AU Bennett, GG Wolin, KY Puleo, EM Masse, LC Atienza, AA AF Bennett, Gary G. Wolin, Kathleen Y. Puleo, Elaine M. Masse, Louise C. Atienza, Audie A. TI Awareness of National Physical Activity Recommendations for Health Promotion among US Adults SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE HINTS; EXERCISE; DIET; PHYSICAL INACTIVITY ID AMERICAN-HEART-ASSOCIATION; OF-SPORTS-MEDICINE; PERCEIVED RISK; CANCER-SOCIETY; PUBLIC-HEALTH; UNITED-STATES; DISEASE; PREVENTION; KNOWLEDGE; AGENDA AB BENNETT, G. G., K. Y. WOLIN. E. M. PULEO, L. C. MASSE, and A. A. ATIENZA. Awareness of National Physical Activity Recommendations for Health Promotion among US Adults. Med. Sci. Sports Exerc., Vol. 41, No. 10, pp. 1849-1855, 2009. Purpose: To examine whether knowledge of the 1995 Centers for Disease Control and Prevention (CDC) and the American College of Sports Medicine (ACSM) national physical activity recommendations varies by sociodemographic, behavioral, and communication-related factors. Methods: Cross-sectional analyses of 2381 participants in the 2005 Health Information National Trends Survey, a national probability sample of the US population contacted via random-digit dial. Results: Only a third of respondents were accurately knowledgeable of the CDC/ACSM physical activity recommendations. Recommendation knowledge was higher among women (OR 1.70; 95% confidence interval (CI) = 1.35-2.14) than men, the employed compared with those not currently working (OR = 0.73 95% CI = 0.55-0.95), foreign-born individuals (OR = 1.62; 95% CI = 1.15-2.30) compared with the US-born, and those meeting CDC/ACSM recommendations vs those who do not (OR = 0.74: 95% CI = 0.58-0.96). Conclusions: There is riot widespread knowledge of the consensus national physical activity recommendations. These findings highlight the need for more effective campaigns to promote physical activity among the American public. C1 [Bennett, Gary G.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bennett, Gary G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolin, Kathleen Y.] Washington Univ, Sch Med, St Louis, MO USA. [Puleo, Elaine M.] Univ Massachusetts Amherst, Amherst, MA USA. [Masse, Louise C.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Atienza, Audie A.] NCI, Bethesda, MD 20892 USA. RP Bennett, GG (reprint author), Duke Univ, Box 90086,9 Flowers Dr, Durham, NC 27708 USA. EM gary.bennett@duke.edu RI Wolin, Kathleen/I-2154-2014 OI Wolin, Kathleen/0000-0001-7950-9042 FU Dana-Farber/ Harvard Cancer Center; NCI [1K22CA126992]; US NCI FX Present address for Gary G. Bennett is Duke University, Durham, NC. NR 46 TC 30 Z9 30 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD OCT PY 2009 VL 41 IS 10 BP 1849 EP 1855 DI 10.1249/MSS.0b013e3181a52100 PG 7 WC Sport Sciences SC Sport Sciences GA 499FI UT WOS:000270202700003 PM 19727030 ER PT J AU Mathias, RA Deepa, M Deepa, R Wilson, AF Mohan, V AF Mathias, Rasika A. Deepa, Mohan Deepa, Raj Wilson, Alexander F. Mohan, Vishwanathan TI Heritability of quantitative traits associated with type 2 diabetes mellitus in large multiplex families from South India SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID METABOLIC SYNDROME; INSULIN-RESISTANCE; CARDIOVASCULAR RISK; GENE POLYMORPHISMS; GLUCOSE-TOLERANCE; LINKAGE ANALYSIS; ASIAN INDIANS; OBESITY; POPULATION; PREVALENCE AB India is a major contributor to the global public health burden of diabetes. We have undertaken a family Study of large multiplex families from Chennai, South India, and report on the familial aggregation of quantitative traits associated with type 2 diabetes mellitus in these pedigrees. Five hundred twenty-four individuals older than 19 years from 26 large multiplex pedigrees were ascertained. Detailed questionnaires and phenotype data were obtained on all participating individuals including fasting blood glucose, fasting insulin, lipid profiles, height, weight, and other anthropometric and clinical measures. Heritability estimates were calculated for all quantitative traits at the univariate level, and bivariate analyses were done to determine the correlation in genetic and environmental control across these quantitative traits. Heritability estimates ranged from 0.21 to 0.72. The heritability estimates for traits most directly related to type 2 diabetes mellitus were 0.24 +/- 0.08 for fasting blood glucose and 0.41 +/- 0.09 for fasting insulin. In addition, there was evidence for common genetic control for many pairs of these traits. These bivariate analyses suggested common genes for Casting insulin and central obesity measures (body mass index, waist, and hip), with complete genetic correlation between fasting insulin and waist. Quantitative traits associated with type 2 diabetes mellitus have heritabilities suggestive of sonic familial or genetic effect. The evidence for pleiotropic control of insulin and central obesity-related traits supports the presence of an insulin resistance syndrome in South Asians with a tendency for central obesity. Published by Elsevier Inc. C1 [Mathias, Rasika A.; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. [Deepa, Mohan; Deepa, Raj; Mohan, Vishwanathan] WHO Collaborating Ctr Noncommunicable Dis Prevent, Madras Diabet Res Fdn, Madras 600086, Tamil Nadu, India. [Deepa, Mohan; Deepa, Raj; Mohan, Vishwanathan] WHO Collaborating Ctr Noncommunicable Dis Prevent, Dr Mohans Diabet Specialties Ctr, Madras 600086, Tamil Nadu, India. RP Mathias, RA (reprint author), NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. EM rmathias1@mail.nih.gov RI Wilson, Alexander/C-2320-2009 FU National Human Genome Research Institute, National Institutes of Health FX The authors would like to thank the clinical coordinators Uma Shankari G, Rajeshwari K, Maria Margret Susan, and Suresh T and the laboratory technicians Ganga Kalyani E, Anitha D, Sridevi K, Sasikala K, Sathish Raj S, and Ms Nazeera R for their help in subject recruitment and sample processing. The authors thank Dr Linda Kao for her help and advice in the preparation of this manuscript. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 37 TC 20 Z9 20 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2009 VL 58 IS 10 BP 1439 EP 1445 DI 10.1016/j.metabol.2009.04.041 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 500TF UT WOS:000270327100011 PM 19570552 ER PT J AU Scott, I AF Scott, Iain TI Degradation of RIG-I following cytomegalovirus infection is independent of apoptosis SO MICROBES AND INFECTION LA English DT Article DE RIG-I; MAVS; IPS-1; Cardif; vMIA; UL37x1; Cleavage; Apoptosis; Cytomegalovirus ID ANTIVIRAL SIGNALING PROTEIN; HEPATITIS-C VIRUS; ADAPTER PROTEIN; INNATE IMMUNITY; MITOCHONDRIA; MAVS; ACTIVATION; INHIBITOR; CLEAVAGE; PATHWAY AB Many viruses have evolved strategies to either evade or hijack host cell immune programs, as a means of promoting their own reproduction. For example, the human cytomegalovirus (HCMV) immediate-early protein vMIA/UL37ex1 inhibits host cell apoptosis, and its expression during infection aids virus replication. Here it is shown that stable expression of vMIA/UL37ex1 reduces cleavage of the innate immune response-proteins MAVS and RIG-1 by caspases during apoptosis. Unexpectedly, it is demonstrated that RIG-1, but not MAVS, is degraded during HCMV infection. This process occurs in a non-apoptotic manner, and provides new evidence that HCMV may have evolved a unique strategy to evade RIG-1-mediated immune responses. Published by Elsevier Masson SAS. C1 [Scott, Iain] NINDS, Biochem Sect, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Scott, I (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10-CRC,Room 5-3216,9000 Rockville Pike, Bethesda, MD 20892 USA. EM scotti@mail.nih.gov FU National Institute of Neurological Disorders and Stroke; National Institutes of Health FX The author thanks Richard Youle for support and equipment, Chad Williamson for help and advice with viral experiments, Wade Gibson for helpful discussions and both Victor Goldmacher and Kui Li for materials. This research was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 23 TC 12 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD OCT PY 2009 VL 11 IS 12 BP 973 EP 979 DI 10.1016/j.micinf.2009.07.001 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 504QI UT WOS:000270631700009 PM 19591957 ER PT J AU Rayavara, K Rajapandi, T Wollenberg, K Kabat, J Fischer, ER Desai, SA AF Rayavara, Kempaiah Rajapandi, Thavamani Wollenberg, Kurt Kabat, Juraj Fischer, Elizabeth R. Desai, Sanjay A. TI A complex of three related membrane proteins is conserved on malarial merozoites SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Apicomplexa; Plasmodium; Merozoite; Transmembrane proteins; Heterologous expression ID PLASMODIUM-FALCIPARUM; ERYTHROCYTE INVASION; SURFACE; CELLS; EXPRESSION; PARASITE; BACULOVIRUS; ANTIGENS; VECTORS; INSECT AB Invasion of human red blood cells by the malaria parasite Plasmodium falciparum is a coordinated, multi-step process. Here, we describe three novel integral membrane proteins that colocalize on the inner membrane complex immediately beneath the merozoite plasma membrane. Each has six predicted transmembrane domains and is conserved in diverse apicomplexan parasites. Immunoprecipitation studies using specific antibodies reveal that these proteins assemble into a heteromeric complex. Each protein was also expressed on insect cells using the baculovirus vector system with a truncated SUMO tag that facilitates maximal expression and protein purification while permitting cleavage with SUMO protease to release unmodified parasite protein. The expressed proteins were successfully reconstituted into artificial liposomes, but were not recognized by human immune sera. Because all three genes are highly conserved in apicomplexan parasites, the complex formed by their encoded proteins likely serves an essential role for invasive merozoites. Published by Elsevier B.V. C1 [Rayavara, Kempaiah; Rajapandi, Thavamani; Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kabat, Juraj; Fischer, Elizabeth R.] NIAID, RTB, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sdesai@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Jose Riberio for help with bioinformatics, Sanjay Singh and Rick Fairhurst for providing antibodies and human immune sera, and Owen Schwartz and Meggan Czapiga for help with confocal microscopy and deconvolution of images. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 27 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD OCT PY 2009 VL 167 IS 2 BP 135 EP 143 DI 10.1016/j.molbiopara.2009.05.006 PG 9 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 475NM UT WOS:000268366600006 PM 19465059 ER PT J AU Perez-Victoria, FJ Bonifacino, JS AF Perez-Victoria, F. Javier Bonifacino, Juan S. TI Dual Roles of the Mammalian GARP Complex in Tethering and SNARE Complex Assembly at the trans-Golgi Network SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN COMPLEX; ORGANELLE IDENTITY; MEMBRANE-FUSION; EARLY ENDOSOME; BINDING-SITES; TLG1P; RAB5; HOPS; IDENTIFICATION; PURIFICATION AB Tethering factors and SNAREs control the last two steps of vesicular trafficking: the initial interaction and the fusion, respectively, of transport vesicles with target membranes. The Golgi-associated retrograde protein (GARP) complex regulates retrograde transport from endosomes to the trans-Golgi network (TGN). Although GARP has been proposed to function as a tethering factor at the TGN, direct evidence for such a role is still lacking. Herein we report novel and specific interactions of the mammalian GARP complex with SNAREs that participate in endosome-to-TGN transport, namely, syntaxin 6, syntaxin 16, and Vamp4. These interactions depend on the N-terminal regions of Vps53 and Vps54 and the SNARE motif of the SNAREs. We show that GARP functions upstream of the SNAREs, regulating their localization and assembly into SNARE complexes. However, interactions of GARP with SNAREs are insufficient to promote retrograde transport, because deletion of the C-terminal region of Vps53 precludes GARP function without affecting GARP-SNARE interactions. Finally, we present in vitro data consistent with a tethering role for GARP, which is disrupted by deletion of the Vps53 C-terminal region. These findings indicate that GARP orchestrates retrograde transport from endosomes to the TGN by promoting vesicle tethering and assembly of SNARE complexes in consecutive, independent steps. C1 [Bonifacino, Juan S.] NICHD, Cell Biol & Metab Program, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHD, Cell Biol & Metab Program, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU NIH; Ministerio de Educacion y Ciencia of Spain FX This work was funded by the Intramural Program of NICHD of the NIH. F.J.P.-V. was the recipient of a postdoctoral fellowship from the Ministerio de Educacion y Ciencia of Spain. NR 47 TC 60 Z9 62 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2009 VL 29 IS 19 BP 5251 EP 5263 DI 10.1128/MCB.00495-09 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 493AT UT WOS:000269706000005 PM 19620288 ER PT J AU Ueda, T Furusawa, T Kurahashi, T Tessarollo, L Bustin, M AF Ueda, Tetsuya Furusawa, Takashi Kurahashi, Toshihiro Tessarollo, Lino Bustin, Michael TI The Nucleosome Binding Protein HMGN3 Modulates the Transcription Profile of Pancreatic beta Cells and Affects Insulin Secretion SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TISSUE-SPECIFIC EXPRESSION; CHROMOSOMAL-PROTEINS; DIABETES-MELLITUS; GLUT2 GENE; CHROMATIN; ACTIVATION; MUTATIONS; TRANSPORT; CHANNELS; ISOFORMS AB Improper glucose-stimulated insulin secretion from pancreatic beta cells is a major factor in the onset of type 2 diabetes. We now report that HMGN3, a nuclear protein that binds to nucleosomes and affects chromatin function, is highly expressed in beta cells and that in mice, loss of HMGN3 impairs glucose-stimulated insulin secretion and leads to a diabetic phenotype. In pancreatic beta cells, loss of HMGN3 affects the transcription of several genes involved in glucose-stimulated insulin secretion, including that of the Glut2 glucose transporter. Chromatin immunoprecipitation reveals that HMGN3 and the transcription factor PDX1 mutually reinforce their specific binding to the chromatin in the promoter of the Glut2 gene, thereby regulating GLUT2 protein levels in pancreatic islets and in beta cells. Our results identify a new regulator of glucose homeostasis and demonstrate a link between the activity of a nucleosome binding structural protein and the regulation of insulin secretion. C1 [Ueda, Tetsuya; Furusawa, Takashi; Kurahashi, Toshihiro; Bustin, Michael] NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU NCI, NIH FX This research was supported by the Center for Cancer Research, intramural program of the NCI, NIH. NR 44 TC 22 Z9 23 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2009 VL 29 IS 19 BP 5264 EP 5276 DI 10.1128/MCB.00526-09 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 493AT UT WOS:000269706000006 PM 19651901 ER PT J AU Storbeck, CJ Wagner, S O'Reilly, P McKay, M Parks, RJ Westphal, H Sabourin, LA AF Storbeck, Chris J. Wagner, Simona O'Reilly, Paul McKay, Marlene Parks, Robin J. Westphal, Heiner Sabourin, Luc A. TI The Ldb1 and Ldb2 Transcriptional Cofactors Interact with the Ste20-like Kinase SLK and Regulate Cell Migration SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID STE20-RELATED KINASE; HOMEODOMAIN PROTEINS; LIM; DOMAIN; ADHESION; BINDING; ACTIVATION; MICROTUBULE; EXPRESSION; DLDB/CHIP AB Cell migration involves a multitude of signals that converge on cytoskeletal reorganization, essential for development, immune responses, and tissue repair. Here, we show that the microtubule-associated Ste20 kinase SLK, required for cell migration, interacts with the LIM domain binding transcriptional cofactor proteins Ldb1/CLIM2 and Ldb2/CLIM1/NLI. We demonstrate that Ldb1 and 2 bind directly to the SLK carboxy-terminal AT1-46 homology domain in vitro and in vivo. We find that Ldb1 and -2 colocalize with SLK in migrating cells and that both knockdown and overexpression of either factor results in increased motility. Supporting this, knockdown of Ldb1 increases focal adhesion turnover and enhances migration in fibroblasts. We propose that Ldb1/2 function to maintain SLK in an inactive state before its activation. These findings highlight a novel function for Ldb1 and -2 and expand their role to include the control of cell migration. C1 [Storbeck, Chris J.; Wagner, Simona; O'Reilly, Paul; Sabourin, Luc A.] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada. [McKay, Marlene; Parks, Robin J.; Sabourin, Luc A.] Ottawa Hosp, Res Inst, Ottawa, ON K1Y 4E9, Canada. [Westphal, Heiner] NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Sabourin, LA (reprint author), Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada. EM lsabourin@ohri.ca FU Canadian Institute for Health Research; MDAUSA; Canadian Breast Cancer Foundation; Premier's Research for Excellence Award; Canadian Heart and Stroke Foundation; Ontario Graduate Scholarships in Science and Technology; Natural Sciences and Engineering Research Council FX We thank Kim Wong and Doris Parolin for valuable help with confocal microscopy and live imaging. This work was supported by the Canadian Institute for Health Research, MDAUSA, the Canadian Breast Cancer Foundation, and a Premier's Research for Excellence Award. C. J. S. is the recipient of a Canadian Heart and Stroke Foundation Fellowship. L. A. S. is the recipient of a Canadian Institutes of Health Research scholar award. P. O. and S. W. are the recipients of Ontario Graduate Scholarships in Science and Technology and Natural Sciences and Engineering Research Council studentships, respectively. NR 21 TC 18 Z9 21 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 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2009 VL 20 IS 19 BP 4174 EP 4182 DI 10.1091/mbc.E08-07-0707 PG 9 WC Cell Biology SC Cell Biology GA 501BF UT WOS:000270352400005 PM 19675209 ER PT J AU Cardinale, S Bergmann, JH Kelly, D Nakano, M Valdivia, MM Kimura, H Masumoto, H Larionov, V Earnshaw, WC AF Cardinale, Stefano Bergmann, Jan H. Kelly, David Nakano, Megumi Valdivia, Manuel M. Kimura, Hiroshi Masumoto, Hiroshi Larionov, Vladimir Earnshaw, William C. TI Hierarchical Inactivation of a Synthetic Human Kinetochore by a Chromatin Modifier SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ZINC-FINGER PROTEINS; HISTONE H3; CENP-A; CENTROMERE FUNCTION; VERTEBRATE CELLS; DNA-BINDING; HETEROCHROMATIN; COMPLEX; DOMAIN; KAP-1 AB We previously used a human artificial chromosome ( HAC) with a synthetic kinetochore that could be targeted with chromatin modifiers fused to tetracycline repressor to show that targeting of the transcriptional repressor tTS within kinetochore chromatin disrupts kinetochore structure and function. Here we show that the transcriptional corepressor KAP1, a downstream effector of the tTS, can also inactivate the kinetochore. The disruption of kinetochore structure by KAP1 subdomains does not simply result from loss of centromeric CENP-A nucleosomes. Instead it reflects a hierarchical disruption of the outer kinetochore, with CENP-C levels falling before CENP-A levels and, in certain instances, CENP-H being lost more readily than CENP-C. These results suggest that this novel approach to kinetochore dissection may reveal new patterns of protein interactions within the kinetochore. C1 [Cardinale, Stefano; Bergmann, Jan H.; Kelly, David; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Nakano, Megumi; Larionov, Vladimir] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Valdivia, Manuel M.] Univ Cadiz, Dept Bioquim & Biol Mol, Fac Ciencias, Cadiz 11510, Spain. [Kimura, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. [Nakano, Megumi; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, Chiba 2920818, Japan. RP Earnshaw, WC (reprint author), Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. EM bill.earnshaw@ed.ac.uk RI Cardinale, Stefano/F-4024-2014; OI Martinez Valdivia, Manuel Jesus/0000-0002-2888-849X; Cardinale, Stefano/0000-0003-4357-9246 FU Darwin Trust of Edinburgh; Wellcome Trust; National Institutes of Health; National Cancer Institute; Center for Cancer Research; Ministry of Education, Science, Sports and Culture of Japan; Ministerio de Ciencia y Tecnologia [SAF2007-61863]; MEXT of Japan FX We thank David Schultz (Wistar Institute, Philadelphia, PA) for the gift of KAP1 wild-type and mutant clones. S. C. and J. H. B. were funded by Ph. D. studentships from The Darwin Trust of Edinburgh and The Wellcome Trust, respectively. This research was supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (V. L.); a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (H. M.); the Ministerio de Ciencia y Tecnologia (SAF2007-61863; M. M. V.); and the Genome Network project and Grants-in-aid from the MEXT of Japan (H. K.). Work in the W. C. E. lab is funded by The Wellcome Trust, of which he is a Principal Research Fellow. NR 49 TC 40 Z9 40 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 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2009 VL 20 IS 19 BP 4194 EP 4204 DI 10.1091/mbc.E09-06-0489 PG 11 WC Cell Biology SC Cell Biology GA 501BF UT WOS:000270352400007 PM 19656847 ER PT J AU To, KKW Robey, RW Knutsen, T Zhan, ZR Ried, T Bates, SE AF To, Kenneth K. W. Robey, Robert W. Knutsen, Turid Zhan, Zhirong Ried, Thomas Bates, Susan E. TI Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2 SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID BINDING CASSETTE TRANSPORTER; BREAST-CANCER CELLS; MULTIDRUG-RESISTANCE; MESSENGER-RNA; METHOTREXATE RESISTANCE; UNTRANSLATED REGION; CARCINOMA CELLS; OVARIAN-CANCER; STEM-CELLS; MICRORNAS AB Overexpression of ABCG2 has been reported in cell lines selected for drug resistance and it is widely believed to be important in the clinical pharmacology of anticancer drugs. We and others have previously identified and validated two microRNAs (miRNA; hsa-miR-519c and hsa-miR-520h) targeting ABCG2. In this study, the shortening of the ABCG2 3' untranslated region (3'UTR) was found to be a common phenomenon in several ABCG2-overexpressing resistant cell lines, which as a result removes the hsa-miR-519c binding site and its repressive effects on mRNA stability and translation blockade, thereby contributing to drug resistance. On the other hand, reduced expression of hsa-miR-520h, previously thought to have allowed ABCG2 overexpression, was found to be caused by the sequestering of the miRNA by the highly expressed ABCG2. In drug-sensitive cells, inhibitors against hsa-miR-519c and hsa-miR-520h could augment the cytotoxic effect of mitoxantrone, suggesting a substantial role for both miRNAs in controlling ABCG2 level and thereby anticancer drug response. However, in drug-resistant cells, altering the levels of the two miRNAs did not have any effect on sensitivity to mitoxantrone. Taken together, these studies suggest that in ABCG2-overexpressing drug-resistant cells, hsa-miR-519c is unable to affect ABCG2 expression because the mRNA lacks its binding site, whereas hsa-miR-520h is sequestered and unable to limit ABCG2 expression. Given the recent observation that a truncated 3'UTR is also observed in ABCG2-overexpressing human embryonic stem cells, our results in drug-resistant cell lines suggest that 3'UTR truncation is a relatively common mechanism of ABCG2 regulation. [Mol Cancer Ther 2009;8(10):2959-68] C1 [To, Kenneth K. W.] Chinese Univ Hong Kong, Sch Pharm, Hong Kong, Hong Kong, Peoples R China. [To, Kenneth K. W.; Robey, Robert W.; Zhan, Zhirong; Bates, Susan E.] NCI, Mol Therapeut Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Knutsen, Turid; Ried, Thomas] NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP To, KKW (reprint author), Chinese Univ Hong Kong, Sch Pharm, Hong Kong, Hong Kong, Peoples R China. EM kennethto@cuhk.edu.hk RI To, Kenneth /M-4500-2013 OI To, Kenneth /0000-0003-2755-0283 FU NIH; National Cancer Institute; Center for Cancer Research, Medical Oncology Branch FX Grant support: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Medical Oncology Branch. NR 46 TC 61 Z9 69 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2009 VL 8 IS 10 BP 2959 EP 2968 DI 10.1158/1535-7163.MCT-09-0292 PG 10 WC Oncology SC Oncology GA 507IJ UT WOS:000270845500019 PM 19825807 ER PT J AU Foreman, JE Sorg, JM McGinnis, KS Rigas, B Williams, JL Clapper, ML Gonzalez, FJ Peters, JM AF Foreman, Jennifer E. Sorg, Joseph M. McGinnis, Kathleen S. Rigas, Basil Williams, Jennie L. Clapper, Margie L. Gonzalez, Frank J. Peters, Jeffrey M. TI Regulation of Peroxisome Proliferator-Activated Receptor-beta/delta by the APC/beta-CATENIN Pathway and Nonsteroidal Antiinflammatory Drugs SO MOLECULAR CARCINOGENESIS LA English DT Article DE colon cancer; PPAR beta/delta; gene expression; NSAIDs ID COLORECTAL-CANCER CELLS; PPAR-DELTA; COLON CARCINOGENESIS; LIGAND ACTIVATION; APC(MIN/+) MICE; TARGET GENES; BETA-CATENIN; EXPRESSION; METABOLISM; GAMMA AB Studies indicate that peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) can either attenuate or potentiate colon cancer. One hypothesis suggests that PPAR beta/delta is upregulated by the adenomatous polyposis coli (APC)/beta-CATENIN pathway and a related hypothesis suggests that PPAR beta/delta is downregulated by nonsteroidal antiinflammatory drugs (NSAIDs). The present study examined these possibilities using in vivo and in vitro models. While APC/beta-CATENIN-dependent expression of CYCLIN D1 was observed in vivo and in vitro, expression of PPAR beta/delta was not different in colon or intestinal polyps from wild-type or Apc(min) heterozygous mice or in human colon cancer cell lines with mutations in APC and/or beta-CATENIN. No difference in the level of PPAR beta/delta was found in colon from wild-type or Apc(min) heterozygous mice following treatment with NO-donating aspirin (NO-ASA). NSAIDs inhibited cell growth in RKO (wild-type APC) and DLD1 (mutant APC) human colon cancer cell lines but expression of PPAR beta/delta was not downregulated in these cell lines in response to a broad concentration range of celecoxib, indomethacin, NS-398, or nimesulide. However, indomethacin caused an increase in PPAR beta/delta mRNA and protein that was accompanied with increased expression of a known PPAR beta/delta target gene. Interestingly, expression of PPAR alpha was also increased in the human colon cancer cell lines by several NSAIDs at the highest concentration examined. Results from these studies provide additional evidence indicating that PPAR beta/delta is not upregulated by the APC/beta-CATENIN pathway. Further, these studies suggest that increased PPAR beta/delta and/or PPAR alpha by NSAIDs in human colon cancer cell lines could contribute to the mechanisms underlying the chemopreventive effects of NSAIDs. (C) 2009 Wiley-Liss, Inc. C1 [Foreman, Jennifer E.; Sorg, Joseph M.; McGinnis, Kathleen S.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Rigas, Basil; Williams, Jennie L.] SUNY Stony Brook, Canc Prevent Div, Stony Brook, NY 11794 USA. [Clapper, Margie L.] Fox Chase Canc Ctr, Canc Prevent & Control Program, Philadelphia, PA 19111 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. RI Peters, Jeffrey/D-8847-2011 FU [CA129467]; [CA97999]; [CA124533]; [CA92423] FX We gratefully acknowledge Drs. Andrew Billin and Timothy Willson for providing GW0742. This work was Supported in part by CA129467 (M.L.C.), CA97999, CA124533 U.M.P.), and CA92423 (B.R.). NR 31 TC 24 Z9 24 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2009 VL 48 IS 10 BP 942 EP 952 DI 10.1002/mc.20546 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 503AF UT WOS:000270502000008 PM 19415698 ER PT J AU Tomarev, SI Nakaya, N AF Tomarev, Stanislav I. Nakaya, Naoki TI Olfactomedin Domain-Containing Proteins: Possible Mechanisms of Action and Functions in Normal Development and Pathology SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Olfactomedin; Myocilin; Glaucoma; Eye; Brain; Neurogenesis; Olfactomedin domain-containing protein; Neural crest ID TRABECULAR MESHWORK CELLS; OPEN-ANGLE GLAUCOMA; ALPHA-LATROTOXIN RECEPTOR; GENE-EXPRESSION PROFILE; SEQUENCE TAG ANALYSIS; SECRETED GLYCOPROTEIN; TRANSCRIPTION FACTOR; AQUEOUS-HUMOR; SEA-URCHIN; IN-VIVO AB A family of olfactomedin domain-containing proteins consists of at least 13 members in mammals. Although the first protein belonging to this family, olfactomedin, was isolated and partially characterized from frog olfactory neuroepithelim almost 20 years ago, the functions of many family members remain elusive. Most of the olfactomedin domain-containing proteins, similar to frog olfactomedin, are secreted glycoproteins that demonstrate specific expression patterns. Other family members are membrane-bound proteins that may serve as receptors. More than half of the olfactomedin domain-containing genes are expressed in neural tissues. Data obtained over the last several years demonstrate that olfactomedin domain-containing proteins play important roles in neurogenesis, neural crest formation, dorsal ventral patterning, cell-cell adhesion, cell cycle regulation, and tumorigenesis and may serve as modulators of critical signaling pathways (Wnt, bone morphogenic protein). Mutations in two genes encoding myocilin and olfactomedin 2 were implicated in glaucoma, and a growing number of evidence indicate that other genes belonging to the family of olfactomedin domain-containing proteins may contribute to different human disorders including psychiatric disorders. In this review, we summarize recent advances in understanding the possible roles of these proteins with special emphasis on the proteins that are preferentially expressed and function in neural tissues. C1 [Tomarev, Stanislav I.; Nakaya, Naoki] NEI, Sect Mol Mech Glaucoma, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, Sect Mol Mech Glaucoma, Mol & Dev Biol Lab, NIH, 5635 Fishers Lane,Room 1124, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov FU Intramural NIH HHS [Z01 EY000318-10] NR 124 TC 68 Z9 68 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2009 VL 40 IS 2 BP 122 EP 138 DI 10.1007/s12035-009-8076-x PG 17 WC Neurosciences SC Neurosciences & Neurology GA 490VC UT WOS:000269534500003 PM 19554483 ER PT J AU Huang, XP Setola, V Yadav, PN Allen, JA Rogan, SC Hanson, BJ Revankar, C Robers, M Doucette, C Roth, BL AF Huang, Xi-Ping Setola, Vincent Yadav, Prem N. Allen, John A. Rogan, Sarah C. Hanson, Bonnie J. Revankar, Chetana Robers, Matt Doucette, Chris Roth, Bryan L. TI Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine(2B) Receptor Agonists: Implications for Drug Safety Assessment SO MOLECULAR PHARMACOLOGY LA English DT Article ID VALVULAR HEART-DISEASE; SPRAGUE-DAWLEY RATS; DOPAMINE AGONISTS; 5-HT2B RECEPTORS; IN-VITRO; FENFLURAMINE; SEROTONIN; VALVES AB Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT2B) receptor agonists. We have shown that activation of 5-HT2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT2B receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT2B receptor agonists (hits); 14 of these had previously been identified as 5-HT2B receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT2B receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT2B receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease. C1 [Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N.; Allen, John A.; Rogan, Sarah C.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Program Neurosci, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Carolina Integrated Chem Biol & Drug Discovery Ct, Chapel Hill, NC 27514 USA. [Allen, John A.; Roth, Bryan L.] Univ N Carolina, Sch Med, Ctr Neurodev Disorders, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Sch Pharm, Dept Med Chem & Nat Prod, Chapel Hill, NC 27514 USA. [Huang, Xi-Ping; Setola, Vincent; Roth, Bryan L.] NIMH, Psychoact Drug Screening Program, Bethesda, MD USA. [Hanson, Bonnie J.; Revankar, Chetana; Robers, Matt; Doucette, Chris] Invitrogen Corp, Madison, WI USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, 120 Mason Farm Rd, Chapel Hill, NC 27514 USA. EM bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010; Allen, John/D-6141-2011 FU National Institutes of Health National Institute of Mental Health [R01-MH61887, U19-MH82441, HHSN-271-2008-00025]; National Institutes of Health National Institute of Child Health & Human Development [T32-HD040127]; University of North Carolina Neurodevelopmental Disorders Research Center; University of North Carolina Medical Scientist Training Program FX This work was supported in part by the National Institutes of Health National Institute of Mental Health [Grants R01-MH61887, U19-MH82441, HHSN-271-2008-00025]; National Institutes of Health National Institute of Child Health & Human Development [Grant T32-HD040127]; the University of North Carolina Neurodevelopmental Disorders Research Center; and the University of North Carolina Medical Scientist Training Program. NR 23 TC 56 Z9 56 U1 1 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2009 VL 76 IS 4 BP 710 EP 722 DI 10.1124/mol.109.058057 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 497AZ UT WOS:000270027000004 PM 19570945 ER PT J AU Kessl, JJ Eidahl, JO Shkriabai, N Zhao, ZJ Mckee, CJ Hess, S Burke, TR Kvaratskhelia, M AF Kessl, Jacques J. Eidahl, Jocelyn O. Shkriabai, Nikolozi Zhao, Zhuojun McKee, Christopher J. Hess, Sonja Burke, Terrence R., Jr. Kvaratskhelia, Mamuka TI An Allosteric Mechanism for Inhibiting HIV-1 Integrase with a Small Molecule SO MOLECULAR PHARMACOLOGY LA English DT Article ID VIRAL-DNA BINDING; L-CHICORIC ACID; CRYSTAL-STRUCTURE; COMPLEX-FORMATION; CATALYTIC DOMAIN; COACTIVATOR P75; HUMAN-CELLS; IN-VITRO; LEDGF/P75; IDENTIFICATION AB HIV-1 integrase (IN) is a validated target for developing antiretroviral inhibitors. Using affinity acetylation and mass spectrometric (MS) analysis, we previously identified a tetra-acetylated inhibitor (2E)-3-[3,4-bis(acetoxy)phenyl]-2-propenoate-N-[(2E)3-[3,4-bis(acetyloxy) phenyl]-1-oxo-2-propenyl]-L-serine methyl ester; compound 1] that selectively modified Lys173 at the IN dimer interface. Here we extend our efforts to dissect the mechanism of inhibition and structural features that are important for the selective binding of compound 1. Using a subunit exchange assay, we found that the inhibitor strongly modulates dynamic interactions between IN subunits. Restricting such interactions does not directly interfere with IN binding to DNA substrates or cellular cofactor lens epithelium-derived growth factor, but it compromises the formation of the fully functional nucleoprotein complex. Studies comparing compound 1 with a structurally related IN inhibitor, the tetra-acetylated-chicoric acid derivative (2R, 3R)-2,3-bis[[(2E)-3-[3,4-bis(acetyloxy)phenyl]1-oxo-2-propen-1-yl] oxy]-butanedioic acid (compound 2), indicated striking mechanistic differences between these agents. The structures of the two inhibitors differ only in their central linker regions, with compounds 1 and 2 containing a single methyl ester group and two carboxylic acids, respectively. MS experiments highlighted the importance of these structural differences for selective binding of compound 1 to the IN dimer interface. Moreover, molecular modeling of compound 1 complexed to IN identified a potential inhibitor binding cavity and provided structural clues regarding a possible role of the central methyl ester group in establishing an extensive hydrogen bonding network with both interacting subunits. The proposed mechanism of action and binding site for the small-molecule inhibitor identified in the present study provide an attractive venue for developing allosteric inhibitors of HIV-1 IN. C1 [Kessl, Jacques J.; Eidahl, Jocelyn O.; Shkriabai, Nikolozi; Zhao, Zhuojun; McKee, Christopher J.; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Kessl, Jacques J.; Eidahl, Jocelyn O.; Shkriabai, Nikolozi; Zhao, Zhuojun; McKee, Christopher J.; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Hess, Sonja] CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, CA 91125 USA. [Burke, Terrence R., Jr.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Kvaratskhelia, M (reprint author), Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, 500 W 12th Ave,Room 238,LM Pk Hall, Columbus, OH 43210 USA. EM kvaratskhelia.1@osu.edu RI Hess, Sonja/K-4842-2013; Burke, Terrence/N-2601-2014; Kessl, Jacques/J-6073-2015 OI Hess, Sonja/0000-0002-5904-9816; FU National Institutes of Health National Institute of Allergy and Infectious Diseases [AI062520, AI077341]; Intramural Research Programs of the National Institutes of Health Center for Cancer Research; National Institutes of Health National Cancer Institute; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by National Institutes of Health National Institute of Allergy and Infectious Diseases [Grants AI062520, AI077341]; and by the Intramural Research Programs of the National Institutes of Health Center for Cancer Research, the National Institutes of Health National Cancer Institute, and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 37 Z9 37 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2009 VL 76 IS 4 BP 824 EP 832 DI 10.1124/mol.109.058883 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 497AZ UT WOS:000270027000014 PM 19638533 ER PT J AU Federhen, S Hotton, C Mizrachi, I AF Federhen, Scott Hotton, Carol Mizrachi, Ilene TI Comments on the paper by Pleijel et al. (2008): Vouching for GenBank SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Letter C1 [Federhen, Scott; Hotton, Carol; Mizrachi, Ilene] Natl Lib Med, NCBI, NIH, Bethesda, MD USA. RP Federhen, S (reprint author), Natl Lib Med, NCBI, NIH, 8600 Rockville Pike, Bethesda, MD USA. EM federhen@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 0 TC 4 Z9 4 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD OCT PY 2009 VL 53 IS 1 BP 357 EP 358 DI 10.1016/j.ympev.2009.04.016 PG 2 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 484SN UT WOS:000269067900035 PM 19410006 ER PT J AU Meyer-Lindenberg, A Kolachana, B Gold, B Olsh, A Nicodemus, KK Mattay, V Dean, M Weinberger, DR AF Meyer-Lindenberg, A. Kolachana, B. Gold, B. Olsh, A. Nicodemus, K. K. Mattay, V. Dean, M. Weinberger, D. R. TI Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans SO MOLECULAR PSYCHIATRY LA English DT Article DE vasopressin; AVPR1A; fMRI; neuroimaging; autism ID ANXIETY-RELATED BEHAVIOR; INDIVIDUAL-DIFFERENCES; SOCIAL COMMUNICATION; SUSCEPTIBILITY GENE; NEURAL CIRCUITRY; GAZE-FIXATION; HUMAN BRAIN; VASOPRESSIN; OXYTOCIN; ASSOCIATION AB In mammals, the neuropeptide vasopressin is a key molecule for complex emotional and social behaviours. Two microsatellite polymorphisms, RS1 and RS3, near the promoter of AVPR1A, encoding the receptor subtype most heavily implicated in behaviour regulation, have been linked to autism and behavioural traits. However, the impact of these variants on human brain function is unknown. Here we show that human amygdala function is strongly associated with genetic variation in AVPR1A. Using an imaging genetics approach in a sample of 121 volunteers studied with an emotional face-matching paradigm, we found that differential activation of amygdala is observed in carriers of risk alleles for RS3 and RS1. Alleles in RS1 previously reported to be significantly over- and undertransmitted to autistic probands showed opposing effects on amygdala activation. Furthermore, we show functional difference in human brain between short and long repeat lengths that mirror findings recently obtained in a corresponding variant in voles. Our results indicate a neural mechanism mediating genetic risk for autism through an impact on amygdala signalling and provide a rationale for exploring therapeutic strategies aimed at abnormal amygdala function in this disorder. Molecular Psychiatry (2009) 14, 968-975; doi:10.1038/mp.2008.54; published online 20 May 2008 C1 [Weinberger, D. R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH,DHHS, Bethesda, MD 20892 USA. [Meyer-Lindenberg, A.] NIMH, Unit Syst Neurosci Psychiat, NIH, DHHS, Bethesda, MD 20892 USA. [Meyer-Lindenberg, A.; Mattay, V.] NIMH, Neuroimaging Core Facil, NIH, DHHS, Bethesda, MD 20892 USA. [Meyer-Lindenberg, A.] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. [Gold, B.; Olsh, A.; Dean, M.] NCI Frederick, Human Genet Sect, Lab Genom Divers, Ctr Canc Res, Frederick, MD USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH,DHHS, Room 4S-235,MSC1379,10 Ctr Dr, Bethesda, MD 20892 USA. EM weinberd@intra.nimh.nih.gov RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU NIH; NIMH; NCI FX This work was supported by the Intramural Research Program of the NIH, NIMH and NCI. We thank Dr Andrew Singleton for his technical advice resolving the microsatellites. NR 52 TC 86 Z9 88 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2009 VL 14 IS 10 BP 968 EP 975 DI 10.1038/mp.2008.54 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 500UM UT WOS:000270331000007 PM 18490926 ER PT J AU Thomas, JD Majumdar, S Sloan, KB AF Thomas, Joshua Denver Majumdar, Susruta Sloan, Kenneth Berry TI Soft Alkyl Ether Prodrugs of a Model Phenolic Drug: The Effect of Incorporation of Ethyleneoxy Groups on Transdermal Delivery SO MOLECULES LA English DT Article DE topical delivery; Roberts-Sloan equation; water solubility; lipid solubility; prodrugs ID IN-VITRO EVALUATION; TOPICAL DELIVERY; HUMAN SKIN; WATER SOLUBILITY; DERMAL PRODRUGS; ACETAMINOPHEN; 6-MERCAPTOPURINE; NALTREXONE; DIFFUSION; ESTERS AB Two different types of soft alkyl ether prodrugs incorporating ethyleneoxy groups into the promoiety have been synthesized for a model phenol (acetaminophen, APAP): alkyloxycarbonyloxymethyl type (AOCOM) and N-alkyl-N-alkyloxycarbonyl-aminomethyl type (NANAOCAM). The solubilities in isopropyl myristate, S(IPM), and water, S(AQ), partition coefficients between IPM and pH 4.0 buffer, K(IPM:4.0), and the delivery of total species containing APAP through hairless mouse skin from IPM, J(MMIPM), have been measured for the prodrugs. The J(MMIPM) values were accurately predicted by the Roberts-Sloan (RS) equation. Only modest increases in J(MMIPM) were realized (about 1.4 times) by each type. The only prodrug that was more water soluble and more lipid soluble than APAP did not improve J(MMIPM) of APAP. This result may be due to the strong association of water molecules with the ethyleneoxy groups, and especially the triethyleneoxy derivative, which dramatically increases the molecular weight and depresses J(MMIPM). C1 [Sloan, Kenneth Berry] Univ Florida, Dept Med Chem, Gainesville, FL 32610 USA. [Majumdar, Susruta] Mem Sloan Kettering Canc Ctr, Lab Mol Pharmacol & Chem, New York, NY 10021 USA. [Thomas, Joshua Denver] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Sloan, KB (reprint author), Univ Florida, Dept Med Chem, POB 100485, Gainesville, FL 32610 USA. EM sloan@cop.ufl.edu FU NCI NIH HHS [P30 CA008748] NR 27 TC 9 Z9 9 U1 0 U2 9 PU MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD OCT PY 2009 VL 14 IS 10 BP 4231 EP 4245 DI 10.3390/molecules14104231 PG 15 WC Chemistry, Organic SC Chemistry GA 512QP UT WOS:000271265300029 PM 19924060 ER PT J AU Bielekova, B Richert, N Howard, T Packer, AN Blevins, G Ohayon, J McFarland, HF Sturzebecher, CS Martin, R AF Bielekova, Bibiana Richert, Nancy Howard, Thomas Packer, Amy N. Blevins, Gregg Ohayon, Joan McFarland, Henry F. Stuerzebecher, Claus-Steffen Martin, Roland TI Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood-brain barrier disruption in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Article DE multiple sclerosis; blood-brain barrier; rolipram; phosphodiesterase-4; autoimmunity; clinical trial ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; REGULATORY T-CELLS; INTERFERON-BETA; INDUCED ARTHRITIS; OUTCOME MEASURE; CLINICAL-TRIAL; LEWIS RATS; IV; DISEASE AB Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear. C1 [Martin, Roland] Univ Clin Eppendorf, Inst Neuroimmunol & Clin MS Res, Ctr Mol Neurobiol Hamburg, Univ Med Ctr Eppendorf, D-20251 Hamburg, Germany. [Blevins, Gregg] Univ Alberta, Div Neurol, Edmonton, AB T6G 2G3, Canada. [Stuerzebecher, Claus-Steffen] Grunenthal, D-52078 Aachen, Germany. [Bielekova, Bibiana; Richert, Nancy; Howard, Thomas; Packer, Amy N.; Blevins, Gregg; Ohayon, Joan; McFarland, Henry F.; Martin, Roland] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), Univ Clin Eppendorf, Inst Neuroimmunol & Clin MS Res, Ctr Mol Neurobiol Hamburg, Univ Med Ctr Eppendorf, Falkenried 94, D-20251 Hamburg, Germany. EM roland.martin@zmnh.uni-hamburg.de FU NINDS/NIH FX Our thanks go to Helen Griffith and Angela Kokkinis for expert nursing support and to Azita Kashani for help with processing of apheresis samples. The clinical trial was supported by the Intramural research program of the NINDS/NIH, in part through a Bench-to-Bedside intramural research grant to R Martin. Rolipram raw material was provided to the NINDS investigators by Schering AG, Germany, under Collaborative Research and Development Agreement (CRADA). NR 38 TC 17 Z9 17 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD OCT PY 2009 VL 15 IS 10 BP 1206 EP 1214 DI 10.1177/1352458509345903 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 508AV UT WOS:000270900100009 PM 19776093 ER PT J AU Dwivedi, D Johri, BN Ineichen, K Wray, V Wiemken, A AF Dwivedi, Deepti Johri, Bhavdish N. Ineichen, Kurt Wray, Victor Wiemken, Andres TI Impact of antifungals producing rhizobacteria on the performance of Vigna radiata in the presence of arbuscular mycorrhizal fungi SO MYCORRHIZA LA English DT Article DE Antifungal-producing bacteria; PGPR; Mycorrhiza helper bacteria; AMF ID PSEUDOMONAS-FLUORESCENS CHA0; BIOLOGICAL-CONTROL; PLANT-GROWTH; METABOLITE 2,4-DIACETYLPHLOROGLUCINOL; ANTIBIOTIC PRODUCTION; ROCK PHOSPHATE; MAIZE PLANTS; SOIL; RHIZOSPHERE; BACTERIA AB Plant growth-promoting rhizobacteria (PGPR) that produce antifungal metabolites are potential threats for the arbuscular mycorrhizal (AM) fungi known for their beneficial symbiosis with plants that is crucially important for low-input sustainable agriculture. To address this issue, we used a compartmented container system where test plants, Vigna radiata, could only reach a separate nutrient-rich compartment indirectly via the hyphae of AM fungi associated with their roots. In this system, where plants depended on nutrient uptake via AM symbiosis, we explored the impact of various PGPR. Plants were inoculated with or without a consortium of four species of AM fungi (Glomus coronatum, Glomus etunicatum, Glomus constrictum, and Glomus intraradices), and one or more of the following PGPR strains: phenazine producing (P(+)) and phenazine-less mutant (P(-)), diacetylphloroglucinol (DAPG) producing (G(+)) and DAPG-less mutant (G(-)) strains of Pseudomonas fluorescens, and an unknown antifungal metabolite-producing Alcaligenes faecalis strain, SLHRE425 (D). PGPR exerted only a small if any effect on the performance of AM symbiosis. G(+) enhanced AM root colonization and had positive effects on shoot growth and nitrogen content when added alone, but not in combination with P(+). D negatively influenced AM root colonization, but did not affect nutrient acquisition. Principal component analysis of all treatments indicated correlation between root weight, shoot weight, and nutrient uptake by AM fungus. The results indicate that antifungal metabolites producing PGPR do not necessarily interfere with AM symbiosis and may even promote it thus carefully chosen combinations of such bioinoculants could lead to better plant growth. C1 [Dwivedi, Deepti; Johri, Bhavdish N.] GB Pant Univ Agr & Technol, Dept Microbiol, Pantnagar 263145, Uttar Pradesh, India. [Dwivedi, Deepti] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Dwivedi, Deepti; Ineichen, Kurt; Wiemken, Andres] Univ Basel, Dept Bot, CH-4056 Basel, Switzerland. [Wray, Victor] Helmholtz Ctr Infect Res, Dept Biol Struct, D-38124 Braunschweig, Germany. RP Dwivedi, D (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM dwivedid@niehs.nih.gov FU Indo-Swiss Collaboration in Biotechnology (ISCB) FX The authors would like to thank Alok Adholeya for providing some mycorrhizal inocula; Genevieve Defago and Linda Thomashow for providing the Pseudomonas cultures; and David Roesti, Feng He, and Bharani Kumar for statistical analysis and interpretation. We thank Roel M. Schaaper, Rajesh Kasiviswanathan, and Greg Stuart for critical comments on the manuscript. This work was funded by Indo-Swiss Collaboration in Biotechnology (ISCB). NR 66 TC 8 Z9 8 U1 3 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6360 J9 MYCORRHIZA JI Mycorrhiza PD OCT PY 2009 VL 19 IS 8 BP 559 EP 570 DI 10.1007/s00572-009-0253-2 PG 12 WC Mycology SC Mycology GA 495TX UT WOS:000269919000005 PM 19458967 ER PT J AU Bhirde, AA Sousa, AA Patel, V Azari, AA Gutkind, JS Leapman, RD Rusling, JF AF Bhirde, Ashwin A. Sousa, Alioscka A. Patel, Vyomesh Azari, Afrouz A. Gutkind, J. Silvio Leapman, Richard D. Rusling, James F. TI Imaging the distribution of individual platinum-based anticancer drug molecules attached to single-wall carbon nanotubes SO NANOMEDICINE LA English DT Article DE cisplatin; drug delivery; EGF; squamous cell carcinoma; scanning transmission electron microscopic tomography; scanning transmission electron microscopy; single-wall carbon nanotube ID TRANSMISSION ELECTRON-MICROSCOPE; THERAPEUTIC APPLICATIONS; CANCER-THERAPY; DELIVERY; NANOPARTICLES; STEM; TRANSPORTERS; TOMOGRAPHY; SYSTEM; CELLS AB Aims: To image the distribution of drug molecules attached to single-wall carbon nanotubes (SWNTs). Materials & methods: Herein we report the use of scanning transmission electron microscopy (STEM) for atomic scale visualization and cluantitation of single platinum-based drug molecules attached to SWNTs designed for targeted drug delivery. Fourier transform infrared spectroscopy and energy-dispersive x-ray spectroscopy were used for characterization of the SWNT drug conjugates. Results: Z-contrast STEM imaging enabled visualization of the first-line anticancer drug cisplatin on the nanotubes at single molecule level. The identity and presence of cisplatin on the nanotubes was confirmed using energy-dispersive x-ray spectroscopy and Fourier transform infrared spectroscopy. STEM tomography was also used to provide additional insights concerning the nanotube conjugates. Finally, our observations provide a rationale for exploring the use of SWNT bioconjugates to selectively target and kill squamous cancer cells. Conclusion: Z-contrast STEM imaging provides a means for direct visualization of heavy metal containing molecules (i.e., cisplatin) attached to surfaces of carbon SWNTs along with distribution and quantitation. C1 [Sousa, Alioscka A.; Azari, Afrouz A.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Bhirde, Ashwin A.; Rusling, James F.] Univ Connecticut, Storrs, CT 06269 USA. [Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Rusling, James F.] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Farmington, CT 06032 USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, 13 South Dr,Bldg 13,Room 3N17, Bethesda, MD 20892 USA. EM leapmanr@mail.nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU National Institute of Dental and Craniofacial Research; National Institute of Biomedical Imaging and Bioengineering; NIH; NIEHS/NIH [ES013557] FX This research was supported by the Intramural Programs of the National Institute of Dental and Craniofacial Research, the National Institute of Biomedical Imaging and Bioengineering, NIH and in part by PHS grant ES013557 from NIEHS/NIH to University CT The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 39 TC 10 Z9 10 U1 2 U2 8 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD OCT PY 2009 VL 4 IS 7 BP 763 EP 772 DI 10.2217/NNM.09.56 PG 10 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 516MZ UT WOS:000271547900012 PM 19839812 ER PT J AU Klamt, F Zdanov, S Levine, RL Pariser, A Zhang, YQ Zhang, BL Yu, LR Veenstra, TD Shacter, E AF Klamt, Fabio Zdanov, Stephanie Levine, Rodney L. Pariser, Ashley Zhang, Yaqin Zhang, Baolin Yu, Li-Rong Veenstra, Timothy D. Shacter, Emily TI Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin SO NATURE CELL BIOLOGY LA English DT Article ID HYPOCHLOROUS ACID; CELL-DEATH; PERMEABILITY TRANSITION; HYDROGEN-PEROXIDE; MITOCHONDRIAL PERMEABILITY; LYMPHOMA-CELLS; STRESS; CYSTEINE; CANCER; CHLORAMINES AB Physiological oxidants that are generated by activated phagocytes comprise the main source of oxidative stress during inflammation(1,2). Oxidants such as taurine chloramine (TnCl) and hydrogen peroxide (H(2)O(2)) can damage proteins and induce apoptosis, but the role of specific protein oxidation in this process has not been defined. We found that the actin-binding protein cofilin is a key target of oxidation. When oxidation of this single regulatory protein is prevented, oxidant-induced apoptosis is inhibited. Oxidation of cofilin causes it to lose its affinity for actin and to translocate to the mitochondria, where it induces swelling and cytochrome c release by mediating opening of the permeability transition pore (PTP). This occurs independently of Bax activation and requires both oxidation of cofilin Cys residues and dephosphorylation at Ser 3. Knockdown of endogenous cofilin using targeted siRNA inhibits oxidant-induced apoptosis, which is restored by re-expression of wild-type cofilin but not by cofilin containing Cys to Ala mutations. Exposure of cofilin to TnCl results in intramolecular disulphide bonding and oxidation of Met residues to Met sulphoxide, but only Cys oxidation causes cofilin to induce mitochondrial damage. C1 [Klamt, Fabio; Zdanov, Stephanie; Pariser, Ashley; Zhang, Yaqin; Zhang, Baolin; Shacter, Emily] US FDA, Biochem Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Klamt, Fabio] Univ Fed Rio Grande do Sul, Ctr Oxidat Stress Res, Dept Biochem, ICBS, BR-90035003 Porto Alegre, RS, Brazil. [Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Yu, Li-Rong] US FDA, Ctr Prote, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Yu, Li-Rong; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Shacter, E (reprint author), US FDA, Biochem Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM emily.shacter@fda.hhs.gov RI Zdanov, Stephanie/G-2524-2012; Levine, Rodney/D-9885-2011 FU Intramural NIH HHS [Z01 HL000225-31]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 38 TC 114 Z9 115 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD OCT PY 2009 VL 11 IS 10 BP 1241 EP U193 DI 10.1038/ncb1968 PG 18 WC Cell Biology SC Cell Biology GA 501KZ UT WOS:000270382000014 PM 19734890 ER PT J AU Pegoraro, G Kubben, N Wickert, U Gohler, H Hoffmann, K Misteli, T AF Pegoraro, Gianluca Kubben, Nard Wickert, Ute Goehler, Heike Hoffmann, Katrin Misteli, Tom TI Ageing-related chromatin defects through loss of the NURD complex SO NATURE CELL BIOLOGY LA English DT Article ID HUTCHINSON-GILFORD-PROGERIA; PROTEIN-INTERACTION NETWORK; HUMAN-CELLS; S-PHASE; METHYLATION; TRANSCRIPTION; STABILITY; ENHANCER; DISEASE; GENOME AB Physiological and premature ageing are characterized by multiple defects in chromatin structure and accumulation of persistent DNA damage. Here we identify the NURD chromatin remodelling complex as a key modulator of these ageing-associated chromatin defects. We demonstrate loss of several NURD components during premature and normal ageing and we find an ageing-associated reduction in HDAC1 activity. Silencing of individual NURD subunits recapitulated chromatin defects associated with ageing and we provide evidence that structural chromatin defects precede DNA damage accumulation. These results outline a molecular mechanism for chromatin defects during ageing. C1 [Pegoraro, Gianluca; Kubben, Nard; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Kubben, Nard] Maastricht Univ, Dept Expt & Mol Cardiol, Cardiovasc Res Inst Maastricht, Maastricht, Netherlands. [Wickert, Ute] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany. [Goehler, Heike] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Hoffmann, Katrin] Humboldt Univ, Inst Med Genet, Charite Berlin, D-13353 Berlin, Germany. [Hoffmann, Katrin] Max Planck Inst Mol Genet Dev & Dis, D-14195 Berlin, Germany. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Pegoraro, Gianluca/0000-0003-2843-9464 FU Telethon Italy Foundation; Italian Association for Cancer Research (AIRC); Deutsche Forschungsgemeinschaft (DFG) [A4, Z2]; NIH; NCI; Center for Cancer Research FX We thank P. Scaffidi and A. Marcello for critical reading of the manuscript, and P. Scaffidi for sharing data and providing numerous suggestions during the course of the experiments. Fluorescence imaging was performed with the assistance of T. Karpova at the NCI Fluorescence Imaging Microscopy Facility. FACS cell cycle acquisition and analysis was performed with the help of K. McKinnon at the NCI FACS facility. We also thank T. Jenuwein, B. Stillman and T. Dittmer for providing reagents. We thank H. Herrmann and E. Wanker for their support with the Y2H screening and subsequent confirmation studies. G. P. was partly supported by postdoctoral fellowships from the Telethon Italy Foundation and the Italian Association for Cancer Research (AIRC). K. H. and H. G. were supported by The Deutsche Forschungsgemeinschaft (DFG, SFB 577, projects A4 and Z2). This work was supported by an Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 26 TC 131 Z9 134 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD OCT PY 2009 VL 11 IS 10 BP 1261 EP U251 DI 10.1038/ncb1971 PG 18 WC Cell Biology SC Cell Biology GA 501KZ UT WOS:000270382000017 PM 19734887 ER PT J AU Yuan, J Johnson, RL Huang, RL Wichterman, J Jiang, HY Hayton, K Fidock, DA Wellems, TE Inglese, J Austin, CP Su, XZ AF Yuan, Jing Johnson, Ronald L. Huang, Ruili Wichterman, Jennifer Jiang, Hongying Hayton, Karen Fidock, David A. Wellems, Thomas E. Inglese, James Austin, Christopher P. Su, Xin-zhuan TI Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum SO NATURE CHEMICAL BIOLOGY LA English DT Article ID CHLOROQUINE RESISTANCE; MALARIA PARASITES; DRUG-RESISTANCE; FOLIC-ACID; GENOME; IDENTIFICATION; TRIAMTERENE; ANTIMALARIALS; PYRIMETHAMINE; SENSITIVITY AB Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits. C1 [Yuan, Jing; Jiang, Hongying; Hayton, Karen; Wellems, Thomas E.; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Johnson, Ronald L.; Huang, Ruili; Wichterman, Jennifer; Inglese, James; Austin, Christopher P.] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Fidock, David A.] Columbia Univ, Dept Microbiol & Immunol, New York, NY USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM xsu@niaid.nih.gov OI Fidock, David/0000-0001-6753-8938; Su, Xinzhuan/0000-0003-3246-3248 FU Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; NIH FX This work was supported by the Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, and by the National Human Genome Research Institute and the NIH Roadmap for Medical Research, all at the US National Institutes of Health. We thank J. Sa, J. Mu, L. Jiang, D. Raj and M. J. Lopez Barragan for help in drug assays; P. Shinn and D. VanLeer for compound management; D. Leja for assistance in artworks and NIAID intramural editor B. R. Marshall for assistance. NR 45 TC 39 Z9 39 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2009 VL 5 IS 10 BP 765 EP 771 DI 10.1038/nchembio.215 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 497EV UT WOS:000270039900015 PM 19734910 ER PT J AU O'Brien, TR AF O'Brien, Thomas R. TI Interferon-alfa, interferon-lambda and hepatitis C SO NATURE GENETICS LA English DT Editorial Material ID VIRUS-REPLICATION; INFECTION; PEGINTERFERON; RIBAVIRIN; IL-29 AB Three new studies report genetic variants near IL28B, which encodes interferon-lambda 3 (interleukin 28B), are associated with response to treatment of chronic hepatitis C virus infection with interferon-alfa/ribavirin combination therapy. This renews interest in how interferons suppress viremia and could lead to improved clinical decisions for chronic HCV infection treatment based on individual genotype. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP O'Brien, TR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov NR 15 TC 53 Z9 54 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2009 VL 41 IS 10 BP 1048 EP 1050 DI 10.1038/ng.453 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 500UG UT WOS:000270330400003 PM 19749756 ER PT J AU Yeager, M Chatterjee, N Ciampa, J Jacobs, KB Gonzalez-Bosquet, J Hayes, RB Kraft, P Wacholder, S Orr, N Berndt, S Yu, K Hutchinson, A Wang, ZM Amundadottir, L Feigelson, HS Thun, MJ Diver, WR Albanes, D Virtamo, J Weinstein, S Schumacher, FR Cancel-Tassin, G Cussenot, O Valeri, A Andriole, GL Crawford, ED Haiman, CA Henderson, B Kolonel, L Le Marchand, L Siddiq, A Riboli, E Key, TJ Kaaks, R Isaacs, W Isaacs, S Wiley, KE Gronberg, H Wiklund, F Stattin, P Xu, JF Zheng, SL Sun, JL Vatten, LJ Hveem, K Kumle, M Tucker, M Gerhard, DS Hoover, RN Fraumeni, JF Hunter, DJ Thomas, G Chanock, SJ AF Yeager, Meredith Chatterjee, Nilanjan Ciampa, Julia Jacobs, Kevin B. Gonzalez-Bosquet, Jesus Hayes, Richard B. Kraft, Peter Wacholder, Sholom Orr, Nick Berndt, Sonja Yu, Kai Hutchinson, Amy Wang, Zhaoming Amundadottir, Laufey Feigelson, Heather Spencer Thun, Michael J. Diver, W. Ryan Albanes, Demetrius Virtamo, Jarmo Weinstein, Stephanie Schumacher, Fredrick R. Cancel-Tassin, Geraldine Cussenot, Olivier Valeri, Antoine Andriole, Gerald L. Crawford, E. David Haiman, Christopher A. Henderson, Brian Kolonel, Laurence Le Marchand, Loic Siddiq, Afshan Riboli, Elio Key, Timothy J. Kaaks, Rudolf Isaacs, William Isaacs, Sarah Wiley, Kathleen E. Gronberg, Henrik Wiklund, Fredrik Stattin, Par Xu, Jianfeng Zheng, S. Lilly Sun, Jielin Vatten, Lars J. Hveem, Kristian Kumle, Merethe Tucker, Margaret Gerhard, Daniela S. Hoover, Robert N. Fraumeni, Joseph F., Jr. Hunter, David J. Thomas, Gilles Chanock, Stephen J. TI Identification of a new prostate cancer susceptibility locus on chromosome 8q24 SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COLORECTAL-CANCER; MULTIPLE LOCI; RISK; VARIANT; RANGE; SCAN AB We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. We identify a new association with prostate cancer risk on chromosome 8q24 (rs620861, P = 1.3 x 10(-10), heterozygote OR = 1.17, 95% CI 1.10-1.24; homozygote OR = 1.33, 95% CI 1.21-1.45). This defines a new locus associated with prostate cancer susceptibility on 8q24. C1 [Yeager, Meredith; Hutchinson, Amy; Wang, Zhaoming] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Yeager, Meredith; Chatterjee, Nilanjan; Ciampa, Julia; Gonzalez-Bosquet, Jesus; Hayes, Richard B.; Wacholder, Sholom; Orr, Nick; Berndt, Sonja; Yu, Kai; Hutchinson, Amy; Wang, Zhaoming; Amundadottir, Laufey; Albanes, Demetrius; Weinstein, Stephanie; Tucker, Margaret; Hoover, Robert N.; Fraumeni, Joseph F., Jr.; Thomas, Gilles; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Kraft, Peter; Schumacher, Fredrick R.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Feigelson, Heather Spencer; Thun, Michael J.; Diver, W. Ryan] Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Schumacher, Fredrick R.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine] Hop Tenon, CeRePP, AP HP, F-75970 Paris, France. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Crawford, E. David] Univ Colorado Denver & Hlth Sci Ctr, Dept Surg, Denver, CO USA. [Haiman, Christopher A.; Henderson, Brian] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90033 USA. [Kolonel, Laurence; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Siddiq, Afshan; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. [Key, Timothy J.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Kaaks, Rudolf] German Canc Res Ctr, Div Clin Epidemiol, DKFZ, D-6900 Heidelberg, Germany. [Isaacs, William; Isaacs, Sarah; Wiley, Kathleen E.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Stattin, Par] Umea Univ, Dept Surg Preoperat Sci Urol & Androl, Umea, Sweden. [Xu, Jianfeng; Zheng, S. Lilly; Sun, Jielin] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Vatten, Lars J.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway. [Kumle, Merethe] Univ Tromso, Inst Community Med, Tromso, Norway. [Gerhard, Daniela S.] NCI, Off Canc Genom, NIH, DHHS, Bethesda, MD 20892 USA. [Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Channing Lab, Sch Med, Boston, MA 02115 USA. RP Yeager, M (reprint author), NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. EM yeagerm@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Albanes, Demetrius/B-9749-2015; Amundadottir, Laufey/L-7656-2016; OI Amundadottir, Laufey/0000-0003-1859-8971; Hayes, Richard/0000-0002-0918-661X; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU NCI; National Institutes of Health (NIH) [HHSN261200800001E]; [CA129684]; [CA131338] FX This project was funded in part using grants CA129684 to J.X. and CA131338 to S.L.Z. This project was funded in whole or in part with federal funds from the NCI, National Institutes of Health (NIH), 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 (DHHS), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 15 TC 153 Z9 156 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2009 VL 41 IS 10 BP 1055 EP 1057 DI 10.1038/ng.444 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 500UG UT WOS:000270330400005 PM 19767755 ER PT J AU Harold, D Abraham, R Hollingworth, P Sims, R Gerrish, A Hamshere, ML Pahwa, JS Moskvina, V Dowzell, K Williams, A Jones, N Thomas, C Stretton, A Morgan, AR Lovestone, S Powell, J Proitsi, P Lupton, MK Brayne, C Rubinsztein, DC Gill, M Lawlor, B Lynch, A Morgan, K Brown, KS Passmore, PA Craig, D McGuinness, B Todd, S Holmes, C Mann, D Smith, AD Love, S Kehoe, PG Hardy, J Mead, S Fox, N Rossor, M Collinge, J Maier, W Jessen, F Schurmann, B van den Bussche, H Heuser, I Kornhuber, J Wiltfang, J Dichgans, M Frolich, L Hampel, H Hull, M Rujescu, D Goate, AM Kauwe, JSK Cruchaga, C Nowotny, P Morris, JC Mayo, K Sleegers, K Bettens, K Engelborghs, S De Deyn, PP Van Broeckhoven, C Livingston, G Bass, NJ Gurling, H McQuillin, A Gwilliam, R Deloukas, P Al-Chalabi, A Shaw, CE Tsolaki, M Singleton, AB Guerreiro, R Muhleisen, TW Nothen, MM Moebus, S Jockel, KH Klopp, N Wichmann, HE Carrasquillo, MM Pankratz, VS Younkin, SG Holmans, PA O'Donovan, M Owen, MJ Williams, J AF Harold, Denise Abraham, Richard Hollingworth, Paul Sims, Rebecca Gerrish, Amy Hamshere, Marian L. Pahwa, Jaspreet Singh Moskvina, Valentina Dowzell, Kimberley Williams, Amy Jones, Nicola Thomas, Charlene Stretton, Alexandra Morgan, Angharad R. Lovestone, Simon Powell, John Proitsi, Petroula Lupton, Michelle K. Brayne, Carol Rubinsztein, David C. Gill, Michael Lawlor, Brian Lynch, Aoibhinn Morgan, Kevin Brown, Kristelle S. Passmore, Peter A. Craig, David McGuinness, Bernadette Todd, Stephen Holmes, Clive Mann, David Smith, A. David Love, Seth Kehoe, Patrick G. Hardy, John Mead, Simon Fox, Nick Rossor, Martin Collinge, John Maier, Wolfgang Jessen, Frank Schuermann, Britta van den Bussche, Hendrik Heuser, Isabella Kornhuber, Johannes Wiltfang, Jens Dichgans, Martin Froelich, Lutz Hampel, Harald Huell, Michael Rujescu, Dan Goate, Alison M. Kauwe, John S. K. Cruchaga, Carlos Nowotny, Petra Morris, John C. Mayo, Kevin Sleegers, Kristel Bettens, Karolien Engelborghs, Sebastiaan De Deyn, Peter P. Van Broeckhoven, Christine Livingston, Gill Bass, Nicholas J. Gurling, Hugh McQuillin, Andrew Gwilliam, Rhian Deloukas, Panagiotis Al-Chalabi, Ammar Shaw, Christopher E. Tsolaki, Magda Singleton, Andrew B. Guerreiro, Rita Muehleisen, Thomas W. Noethen, Markus M. Moebus, Susanne Joeckel, Karl-Heinz Klopp, Norman Wichmann, H-Erich Carrasquillo, Minerva M. Pankratz, V. Shane Younkin, Steven G. Holmans, Peter A. O'Donovan, Michael Owen, Michael J. Williams, Julie TI Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease SO NATURE GENETICS LA English DT Article ID AMYLOID-PRECURSOR-PROTEIN; SINGLE-NUCLEOTIDE POLYMORPHISMS; APOLIPOPROTEIN-J; CEREBROSPINAL-FLUID; BETA-PROTEIN; LARGE-SCALE; SUSCEPTIBILITY LOCI; MOUSE MODEL; IN-VITRO; CLUSTERIN AB We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5. to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86). C1 [Harold, Denise; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Hamshere, Marian L.; Pahwa, Jaspreet Singh; Moskvina, Valentina; Dowzell, Kimberley; Williams, Amy; Jones, Nicola; Thomas, Charlene; Stretton, Alexandra; Morgan, Angharad R.; Holmans, Peter A.; O'Donovan, Michael; Owen, Michael J.; Williams, Julie] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol,Sch Med, Cardiff, S Glam, Wales. [Lovestone, Simon] Kings Coll London, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth, S London & Maudsley Natl Hlth Serv Fdn Trust, London WC2R 2LS, England. [Powell, John; Proitsi, Petroula; Lupton, Michelle K.] Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England. [Brayne, Carol] Univ Cambridge, Inst Publ Hlth, Cambridge, England. [Rubinsztein, David C.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn] St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland. [Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn] Trinity Coll Dublin, Dublin, Ireland. [Morgan, Kevin; Brown, Kristelle S.] Univ Nottingham, Queens Med Ctr, Inst Genet, Nottingham NG7 2RD, England. [Passmore, Peter A.; Craig, David; McGuinness, Bernadette; Todd, Stephen] Queens Univ Belfast, Ageing Grp, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland. [Holmes, Clive] Univ Southampton, Div Clin Neurosci, Sch Med, Southampton, Hants, England. [Mann, David] Univ Manchester, Clin Neurosci Res Grp, Greater Manchester Neurosci Ctr, Salford, Lancs, England. [Smith, A. David] Univ Oxford, John Radcliffe Hosp, Oxford Project Investigate Memory & Ageing, Oxford OX3 9DU, England. [Love, Seth; Kehoe, Patrick G.] Univ Bristol, Dementia Res Grp, Inst Clin Neurosci, Frenchay Hosp, Bristol, Avon, England. [Hardy, John] Inst Neurol, Dept Mol Neurosci Ctr, London WC1N 3BG, England. [Hardy, John] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England. [Mead, Simon; Collinge, John] UCL Inst Neurol, MRC, Prion Unit, London, England. [Fox, Nick; Rossor, Martin] UCL Inst Neurol, Dementia Res Ctr, Dept Neurodegenerat Dis, London, England. [Maier, Wolfgang; Jessen, Frank; Schuermann, Britta] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. [van den Bussche, Hendrik] Univ Med Ctr Hamburg Eppendorf, Inst Primary Med Care, Hamburg, Germany. [Heuser, Isabella] Charite, Dept Psychiat, Berlin, Germany. [Kornhuber, Johannes] Univ Erlangen Nurnberg, Dept Psychiat & Psychotherapy, Erlangen, Germany. [Wiltfang, Jens] Univ Duisburg Essen, Dept Psychiat & Psychotherapy, Landschaftsverband Rheinland Hosp Essen, Essen, Germany. [Dichgans, Martin] Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Dichgans, Martin] Klinikum Univ Munchen, Dept Neurol, Munich, Germany. [Froelich, Lutz] Univ Heidelberg, Dept Geriatr Psychiat, Cent Inst Mental Hlth, Med Fac Mannheim, D-6800 Mannheim, Germany. [Hampel, Harald] Univ Dublin Trinity Coll, Discipline Psychiat, Sch Med, Dublin 2, Ireland. [Hampel, Harald] Univ Dublin Trinity Coll, Inst Neurosci, Lab Neuroimaging & Biomarker Res, Dublin 2, Ireland. [Hampel, Harald; Rujescu, Dan] Univ Munich, Dept Psychiat, Alzheimer Mem Ctr, D-8000 Munich, Germany. [Hampel, Harald; Rujescu, Dan] Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, D-8000 Munich, Germany. [Huell, Michael] Univ Freiburg, Ctr Geriatr Med, Sch Med, Freiburg, Germany. [Huell, Michael] Univ Freiburg, Sect Gerontopsychiat & Neuropsychol, Sch Med, Freiburg, Germany. [Goate, Alison M.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Goate, Alison M.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Goate, Alison M.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Kauwe, John S. K.] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. [Sleegers, Kristel; Bettens, Karolien; Van Broeckhoven, Christine] VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, Antwerp, Belgium. [Sleegers, Kristel; Bettens, Karolien; Engelborghs, Sebastiaan; De Deyn, Peter P.; Van Broeckhoven, Christine] Inst Born Bunge, Antwerp, Belgium. [Sleegers, Kristel; Bettens, Karolien; Engelborghs, Sebastiaan; De Deyn, Peter P.; Van Broeckhoven, Christine] Univ Antwerp, B-2020 Antwerp, Belgium. [Engelborghs, Sebastiaan; De Deyn, Peter P.] Ziekenhuis Netwerk Antwerpen Middelheim, Memory Clin, Antwerp, Belgium. [Engelborghs, Sebastiaan; De Deyn, Peter P.] Ziekenhuis Netwerk Antwerpen Middelheim, Dept Neurol, Antwerp, Belgium. [Livingston, Gill; Bass, Nicholas J.; Gurling, Hugh; McQuillin, Andrew] UCL, Dept Mental Hlth Sci, London, England. [Gwilliam, Rhian; Deloukas, Panagiotis] Wellcome Trust Sanger Inst, Cambridge, England. [Al-Chalabi, Ammar; Shaw, Christopher E.] Kings Coll London, MRC, Ctr Neurodegenerat Res, Dept Clin Neurosci,Inst Psychiat, London WC2R 2LS, England. [Tsolaki, Magda] Aristotle Univ Thessaloniki, Dept Neurol 3, GR-54006 Thessaloniki, Greece. [Singleton, Andrew B.; Guerreiro, Rita] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Moebus, Susanne; Joeckel, Karl-Heinz] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Klopp, Norman; Wichmann, H-Erich] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Carrasquillo, Minerva M.; Younkin, Steven G.] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA. [Pankratz, V. Shane] Mayo Clin & Mayo Fdn, Div Biomed Stat & Informat, Rochester, MN 55905 USA. RP Williams, J (reprint author), Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol,Sch Med, Cardiff, S Glam, Wales. EM owenmj@cardiff.ac.uk; williamsj@cardiff.ac.uk RI Rubinsztein, David/C-3472-2011; Singleton, Andrew/C-3010-2009; Mead, Simon/E-9414-2011; Powell, John/G-4412-2011; Kauwe, John/B-2034-2009; Morris, John/A-1686-2012; Hardy, John/C-2451-2009; passmore, anthony/C-9824-2009; Lovestone, Simon/E-8725-2010; Todd, Stephen/A-4299-2009; Livingston, Gill/C-7081-2008; Al-Chalabi, Ammar/E-5361-2010; McGuinness, Bernadette/A-4056-2010; Love, Seth/E-6545-2012; Jessen, Frank/E-7655-2012; Hull, Michael/F-2618-2012; Guerreiro, Rita/A-1327-2011; Deloukas, Panos/B-2922-2013; Gurling, Hugh/A-5029-2010; Goldsmith, Seraphina/M-7829-2013; Kornhuber, Johannes/B-9613-2014; Fox, Nick/B-1319-2009; Holmans, Peter/F-4518-2015; Smith, Anthony/A-4233-2010; McQuillin, Andrew/C-1623-2008; OI Mead, Simon/0000-0002-4326-1468; Powell, John/0000-0001-6124-439X; Kauwe, John/0000-0001-8641-2468; Al-Chalabi, Ammar/0000-0002-4924-7712; O'Donovan, Michael/0000-0001-7073-2379; Gill, Michael/0000-0003-0206-5337; Harold, Denise/0000-0001-5195-0143; Cruchaga, Carlos/0000-0002-0276-2899; Escott-Price, Valentina/0000-0003-1784-5483; Nothen, Markus/0000-0002-8770-2464; Todd, Stephen/0000-0002-2312-9195; Deloukas, Panos/0000-0001-9251-070X; Goldsmith, Seraphina/0000-0003-4379-988X; Kornhuber, Johannes/0000-0002-8096-3987; Fox, Nick/0000-0002-6660-657X; Holmans, Peter/0000-0003-0870-9412; Smith, Anthony/0000-0002-1095-6722; McQuillin, Andrew/0000-0003-1567-2240; Wiltfang, Jens/0000-0003-1492-5330 FU Wellcome Trust; Medical Research Council (MRC, UK); Alzheimer's Research Trust (ART); Welsh Assembly Government; Mercer's Institute for Research on Ageing; South West Dementia Brain Bank; Charles Wolfson Charitable Trust; Motor Neurone Disease Association; US National Institutes of Health (NIH); Barnes Jewish Foundation; Charles and Joanne Knight Alzheimer's Research Initiative; Robert and Clarice Smith and Abigail Van Buren AD Research Program; UCL Hospital/UCL Biomedical Centre; Lundbeck; German Federal Ministry of Education and Research (BMBF); Competence Network Dementia and Competence Network Degenerative Dementia; Alfried Krupp von Bohlen und Halbach-Stiftung; Helmholtz Zentrum Munchen; German National Genome Research Network; Munich Center of Health Sciences; Heinz Nixdorf Foundation; US National Institute of Neurological Disorders and Stroke; National Institute on Aging (NIA); IRP; Department of Health and Human Services [Z01 AG000950-06]; National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation International; VIB Genetic Service Facility; Biobank of the Institute Born-Bunge; Special Research Fund of the University of Antwerp; Fund for Scientific Research-Flanders; Foundation for Alzheimer Research; Belgian Federal Science Policy Office FX Warden, D Lehmann, N. Leigh, J. Uphill, J. Beck, T. Campbell, S. Klier, G. Adamson, J. Wyatt, M. L. Perez, T. Meitinger, P. Lichtner, G. Eckstein, N. Graff-Radford, R. Petersen, D. Dickson, G. Fischer, H. Bickel, H. Jahn, H. Kaduszkiewicz, C. Luckhaus, S. Riedel-Heller, S. Wolf, S. Weyerer, the Helmholtz Zentrum Munchen genotyping staff, E. Reiman, TGEN and the NIMH AD Genetics Initiative. We thank Advanced Research Computing @ Cardiff (ARCCA), which facilitated data analysis. NR 59 TC 1200 Z9 1229 U1 11 U2 174 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2009 VL 41 IS 10 BP 1088 EP U61 DI 10.1038/ng.440 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 500UG UT WOS:000270330400011 PM 19734902 ER PT J AU Eeles, RA Kote-Jarai, Z Al Olama, AA Giles, GG Guy, M Severi, G Muir, K Hopper, JL Henderson, BE Haiman, CA Schleutker, J Hamdy, FC Neal, DE Donovan, JL Stanford, JL Ostrander, EA Ingles, SA John, EM Thibodeau, SN Schaid, D Park, JY Spurdle, A Clements, J Dickinson, JL Maier, C Vogel, W Dork, T Rebbeck, TR Cooney, KA Cannon-Albright, L Chappuis, PO Hutter, P Zeegers, M Kaneva, R Zhang, HW Lu, YJ Foulkes, WD English, DR Leongamornlert, DA Tymrakiewicz, M Morrison, J Ardern-Jones, AT Hall, AL O'Brien, LT Wilkinson, RA Saunders, EJ Page, EC Sawyer, EJ Edwards, SM Dearnaley, DP Horwich, A Huddart, RA Khoo, VS Parker, CC Van As, N Woodhouse, CJ Thompson, A Christmas, T Ogden, C Cooper, CS Southey, MC Lophatananon, A Liu, JF Kolonel, LN Le Marchand, L Wahlfors, T Tammela, TL Auvinen, A Lewis, SJ Cox, A FitzGerald, LM Koopmeiners, JS Karyadi, DM Kwon, EM Stern, MC Corral, R Joshi, AD Shahabi, A McDonnell, SK Sellers, TA Pow-Sang, J Chambers, S Aitken, J Gardiner, RA Batra, J Kedda, MA Lose, F Polanowski, A Patterson, B Serth, J Meyer, A Luedeke, M Stefflova, K Ray, AM Lange, EM Farnham, J Khan, H Slavov, C Mitkova, A Cao, GW Easton, DF AF Eeles, Rosalind A. Kote-Jarai, Zsofia Al Olama, Ali Amin Giles, Graham G. Guy, Michelle Severi, Gianluca Muir, Kenneth Hopper, John L. Henderson, Brian E. Haiman, Christopher A. Schleutker, Johanna Hamdy, Freddie C. Neal, David E. Donovan, Jenny L. Stanford, Janet L. Ostrander, Elaine A. Ingles, Sue A. John, Esther M. Thibodeau, Stephen N. Schaid, Daniel Park, Jong Y. Spurdle, Amanda Clements, Judith Dickinson, Joanne L. Maier, Christiane Vogel, Walther Doerk, Thilo Rebbeck, Timothy R. Cooney, Kathleen A. Cannon-Albright, Lisa Chappuis, Pierre O. Hutter, Pierre Zeegers, Maurice Kaneva, Radka Zhang, Hong-Wei Lu, Yong-Jie Foulkes, William D. English, Dallas R. Leongamornlert, Daniel A. Tymrakiewicz, Malgorzata Morrison, Jonathan Ardern-Jones, Audrey T. Hall, Amanda L. O'Brien, Lynne T. Wilkinson, Rosemary A. Saunders, Edward J. Page, Elizabeth C. Sawyer, Emma J. Edwards, Stephen M. Dearnaley, David P. Horwich, Alan Huddart, Robert A. Khoo, Vincent S. Parker, Christopher C. Van As, Nicholas Woodhouse, Christopher J. Thompson, Alan Christmas, Tim Ogden, Chris Cooper, Colin S. Southey, Melissa C. Lophatananon, Artitaya Liu, Jo-Fen Kolonel, Laurence N. Le Marchand, Loic Wahlfors, Tiina Tammela, Teuvo L. Auvinen, Anssi Lewis, Sarah J. Cox, Angela FitzGerald, Liesel M. Koopmeiners, Joseph S. Karyadi, Danielle M. Kwon, Erika M. Stern, Mariana C. Corral, Roman Joshi, Amit D. Shahabi, Ahva McDonnell, Shannon K. Sellers, Thomas A. Pow-Sang, Julio Chambers, Suzanne Aitken, Joanne Gardiner, R. A. (Frank) Batra, Jyotsna Kedda, Mary Anne Lose, Felicity Polanowski, Andrea Patterson, Briony Serth, Juergen Meyer, Andreas Luedeke, Manuel Stefflova, Klara Ray, Anna M. Lange, Ethan M. Farnham, Jim Khan, Humera Slavov, Chavdar Mitkova, Atanaska Cao, Guangwen Easton, Douglas F. CA British Assoc Urological Surg UK ProtecT Study Collaborators PRACTICAL Consortium TI Identification of seven new prostate cancer susceptibility loci through a genome-wide association study SO NATURE GENETICS LA English DT Article ID AUSTRALIAN CASE-CONTROL; MULTIPLE; RISK; VARIANTS; ANTIGEN AB Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)). C1 [Eeles, Rosalind A.; Kote-Jarai, Zsofia; Guy, Michelle; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Hall, Amanda L.; O'Brien, Lynne T.; Wilkinson, Rosemary A.; Saunders, Edward J.; Page, Elizabeth C.; Sawyer, Emma J.; Edwards, Stephen M.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Cooper, Colin S.] Inst Canc Res, Surrey, England. [Eeles, Rosalind A.; Ardern-Jones, Audrey T.; Hall, Amanda L.; Page, Elizabeth C.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Christmas, Tim; Ogden, Chris] Royal Marsden Natl Hlth Serv Fdn Trust, Surrey, England. [Eeles, Rosalind A.; Ardern-Jones, Audrey T.; Hall, Amanda L.; Page, Elizabeth C.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Christmas, Tim; Ogden, Chris] Royal Marsden Natl Hlth Serv Fdn Trust, London, England. [Al Olama, Ali Amin; Morrison, Jonathan; Easton, Douglas F.] Univ Cambridge, Canc Res UK Genet Epidemiol Unit, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge, England. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Giles, Graham G.; Severi, Gianluca; Hopper, John L.; English, Dallas R.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Carlton, Vic 3053, Australia. [Muir, Kenneth; Lophatananon, Artitaya; Liu, Jo-Fen] Univ Nottingham, Sch Med, Queens Med Ctr, Nottingham, England. [Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Schleutker, Johanna; Wahlfors, Tiina] Univ Tampere, Inst Med Technol, FIN-33101 Tampere, Finland. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg, Oxford, England. [Neal, David E.] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Cambridge, England. [Donovan, Jenny L.; Lewis, Sarah J.] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Stanford, Janet L.; FitzGerald, Liesel M.; Koopmeiners, Joseph S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Ostrander, Elaine A.; Karyadi, Danielle M.; Kwon, Erika M.] NHGRI, NIH, Bethesda, MD 20892 USA. [John, Esther M.] No Calif Canc Ctr, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Thibodeau, Stephen N.; Schaid, Daniel; McDonnell, Shannon K.] Mayo Clin, Rochester, MN USA. [Park, Jong Y.; Sellers, Thomas A.; Pow-Sang, Julio] Univ S Florida, H Lee Moffitt Canc Ctr, Div Canc Prevent & Control, Tampa, FL 33682 USA. [Spurdle, Amanda; Lose, Felicity] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4006, Australia. [Clements, Judith; Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity] Queensland Univ Technol, Australian Prostate Canc Res Ctr Queensland, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Clements, Judith; Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity] Queensland Univ Technol, Sch Life Sci, Brisbane, Qld 4001, Australia. [Clements, Judith; Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity] Queensland Univ Technol, Sch Publ Hlth, Brisbane, Qld 4001, Australia. [Dickinson, Joanne L.; Polanowski, Andrea; Patterson, Briony] Univ Tasmania, Menzies Res Inst, Hobart, Tas, Australia. [Maier, Christiane; Vogel, Walther; Luedeke, Manuel] Inst Human Genet & Anthropol, Ulm, Germany. [Doerk, Thilo] Hannover Med Sch, Clin Obstet, D-3000 Hannover, Germany. [Doerk, Thilo] Hannover Med Sch, Clin Gynaecol, D-3000 Hannover, Germany. [Rebbeck, Timothy R.; Stefflova, Klara] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.; Stefflova, Klara] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Cooney, Kathleen A.; Ray, Anna M.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Cooney, Kathleen A.; Ray, Anna M.] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI USA. [Cannon-Albright, Lisa; Farnham, Jim] Univ Utah, Sch Med, Dept Biomed Informat, Salt Lake City, UT USA. [Chappuis, Pierre O.] Univ Hosp Geneva, Div Med Genet, Geneva, Switzerland. [Chappuis, Pierre O.] Univ Hosp Geneva, Div Oncol, Geneva, Switzerland. [Hutter, Pierre] Inst Cent Hop Valaisans, Div Med Genet, Sion, Switzerland. [Zeegers, Maurice; Khan, Humera] Univ Birmingham, Unit Genet Epidemiol, Dept Publ Hlth Epidemiol & Biostat, Sch Med, Birmingham B15 2TT, W Midlands, England. [Zeegers, Maurice] Maastricht Univ, Dept Complex Genet, Cluster Genet & Cell Biol, Nutr & Toxicol Res Inst,Med Ctr, Maastricht, Netherlands. [Kaneva, Radka; Mitkova, Atanaska] Med Univ Sofia, Mol Med Ctr, Sofia, Bulgaria. [Kaneva, Radka; Mitkova, Atanaska] Med Univ Sofia, Dept Chem & Biochem, Sofia, Bulgaria. [Zhang, Hong-Wei; Cao, Guangwen] Second Mil Med Univ, Dept Epidemiol, Shanghai, Peoples R China. [Lu, Yong-Jie] Univ London, Inst Canc, Barts & London Sch Med & Dent, London, England. [Foulkes, William D.] McGill Univ, Program Canc Genet, Montreal, PQ, Canada. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Lophatananon, Artitaya] Chulabhorn Canc Res Ctr, Bangkok, Thailand. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Tammela, Teuvo L.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Tammela, Teuvo L.] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Auvinen, Anssi] Univ Tampere, Tampere Sch Publ Hlth, FIN-33101 Tampere, Finland. [Cox, Angela] Univ Sheffield, Inst Canc Studies, Sheffield, S Yorkshire, England. [Koopmeiners, Joseph S.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. [Chambers, Suzanne; Aitken, Joanne] Canc Council Queensland, Viertel Ctr Res Canc Control, Brisbane, Qld, Australia. [Aitken, Joanne] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Gardiner, R. A. (Frank)] Univ Queensland, Dept Surg, Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia. [Serth, Juergen] Hannover Med Sch, Urol Clin, D-3000 Hannover, Germany. [Serth, Juergen] Hannover Med Sch, Clin Urol Oncol, D-3000 Hannover, Germany. [Meyer, Andreas] Hannover Med Sch, Dept Radiat Oncol, D-3000 Hannover, Germany. [Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Slavov, Chavdar] Med Univ Sofia, Dept Urol, Alexandrovska Univ Hosp, Sofia, Bulgaria. RP Eeles, RA (reprint author), Inst Canc Res, Surrey, England. EM rosalind.eeles@icr.ac.uk RI Gardiner, Robert/G-2096-2010; Spurdle, Amanda/A-4978-2011; Batra, Jyotsna/B-4130-2011; Thomson, Russell/H-5653-2012; Dickinson, Joanne/J-7728-2014; Chambers, Suzanne/H-5957-2012; Dork, Thilo/J-8620-2012; O'Mara, Tracy/M-7508-2016; OI Clements, Judith/0000-0001-6026-1964; English, Dallas/0000-0001-7828-8188; Ostrander, Elaine/0000-0001-6075-9738; Evans, Gareth/0000-0002-8482-5784; Saunders, Ed/0000-0003-4343-3570; Farnham, James/0000-0002-8213-949X; Lewis, Sarah/0000-0003-4311-6890; Auvinen, Anssi/0000-0003-1125-4818; Neal, David/0000-0002-6033-5086; Leongamornlert, Daniel/0000-0002-3486-3168; Graham, John/0000-0003-3381-9787; albright, lisa/0000-0003-2602-3668; foulkes, william/0000-0001-7427-4651; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099; Spurdle, Amanda/0000-0003-1337-7897; Thomson, Russell/0000-0003-4949-4120; O'Mara, Tracy/0000-0002-5436-3232; van As, Nicholas/0000-0001-6829-8788; Clarke, Noel/0000-0001-7776-8059; Lose, Felicity/0000-0001-8337-3547; Eeles, Rosalind/0000-0002-3698-6241 FU Cancer Research UK [10118, 10588, C1287/A10118, C16913/A6135, C16913/A6835, C5047/A10692, C5047/A3354, C5047/A7357, C522/A8649]; Department of Health; Intramural NIH HHS; Medical Research Council [G0500966, G0501019]; NCI NIH HHS [P50 CA097186-08, CA54281, CA56678, CA63464, CA92579, CA97186, N01 PC035141, N01-PC-35141, P50 CA069568, P50 CA069568-12, P50 CA097186, P50 CA105641, P50 CA105641-05, R01 CA056678, R01 CA056678-05, R01 CA063464, R01 CA063464-10, R01 CA072818, R01 CA072818-09, R01 CA084979, R01 CA084979-05, R01 CA092579, R01 CA092579-05, R01 CA128813, R01 CA128813-02, R01CA128813, R01CA84979, R37 CA054281, R37 CA054281-17, U01 CA089600, U01 CA089600-04]; NCRR NIH HHS [M01 RR000064-41, M01 RR00064] NR 17 TC 264 Z9 274 U1 2 U2 34 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 OCT PY 2009 VL 41 IS 10 BP 1116 EP U97 DI 10.1038/ng.450 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 500UG UT WOS:000270330400016 PM 19767753 ER PT J AU Prickett, TD Agrawal, NS Wei, XM Yates, KE Lin, JC Wunderlich, JR Cronin, JC Cruz, P Rosenberg, SA Samuels, Y AF Prickett, Todd D. Agrawal, Neena S. Wei, Xiaomu Yates, Kristin E. Lin, Jimmy C. Wunderlich, John R. Cronin, Julia C. Cruz, Pedro Rosenberg, Steven A. Samuels, Yardena CA NISC Comparative Sequencing Progra TI Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4 SO NATURE GENETICS LA English DT Article ID GROWTH-FACTOR RECEPTOR; SOMATIC MUTATIONS; BREAST-CANCER; KINASE DOMAIN; INHIBITOR; CELLS; ACTIVATION; RESISTANCE; LAPATINIB; PATHWAYS AB Tyrosine phosphorylation is important in signaling pathways underlying tumorigenesis. We performed a mutational analysis of the protein tyrosine kinase (PTK) gene family in cutaneous metastatic melanoma. We identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. We found ERBB4 mutations in 19% of individuals with melanoma and found mutations in two other kinases (FLT1 and PTK2B) in 10% of individuals with melanomas. We examined seven missense mutations in the most commonly altered PTK gene, ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in individual melanomas. C1 [Prickett, Todd D.; Agrawal, Neena S.; Wei, Xiaomu; Yates, Kristin E.; Cronin, Julia C.; Samuels, Yardena] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Lin, Jimmy C.] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD USA. [Wunderlich, John R.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Cruz, Pedro] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [NISC Comparative Sequencing Progra] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. RP Samuels, Y (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov FU National Human Genome Research Institute; National Cancer Institute; National Institutes of Health, USA FX We thank B. Vogelstein, T. Waldman, D. Bell, P. Meltzer, L. Brody, G. Merlino, S. Gutkind and I. Cardenas-Navia for their helpful comments on the manuscript; members of the NISC Comparative Sequencing Program for generating the sequence data analyzed here; and S. Anderson and M. Kirby for assistance with FACS analysis. This work supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, National Institutes of Health, USA. NR 30 TC 192 Z9 195 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2009 VL 41 IS 10 BP 1127 EP U112 DI 10.1038/ng.438 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 500UG UT WOS:000270330400018 PM 19718025 ER PT J AU Urban, TJ Weintrob, AC Fellay, J Colombo, S Shianna, KV Gumbs, C Rotger, M Pelak, K Dang, KK Detels, R Martinson, JJ O'Brien, SJ Letvin, NL McMichael, AJ Haynes, BF Carrington, M Telenti, A Michael, NL Goldstein, DB AF Urban, Thomas J. Weintrob, Amy C. Fellay, Jacques Colombo, Sara Shianna, Kevin V. Gumbs, Curtis Rotger, Margalida Pelak, Kimberly Dang, Kristen K. Detels, Roger Martinson, Jeremy J. O'Brien, Stephen J. Letvin, Norman L. McMichael, Andrew J. Haynes, Barton F. Carrington, Mary Telenti, Amalio Michael, Nelson L. Goldstein, David B. TI CCL3L1 and HIV/AIDS susceptibility SO NATURE MEDICINE LA English DT Letter ID GENE COPY NUMBER; HIV-1-INFECTED INDIVIDUALS; HIV-1 INFECTION; CHEMOKINE; ASSOCIATION; MIP-1-ALPHA; ACCURATE C1 [Urban, Thomas J.; Fellay, Jacques; Gumbs, Curtis; Pelak, Kimberly; Dang, Kristen K.; Goldstein, David B.] Duke Univ, Duke Inst Genome Sci & Policy, Ctr Human Genome Variat, Durham, NC 27706 USA. [Weintrob, Amy C.] Walter Reed Army Med Ctr, Infect Dis Clin Res Program, Washington, DC 20307 USA. [Colombo, Sara; Rotger, Margalida; Telenti, Amalio] Univ Hosp Ctr, Inst Microbiol, Lausanne, Switzerland. [Colombo, Sara; Rotger, Margalida; Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Detels, Roger] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Martinson, Jeremy J.] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA USA. [McMichael, Andrew J.] John Radcliffe Hosp, Weatherall Inst Mol Med, Human Immunol Unit, MRC, Oxford OX3 9DU, England. [Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Carrington, Mary] NCI, SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA. [Michael, Nelson L.] US Mil HIV Res Program, Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD USA. RP Urban, TJ (reprint author), Duke Univ, Duke Inst Genome Sci & Policy, Ctr Human Genome Variat, Durham, NC 27706 USA. EM d.goldstein@duke.edu RI SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; Fellay, Jacques/A-6681-2009; OI Fellay, Jacques/0000-0002-8240-939X; Martinson, Jeremy/0000-0003-4673-7238 FU Medical Research Council [MC_U137884177]; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [U19 AI067854-05, U19 AI067854] NR 13 TC 44 Z9 44 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2009 VL 15 IS 10 BP 1110 EP 1112 DI 10.1038/nm1009-1110 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 504EC UT WOS:000270596400012 PM 19812560 ER PT J AU Plum, L Lin, HV Dutia, R Tanaka, J Aizawa, KS Matsumoto, M Kim, AJ Cawley, NX Paik, JH Loh, YP DePinho, RA Wardlaw, SL Accili, D AF Plum, Leona Lin, Hua V. Dutia, Roxanne Tanaka, Jun Aizawa, Kumiko S. Matsumoto, Michihiro Kim, Andrea J. Cawley, Niamh X. Paik, Ji-Hye Loh, Y. Peng DePinho, Ronald A. Wardlaw, Sharon L. Accili, Domenico TI The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake SO NATURE MEDICINE LA English DT Article ID PROTHYROTROPIN-RELEASING HORMONE; PROHORMONE CONVERTASES; BETA-ENDORPHIN; BODY-WEIGHT; CPE(FAT)/CPE(FAT) MICE; STIMULATING HORMONE; ENERGY HOMEOSTASIS; LEPTIN; PEPTIDE; INSULIN AB Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1(-/-) mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of alpha-melanocyt-estimulating hormone (alpha-Msh) and carboxy-cleaved beta-endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1(-/-) mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc-Foxo1(-/-) mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications. C1 [Plum, Leona; Lin, Hua V.; Dutia, Roxanne; Tanaka, Jun; Aizawa, Kumiko S.; Matsumoto, Michihiro; Kim, Andrea J.; Wardlaw, Sharon L.; Accili, Domenico] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY 10027 USA. [Plum, Leona; Lin, Hua V.; Dutia, Roxanne; Tanaka, Jun; Aizawa, Kumiko S.; Matsumoto, Michihiro; Kim, Andrea J.; Wardlaw, Sharon L.; Accili, Domenico] Columbia Univ, Dept Med, New York, NY USA. [Matsumoto, Michihiro] Int Med Ctr Japan, Dept Clin Pharmacol, Tokyo, Japan. [Cawley, Niamh X.; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, Cellular Neurobiol Sect, Bethesda, MD USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA. RP Accili, D (reprint author), Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY 10027 USA. EM da230@columbia.edu FU Deutsche Forschungsgemeinschaft [PL542/1-1]; US National Institutes of Health [DK57539, DK58282, DK80003, DK63608]; Robert A. and Renee E. Belfer Family Institute for Innovative Cancer Science FX Supported by Deutsche Forschungsgemeinschaft PL542/1-1 (L.P.), US National Institutes of Health DK57539 and DK58282 (D.A.), DK80003 (S.L.W.) and DK63608 (Columbia Diabetes and Endocrinology Research Center). We thank R. Leibel for insightful discussions, L. Zeltser and S. Padilla for help with in situ hybridization, N. Seidah (Clinical Research Institute of Montreal) and D. Good (University of Massachusetts) for plasmids encoding pCsk1, A. White (University of Manchester) for neuropeptide antisera, and M. Low (Oregon Health Sciences University) for Pomc-Gfp transgenic mice, Y. Liu for technical assistance and members of the Accili and Wardlaw laboratories for stimulating discussions. R.A.D. is an American Cancer Society Research Professor and an Ellison Medical Foundation Senior Scholar and is supported by the Robert A. and Renee E. Belfer Family Institute for Innovative Cancer Science. NR 55 TC 78 Z9 80 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2009 VL 15 IS 10 BP 1195 EP U125 DI 10.1038/nm.2026 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 504EC UT WOS:000270596400032 PM 19767734 ER PT J AU Hohmann-Marriott, MF Sousa, AA Azari, AA Glushakova, S Zhang, GF Zimmerberg, J Leapman, RD AF Hohmann-Marriott, Martin F. Sousa, Alioscka A. Azari, Afrouz A. Glushakova, Svetlana Zhang, Guofeng Zimmerberg, Joshua Leapman, Richard D. TI Nanoscale 3D cellular imaging by axial scanning transmission electron tomography SO NATURE METHODS LA English DT Article ID PLASMODIUM-FALCIPARUM; BIOLOGICAL SPECIMENS; STEM TOMOGRAPHY; RESOLUTION; ULTRASTRUCTURE; ORGANIZATION; ARCHITECTURE; MICROSCOPY AB Electron tomography provides three-dimensional structural information about supramolecular assemblies and organelles in a cellular context, but image degradation, caused by scattering of transmitted electrons, limits applicability in specimens thicker than 300 nm. We found that scanning transmission electron tomography of 1,000-nm-thick samples using axial detection provided resolution comparable to that of conventional electron tomography. We demonstrated the method by reconstructing a human erythrocyte infected with the malaria parasite Plasmodium falciparum. C1 [Hohmann-Marriott, Martin F.; Sousa, Alioscka A.; Azari, Afrouz A.; Zhang, Guofeng; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Glushakova, Svetlana; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. EM sousaali@mail.nih.gov; leapmanr@mail.nih.gov FU National Institute of Biomedical Imaging and Bioengineering; Eunice Kennedy Shriver National Institute; Child Health and Human Development of the National Institutes of Health; US National Research Council FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. We thank T. Reese for help with the freeze-substitution technique. M. F. H.-M. acknowledges support through the Joint National Institute of Standards and Technology-National Institute of Biomedical Imaging and Bioengineering Postdoctoral Associateship program of the US National Research Council. NR 21 TC 60 Z9 60 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD OCT PY 2009 VL 6 IS 10 BP 729 EP 732 DI 10.1038/NMETH.1367 PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 501BX UT WOS:000270355200016 PM 19718033 ER PT J AU Oesch, N Diamond, J AF Oesch, Nicholas Diamond, Jeffrey TI A night vision neuron gets a day job SO NATURE NEUROSCIENCE LA English DT Editorial Material ID INNER PLEXIFORM LAYER; AII AMACRINE CELLS; MOUSE RETINA; GANGLION-CELLS; RABBIT RETINA; DEPOLARIZING BIPOLAR; CAT RETINA; ROD; RESPONSES; PATHWAY AB During the day, certain retinal ganglion cells respond specifically to dark, approaching stimuli. A study finds that the retinal circuit that gives rise to this response makes use of an amacrine cell that was previously known for its role in night vision circuitry, demonstrating that some neurons lead double lives. C1 [Oesch, Nicholas; Diamond, Jeffrey] US Natl Inst Neurol Disorders & Stroke, US Natl Inst Hlth, Bethesda, MD USA. RP Oesch, N (reprint author), US Natl Inst Neurol Disorders & Stroke, US Natl Inst Hlth, Bethesda, MD USA. EM diamondj@ninds.nih.gov NR 14 TC 4 Z9 4 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2009 VL 12 IS 10 BP 1209 EP 1211 DI 10.1038/nn1009-1209 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 498US UT WOS:000270170200002 PM 19783975 ER PT J AU Menendez, D Inga, A Resnick, MA AF Menendez, Daniel Inga, Alberto Resnick, Michael A. TI The expanding universe of p53 targets SO NATURE REVIEWS CANCER LA English DT Review ID TUMOR-SUPPRESSOR P53; WILD-TYPE P53; CELL-CYCLE ARREST; NF-KAPPA-B; FACTOR-BINDING-SITES; SINGLE-NUCLEOTIDE POLYMORPHISM; MASTER REGULATORY NETWORK; ESTROGEN-RECEPTOR-ALPHA; C-TERMINAL DOMAIN; PROTEIN-KINASE-C AB The p53 tumour suppressor is modified through mutation or changes in expression in most cancers, leading to the altered regulation of hundreds of genes that are directly influenced by this sequence-specific transcription factor. Central to the p53 master regulatory network are the target response element (RE) sequences. The extent of p53 transactivation and transcriptional repression is influenced by many factors, including p53 levels, cofactors and the specific RE sequences, all of which contribute to the role that p53 has in the aetiology of cancer. This Review describes the identification and functionality of REs and highlights the inclusion of non-canonical REs that expand the universe of genes and regulation mechanisms in the p53 tumour suppressor network. C1 [Menendez, Daniel; Resnick, Michael A.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Inga, Alberto] IST, Natl Inst Canc Res, Unit Mol Mutagenesis & DNA Repair, I-16132 Genoa, Italy. RP Resnick, MA (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov RI Xie, Huangming/B-2260-2012 FU National Institute of Environmental Health Sciences [1 Z01 ES065079]; Italian Association for Cancer Research FX This work was supported by intramural research funds from the National Institute of Environmental Health Sciences project 1 Z01 ES065079 (to D.M. and M.A.R.) and partially supported by the Italian Association for Cancer Research (to A.I.). NR 203 TC 285 Z9 292 U1 3 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD OCT PY 2009 VL 9 IS 10 BP 724 EP 737 DI 10.1038/nrc2730 PG 14 WC Oncology SC Oncology GA 497YZ UT WOS:000270102800010 PM 19776742 ER PT J AU Ivy, SP Wick, JY Kaufman, BM AF Ivy, S. Percy Wick, Jeannette Y. Kaufman, Bennett M. TI An overview of small-molecule inhibitors of VEGFR signaling SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID ENDOTHELIAL-GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; ADVANCED SOLID TUMORS; VASCULAR-PERMEABILITY FACTOR; ORALLY-ACTIVE INHIBITOR; FOCAL ADHESION KINASE; HIPPEL-LINDAU-DISEASE; I DOSE-ESCALATION; PHASE-I; ANTITUMOR-ACTIVITY AB VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure-activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics. C1 [Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Wick, Jeannette Y.] NCI, Pharmaceut Management Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Kaufman, Bennett M.] PSI Int Inc, Fairfax, VA USA. RP Ivy, SP (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, 6130 Execut Blvd,Suite 7131, Rockville, MD 20852 USA. EM ivyp@ctep.nci.nih.gov NR 98 TC 174 Z9 178 U1 2 U2 44 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD OCT PY 2009 VL 6 IS 10 BP 569 EP 579 DI 10.1038/nrclinonc.2009.130 PG 11 WC Oncology SC Oncology GA 498SP UT WOS:000270163800008 PM 19736552 ER PT J AU Milescu, M Bosmans, F Lee, S Alabi, AA Il Kim, J Swartz, KJ AF Milescu, Mirela Bosmans, Frank Lee, Seungkyu Alabi, AbdulRasheed A. Il Kim, Jae Swartz, Kenton J. TI Interactions between lipids and voltage sensor paddles detected with tarantula toxins SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID DEPENDENT K+ CHANNEL; POTASSIUM CHANNEL; PROTEIN INTERACTIONS; SENSING DOMAINS; GATING MODIFIER; SODIUM-CHANNELS; MUTANT CYCLES; MEMBRANE; HANATOXIN; ACTIVATION AB Voltage-activated ion channels open and close in response to changes in voltage, a property that is essential for generating nerve impulses. Studies on voltage-activated potassium (Kv) channels show that voltage-sensor activation is sensitive to the composition of lipids in the surrounding membrane. Here we explore the interaction of lipids with S1-S4 voltage-sensing domains and find that the conversion of the membrane lipid sphingomyelin to ceramide-1-phosphate alters voltage-sensor activation in an S1-S4 voltage-sensing protein lacking an associated pore domain, and that the S3b-S4 paddle motif determines the effects of lipid modification on Kv channels. Using tarantula toxins that bind to paddle motifs within the membrane, we identify mutations in the paddle motif that weaken toxin binding by disrupting lipid-paddle interactions. Our results suggest that lipids bind to voltage-sensing domains and demonstrate that the pharmacological sensitivities of voltage-activated ion channels are influenced by the surrounding lipid membrane. C1 [Milescu, Mirela; Bosmans, Frank; Alabi, AbdulRasheed A.; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Bosmans, Frank] Katholieke Univ Leuven, Toxicol Lab, Leuven, Belgium. [Lee, Seungkyu; Il Kim, Jae] Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju, South Korea. RP Milescu, M (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Mirela.Milescu@nih.gov; Kenton.Swartz@nih.gov RI Bosmans, Frank/A-9660-2013 OI Bosmans, Frank/0000-0002-6476-235X FU Intramural Research Program of the NINDS; National Insitutes of Health (NIH); NIH-FWO FX We thank M. Holmgren, J. Kumar, M. Mayer, J. Mindell, S. Silberberg and members of the Swartz laboratory for helpful discussions and the US National Institute of Neurological Disorders and Stroke (NINDS) DNA sequencing facility for DNA sequencing. We thank Y. Okamura ( Okazaki Center for Integrative Biosciences) for providing Ci-VSP complementary DNA, Y. Xu and Z. Lu ( University of Pennsylvania) for supplying recombinant SMaseD and W. Schmalhofer and M. Garcia ( Merck Research Labs) for supplying 125I-GxTx-1E. This work was supported by the Intramural Research Program of the NINDS, National Insitutes of Health (NIH) ( to K. J. S.) and by an NIH-FWO postdoctoral fellowship ( to F. B.). NR 45 TC 80 Z9 81 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD OCT PY 2009 VL 16 IS 10 BP 1080 EP U102 DI 10.1038/nsmb.1679 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 503EA UT WOS:000270514200016 PM 19783984 ER PT J AU Li, GZ Meng, HH Yang, MQ Yang, JY AF Li, Guo-Zheng Meng, Hao-Hua Yang, Mary Qu Yang, Jack Y. TI Combining support vector regression with feature selection for multivariate calibration SO NEURAL COMPUTING & APPLICATIONS LA English DT Article DE Multivariate calibration; Feature selection; Support vector regression; Artificial neural networks; Partial least square ID MACHINES AB Multivariate calibration is a classic problem in the analytical chemistry field and frequently solved by partial least squares (PLS) and artificial neural networks (ANNs) in the previous works. The spaciality of multivariate calibration is high dimensionality with small sample. Here, we apply support vector regression (SVR) as well as ANNs, and PLS to the multivariate calibration problem in the determination of the three aromatic amino acids (phenylalanine, tyrosine and tryptophan) in their mixtures by fluorescence spectroscopy. The results of the leave-one-out method show that SVR performs better than other methods, and appear to be one good method for this task. Furthermore, feature selection is performed for SVR to remove redundant features and a novel algorithm named Prediction RIsk based FEature selection for support vector Regression (PRIFER) is proposed. Results on the above multivariate calibration data set show that PRIFER is a powerful tool for solving the multivariate calibration problems. C1 [Li, Guo-Zheng] Tongji Univ, Dept Control Sci & Engn, Shanghai 201804, Peoples R China. [Meng, Hao-Hua] Shanghai Univ, Sch Comp Engn & Sci, Shanghai 200072, Peoples R China. [Yang, Mary Qu] US Dept HHS, Natl Human Genome Res Inst, NIH, Rockville, MD 20852 USA. [Yang, Jack Y.] Harvard Univ, Sch Med, Cambridge, MA 02140 USA. RP Li, GZ (reprint author), Tongji Univ, Dept Control Sci & Engn, Shanghai 201804, Peoples R China. EM drgzli@gmail.com RI Li, Guo-Zheng /D-5744-2011 OI Li, Guo-Zheng /0000-0001-5568-0347 FU Nature Science Foundation of China [20503015, 60873129]; Shanghai Rising-Star Program [08QA14032]; Institute of Systems Biology of Shanghai University FX Thanks to the late professor Nian-Yi Chen for his advices to this paper. This work was supported in part by the Nature Science Foundation of China under grant no. 20503015 and 60873129, the Shanghai Rising-Star Program under grant no. 08QA14032 and open funding by Institute of Systems Biology of Shanghai University. NR 28 TC 16 Z9 19 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-0643 J9 NEURAL COMPUT APPL JI Neural Comput. Appl. PD OCT PY 2009 VL 18 IS 7 BP 813 EP 820 DI 10.1007/s00521-008-0202-6 PG 8 WC Computer Science, Artificial Intelligence SC Computer Science GA 495SC UT WOS:000269914300015 ER PT J AU Kinney, JW Sanchez-Alavez, M Barr, AM Criado, JR Crawley, JN Behrens, MM Henriksen, SJ Bartfai, T AF Kinney, Jefferson W. Sanchez-Alavez, Manuel Barr, Alasdair M. Criado, Jose R. Crawley, Jacqueline N. Behrens, M. Margarita Henriksen, Steven J. Bartfai, Tamas TI Impairment of memory consolidation by galanin correlates with in vivo inhibition of both LTP and CREB phosphorylation SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE Galanin; pCREB; Morris water maze; LTP; In vivo; Learning and memory ID LONG-TERM POTENTIATION; RAT VENTRAL HIPPOCAMPUS; SYNAPTIC PLASTICITY; ADENYLATE-CYCLASE; DENTATE GYRUS; PHOSPHOINOSITIDE TURNOVER; ACETYLCHOLINE-RELEASE; RECEPTOR SUBTYPES; PROTEIN; TRANSMISSION AB Changes in the state of CREB phosphorylation and in LTP in the hippocampus have been associated with learning and memory. Here we show that galanin, the neuropeptide released in the hippocampal formation from cholinergic and noradrenergic fibers, that has been shown to produce impairments in memory consolidation in the Morris water maze task inhibits both LTP and CREB phosphorylation in the rat hippocampus in vivo. While there are many transmitters regulating CREB phosphorylation none has been shown to suppress behaviorally-induced hippocampal CREB phosphorylation as potently as galanin. The in vivo inhibition of dentate gyrus-LTP and of CREB phosphorylation by the agonist occupancy of GalR1 and GalR2-type galanin receptors provides strong in vivo cellular and molecular correlates to galanin-induced learning deficits and designates galanin as a major regulator of the memory consolidation process. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kinney, Jefferson W.] Univ Nevada, Dept Psychol, Las Vegas, NV 89154 USA. [Sanchez-Alavez, Manuel; Barr, Alasdair M.; Behrens, M. Margarita; Bartfai, Tamas] Scripps Res Inst, Dept Neuropharmacol, Harold Dorris Neurol Res Ctr, La Jolla, CA 92037 USA. [Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Kinney, JW (reprint author), 4505 Maryland Pkwy,POB 455030, Las Vegas, NV 89154 USA. EM Jefferson.kinney@unlv.edu RI yu, yan/C-2322-2012; Behrens, M. Margarita/K-2576-2014 FU Intramural NIH HHS [Z01 MH002179-22]; NIMH NIH HHS [R01 MH074055, R01 MH074055-02] NR 55 TC 16 Z9 19 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 EI 1095-9564 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD OCT PY 2009 VL 92 IS 3 BP 429 EP 438 DI 10.1016/j.nlm.2009.06.005 PG 10 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 594JC UT WOS:000277532500018 PM 19531380 ER PT J AU Traore, M Landoure, G Motley, W Sangare, M Meilleur, K Coulibaly, S Traore, S Niare, B Mochel, F La Pean, A Vortmeyer, A Mani, H Fischbeck, KH AF Traore, M. Landoure, G. Motley, W. Sangare, M. Meilleur, K. Coulibaly, S. Traore, S. Niare, B. Mochel, F. La Pean, A. Vortmeyer, A. Mani, H. Fischbeck, K. H. TI Novel mutation in the NHLRC1 gene in a Malian family with a severe phenotype of Lafora disease SO NEUROGENETICS LA English DT Article DE Clinical neurology; Epilepsy/seizures; Myoclonus; Dementia; Genetics ID PROGRESSIVE MYOCLONUS EPILEPSY; DIAGNOSTIC PITFALLS; SKIN BIOPSY; LATE-ONSET; DEGRADATION; PROTEINS; COMPLEX AB We studied a Malian family with parental consanguinity and two of eight siblings affected with late-childhood-onset progressive myoclonus epilepsy and cognitive decline, consistent with the diagnosis of Lafora disease. Genetic analysis showed a novel homozygous single-nucleotide variant in the NHLRC1 gene, c.560A > C, producing the missense change H187P. The changed amino acid is highly conserved, and the mutation impairs malin's ability to degrade laforin in vitro. Pathological evaluation showed manifestations of Lafora disease in the entire brain, with particularly severe involvement of the pallidum, thalamus, and cerebellum. Our findings document Lafora disease with severe manifestations in the West African population. C1 [Landoure, G.] UCL, Royal Free Hosp, London NW3 2PF, England. [Traore, M.; Landoure, G.; Sangare, M.; Coulibaly, S.; Traore, S.; Niare, B.] Univ Bamako, Dept Neurosci, Bamako, Mali. [Landoure, G.; Motley, W.; Sangare, M.; Meilleur, K.; Mochel, F.; La Pean, A.; Vortmeyer, A.; Fischbeck, K. H.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Meilleur, K.] NINR, NIH, Bethesda, MD 20892 USA. [Meilleur, K.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Mochel, F.] Hop La Pitie Salpetriere, INSERM, U679, Paris, France. [Mani, H.] NCI, NIH, Bethesda, MD 20892 USA. RP Landoure, G (reprint author), UCL, Royal Free Hosp, Rowland Hill St,1st Floor,Room 1-7012, London NW3 2PF, England. EM g.landoure@ucl.ac.uk FU National Institute of Neurological Disorders and Stroke; Teaching Hospital and Medical School of Point G of the University of Bamako FX This work was supported by the intramural program of the National Institute of Neurological Disorders and Stroke at NIH and the Teaching Hospital and Medical School of Point G of the University of Bamako. We are grateful to the patients and their families for participating in this study. We thank Drs. Aldiouma Guindo and Seidina Diakite for the use of their lab in Mali (Malaria Pathogenesis and Protection Unit) and Drs. Matthew Gentry and Jack Dixon for providing the reagents and advice for the functional assays. We declare that experiments comply with the current laws of Mali and the United States of America. NR 28 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD OCT PY 2009 VL 10 IS 4 BP 319 EP 323 DI 10.1007/s10048-009-0190-4 PG 5 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 501MM UT WOS:000270386000006 PM 19322595 ER PT J AU Sarlls, JE Pierpaoli, C AF Sarlls, Joelle E. Pierpaoli, Carlo TI In vivo diffusion tensor imaging of the human optic chiasm at sub-millimeter resolution SO NEUROIMAGE LA English DT Article ID FAST SPIN-ECHO; WHITE-MATTER; WEIGHTED MRI; HUMAN BRAIN; NERVE; ARCHITECTURE; ORIENTATION; ANISOTROPY; FRAMEWORK; TRACKING AB In this work we report findings from an in vivo diffusion tensor imaging (DTI) study of the human optic chiasm at sub-millimeter voxel resolution. Data were collected at 3 T using a diffusion-weighted radial-FSE sequence, which provides images free from typical magnetic susceptibility artifacts. The general DTI features observed in the optic chiasm region were consistent across subjects. They included a central area with high anisotropy and highest diffusivity in a predominately right/left direction corresponding to the decussation of nasal hemiretinae fibers, surrounded by a band of low anisotropy reflecting heterogeneous orientation of fibers within the voxel, and a lateral area with high anisotropy and highest diffusivity in a predominately anterior/posterior direction corresponding to temporal hemiretinae fibers that do not cross. Animal studies indicate that there is a significant dorsal-ventral reorganization of the retinotopic distribution of fibers along the optic pathways. We found that diffusion ellipsoids in the central portion of the optic chiasm show considerable planar anisotropy in the coronal plane indicating fiber crossings in the superior/inferior direction, rather than strictly right/left. This architectural feature of the chiasm suggests that dorso-ventral reorganization of fibers in the optic pathways also occurs in humans. We have shown that by collecting sub-millimeter resolution data, DTI can be used to investigate fine details of small and complex white matter structures, in vivo, with a clinical scanner. High spatial resolution, however, is necessary in the slice direction as well as in-plane to reduce the CSF contribution to the signal and to increase fiber coherence within voxels. Published by Elsevier Inc. C1 [Sarlls, Joelle E.; Pierpaoli, Carlo] NICHHD, NIH, Bethesda, MD 20892 USA. RP Sarlls, JE (reprint author), NICHHD, NIH, Bldg 13,Room 3W16,13 South Dr, Bethesda, MD 20892 USA. EM sarllsjo@mail.nih.gov RI Pierpaoli, Carlo/E-1672-2011 FU NIMH [00M0085] FX The authors would like to thank Dr. Cheng Guan Koay for his assistance in implementing the calculation of dispersion measures for the averaged eigenvectors in an ROI. We Would like to thank Dr. Peter Basser for his comments and suggestions and Dr. Stefano Marenco for his essential contributions. We would also like to thank Christie Rebsch for her time and efforts put toward this work. The authors thank Liz Salak for editing the manuscript. This study was partly funded by NIMH through protocol 00M0085, V.S. Mattay principal investigator. NR 36 TC 8 Z9 9 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2009 VL 47 IS 4 BP 1244 EP 1251 DI 10.1016/j.neuroimage.2009.05.098 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 484HN UT WOS:000269035100014 PM 19520170 ER PT J AU Luo, QF Lu, H Lu, HB Senseman, D Worsley, K Yang, YH Gao, JH AF Luo, Qingfei Lu, Huo Lu, Hanbing Senseman, David Worsley, Keith Yang, Yihong Gao, Jia-Hong TI Physiologically evoked neuronal current MRI in a bloodless turtle brain: Detectable or not? SO NEUROIMAGE LA English DT Article ID HUMAN OPTIC-NERVE; MAGNETIC-FIELDS; VISUAL-CORTEX; ELECTRICAL-ACTIVITY; SIGNAL MODULATION; PYRAMIDAL NEURONS; SNAIL GANGLIA; RESONANCE; STIMULATION; FMRI AB Contradictory reports regarding the detection of neuronal currents have left the feasibility of neuronal Current MRI (ncMRI) an open question. Most previous ncMRI studies in human subjects are suspect due to their inability to separate or eliminate hemodynamic effects. In this study, we used a bloodless turtle brain preparation that eliminates hemodynamic effects, to explore the feasibility of detecting visually-evoked ncMRI signals at 9.4 T Intact turtle brains, with eyes attached, were dissected from the cranium and placed in artificial cerebral spinal fluid. Light flashes were delivered to the eyes to evoke neuronal activity. Local field potential (LFP) and MRI signals were measured in an interleaved fashion. Robust visually-evoked LFP signals were observed in turtle brains, but no significant signal changes synchronized with neuronal currents were found in the ncMRI images. In this study, detection thresholds of 0.1% and 0.1 degrees were set for MRI magnitude and phase signal changes, respectively. The absence of significant signal changes in the MRI images suggests that visually-evoked ncMRI signals in the turtle brain are below these detectable levels. (C) 2009 Elsevier Inc. All rights reserved. C1 [Luo, Qingfei; Gao, Jia-Hong] Univ Chicago, Brain Res Imaging Ctr, Chicago, IL 60637 USA. [Luo, Qingfei; Gao, Jia-Hong] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Lu, Huo] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, San Antonio, TX 78229 USA. [Lu, Hanbing; Yang, Yihong] NIDA, NIH, Baltimore, MD 21224 USA. [Senseman, David] Univ Texas San Antonio, Dept Biol, San Antonio, TX 78249 USA. [Worsley, Keith] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. [Gao, Jia-Hong] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. RP Gao, JH (reprint author), Univ Chicago, Brain Res Imaging Ctr, 5841 S Maryland Ave,MC 2026, Chicago, IL 60637 USA. EM jgao@uchicago.edu OI Luo, Qingfei/0000-0002-1078-799X FU NIH [RO1 EB004753]; NIH/NIDA FX This work was supported by a NIH grant (RO1 EB004753 to JHG) and the Intramural Research Program of the NIH/NIDA. NR 47 TC 20 Z9 20 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2009 VL 47 IS 4 BP 1268 EP 1276 DI 10.1016/j.neuroimage.2009.06.017 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 484HN UT WOS:000269035100017 PM 19539040 ER PT J AU Geng, XJ Christensen, GE Gu, H Ross, TJ Yang, YH AF Geng, Xiujuan Christensen, Gary E. Gu, Hong Ross, Thomas J. Yang, Yihong TI Implicit reference-based group-wise image registration and its application to structural and functional MRI SO NEUROIMAGE LA English DT Article ID BRAIN ANATOMY; AUTOMATIC CONSTRUCTION; SPATIAL NORMALIZATION; NONRIGID REGISTRATION; SHAPE MODELS; ATLAS; VISUALIZATION; POPULATION; VALIDATION AB In this study, an implicit reference group-wise (IRG) registration with a small deformation, linear elastic model was used to jointly estimate correspondences between a set of MRI images. The performance of pair-wise and group-wise registration algorithms was evaluated for spatial normalization of structural and functional MRI data. Traditional spatial normalization is accomplished by group-to-reference (G2R) registration in which a group of images are registered pair-wise to a reference image. G2R registration is limited due to bias associated with selecting a reference image. In contrast, implicit reference group-wise (IRG) registration estimates correspondences between a group of images by jointly registering the images to ail implicit reference corresponding to the group average. The implicit reference is estimated during IRG registration eliminating the bias associated with selecting a specific reference image. Registration performance was evaluated using segmented T1-weighted magnetic resonance images from the Nonrigid Image Registration Evaluation Project (NIREP), DTI and fMRI images. Implicit reference pair-wise (IRP) registration-a special case of IRG registration for two images-is shown to produce better relative overlap than IRG for pair-wise registration using the same small deformation, linear elastic registration model. However, IRP-G2R registration is shown to have significant transitivity error, i.e., significant inconsistencies between correspondences defined by different pair-wise transformations. In contrast, IRG registration produces consistent correspondence between images in a group at the cost of slightly reduced pair-wise RO accuracy compared to IRP-G2R. IRG spatial normalization of the fractional anisotropy (FA) maps of DTI is shown to have smaller FA variance compared with G2R methods using the same elastic registration model. Analyses of fMRI data sets with sensorimotor and visual tasks show that IRG registration, on average, increases the statistical detectability of brain activation compared to G2R registration. (C) 2009 Elsevier Inc. All rights reserved. C1 [Geng, Xiujuan; Gu, Hong; Ross, Thomas J.; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD USA. [Christensen, Gary E.] Univ Iowa, Dept Elect & Comp Engn, Iowa City, IA 52242 USA. RP Geng, XJ (reprint author), NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD USA. EM gengx@nida.nih.gov RI Ross, Thomas/B-7469-2008; Geng, Xiujuan/I-3852-2012 OI Ross, Thomas/0000-0002-7745-3572; FU National Institute on Drug Abuse (NIDA); National Institute of Health (NIH) [EB004126] FX This work was supported in part by the intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institute of Health (NIH) and NIH grant EB004126. NR 39 TC 31 Z9 31 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2009 VL 47 IS 4 BP 1341 EP 1351 DI 10.1016/j.neuroimage.2009.04.024 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 484HN UT WOS:000269035100024 PM 19371788 ER PT J AU Deuker, L Bullmore, ET Smith, M Christensen, S Nathan, PJ Rockstroh, B Bassett, DS AF Deuker, Lorena Bullmore, Edward T. Smith, Marie Christensen, Soren Nathan, Pradeep J. Rockstroh, Brigitte Bassett, Danielle S. TI Reproducibility of graph metrics of human brain functional networks SO NEUROIMAGE LA English DT Article ID SMALL-WORLD NETWORKS; WORKING-MEMORY; THEORETICAL ANALYSIS; CONNECTIVITY; SCHIZOPHRENIA; EEG; SYNCHRONIZATION; METAANALYSIS AB Graph theory provides many metrics of complex network organization that can be applied to analysis of brain networks derived from neuroimaging data. Here we investigated the test-retest reliability of graph metrics of functional networks derived from magnetoencephalography (MEG) data recorded in two sessions from 16 healthy volunteers who were studied at rest and during performance of the n-back working memory task in each session. For each subject's data at each session, we used a wavelet filter to estimate the mutual information (MI) between each pair of MEG sensors in each of the classical frequency intervals from gamma to low 6 in the overall range 1-60 Hz. Undirected binary graphs were generated by thresholding the MI matrix and 8 global network metrics were estimated: the clustering coefficient, path length, small-worldness, efficiency, cost-efficiency, assortativity, hierarchy, and synchronizability. Reliability of each graph metric was assessed using the intraclass correlation (ICC). Good reliability was demonstrated for most metrics applied to the n-back data (mean ICC=0.62). Reliability was greater for metrics in lower frequency networks. Higher frequency gamma and beta-band networks were less reliable at a global level but demonstrated high reliability of nodal metrics in frontal and parietal regions. Performance of the n-back task was associated with greater reliability than measurements on resting state data. Task practice was also associated with greater reliability. Collectively these results suggest that graph metrics are sufficiently reliable to be considered for future longitudinal studies of functional brain network changes. (C) 2009 Elsevier Inc. All rights reserved. C1 [Deuker, Lorena; Bullmore, Edward T.; Nathan, Pradeep J.; Bassett, Danielle S.] Univ Cambridge, Addenbrookes Hosp, Brain Mapping Unit, Dept Psychiat,Behav & Clin Neurosci Inst, Cambridge CB2 2QQ, England. [Deuker, Lorena; Rockstroh, Brigitte] Univ Constance, Dept Psychol, D-7750 Constance, Germany. [Bullmore, Edward T.; Christensen, Soren; Nathan, Pradeep J.] Addenbrookes Hosp, GSK Clin Unit Cambridge, Cambridge, England. [Smith, Marie] MRC Cognit, Cambridge, England. [Smith, Marie] Brain Sci Unit, Cambridge, England. [Bassett, Danielle S.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Bassett, Danielle S.] Univ Cambridge, Dept Phys, Biol Soft Syst Sector, Cambridge CB2 2QQ, England. RP Bullmore, ET (reprint author), Univ Cambridge, Addenbrookes Hosp, Brain Mapping Unit, Dept Psychiat,Behav & Clin Neurosci Inst, Cambridge CB2 2QQ, England. EM etb23@cam.ac.uk; dp317@cam.ac.uk RI Smith, Marie/N-8491-2013; Bullmore, Edward/C-1706-2012 OI Bullmore, Edward/0000-0002-8955-8283 FU GlaxoSmithKline; Brain Sciences Unit; Wellcome Trust; MRC; German Academic Exchange Service (DAAD); National Institutes of Health Graduate Partnerships Program FX This experiment was sponsored by GlaxoSmithKline and conducted at the MRC Cognition and Brain Sciences Unit and the Wellcome Trust and MRC-funded Behavioural and Clinical Neurosciences Institute, Cambridge UK. Software development was Supported by a Human Brain Project grant from the National Institute of Biomedical Imaging and Bioengineering and the National Institute of Mental Health. LD was supported by a scholarship from the German Academic Exchange Service (DAAD). DSB was supported by the National Institutes of Health Graduate Partnerships Program. NR 32 TC 96 Z9 96 U1 0 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2009 VL 47 IS 4 BP 1460 EP 1468 DI 10.1016/j.neuroimage.2009.05.035 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 484HN UT WOS:000269035100035 PM 19463959 ER PT J AU de Zwart, JA van Gelderen, P Jansma, JM Fukunaga, M Bianciardi, M Duyn, JH AF de Zwart, Jacco A. van Gelderen, Peter Jansma, J. Martijn Fukunaga, Masaki Bianciardi, Marta Duyn, Jeff H. TI Hemodynamic nonlinearities affect BOLD fMRI response timing and amplitude SO NEUROIMAGE LA English DT Article ID CEREBRAL-BLOOD-FLOW; IMPULSE-RESPONSE; FUNCTIONAL MRI; SOMATOSENSORY CORTEX; HUMAN BRAIN; STIMULUS; EVENT; RAT; DYNAMICS; SYSTEM AB The interpretation of functional magnetic resonance imaging (fMRI) studies based on blood oxygen-level dependent (BOLD) contrast generally relies on the assumption of a linear relationship between evoked neuronal activity and fMRI response. While nonlinearities in this relationship have been suggested by a number of studies, it remains unclear to what extent they relate to the neurovascular response and are therefore inherent to BOLD fMRI Full characterization of potential vascular nonlinearities is required for accurate inferences about the neuronal system under study. To investigate the extent of vascular nonlinearities, evoked activity was studied in. humans with BOLD fMRI (n = 28) and magneto-encephalography (MEG) (n = 5). Brief (600-800 ms) rapidly repeated (1 Hz) visual stimuli were delivered using a Stimulation paradigm that minimized neuronal nonlinearities. Nevertheless, BOLD fMRI experiments showed substantial remaining nonlinearities. The smallest stimulus separation (200-400 ms) resulted in significant response broadening (15-20% amplitude decrease; 10-12% latency increase: 6-14% duration increase) with respect to a linear prediction. The substantial slowing and widening of the response in the presence of preceding stimuli suggest a vascular rather than neuronal origin to the observed nonlinearity. This was confirmed by the MEG data, which showed no significant neuro-electric nonlinear interactions between stimuli as little as 200 ms apart. The presence of substantial vascular nonlinearities has important implications for rapid event-related studies by fMRI and other imaging modalities that infer neuronal activity from hemodynamic parameters. Published by Elsevier Inc. C1 [de Zwart, Jacco A.; van Gelderen, Peter; Jansma, J. Martijn; Fukunaga, Masaki; Bianciardi, Marta; Duyn, Jeff H.] NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. RP de Zwart, JA (reprint author), NINDS, Adv MRI Sect, LFMI, NIH, Bldg 10,Rm B1D-728,9000 Rockville Pk-MSC 1065, Bethesda, MD 20892 USA. EM jacco.deZwart@nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 FU Intramural NIH HHS [Z99 NS999999] NR 44 TC 20 Z9 20 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2009 VL 47 IS 4 BP 1649 EP 1658 DI 10.1016/j.neuroimage.2009.06.001 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 484HN UT WOS:000269035100053 PM 19520175 ER PT J AU Stroth, N Eiden, LE AF Stroth, N. Eiden, L. E. TI PACAP REGULATES NEUROPEPTIDE EXPRESSION AT THE SYMPATHOADRENAL SYNAPSE DURING METABOLIC STRESS SO NEUROPEPTIDES LA English DT Meeting Abstract CT Joint Meeting of the European-Neuropeptides-Club/Summer Neuropeptides Conference CY JUL 20-23, 2009 CL Salzburg, AUSTRIA SP European Neuropeptides Club C1 [Stroth, N.; Eiden, L. E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD OCT PY 2009 VL 43 IS 5 BP 411 EP 411 PG 1 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 521AH UT WOS:000271890700013 ER PT J AU Eiden, LE AF Eiden, L. E. TI Neuropeptide signaling and the stress transcriptome SO NEUROPEPTIDES LA English DT Meeting Abstract CT Joint Meeting of the European-Neuropeptides-Club/Summer Neuropeptides Conference CY JUL 20-23, 2009 CL Salzburg, AUSTRIA SP European Neuropeptides Club C1 [Eiden, L. E.] NIMH, Mol Neurosci Sect, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD OCT PY 2009 VL 43 IS 5 BP 440 EP 441 PG 2 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 521AH UT WOS:000271890700107 ER PT J AU Moody, TW Berna, M Mantey, S Jensen, RT AF Moody, T. W. Berna, M. Mantey, S. Jensen, R. T. TI NMB causes transactivation of EGF receptors in lung cancer cells SO NEUROPEPTIDES LA English DT Meeting Abstract CT Joint Meeting of the European-Neuropeptides-Club/Summer Neuropeptides Conference CY JUL 20-23, 2009 CL Salzburg, AUSTRIA SP European Neuropeptides Club C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD OCT PY 2009 VL 43 IS 5 BP 444 EP 444 PG 1 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 521AH UT WOS:000271890700121 ER PT J AU Cservenak, M Palkovits, M Usdin, TB Dobolyi, A AF Cservenak, M. Palkovits, M. Usdin, T. B. Dobolyi, A. TI Activation of posterior thalamic TIP39 neurons in mother rats SO NEUROPEPTIDES LA English DT Meeting Abstract CT Joint Meeting of the European-Neuropeptides-Club/Summer Neuropeptides Conference CY JUL 20-23, 2009 CL Salzburg, AUSTRIA SP European Neuropeptides Club C1 [Cservenak, M.; Palkovits, M.; Dobolyi, A.] Hungarian Acad Sci, Dept Anat Histol & Embryol, Neuromorphol & Neuroendocrine Res Lab, Budapest, Hungary. [Cservenak, M.; Palkovits, M.; Dobolyi, A.] Semmelweis Univ, H-1085 Budapest, Hungary. [Usdin, T. B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. RI Palkovits, Miklos/F-2707-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD OCT PY 2009 VL 43 IS 5 BP 449 EP 450 PG 2 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 521AH UT WOS:000271890700139 ER PT J AU Krasnova, IN Hodges, AB Ladenheim, B Rhoades, R Phillip, CG Cesena, A Ivanova, E Hohmann, CF Cadet, JL AF Krasnova, Irina N. Hodges, Amber B. Ladenheim, Bruce Rhoades, Raina Phillip, Crystal G. Cesena, Angela Ivanova, Ekaterina Hohmann, Christine F. Cadet, Jean Lud TI Methamphetamine treatment causes delayed decrease in novelty-induced locomotor activity in mice SO NEUROSCIENCE RESEARCH LA English DT Article DE Methamphetamine; Dopamine; Neurotoxicity; Striatum; Cortex; Novelty-induced locomotor activity ID INDUCED NEURONAL APOPTOSIS; INDUCED NEUROTOXICITY; RECOGNITION MEMORY; DOPAMINE TRANSPORTERS; PSYCHIATRIC-SYMPTOMS; PARKINSONS-DISEASE; NONHUMAN-PRIMATES; BASAL GANGLIA; MOTOR; RATS AB Methamphetamine (METH) is a psychostimulant that causes damage to dopamine (DA) axons and to non-monoaminergic neurons in the brain. The aim of the present study was to investigate short- and long-term effects of neurotoxic METH treatment on novelty-induced locomotor activity in mice. Male BALB/c mice, 12-14 weeks old, were injected with saline or METH (i.p., 7.5 mg/kg x 4 times, every 2 h). Behavior and neurotoxic effects were assessed at 10 days, 3 and 5 months following drug treatment. METH administration caused marked decreases in DA levels in the mouse striatum and cortex at 10 days post-drug. However, METH did not induce any changes in novelty-induced locomotor activity. At 3 and 5 months after treatment METH-exposed mice showed significant recovery of DA levels in the striatum and cortex. In contrast, these animals demonstrated significant decreases in locomotor activity at 5 months in comparison to aged-matched control mice. Further assessment of METH toxicity using TUNEL staining showed that the drug induced increased cell death in the striatum and cortex at 3 days after administration. Taken together, these data suggest that delayed deficits in novelty-induced locomotor activity observed in METH-exposed animals are not due to neurodegeneration of DA terminals but to combined effects of METH and age-dependent dysfunction of non-DA intrinsic striatal and/or corticostriatal neurons. Published by Elsevier Ireland Ltd and the Japan Neuroscience Society. C1 [Krasnova, Irina N.; Ladenheim, Bruce; Cesena, Angela; Ivanova, Ekaterina; Cadet, Jean Lud] Natl Inst Drug Abuse, Mol Neuropsychiat Res Branch, NIH, DHHS, Baltimore, MD 21224 USA. [Hodges, Amber B.; Rhoades, Raina; Phillip, Crystal G.; Hohmann, Christine F.] Morgan State Univ, Dept Biol, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), Natl Inst Drug Abuse, Mol Neuropsychiat Res Branch, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU NIH/DHHS [3SO6 GM051971, U54 MH066417, R25 CM058904] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse of the NIH/DHHS (to I.N.K., B.L., A-C., E.I. and J.LC.), and by grants 3SO6 GM051971 and U54 MH066417 (to C.F.H.) and R25 CM058904 (to R.R. and C.G.P.). NR 62 TC 12 Z9 12 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD OCT PY 2009 VL 65 IS 2 BP 160 EP 165 DI 10.1016/j.neures.2009.06.007 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 498SJ UT WOS:000270163100006 PM 19559060 ER PT J AU Machado-Vieira, R Manji, HK Zarate, CA AF Machado-Vieira, Rodrigo Manji, Husseini K. Zarate, Carlos A. TI The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology and Therapeutics of Mood Disorders SO NEUROSCIENTIST LA English DT Review DE glutamate; tripartite; bipolar disorder; ketamine; riluzole ID METHYL-D-ASPARTATE; MAJOR DEPRESSIVE DISORDER; OPEN-LABEL TRIAL; MAGNETIC-RESONANCE SPECTROSCOPY; SEROTONIN REUPTAKE INHIBITORS; OBSESSIVE-COMPULSIVE DISORDER; ANTERIOR CINGULATE ACTIVITY; BIPOLAR AFFECTIVE-DISORDER; MGLU5 RECEPTOR ANTAGONIST; GAMMA-AMINOBUTYRIC-ACID AB Bipolar disorder and major depressive disorder are common, chronic, and recurrent mood disorders that affect the lives of millions of individuals worldwide. Growing evidence suggests that glutamatergic system dysfunction is directly involved in mood disorders. This article describes the role of the "tripartite glutamatergic synapse," comprising presynaptic and post-synaptic neurons and glial cells, in the pathophysiology and therapeutics of mood disorders. Glutamatergic neurons and glia directly control synaptic and extrasynaptic glutamate levels/release through integrative effects that target glutamate excitatory amino acid transporters, postsynaptic density proteins, ionotropic receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], N-methyl-D-aspartate [NAIDA], and kainate) and metabotropic receptors. This article also explores the glutamatergic modulators riluzole and ketamine, which are considered valuable proof-of-concept agents for developing the next generation of antidepressants and mood stabilizers. In therapeutically relevant paradigms ketamine preferentially targets postsynaptic AMPA/NMDA receptors, and riluzole preferentially targets presynaptic voltage-operated channels and glia. C1 [Machado-Vieira, Rodrigo; Zarate, Carlos A.] NIMH, Expt Therapeut Mood & Anxiety Disorders Res Progr, NIH, Bethesda, MD 20892 USA. [Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut Mood & Anxiety Disorders Program, Mark O Hatfield Clin Res Ctr, 10 Ctr Dr,CRC,Unit 4 SE,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural NIH HHS [Z01 MH002828-05, Z01 MH002857-03] NR 149 TC 89 Z9 95 U1 7 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2009 VL 15 IS 5 BP 525 EP 539 DI 10.1177/1073858409336093 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 500LP UT WOS:000270303800018 PM 19471044 ER PT J AU Koenigs, M Grafman, J AF Koenigs, Michael Grafman, Jordan TI Posttraumatic Stress Disorder: The Role of Medial Prefrontal Cortex and Amygdala SO NEUROSCIENTIST LA English DT Review DE posttraumatic stress disorder; prefrontal cortex; amygdala; emotion ID CONDITIONED FEAR; ORBITOFRONTAL CORTEX; MAJOR DEPRESSION; COMBAT VETERANS; EXTINCTION; BRAIN; PTSD; HUMANS; ACTIVATION; VIETNAM AB Posttraumatic stress disorder (PTSD) is characterized by recurrent distressing memories of an emotionally traumatic event. In this review, the authors present neuroscientific data highlighting the function of two brain areas-the amygdala and ventromedial prefrontal cortex (vmPFC)-in PTSD and related emotional processes. A convergent body of human and nonhuman Studies suggests that the amygdala mediates the acquisition and expression of conditioned fear and the enhancement of emotional memory, whereas the vmPFC mediates the extinction of conditioned fear and the volitional regulation of negative emotion. It has been theorized that the vmPFC exerts inhibition on the amygdala, and that a defect in this inhibition could account for the symptoms of PTSD. This theory is supported by functional imaging studies of PTSD patients, who exhibit hypoactivity in the vmPFC but hyperactivity in the amygdala. A recent study of brain-injured and trauma-exposed combat veterans confirms that amygdala damage reduces the likelihood of developing PTSD. But contrary to the prediction of the top-down inhibition model, vmPFC damage also reduces the likelihood of developing PTSD. The putative roles of the amygdala and the vmPFC in the pathophysiology of PTSD, as well as implications for potential treatments, are discussed in light of these results. C1 [Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Koenigs, Michael] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. RP Grafman, J (reprint author), Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; Koenigs, Michael/0000-0002-5799-4881 FU National Institute of Neurological Disorders and Stroke intramural research [DAMD17-01-1-0675] FX This work was Supported in part by the National Institute of Neurological Disorders and Stroke intramural research program, DAMD17-01-1-0675 (J.G.) NR 59 TC 93 Z9 98 U1 9 U2 31 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2009 VL 15 IS 5 BP 540 EP 548 DI 10.1177/1073858409333072 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 500LP UT WOS:000270303800019 PM 19359671 ER PT J AU Yamada, S Lonser, RR Colohan, ART Yamada, SM Won, DJ AF Yamada, Shokei Lonser, Russell R. Colohan, Austin R. T. Yamada, Shoko M. Won, Daniel J. TI BYPASS COAPTATION FOR CERVICAL ROOT AVULSION: INDICATIONS FOR OPTIMAL OUTCOME SO NEUROSURGERY LA English DT Article DE Bypass coaptation; Cervical root avulsion; Nerve regeneration ID BRACHIAL-PLEXUS INJURY; CONFIGURATION; NEUROTIZATION AB OBJECTIVE: Previously, we reported bypass coaptation of the C3 and C4 anterior rami to the upper trunk of the brachial plexus for restoration of the muscles denervated as a result of C5 and C6 nerve root avulsion. This procedure is thought to be superior to the transfer of individual peripheral nerve fibers to the brachial plexus branches. Therefore, the benefits of the bypass coaptation procedures in the treatment of various root avulsions are presented. METHODS: Twenty-six patients were selected as suitable candidates for bypass coaptation procedures. They were divided into 3 groups: 1) Erb-Duchenne palsy due to C5 and C6 root avulsion, 2) Klumpke palsy due to C8 and T1 root avulsion, and 3) the flail arm (or flail upper limb) due to C5 through T1 root avulsion. The surgical techniques are described in detail. RESULTS: The coaptation procedures for the first group resulted in excellent recovery of all the denervated muscles. The patients in the second group showed reinnervation of the finger muscles and finger sensory distributions in infants within the first year after surgery. The flail arm group regained satisfactory proximal muscle function but only mild distal muscle function. One exception was a child who showed significant recovery in proximal and distal motor and sensory function. CONCLUSION: We recommend the bypass coaptation as a useful procedure for the following categories: Erb-Duchenne palsy due to C5 and C6 root avulsion in all ages, Klumpke palsy due to the C8 and T1 avulsion, and the flail arm due to C5 through T1 avulsion in young children. However, bypass procedures for the flail limb in adults require additional innovative methods to facilitate the growth rate of regenerating nerves. C1 [Yamada, Shokei; Colohan, Austin R. T.] Loma Linda Univ, Dept Neurosurg, Loma Linda, CA 92543 USA. [Lonser, Russell R.] NIH, Dept Neurol Surg, Bethesda, MD 20892 USA. [Yamada, Shoko M.] Teikyo Univ, Ichihara Med Ctr, Dept Neurosurg, Chiba, Japan. [Won, Daniel J.] Kaiser Permanente Med Ctr, Div Pediat, Dept Neurosurg, Fontana, CA USA. RP Yamada, S (reprint author), Loma Linda Univ, Dept Neurosurg, 11234 Anderson St, Loma Linda, CA 92543 USA. EM yamada1000@gmail.com NR 20 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD OCT PY 2009 VL 65 IS 4 BP A203 EP A211 DI 10.1227/01.NEU.0000358615.92344.D1 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 502XB UT WOS:000270492600031 PM 28180833 ER PT J AU Wine, RN McPherson, CA Harry, GJ AF Wine, Robert N. McPherson, Christopher A. Harry, G. Jean TI IGF-1 and pAKT Signaling Promote Hippocampal CA1 Neuronal Survival Following Injury to Dentate Granule Cells SO NEUROTOXICITY RESEARCH LA English DT Article DE Microglia; Hippocampus; Pyramidal neurons; Trimethyltin; IGF-1; pAkt; Seizure ID GROWTH-FACTOR-I; TUMOR-NECROSIS-FACTOR; PROTEIN-KINASE B/AKT; L CALCIUM-CHANNELS; PHOSPHATIDYLINOSITOL 3-KINASE; NERVOUS-SYSTEM; AKT ACTIVATION; MESSENGER-RNA; TNF-ALPHA; CULTURED HIPPOCAMPAL AB Insulin-like growth factor-1 (IGF-1) protects neurons from apoptosis and in vivo offers neuroprotective support to hippocampal CA1 pyramidal neurons following ischemia or seizure. IGF-1 signals through IGF-1 receptors activating phosphytidylinositol 3-kinase (PI3K)/Akt or pMAPK pathways. IGF-1 can be induced with injury and microglia and astrocytes may serve as a source of this neurotrophic factor to promote neuronal survival. An acute systemic injection of trimethyltin (TMT; 2 mg/kg, ip) to mice induces apoptosis of dentate granule neurons within 24 h and a differential response of microglia with ramified microglia present in the CA-1 region. Using this model, we studied the role of IGF-1 in the survival of CA-1 pyramidal neurons under conditions of altered synaptic input due to changes in the dentate gyrus. Within 24 h of injection, IGF-1 mRNA levels were elevated in the hippocampus and IGF-1 protein detected in both astrocytes and microglia. IGF-1 was redistributed within the CA-1 neurons corresponding with an increase in cytoplasmic pAkt, elevated PKB alpha/Akt protein levels, and a decrease in the antagonist, Rho. pMAPK was not detected in CA-1 neurons and ERK2 showed a transient decrease followed by a significant increase, suggesting a lack of recruitment of the pMAPK signaling pathway for neuronal survival. In mice deficient for IGF-1, a similar level of apoptosis was observed in dentate granule neurons as compared to wildtype; however, TMT induced a significant level CA-1 neuronal death, further supporting a role for IGF-1 in the survival of CA-1 neurons. C1 [Wine, Robert N.; McPherson, Christopher A.; Harry, G. Jean] NIEHS, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Mol Toxicol Lab, NIH, POB 12233,MD C1-04, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health FX This research was funded by the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health. NR 90 TC 20 Z9 21 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD OCT PY 2009 VL 16 IS 3 BP 280 EP 292 DI 10.1007/s12640-009-9060-y PG 13 WC Neurosciences SC Neurosciences & Neurology GA 484AG UT WOS:000269014400010 PM 19526277 ER PT J AU Landon, MB Spong, CY Thom, E Carpenter, MW Ramin, SM Casey, B Wapner, RJ Varner, MW Rouse, DJ Thorp, JM Sciscione, A Catalano, P Harper, M Saade, G Lain, KY Sorokin, Y Peaceman, AM Tolosa, JE Anderson, GB AF Landon, Mark B. Spong, Catherine Y. Thom, Elizabeth Carpenter, Marshall W. Ramin, Susan M. Casey, Brian Wapner, Ronald J. Varner, Michael W. Rouse, Dwight J. Thorp, John M., Jr. Sciscione, Anthony Catalano, Patrick Harper, Margaret Saade, George Lain, Kristine Y. Sorokin, Yoram Peaceman, Alan M. Tolosa, Jorge E. Anderson, Garland B. CA Eunice Kennedy Shriver NICHHD Mate TI A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; ADVERSE PREGNANCY OUTCOMES; SERVICES TASK-FORCE; CLINICAL-TRIALS; MELLITUS; MANAGEMENT; HYPERGLYCEMIA; RECOMMENDATIONS; DELIVERY AB Background: It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes. Methods: Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. Results: A total of 958 women were randomly assigned to a study group -- 485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P=0.14). There were no perinatal deaths. However, there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes, including mean birth weight (3302 vs. 3408 g), neonatal fat mass (427 vs. 464 g), the frequency of large-for-gestational-age infants (7.1% vs. 14.5%), birth weight greater than 4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs. 4.0%), and cesarean delivery (26.9% vs. 33.8%). Treatment of gestational diabetes mellitus, as compared with usual care, was also associated with reduced rates of preeclampsia and gestational hypertension (combined rates for the two conditions, 8.6% vs. 13.6%; P=0.01). Conclusions: Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders. (ClinicalTrials.gov number, NCT00069576.) N Engl J Med 2009;361:1339-48. C1 [Landon, Mark B.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver NICHHD, Bethesda, MD USA. [Thom, Elizabeth] George Washington Univ, Ctr Biostat, Washington, DC USA. [Carpenter, Marshall W.] Brown Univ, Dept Obstet, Providence, RI 02912 USA. [Carpenter, Marshall W.] Brown Univ, Dept Gynecol, Providence, RI 02912 USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Casey, Brian] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Wapner, Ronald J.] Columbia Univ, New York, NY USA. [Varner, Michael W.] Univ Utah, Salt Lake City, UT USA. [Rouse, Dwight J.] Univ Alabama, Birmingham, AL USA. [Thorp, John M., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Sciscione, Anthony] Drexel Univ, Philadelphia, PA 19104 USA. [Catalano, Patrick] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Harper, Margaret] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Saade, George; Anderson, Garland B.] Univ Texas Med Branch, Galveston, TX USA. [Lain, Kristine Y.] Univ Pittsburgh, Pittsburgh, PA USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Peaceman, Alan M.] Northwestern Univ, Chicago, IL 60611 USA. [Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Landon, MB (reprint author), Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. EM mark.landon@osumc.edu RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801]; General Clinical Research Centers [M01-RR00034]; National Center for Research Resources [UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801), the General Clinical Research Centers (M01-RR00034), and the National Center for Research Resources (UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234). NR 32 TC 642 Z9 677 U1 10 U2 57 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 OCT 1 PY 2009 VL 361 IS 14 BP 1339 EP 1348 DI 10.1056/NEJMoa0902430 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 500KZ UT WOS:000270300000008 PM 19797280 ER PT J AU Hopkins, JF Panja, S McNeil, SAN Woodson, SA AF Hopkins, Julia F. Panja, Subrata McNeil, Stephanie A. N. Woodson, Sarah A. TI Effect of salt and RNA structure on annealing and strand displacement by Hfq SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SM-LIKE PROTEIN; HELIX-COIL TRANSITION; ESCHERICHIA-COLI HFQ; SMALL REGULATORY RNA; DSRA RNA; SECONDARY STRUCTURE; CHAPERONE ACTIVITY; MOLECULAR BEACONS; BINDING; RPOS AB The Sm-like protein Hfq promotes the association of small antisense RNAs (sRNAs) with their mRNA targets, but the mechanism of Hfq's RNA chaperone activity is unknown. To investigate RNA annealing and strand displacement by Hfq, we used oligonucleotides that mimic functional sequences within DsrA sRNA and the complementary rpoS mRNA. Hfq accelerated at least 100-fold the annealing of a fluorescently labeled molecular beacon to a 16-nt RNA. The rate of strand exchange between the oligonucleotides increased 80-fold. Therefore, Hfq is very active in both helix formation and exchange. However, high concentrations of Hfq destabilize the duplex by preferentially binding the single-stranded RNA. RNA binding and annealing were completely inhibited by 0.5M salt. The target site in DsrA sRNA was 1000-fold less accessible to the molecular beacon than an unstructured oligonucleotide, and Hfq accelerated annealing with DsrA only 2-fold. These and other results are consistent with recycling of Hfq during the annealing reaction, and suggest that the net reaction depends on the relative interaction of Hfq with the products and substrates. C1 [Panja, Subrata; Woodson, Sarah A.] Johns Hopkins Univ, TC Jenkins Dept Biophys, Baltimore, MD 21218 USA. [McNeil, Stephanie A. N.] Johns Hopkins Univ, NIH, Grad Partnership Program, Baltimore, MD 21218 USA. [Hopkins, Julia F.] Johns Hopkins Univ, Program Cellular Mol & Dev Biol & Biophys, Baltimore, MD 21218 USA. RP Woodson, SA (reprint author), Johns Hopkins Univ, TC Jenkins Dept Biophys, 3400 N Charles St, Baltimore, MD 21218 USA. EM swoodson@jhu.edu OI Woodson, Sarah/0000-0003-0170-1987 FU National Institutes of Health [R01 GM46686] FX The National Institutes of Health (R01 GM46686). NR 45 TC 23 Z9 23 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2009 VL 37 IS 18 BP 6205 EP 6213 DI 10.1093/nar/gkp646 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510RR UT WOS:000271109300030 PM 19671524 ER PT J AU Entezam, A Usdin, K AF Entezam, Ali Usdin, Karen TI ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUNTINGTONS-DISEASE GENE; CGG REPEAT; TRANSGENIC MICE; CAG REPEAT; IN-VITRO; REPLICATION; EXPRESSION; INACTIVATION; POPULATION; EXPANSIONS AB Expansion of a tandem repeat tract is responsible for the Repeat Expansion diseases, a group of more than 20 human genetic disorders that includes those like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase protects the genome against one type of repeat expansion in a FX premutation mouse model. By crossing the FX premutation mice to Ataxia Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents repeat expansion. However, our data suggest that the ATM-sensitive mechanism is different from the ATR-sensitive one. Specifically, the effect of the ATM deficiency is more marked when the premutation allele is paternally transmitted and expansions occur more frequently in male offspring regardless of the Atm genotype of the offspring. The gender effect is most consistent with a repair event occurring in the early embryo that is more efficient in females, perhaps as a result of the action of an X-linked DNA repair gene. Our data thus support the hypothesis that two different mechanisms of FX repeat expansion exist, an ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive mechanism that shows a male expansion bias. C1 [Entezam, Ali; Usdin, Karen] NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. [Entezam, Ali] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England. RP Usdin, K (reprint author), NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU NIDDK (National Institutes of Health) FX The Intramural Program of the NIDDK (National Institutes of Health). Funding for open access charge: The Intramural program of NIDDK, National Institutes of Health. NR 37 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2009 VL 37 IS 19 BP 6371 EP 6377 DI 10.1093/nar/gkp666 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514JH UT WOS:000271389900007 PM 19710035 ER PT J AU Rosa, ID Goffart, S Wurm, M Wiek, C Essmann, F Sobek, S Schroeder, P Zhang, HL Krutmann, J Hanenberg, H Schulze-Osthoff, K Mielke, C Pommier, Y Boege, F Christensen, MO AF Rosa, Ilaria Dalla Goffart, Steffi Wurm, Melanie Wiek, Constanze Essmann, Frank Sobek, Stefan Schroeder, Peter Zhang, Hongliang Krutmann, Jean Hanenberg, Helmut Schulze-Osthoff, Klaus Mielke, Christian Pommier, Yves Boege, Fritz Christensen, Morten O. TI Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CULTURED HUMAN-CELLS; N-TERMINAL DOMAIN; MAMMALIAN MITOCHONDRIA; SACCHAROMYCES-CEREVISIAE; LIVING CELLS; HELA-CELLS; III-ALPHA; TRANSCRIPTION; VIVO; MTDNA AB Topoisomerase I is essential for DNA metabolism in nuclei and mitochondria. In yeast, a single topoisomerase I gene provides for both organelles. In vertebrates, topoisomerase I is divided into nuclear and mitochondrial paralogs (Top1 and Top1mt). To assess the meaning of this gene duplication, we targeted Top1 to mitochondria or Top1mt to nuclei. Overexpression in the fitting organelle served as control. Targeting of Top1 to mitochondria blocked transcription and depleted mitochondrial DNA. This was also seen with catalytically inactive Top1 mutants, but not with Top1mt overexpressed in mitochondria. Targeting of Top1mt to the nucleus revealed that it was much less able to interact with mitotic chromosomes than Top1 overexpressed in the nucleus. Similar experiments with Top1/Top1mt hybrids assigned these functional differences to structural divergences in the DNA-binding core domains. We propose that adaptation of this domain to different chromatin environments in nuclei and mitochondria has driven evolutional development and conservation of organelle-restricted topoisomerase I paralogs in vertebrates. C1 [Rosa, Ilaria Dalla; Sobek, Stefan; Mielke, Christian; Boege, Fritz; Christensen, Morten O.] Univ Dusseldorf, Sch Med, Inst Clin Chem, D-40225 Dusseldorf, Germany. [Rosa, Ilaria Dalla; Sobek, Stefan; Mielke, Christian; Boege, Fritz; Christensen, Morten O.] Univ Dusseldorf, Sch Med, Diagnost Lab, D-40225 Dusseldorf, Germany. [Goffart, Steffi] Inst Med Technol, Tampere, Finland. [Wurm, Melanie; Wiek, Constanze; Hanenberg, Helmut] Univ Dusseldorf, Childrens Hosp, Dept Pediat Oncol Hematol & Immunol, Sch Med, D-40225 Dusseldorf, Germany. [Essmann, Frank; Schulze-Osthoff, Klaus] Univ Tubingen, Interfac Inst Biochem, D-72076 Tubingen, Germany. [Schroeder, Peter; Krutmann, Jean] Univ Dusseldorf, Environm Hlth Res Inst, D-40225 Dusseldorf, Germany. [Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Boege, F (reprint author), Univ Dusseldorf, Sch Med, Inst Clin Chem, D-40225 Dusseldorf, Germany. EM boege@med.uni-duesseldorf.de; christensen@med.uni-duesseldorf.de RI Schulze-Osthoff, Klaus/N-9025-2013; Goffart, Steffi/N-3597-2015 OI Schulze-Osthoff, Klaus/0000-0003-1443-2720; Goffart, Steffi/0000-0001-8491-1458 FU Deutsche Forschungsgemeinschaft [CH 713/1-1, HA2322/2-1, SFB 728, GRK 1033]; National Cancer Institute, National Institute of Health FX Deutsche Forschungsgemeinschaft (grants CH 713/1-1, HA2322/2-1, SFB 728 and GRK 1033); Intramural Program of the Center for Cancer Research, National Cancer Institute, National Institute of Health. Funding for open access charge: Deutsche Forschungsgemeinschaft (SFB 728 and GRK 1033). NR 50 TC 3 Z9 3 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2009 VL 37 IS 19 BP 6414 EP 6428 DI 10.1093/nar/gkp708 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514JH UT WOS:000271389900011 ER PT J AU Yeung, ML Bennasser, Y Watashi, K Le, SY Houzet, L Jeang, KT AF Yeung, Man Lung Bennasser, Yamina Watashi, Koichi Le, Shu-Yun Houzet, Laurent Jeang, Kuan-Teh TI Pyrosequencing of small non-coding RNAs in HIV-1 infected cells: evidence for the processing of a viral-cellular double-stranded RNA hybrid SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SMALL INTERFERING RNAS; EMBRYONIC STEM-CELLS; PRIMER-BINDING-SITE; HIV-1 TAR ELEMENT; HEPATITIS-C VIRUS; REVERSE TRANSCRIPTION; MICRORNA EXPRESSION; CAENORHABDITIS-ELEGANS; TYPE-1 REPLICATION AB Small non-coding RNAs of 18-25 nt in length can regulate gene expression through the RNA interference (RNAi) pathway. To characterize small RNAs in HIV-1-infected cells, we performed linker-ligated cloning followed by high-throughput pyrosequencing. Here, we report the composition of small RNAs in HIV-1 productively infected MT4 T-cells. We identified several HIV-1 small RNA clones and a highly abundant small 18-nt RNA that is antisense to the HIV-1 primer-binding site (PBS). This 18-nt RNA apparently originated from the dsRNA hybrid formed by the HIV-1 PBS and the 30 end of the human cellular tRNAlys3. It was found to associate with the Ago2 protein, suggesting its possible function in the cellular RNAi machinery for targeting HIV-1. C1 [Yeung, Man Lung; Bennasser, Yamina; Watashi, Koichi; Houzet, Laurent; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Le, Shu-Yun] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM kj7c@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU NIAID; NCI; IATAP FX NIAID; NCI; IATAP program from the office of the director, National Institutes of Health. Funding for open access charge: National Institutes of Health intramural funds. NR 68 TC 80 Z9 84 U1 3 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2009 VL 37 IS 19 BP 6575 EP 6586 DI 10.1093/nar/gkp707 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514JH UT WOS:000271389900024 PM 19729508 ER PT J AU Dorjsuren, D Wilson, DM Beard, WA McDonald, JP Austin, CP Woodgate, R Wilson, SH Simeonov, A AF Dorjsuren, Dorjbal Wilson, David M., III Beard, William A. McDonald, John P. Austin, Christopher P. Woodgate, Roger Wilson, Samuel H. Simeonov, Anton TI A real-time fluorescence method for enzymatic characterization of specialized human DNA polymerases SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PRONE LESION BYPASS; AURINTRICARBOXYLIC ACID; XERODERMA-PIGMENTOSUM; Y-FAMILY; POL-IOTA; IN-VITRO; REVERSE-TRANSCRIPTASE; TRANSLESION SYNTHESIS; MOLECULAR BEACON; MAMMALIAN-CELLS AB Specialized DNA polymerases are involved in DNA synthesis during base-excision repair and translesion synthesis across a wide range of chemically modified DNA templates. Notable features of these enzymes include low catalytic efficiency, low processivity and low fidelity. Traditionally, in vitro studies of these enzymes have utilized radiolabeled substrates and gel electrophoretic separation of products. We have developed a simple homogeneous fluorescence-based method to study the enzymology of specialized DNA polymerases in real time. The method is based on fluorescent reporter strand displacement from a tripartite substrate containing a quencher-labeled template strand, an unlabeled primer and a fluorophore-labeled reporter. With this method, we could follow the activity of human DNA polymerases beta, eta, iota and kappa under different reaction conditions, and we investigated incorporation of the aberrant nucleotide, 8-oxodGTP, as well as bypass of an abasic site or 8-oxoG DNA template lesion in different configurations. Lastly, we demonstrate that the method can be used for small molecule inhibitor discovery and characterization in highly miniaturized settings, and we report the first nanomolar inhibitors of Y-family DNA polymerases i and g. The fluorogenic method presented here should facilitate mechanistic and inhibitor investigations of these polymerases and is also applicable to the study of highly processive replicative polymerases. C1 [Dorjsuren, Dorjbal; Austin, Christopher P.; Simeonov, Anton] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [McDonald, John P.; Woodgate, Roger] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Simeonov, A (reprint author), NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. EM asimeono@mail.nih.gov FU National Institutes of Health Roadmap for Medical Research; NIA; NIEHS [Z01-ES050158, Z01-ES050161]; NICHD; NHGRI; NIH [1U19CA105010] FX Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Program of NIA, NIEHS, (Z01-ES050158 and Z01-ES050161), NICHD and NHGRI, NIH, and in association with NIH Grant 1U19CA105010. Funding for open access charge: Molecular Libraries Initiative of the NIH Roadmap for Medical Research. NR 64 TC 29 Z9 29 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2009 VL 37 IS 19 AR e128 DI 10.1093/nar/gkp641 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514JH UT WOS:000271389900032 PM 19684079 ER PT J AU Scuteri, A Najjar, SS Orru', M Albai, G Strait, J Tarasov, KV Piras, MG Cao, A Schlessinger, D Uda, M Lakatta, EG AF Scuteri, A. Najjar, S. S. Orru', M. Albai, G. Strait, J. Tarasov, K. V. Piras, M. G. Cao, A. Schlessinger, D. Uda, M. Lakatta, E. G. TI Age- and gender-specific awareness, treatment, and control of cardiovascular risk factors and subclinical vascular lesions in a founder population: The SardiNIA Study SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE Hypertension; Diabetes; Hypercholesterolemia; Subclinical vascular disease; Treatment; Control; Population ID NUTRITION EXAMINATION SURVEY; CORONARY-ARTERY-DISEASE; BLOOD-PRESSURE CONTROL; UNITED-STATES; DIABETES-MELLITUS; MYOCARDIAL-INFARCTION; NATIONAL-HEALTH; HYPERTENSION TREATMENT; INDEPENDENT PREDICTOR; METABOLIC SYNDROME AB Aim: We investigated the gender-specific control of cardiovascular (CV) risk factors and subclinical vascular lesions in a founder population in Italy. Methods and Results: 6148 subjects were enrolled (aged 14-102 years) from four towns. Hypertension (HT), diabetes mellitus (DM) and dyslipidemia (LIP) were defined in accordance with guidelines. A self-reported diagnosis defined awareness of these conditions, and the current use of specific medications as treatment. Prevalence was HT 29.2%, DM 4.8%, LIP 44.1% and was higher in men than in women. Disease prevalence increased with age for every CV risk factor. Men were less likely than women to take anti-HT drugs and to reach BP control (9.9% vs. 16%). Only 17.6% of HT >65 years had a BP <= 140/90 mmHg, though 48.5% were treated. The use of statins was very tow (<1/3 of eligible subjects >65 years, those with the highest treatment rate). The ratio of control-to-treated HT was tower in subjects with, than in those without, thicker carotid arteries (31.5% vs. 38.8%, p < 0.05) or stiffer aortas (26.0% vs. 40.0%, p < 0.05) or carotid plaques (26.3% vs. 41.1%, p < 0.05). Conclusion: A large number of subjects at high CV risk are not treated and the management of subclinical vascular lesions is far from optimal. (C) 2008 Elsevier B.V. All rights reserved. C1 [Scuteri, A.] IRCCS, INRCA, UO Geriatria, I-00189 Rome, Italy. [Orru', M.; Albai, G.; Piras, M. G.; Cao, A.; Uda, M.] CNR, INN, Cagliari, Italy. [Najjar, S. S.; Strait, J.; Tarasov, K. V.; Lakatta, E. G.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Schlessinger, D.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Scuteri, A (reprint author), IRCCS, INRCA, UO Geriatria, Via Cassia 1167, I-00189 Rome, Italy. EM angeloelefante@interfree.it OI Tarasov, Kirill/0000-0001-7799-4670; piras, maria grazia/0000-0001-9004-0900 FU National Institute on Aging (NIA) [N01-AG-1-2109]; National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute on Aging (NIA), National Institutes of Health (NIH). The SardiNIA ("ProgeNIA") team was supported by Contract N01-AG-1-2109 from the NIA. NR 53 TC 27 Z9 27 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0939-4753 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD OCT PY 2009 VL 19 IS 8 BP 532 EP 541 DI 10.1016/j.numecd.2008.11.004 PG 10 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA 547ZV UT WOS:000273929500003 PM 19321325 ER PT J AU Monteiro, JP Freimanis-Hance, L Faria, LB Mussi-Pinhata, MM Korelitz, J Vannucchi, H Queiroz, W Succi, RCM Hazra, R AF Monteiro, Jacqueline P. Freimanis-Hance, Laura Faria, Lidiane B. Mussi-Pinhata, Marisa M. Korelitz, James Vannucchi, Helio Queiroz, Wladimir Succi, Regina C. M. Hazra, Rohan TI Both human immunodeficiency virus-infected and human immunodeficiency virus-exposed, uninfected children living in Brazil, Argentina, and Mexico have similar rates of low concentrations of retinol, beta-carotene, and vitamin E SO NUTRITION RESEARCH LA English DT Article DE beta-carotene; Children; HIV; Retinol; Vitamin E ID ACUTE-PHASE RESPONSE; ALPHA-TOCOPHEROL; A-DEFICIENCY; FILIPINO SCHOOLCHILDREN; NUTRITIONAL ASSESSMENT; MICRONUTRIENT LEVELS; HIV-INFECTION; SERUM; SUPPLEMENTATION; COHORT AB Our objective was to describe the prevalence of low concentrations of retinol, beta-carotene, and vitamin E in a group of human immunodeficiency virus (HIV)-infected Latin American children and a comparison group of HIV-exposed, uninfected children. Our hypothesis was that the rates of low concentrations of these micronutrients would be higher in the HIV-infected group than those in the HIV-exposed, uninfected group. This was a cross-sectional substudy of a larger cohort study at clinical pediatric HIV centers in Latin America. Serum levels of micronutrients were measured in the first stored sample obtained after each child's first birthday by high-performance liquid chromatography. Low concentrations of retinol, beta-carotene, and vitamin E were defined as serum levels below 0.70, 0.35, and 18.0 mu mol/L, respectively. The Population for this analysis was 336 children (124 HIV-infected, 212 HIV-exposed, uninfected) aged I year or older to younger than 4 years. Rates of low concentrations were 74% for retinol, 27% for beta-carotene, and 89% for vitamin E. These rates were not affected by HIV status. Among the HIV-infected children, those treated with anti retrovirals were less likely to have retinol deficiency, but no other HIV-related factors correlated with micronutrient low serum levels. Low concentrations of retinol, beta-carotene, and vitamin E are very common in children exposed to HIV living in Brazil, Argentina, and Mexico, regardless of HIV-infection status. Published by Elsevier Inc. C1 [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. [Monteiro, Jacqueline P.; Faria, Lidiane B.; Mussi-Pinhata, Marisa M.; Vannucchi, Helio] Univ Sao Paulo, BR-14049 Ribeirao Preto, SP, Brazil. [Freimanis-Hance, Laura; Korelitz, James] WESTAT Corp, Rockville, MD 20850 USA. [Queiroz, Wladimir] Inst Infectol Emilio Ribas, Sao Paulo, Brazil. [Succi, Regina C. M.] Univ Fed Sao Paulo, Sao Paulo, Brazil. RP Hazra, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. EM hazrar@mail.nih.gov RI Mussi-Pinhata, Marisa/G-6568-2012; Vannucchi, Helio/B-8060-2013; Monteiro, Jacqueline/F-6987-2012 OI Vannucchi, Helio/0000-0003-4161-3228; FU NICHD [N01-HD-3-3345, N01-DK-8-0001] FX Source of Financial Support: NICHD Contracts #N01-HD-3-3345 and #N01-DK-8-0001. NR 48 TC 12 Z9 13 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0271-5317 J9 NUTR RES JI Nutr. Res. PD OCT PY 2009 VL 29 IS 10 BP 716 EP 722 DI 10.1016/j.nutres.2009.10.001 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 528GW UT WOS:000272432000005 PM 19917451 ER PT J AU Dinsmoor, MJ Gilbert, S Landon, MB Rouse, DJ Spong, CY Varner, MW Caritis, SN Wapner, RJ Sorokin, Y Midovnik, M O'Sullivan, MJ Sibai, BM Langer, O AF Dinsmoor, Mara J. Gilbert, Sharon Landon, Mark B. Rouse, Dwight J. Spong, Catherine Y. Varner, Michael W. Caritis, Steve N. Wapner, Ronald J. Sorokin, Yoram Midovnik, Menachem O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded CA Eunice Kennedy Shriver Natl Inst C TI Perioperative Antibiotic Prophylaxis for Nonlaboring Cesarean Delivery SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 14-17, 2007 CL Reno, NV SP Soc Gynecol Invest ID INTACT MEMBRANES; INFECTION; SECTION AB OBJECTIVE: To estimate the efficacy of antibiotic prophylaxis at the time of nonlaboring cesarean delivery in reducing postpartum infection-related complications. METHODS: We performed a secondary analysis of an observational study of cesarean deliveries performed at 13 centers from 1999-2000. Patients were included if they had cesarean delivery before labor, did not have intrapartum infection, and were not given antibiotics at delivery for reasons other than prophylaxis. The occurrence of postpartum endometritis, wound infection, and other, less common infection-related complications was compared between those who did and did not receive antibiotic prophylaxis. Results were adjusted for smoking, payer status, gestational age and body mass index at delivery, race, diabetes, antepartum infections, presence of anemia, operative time, type of cesarean delivery (primary or repeat), and center. RESULTS: Of the 9,432 women who met study criteria, the 6,006 (64%) who received antibiotic prophylaxis were younger, heavier at delivery, and were more likely to be African American, receive public insurance, and have diabetes. Patients who received antibiotic prophylaxis were less likely to develop postpartum endometritis (121 [2.0%] compared with 88 [2.6%], adjusted odds ratio [OR] 0.40, 95% confidence interval [CI] 0.28-0.59) or wound infection (31 [0.52%] compared with 33 [0.96%], adjusted OR 0.49, 95% CI 0.28-0.86). CONCLUSION: Antibiotic prophylaxis at the time of nonlaboring cesarean delivery significantly reduces the risks of postpartum endometritis and wound infection. (Obstet Gynecol 2009;114:752-6) C1 Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Alabama, Birmingham, AL USA. Univ Utah, Salt Lake City, UT USA. Univ Pittsburgh, Pittsburgh, PA USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Wayne State Univ, Detroit, MI USA. Univ Cincinnati, Cincinnati, OH USA. Univ Miami, Miami, FL USA. Univ Tennessee, Memphis, TN USA. Univ Texas San Antonio, San Antonio, TX USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Dinsmoor, MJ (reprint author), Northwestern Univ, Dept Obstet & Gynecol, Feinberg Sch Med, NorthShore Univ HealthSyst, 2650 Ridge Ave,Walgreen Bldg,Suite 1507, Evanston, IL 60201 USA. EM mdinsmoor@northshore.org RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973 FU NICHD NIH HHS [U10 HD021410, HD21410, HD21414, HD27860, HD27861, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD34210, HD36801, U01 HD036801, U01 HD036801-02, U10 HD021410-14, U10 HD021414-14, U10 HD027860, U10 HD027860-12, U10 HD027861-09, U10 HD027869, U10 HD027869-11, U10 HD027905, U10 HD027905-09, U10 HD027915, U10 HD027915-08, U10 HD027917, U10 HD027917-09, U10 HD034116, U10 HD034116-04, U10 HD034122, U10 HD034122-04, U10 HD034136, U10 HD034136-04, U10 HD034208, U10 HD034208-04, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040512-01, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208] NR 11 TC 21 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2009 VL 114 IS 4 BP 752 EP 756 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 503WY UT WOS:000270573800007 PM 19888031 ER PT J AU Hasan, R Baird, DD Herring, AH Olshan, AF Funk, MLJ Hartmann, KE AF Hasan, Reem Baird, Donna D. Herring, Amy H. Olshan, Andrew F. Funk, Michele L. Jonsson Hartmann, Katherine E. TI Association Between First-Trimester Vaginal Bleeding and Miscarriage SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID THREATENED-ABORTION; EARLY-PREGNANCY; PREDICTION; ULTRASOUND; OUTCOMES; BIRTH AB OBJECTIVE: To estimate the strength of association between first-trimester bleeding and miscarriage, setting aside bleeding at time of loss. METHODS: Women enrolled in a community-based pregnancy cohort study before or during early pregnancy. Detailed first-trimester bleeding data were collected by telephone interview. Bleeding episodes proximal to miscarriage (within 4 days) were excluded. We used discrete-time hazard models to evaluate the association between bleeding and miscarriage. Models were adjusted for maternal age, prior miscarriage, and smoking. Exploratory regression tree analysis was used to evaluate the relative importance of other bleeding characteristics (duration, associated pain, color, timing). RESULTS: Of the 4,510 participants, 1,204 (27%) reported some first-trimester vaginal bleeding or spotting, and 517 miscarriages were observed. Eight percent of those with bleeding reported heavy bleeding episodes. When we evaluated any bleeding, including episodes of only spotting, the unadjusted relative odds ratio (OR) of miscarriage for women with bleeding (n=1,204) was 1.1 (95% confidence interval [CI] 0.9-1.3). However, women who reported heavy bleeding (n=97) had nearly three times the risk of miscarriage compared with women without bleeding during the first trimester (OR 3.0, 95% Cl 1.9-4.6). Adjustment for covariates had little effect on estimates. Further analyses suggested that women with heavy bleeding accompanied by pain were the group accounting for most of the elevated risk. CONCLUSION: Heavy bleeding in the first trimester, particularly when accompanied by pain, is associated with higher risk of miscarriage. Spotting and light episodes are not, especially if lasting only 1-2 days. (Obstet Gynecol 2009;114:860-7) C1 [Hasan, Reem] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. Vanderbilt Univ, Med Ctr, Inst Med & Publ Hlth, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN USA. RP Hasan, R (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, MD A3-05, Res Triangle Pk, NC 27709 USA. EM reem_hasan@med.unc.edu RI Jonsson Funk, Michele/F-6885-2011; Baird, Donna/D-5214-2017 OI Jonsson Funk, Michele/0000-0002-3756-7540; Baird, Donna/0000-0002-5544-2653 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [5R01HD043883, 5R01HD049675]; American Water Works Association Research Foundation [2579]; National Institute of Environmental Health Sciences [P30ES10126] FX The field research was supported in part by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD043883 and 5R01HD049675) and the American Water Works Association Research Foundation (2579). Additional funds were provided by the National Institute of Environmental Health Sciences (Intramural Research Program and P30ES10126). NR 21 TC 27 Z9 27 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2009 VL 114 IS 4 BP 860 EP 867 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 503WY UT WOS:000270573800022 PM 19888046 ER PT J AU Minig, L Trimble, EL Sarsotti, C Sebastiani, MM Spong, CY AF Minig, Lucas Trimble, Edward L. Sarsotti, Carlos Sebastiani, Mario M. Spong, Catherine Y. TI Building the Evidence Base for Postoperative and Postpartum Advice SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ACTIVITY RESTRICTIONS; PHYSICAL-ACTIVITY; WEIGHT RETENTION; WOUND DEHISCENCE; HERNIA REPAIR; WORK; HYSTERECTOMY; SURGERY; RETURN; QUESTIONNAIRE AB Recommendations for activity after obstetric and gynecologic procedures remain based on tradition and anecdote. After reviewing the current evidence base, guidelines, and practice for postdischarge instructions related to physical activity after the most common obstetric and gynecologic surgical procedures, we conclude that the available data do not support many of the recommendations currently provided. Restrictions on lifting and climbing stairs should likely be abandoned. Guidance on driving should focus on the concern regarding cognitive function and analgesics rather than concerns of wound separation/dehiscence. Given the impact of these recommendations on daily life events, consistent, evidence-based advice on when and how women can safely resume exercise, driving, working, and sexual intercourse is critical. The evidence base informing advice for most of these issues is minimal; we need prospective, well-designed studies to help guide us and our patients. (Obstet Gynecol 2009;114:892-900) C1 [Minig, Lucas] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Grp Estudio Disfunc & Rehabil Piso Pelvico, Buenos Aires, DF, Argentina. Hosp Italiano Buenos Aires, Dept Obstet, Buenos Aires, DF, Argentina. NICHHD, Pregnancy & Perinatol Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Minig, L (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bldg 10 B3B406, Bethesda, MD 20892 USA. EM lucasminig@yahoo.com NR 66 TC 12 Z9 12 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2009 VL 114 IS 4 BP 892 EP 900 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 503WY UT WOS:000270573800026 PM 19888050 ER PT J AU Reddy, UM Goldenberg, R Silver, R Smith, GCS Pauli, RM Wapner, RJ Gardosi, J Pinar, H Grafe, M Kupferminc, M Varli, IH Erwich, JJHM Fretts, RC Willinger, M AF Reddy, Uma M. Goldenberg, Robert Silver, Robert Smith, Gordon C. S. Pauli, Richard M. Wapner, Ronald J. Gardosi, Jason Pinar, Halit Grafe, Marjorie Kupferminc, Michael Varli, Ingela Hulthen Erwich, Jan Jaap H. M. Fretts, Ruth C. Willinger, Marian TI Stillbirth Classification-Developing an International Consensus for Research Executive Summary of a National Institute of Child Health and Human Development Workshop SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID UMBILICAL-CORD LENGTH; FETAL-DEATH; FETOMATERNAL HEMORRHAGE; REPRODUCTIVE-PERFORMANCE; CLINICAL-SIGNIFICANCE; PERINATAL-MORTALITY; SERVICE PROGRAM; GESTATIONAL-AGE; BIRTH-WEIGHT; PREGNANCY AB Stillbirth is a major obstetric complication, with 3.2 million stillbirths worldwide and 26,000 stillbirths in the United States every year. The Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop from October 22-24, 2007, to review the pathophysiology of conditions underlying stillbirth to define causes of death. The optimal classification system would identify the pathophysiologic entity initiating the chain of events that irreversibly led to death. Because the integrity of the classification is based on available pathologic, clinical, and diagnostic data, experts emphasized that a complete stillbirth workup should be performed. Experts developed evidence-based characteristics of maternal, fetal, and placental conditions to attribute a condition as a cause of stillbirth. These conditions include infection, maternal medical conditions, antiphospholipid syndrome, heritable thrombophilias, red cell alloimmunization, platelet alloimmunization, congenital malformations, chromosomal abnormalities including confined placental mosaicism, fetomaternal hemorrhage, placental and umbilical cord abnormalities including vasa previa and placental abruption, complications of multifetal gestation, and uterine complications. In all cases, owing to lack of sufficient knowledge about disease states and normal development, there will be a degree of uncertainty regarding whether a specific condition was indeed the cause of death. (Obstet Gynecol 2009,114:901-14) C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. Drexel Univ, Philadelphia, PA 19104 USA. Univ Utah, Salt Lake City, UT USA. Univ Cambridge, Cambridge, England. Univ Wisconsin, Madison, WI USA. Columbia Univ, New York, NY USA. W Midlands Perinatal Inst, Birmingham, W Midlands, England. Brown Univ, Providence, RI 02912 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Karolinska Univ Hosp, Stockholm, Sweden. Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. Harvard Vanguard Med Assoc, Boston, MA USA. RP Reddy, UM (reprint author), 6700 Execut Blvd,Rm 4B03F, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov RI Smith, Gordon/A-8070-2008 OI Smith, Gordon/0000-0003-2124-0997 FU Intramural NIH HHS [Z99 HD999999] NR 72 TC 56 Z9 57 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2009 VL 114 IS 4 BP 901 EP 914 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 503WY UT WOS:000270573800027 PM 19888051 ER PT J AU Pronk, A Coble, J Ji, BT Shu, XO Rothman, N Yang, G Gao, YT Zheng, W Chow, WH AF Pronk, A. Coble, J. Ji, B-T Shu, X-O Rothman, N. Yang, G. Gao, Y-T Zheng, W. Chow, W-H TI Occupational risk of lung cancer among lifetime non-smoking women in Shanghai, China SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID GERMANY; EPIDEMIOLOGY; MEN AB Objectives: Occupational lung carcinogens have been primarily studied in men. The aim of this study was to investigate occupational lung cancer risk in a cohort of Chinese non-smoking women. Methods: In 1996-2000, 71 067 non-smoking women who had held a job outside the home were interviewed for the prospective Shanghai Women's Health Study in China. Exposure to lung carcinogens was assessed by matching occupation and industry titles from lifetime occupational histories with lists of jobs identified by the International Agency for Research on Cancer to have potential exposure to: (1) known (A-list); or (2) suspected (B-list) carcinogens. In addition, similar occupational titles were grouped independent of the a priori defined lists. Relative risks (RRs) were calculated using Cox proportional hazards regression. Results: During follow-up through 2005, 219 incident lung cancer cases were diagnosed. Jobs on the A-list and B-list were held by 0.8-6.7% and 2.7-9.4% of the cohort, respectively. Overall, ever holding any job on the A-list or B-list was not associated with lung cancer incidence. Indications of excess risk were found for two subgroups: painters (A-list) and rubber workers (B-list) (RR = 2.0 and 1.7, respectively, p <= 0.1). An exploratory analysis of 35 occupational categories independent of the lists showed significantly increased risks for leather products/shoes, wood/paper products and miscellaneous production/transportation. The former two of these categories were similar to subgroups of the B-list, but broader than the specific a priori defined jobs. Conclusions: Significantly elevated lung cancer risk was associated with employment in some broad occupational categories that also included jobs with potential exposure to suspected carcinogens (B-list). The results suggest that although similar exposures to those described on the B-list may play a role in this cohort of Chinese women, carcinogenic exposure may not be restricted only to the jobs on the B-list. C1 [Pronk, A.; Coble, J.; Ji, B-T; Rothman, N.; Chow, W-H] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Shu, X-O; Yang, G.; Zheng, W.] Vanderbilt Univ, Sch Med, Dept Med,Vanderbilt Ingram Canc Ctr, Div Epidemiol,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Gao, Y-T] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. RP Pronk, A (reprint author), 6120 Execut Blvd,EPS 8111,MSC 7240, Bethesda, MD 20892 USA. EM pronka@mail.nih.gov FU National Institute of Health (NIH) [R01 CA70867]; Intramural Research Program [N02 CP1101066] FX This research was supported by National Institute of Health (NIH) research grant R01 CA70867 and by the Intramural Research Program contract N02 CP1101066. NR 21 TC 15 Z9 15 U1 1 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD OCT PY 2009 VL 66 IS 10 BP 672 EP 678 DI 10.1136/oem.2008.043695 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 497BB UT WOS:000270027400007 PM 19625285 ER PT J AU Chong, DY Johnson, MW Shen, D Chan, CC Callanan, DG AF Chong, Deborah Y. Johnson, Mark W. Shen, Defen Chan, Chi-Chao Callanan, David G. TI Vitreous Metastases of Primary Cutaneous B-Cell Lymphoma SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE primary cutaneous B-cell lymphoma; metastases; vitritis AB Purpose: To describe two cases of vitreous metastases of primary cutaneous B-cell lymphoma (PCBCL). Methods: Observational case series. Results: A 73-year-old man and an 81-year-old woman, both with a history of PCBCL, diffuse large cell type, presented with decreased visual acuity due to vitritis. Both patients underwent vitreous biopsy that demonstrated B-cell lymphoma, large cell type, and confirmed metastases of cutaneous B-cell lymphoma to the vitreous. Conclusion: PCBCL, diffuse large cell type, is a rare form of non-Hodgkin lymphoma that can metastasize to the vitreous without visible chorioretinal involvement. C1 [Chong, Deborah Y.; Callanan, David G.] Texas Retina Associates, Arlington, TX USA. [Johnson, Mark W.] Univ Michigan, WK Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Shen, Defen; Chan, Chi-Chao] NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Callanan, DG (reprint author), Vandergriff Profess Bldg,1001 N Waldrop Dr,Suite, Arlington, TX 76012 USA. EM dcallanan@texasretina.com FU Intramural NIH HHS [Z01 EY000222-23] NR 5 TC 3 Z9 3 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD OCT PY 2009 VL 17 IS 5 BP 342 EP 344 DI 10.3109/09273940903144705 PG 3 WC Ophthalmology SC Ophthalmology GA 520HF UT WOS:000271832700012 PM 19831568 ER PT J AU Switzer, CH Ridnour, LA Cheng, RYS Sparatore, A Del Soldato, P Moody, TW Vitek, MP Roberts, DD Wink, DA AF Switzer, C. H. Ridnour, L. A. Cheng, R. Y. S. Sparatore, A. Del Soldato, P. Moody, T. W. Vitek, M. P. Roberts, D. D. Wink, D. A. TI Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity SO ONCOGENE LA English DT Article DE dithiolethione; PP2A; Akt; cancer; breast; lung ID PROTEIN PHOSPHATASE 2A; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TUMOR-SUPPRESSOR; HEME OXYGENASE-1; KINASE-B; TYROSINE PHOSPHORYLATION; REGULATORY SUBUNITS; 3T3-L1 ADIPOCYTES; C-MYC; PATHWAY AB The chemopreventative effects of dithiolethione compounds are attributed to their activation of antioxidant response elements (AREs) by reacting with the Nrf2/Keap1 protein complex. In this study, we show anti-proliferative effects of the dithiolethione compound ACS1 in human cancer cell lines (A549 and MDA-MB-231) by increasing the activity of the tumor suppressor protein phoshatase 2A (PP2A). ACS-1 inhibited epidermal growth factor (EGF)-induced cellular proliferation in a concentration-and time-dependent manner. Akt activation, as determined by serine-473 phosphorylation, was inhibited by ACS-1 in cells stimulated with either EGF or fibronectin. Furthermore, ACS-1 inhibited mammalian target of rapamycin signaling and decreased c-myc protein levels. ACS-1 did not proximally alter EGF receptor or integrin signaling, but caused a concentration-dependent increase in PP2A activity. The effect of ACS-1 on Akt activation was not observed in the presence of the PP2A inhibitor okadaic acid. ACS-1 effects on PP2A activity were independent of ARE activation and cAMP formation. In addition to ACS-1, other dithiolethione compounds showed similar effects in reducing Akt activation, suggesting that this class of compounds may have other effects beyond chemoprevention. Oncogene (2009) 28, 3837-3846; doi:10.1038/onc.2009.244; published online 24 August 2009 C1 [Switzer, C. H.; Ridnour, L. A.; Cheng, R. Y. S.; Wink, D. A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Sparatore, A.] Univ Milan, Dipartimento Sci Farmaceut Pietro Pratesi, Milan, Italy. [Del Soldato, P.] Sulfidris, Milan, Italy. [Vitek, M. P.] Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. [Roberts, D. D.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov RI Roberts, David/A-9699-2008; Switzer, Christopher/D-9203-2013; Sparatore, Anna/J-8634-2015; OI Roberts, David/0000-0002-2481-2981; Sparatore, Anna/0000-0003-2135-2649; Cheng, Robert/0000-0003-0287-6439 FU Intramural NIH HHS [Z01 BC010899-01] NR 49 TC 26 Z9 26 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT PY 2009 VL 28 IS 43 BP 3837 EP 3846 DI 10.1038/onc.2009.244 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 512KT UT WOS:000271248400007 PM 19701246 ER PT J AU Shamir, L Ling, SM Scott, W Hochberg, M Ferrucci, L Goldberg, IG AF Shamir, L. Ling, S. M. Scott, W. Hochberg, M. Ferrucci, L. Goldberg, I. G. TI Early detection of radiographic knee osteoarthritis using computer-aided analysis SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Image analysis; Osteoarthritis detection; Early detection ID ARTICULAR-CARTILAGE; IMAGE-ANALYSIS; JOINT SPACE; BONE; SELECTION; SEVERITY; TEXTURE; HIP AB Objective: To determine whether computer-based analysis can detect features predictive of osteoarthritis (OA) development in radiographically normal knees. Method: A systematic computer-aided image analysis method weighted neighbor distances using a compound hierarchy of algorithms representing morphology (WND-CHARM) was used to analyze pairs of weight-bearing knee X-rays. Initial X-rays were all scored as normal Kellgren-Lawrence (KL) grade 0, and on follow-up approximately 20 years later either developed OA (defined as KL grade = 2) or remained normal. Results: The computer-aided method predicted whether a knee would change from KL grade 0 to grade 3 with 72% accuracy (P < 0.00001), and to grade 2 with 62% accuracy (P < 0.01). Although a large part of the predictive signal comes from the image tiles that contained the joint, the region adjacent to the tibial spines provided the strongest predictive signal. Conclusion: Radiographic features detectable using a computer-aided image analysis method can predict the future development of radiographic knee OA. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. C1 [Shamir, L.; Goldberg, I. G.] NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Ling, S. M.; Ferrucci, L.] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Scott, W.] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD 21287 USA. [Hochberg, M.] Univ Maryland, Med Ctr, Dept Med, Baltimore, MD 21201 USA. RP Shamir, L (reprint author), NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM shamirl@mail.nih.gov RI Goldberg, Ilya/H-5307-2011 OI Goldberg, Ilya/0000-0001-8514-6110 FU NIH; National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 33 TC 24 Z9 25 U1 1 U2 5 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2009 VL 17 IS 10 BP 1307 EP 1312 DI 10.1016/j.joca.2009.04.010 PG 6 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 513OR UT WOS:000271332900009 PM 19426848 ER PT J AU Merchant, MS AF Merchant, Melinda S. TI Long-Term Impact of Cancer Care on Activities of Daily Living: Are We Causing Our Sarcoma Survivors to Grow Up Too Quickly? SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID PEDIATRIC SARCOMA; CHILDHOOD-CANCER; HEALTH; LIFE C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Merchant, MS (reprint author), NCI, Pediat Oncol Branch, NIH, 10 Ctr Dr Bldg 10 CRC,Room 1W-3952, Bethesda, MD 20892 USA. EM merchanm@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2009 VL 53 IS 4 BP 531 EP 532 DI 10.1002/pbc.22166 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 487SJ UT WOS:000269295500004 PM 19588522 ER PT J AU Gorlick, R Kolb, EA Houghton, PJ Morton, CL Phelps, D Schaiquevich, P Stewart, C Keir, ST Lock, R Carol, H Reynolds, CP Maris, JM Wu, JR Smith, MA AF Gorlick, Richard Kolb, E. Anders Houghton, Peter J. Morton, Christopher L. Phelps, Doris Schaiquevich, Paula Stewart, Clinton Keir, Stephen T. Lock, Richard Carol, Hernan Reynolds, C. Patrick Maris, John M. Wu, Jianrong Smith, Malcolm A. TI Initial Testing (Stage 1) of Lapatinib by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; lapatinib; preclinical testing ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; CELL-LINES; IN-VIVO; CANCER MODELS; EXPRESSION; CHILDHOOD; OSTEOSARCOMA; GW572016; ERBB2 AB Background. Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer. Methods. Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 mu M. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/ day). Lapatinib pharmacokinetic parameters were determined in scid(-/-) mice. Results. The median IC(50) value for lapatinib against the entire PPTP cell line panel was 6.84 mu M (range, 2.08 to >10.0 mu M). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values. Conclusions. Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets. Pediatr Blood Cancer 2009;53: 594-598. (C) 2009 Wiley-Liss, Inc. C1 [Gorlick, Richard] Yeshiva Univ, Albert Einstein Coll Med, Childrens Hosp Montefiore, Bronx, NY 10467 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Houghton, Peter J.; Morton, Christopher L.; Phelps, Doris; Schaiquevich, Paula; Stewart, Clinton; Wu, Jianrong] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Gorlick, R (reprint author), Yeshiva Univ, Albert Einstein Coll Med, Childrens Hosp Montefiore, 3415 Bainbridge Ave,Rosenthal Rm 300, Bronx, NY 10467 USA. EM rgorlick@montefiore.org RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NOI-CM-42216, CA21765, CA 108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NOI-CM-42216, CA21765, CA 108786. NR 24 TC 21 Z9 21 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2009 VL 53 IS 4 BP 594 EP 598 DI 10.1002/pbc.21989 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 487SJ UT WOS:000269295500015 PM 19554571 ER PT J AU Parks, R Rasch, EK Mansky, PJ Oakley, F AF Parks, Rebecca Rasch, Elizabeth K. Mansky, Patrick J. Oakley, Frances TI Differences in Activities of Daily Living Performance Between Long-Term Pediatric Sarcoma Survivors and a Matched Comparison Group on Standardized Testing SO PEDIATRIC BLOOD & CANCER LA English DT Article DE ADL; late effects; pediatric sarcoma; pediatric sarcoma survivors ID QUALITY-OF-LIFE; CHILDHOOD-CANCER; ADULT SURVIVORS; PROCESS SKILLS; FOLLOW-UP; THERAPY; CARE; OUTCOMES; EDUCATION; CHILDREN AB Background. in a cross-sectional study examining late effects of pediatric sarcoma therapy, long-term Survivors were evaluated on their activities of daily living (ADL) performance. Procedure. Thirty-two persons with Ewing sarcoma family of tumors, rhabdomyosarcoma, and non-rhabdomysarcoma-soft tissue sarcoma enrolled an average of 17 years after treatment. Participants were evaluated using the Assessment of Motor and Process Skills (AMPS) [1], a standardized observational evaluation of ADL task performance. Means and 95% confidence intervals for ADL motor and ADL process ability measures were calculated for four groups: (1) sarcoma survivors, (2) "well" adults matched for age and gender, (3) "well" adults matched for gender that were 10 years older, and (4) "well" adults matched for gender that were 20 years older. Results. ADL motor ability was significantly lower for sarcoma survivors than for the age-and gender-matched comparison group (P<0.05). There was no significant difference between ADL motor ability of sarcoma survivors and the comparison group 10 years older, but sarcoma survivors had significantly better ADL motor ability (P<0.05) than the oldest comparison group (20 years older). Sarcoma survivors had significantly worse ADL process ability than the age-matched group (P< 0.05). There was no difference in ADL process ability between the sarcoma survivors and comparison groups that were 10 and 20 years older. Conclusions. This first report of a clinical evaluation of ADL limitation in pediatric sarcoma survivors treated with intensive multimodal cancer therapy suggests that influences on performance of daily life activities are more common than previously reported. Pediatr Blood Cancer 2009;53: 622-628. Published 2009 Wiley-Liss, Inc. C1 [Parks, Rebecca; Rasch, Elizabeth K.; Oakley, Frances] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Mansky, Patrick J.] NIH, Div Intramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Parks, R (reprint author), Bldg 10-CRC,Room I-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM rparks@nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute FX Grant sponsor: Intramural Research Program of the National Institutes of Health; Grant sponsor: National Cancer Institute. NR 60 TC 6 Z9 6 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2009 VL 53 IS 4 BP 622 EP 628 DI 10.1002/pbc.22101 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 487SJ UT WOS:000269295500020 PM 19533662 ER PT J AU Uzzaman, A Maric, I Noel, P Kettelhut, BV Metcalfe, DD Carter, MC AF Uzzaman, Ashraf Maric, Irina Noel, Pierre Kettelhut, Brett V. Metcalfe, Dean D. Carter, Melody C. TI Pediatric-Onset Mastocytosis: A Long Term Clinical Follow-Up and Correlation With Bone Marrow Histopathology SO PEDIATRIC BLOOD & CANCER LA English DT Article DE bone marrow; cutaneous mastocytosis; KIT; pediatric mastocytosis; serum tryptase; urticaria pigmentosa ID CUTANEOUS MASTOCYTOSIS; SYSTEMIC MASTOCYTOSIS; URTICARIA-PIGMENTOSA; CATALYTIC DOMAIN; TRYPTASE LEVELS; C-KIT; ANAPHYLAXIS; MUTATION; DISEASE; BLOOD AB Background. Pediatric onset mastocytosis Usually presents as Urticaria pigmentosa; and less often as diffuse cutaneous mastocytosis. While the literature indicates that disease often resolves, there has been a move to more aggressive therapy for mastocytosis early in life. We addressed the long term prognosis of pediatric-onset disease by examining 17 children with mastocytosis which we had reported oil in 1989 [1]. Procedure. We successfully contacted 15 of these patients and data was collected regarding their clinical status. Original bone marrow specimens were re-stained, reexamined, and correlated with disease Outcome using consensus criteria. Three of five patients with persistent disease underwent repeat bone marrow biopsies. Results. There was complete regression of disease as defined by cutaneous findings and symptoms (clinical disease severity) in 10 of 15 patients (67%). Three patients had major (20%) and two had partial regression of disease (13%). Repeat marrow examinations on three patients with persistent disease documented systemic mastocytosis based on marrow findings in one patient who had partial regression of disease and was the only patient with initial morphologic evidence of systemic disease. Of the remaining two patients, one demonstrated partial regression and the other major regression of disease; and neither had evidence of systemic mastocytosis. Conclusion. This study demonstrates that initial bone marrow biopsies were prognostic in that those without evidence of systemic disease experienced disease regression; and that the long term prognosis for children managed symptomatically with mastocytosis is highly encouraging. Pediatr Blood Cancer 2009;53: 629-634. (C) 2009 Wiley-Liss, Inc. C1 [Uzzaman, Ashraf; Metcalfe, Dean D.; Carter, Melody C.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Maric, Irina; Noel, Pierre] NIH, Hematol Sect, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Kettelhut, Brett V.] Univ Nebraska Med Ctr, Dept Pediat, Omaha, NE USA. RP Carter, MC (reprint author), Bldg 10,Room 1 1C213,10 Ctr Dr MSC1881, Bethesda, MD 20892 USA. EM mcarter@niaid.nih.gov FU NIH FX Grant sponsor: NIH. NR 20 TC 35 Z9 35 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2009 VL 53 IS 4 BP 629 EP 634 DI 10.1002/pbc.22125 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 487SJ UT WOS:000269295500021 PM 19526526 ER PT J AU Wolters, PL Gropman, AL Martin, SC Smith, MR Hildenbrand, HL Brewer, CC Smith, ACM AF Wolters, Pamela L. Gropman, Andrea L. Martin, Staci C. Smith, Michaele R. Hildenbrand, Hanna L. Brewer, Carmen C. Smith, Ann C. M. TI Neurodevelopment of Children Under 3 Years of Age With Smith-Magenis Syndrome SO PEDIATRIC NEUROLOGY LA English DT Article ID SYNDROME DEL 17P11.2; BEHAVIORAL-PHENOTYPE; DOWN-SYNDROME; MALADAPTIVE BEHAVIOR; LANGUAGE-DEVELOPMENT; CIRCADIAN-RHYTHM; YOUNG-CHILDREN; ORAL-MOTOR; DELETION; DISORDERS AB Systematic data regarding early neurodevelopmental functioning in Smith-Magenis syndrome are limited. Eleven children with Smith-Magenis syndrome less than 3 years of age (mean, 19 months; range, 5-34 months) received prospective multidisciplinary assessments using standardized measures. The total sample scored in the moderately to severely delayed range in cognitive functioning, expressive language, and motor skills and exhibited generalized hypotonia, oral-motor abnormalities, and middle ear dysfunction. Socialization skills were average, and significantly higher than daily living, communication, and motor abilities, which were below average. Mean behavior ratings were in the nonautistic range. According to exploratory analyses, the toddler subgroup scored significantly lower than the infant subgroup in cognition, expressive language, and adaptive behavior, suggesting that the toddlers were more delayed than the infants relative to their respective peers. Infants aged approximately 1 year or younger exhibited cognitive, language, and motor skills that ranged from average to delayed, but with age-appropriate social skills and minimal maladaptive behaviors. At ages 2 to 3 years, the toddlers consistently exhibited cognitive, expressive language, adaptive behavior, and motor delays and mildly to moderately autistic behaviors. Combining age groups in studies may mask developmental and behavioral differences. Increased knowledge of these early neurodevelopmental characteristics should facilitate diagnosis and appropriate intervention. (C) 2009 Published by Elsevier Inc. C1 [Wolters, Pamela L.; Martin, Staci C.] Med Illness Counseling Ctr, Chevy Chase, MD USA. [Gropman, Andrea L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Smith, Ann C. M.] Kelly Govt Solut, Rockville, MD USA. [Wolters, Pamela L.; Martin, Staci C.] NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Smith, Michaele R.; Hildenbrand, Hanna L.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Brewer, Carmen C.] Natl Inst Deafness & Other Commun Disorders, NIH, Otolaryngol Branch, Bethesda, MD USA. [Gropman, Andrea L.; Smith, Ann C. M.] NHGRI, NIH, Off Clin Director, Bethesda, MD 20892 USA. RP Wolters, PL (reprint author), 9030 Old Georgetown Rd,Bldg 82,Room 109, Bethesda, MD 20892 USA. EM woltersp@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Human Genome Research Institute (NIH-NHGRI); National Cancer Institute; NHGRI; NCI [71004-09, N01-SC-07006, HHSN261200477004C]; National Institute oil Deafness and Other Communication Disorders (NIH-NIDCD) [Z01-DC-000064-05] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). National Human Genome Research Institute (NIH-NHGRI). and the National Cancer Institute (NIH-NCI) Center for Cancer Research, through a Bench-to-Bedside award from the NIH Clinical Center to the Medical Genetics Branch of the NHGRI, and by NCI contracts 71004-09. N01-SC-07006, and HHSN261200477004C with the Medical Illness Counseling Center (MICC). Additional support was obtained through the intramural research fund Z01-DC-000064-05 of the National Institute oil Deafness and Other Communication Disorders (NIH-NIDCD). The authors express their sincere appreciation to the families who participated in this research, and also extend their gratitude to the other members of the Smith-Magenis syndrome research team. especially Donna M. Krasnewich. MD, Suzan Parada, RN, Mary Anne-Toledo-Tamula. NIA. Joanne E. Flanagan, MS. OT, and Rebecca Morse. MA. NR 50 TC 13 Z9 13 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD OCT PY 2009 VL 41 IS 4 BP 250 EP 258 DI 10.1016/j.pediatrneuro1.2009.04.015 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 501IY UT WOS:000270376400003 PM 19748044 ER PT J AU McGowan, EC Kostadinov, S McLean, K Gotsch, F Venturini, D Romero, R Laptook, AR Sharma, S AF McGowan, Elisabeth C. Kostadinov, Stefan McLean, Kathryn Gotsch, Francesca Venturini, Deborah Romero, Roberto Laptook, Abbot R. Sharma, Surendra TI Placental IL-10 Dysregulation and Association With Bronchopulmonary Dysplasia Risk SO PEDIATRIC RESEARCH LA English DT Article ID LOW-BIRTH-WEIGHT; NECROSIS-FACTOR-ALPHA; CHRONIC LUNG-DISEASE; HYALINE-MEMBRANE DISEASE; INSTITUTES-OF-HEALTH; PRETERM INFANTS; AMNIOTIC-FLUID; CYTOKINE EXPRESSION; PREMATURE-INFANTS; GENE PROMOTER AB Cytokine profiles in amniotic fluid, cord serum, and tracheal aspirate of premature infants suggest a shift toward a proinflammatory state. Cytokines also contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesize that the initiating events for BPD are reflected in the placenta and propose that placental expression of cytokines provide a blueprint of events leading to BPD. This is I retrospective, case-controlled study of, placental cytokines of premature infants with (n = 49) and without (n = 49) BPD, matched for gender, birth weight, and year of birth at Women and Infants Hospital between 2003 and 2005. Cytokine expression, including IL-6 and IL-10, was determined by immunohistochemistry in membrane rolls, umbilical cords, and placentas. IL-6 was similarly expressed in all tissues of infants with and without BPD. In contrast, anti-inflammatory cytokine IL-10 was less prominent in the placenta of patients with BPD compared with those without BPD. IL-10 expression in the villous trophoblast layer was associated with a reduced odds ratio of developing BPD (adjusted OR 0.08, 95% CI 0.01-0.70, p = 0.02). These results suggest that a placental balance between inflammatory and anti-inflammatory cytokines is crucial to normal lung organogenesis. Importantly, IL-10 seems to be protective against the development of BPD. (Pediatr Res 66: 455-460, 2009) C1 [McGowan, Elisabeth C.; McLean, Kathryn; Venturini, Deborah; Laptook, Abbot R.; Sharma, Surendra] Brown Univ, Warren Alpert Med Sch, Women & Infants Hosp, Dept Pediat, Providence, RI 02915 USA. [Kostadinov, Stefan] Brown Univ, Warren Alpert Med Sch, Women & Infants Hosp, Dept Pathol, Providence, RI 02915 USA. [Gotsch, Francesca; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48210 USA. RP Sharma, S (reprint author), Women & Infants Hosp Rhode Isl, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. EM ssharma@wihri.org FU NIH NCRR [P20RR018728]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS [WSU05056]; NICHD [N01-HD-2-3342] FX Supported in part by the grant front NIH NCRR (P20RR018728), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, and a subcontract WSU05056 under NICHD contract N01-HD-2-3342. NR 37 TC 14 Z9 14 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2009 VL 66 IS 4 BP 455 EP 460 PG 6 WC Pediatrics SC Pediatrics GA 500FZ UT WOS:000270285400018 PM 19581835 ER PT J AU Bocchini, JA Bernstein, HH Bradley, JS Brady, MT Byington, CL Fisher, MC Glode, MP Jackson, MA Keyserling, HL Kimberlin, DW Orenstein, WA Schutze, GE Willoughby, RE Dennehy, PH Frenck, RW Rubin, LG Bell, B Bortolussi, R Clover, RD Fischer, MA Gellin, B Gorman, RL Pratt, RD Lee, L Read, JS Starke, JR Swanson, J Baker, CJ Long, SS Pickering, LK Ledbetter, EO Meissner, HC O'Dell, JD Weinberg, ST Frantz, J AF Bocchini, Joseph A., Jr. Bernstein, Henry H. Bradley, John S. Brady, Michael T. Byington, Carrie L. Fisher, Margaret C. Glode, Mary P. Jackson, Mary Anne Keyserling, Harry L. Kimberlin, David W. Orenstein, Walter A. Schutze, Gordon E. Willoughby, Rodney E. Dennehy, Penelope H. Frenck, Robert W., Jr. Rubin, Lorry G. Bell, Beth Bortolussi, Robert Clover, Richard D. Fischer, Marc A. Gellin, Bruce Gorman, Richard L. Pratt, R. Douglas Lee, Lucia Read, Jennifer S. Starke, Jeffrey R. Swanson, Jack Baker, Carol J. Long, Sarah S. Pickering, Larry K. Ledbetter, Edgar O. Meissner, H. Cody O'Dell, J. Dennis Weinberg, Stuart T. Frantz, Jennifer CA Comm Infect Dis TI Policy Statement-Recommendations for the Prevention and Treatment of Influenza in Children, 2009-2010 SO PEDIATRICS LA English DT Article DE influenza; novel influenza A (H1N1) virus; immunization; live-attenuated influenza vaccine; trivalent inactivated influenza vaccine; vaccine; children; pediatrics ID INFECTIOUS-DISEASES AB The purpose of this statement is to update current recommendations for routine use of trivalent seasonal influenza vaccine and antiviral medications for the prevention and treatment of influenza in children. Pediatrics 2009; 124: 1216-1226 C1 [Bell, Beth; Fischer, Marc A.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Bortolussi, Robert] Canadian Paediat Soc, Ottawa, ON, Canada. [Clover, Richard D.] Amer Acad Family Phys, Leawood, KS USA. [Gorman, Richard L.; Read, Jennifer S.] NIH, Bethesda, MD USA. [Pratt, R. Douglas; Lee, Lucia] US FDA, Rockville, MD 20857 USA. EM jfrantz@aap.org OI Dennehy, Penelope/0000-0002-2259-5370; Byington, Carrie/0000-0002-7350-9495 NR 5 TC 24 Z9 24 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2009 VL 124 IS 4 BP 1216 EP 1226 DI 10.1542/peds.2009-1806 PG 11 WC Pediatrics SC Pediatrics GA 500CI UT WOS:000270274300028 ER PT J AU El-Mohandes, AAE Kiely, M Gantz, MG Blake, SM El-Khorazaty, MN AF El-Mohandes, Ayman A. E. Kiely, Michele Gantz, Marie G. Blake, Susan M. El-Khorazaty, M. Nabil TI Prediction of Birth Weight By Cotinine Levels During Pregnancy in a Population of Black Smokers SO PEDIATRICS LA English DT Article DE birth weight; pregnancy; smoking ID MATERNAL CIGARETTE-SMOKING; GESTATIONAL-AGE; CARBON-MONOXIDE; META-EVALUATION; FETAL-GROWTH; RISK-FACTORS; WOMEN; INTERVENTION; REDUCTION; CESSATION AB OBJECTIVE: The goal was to investigate the association between maternal salivary cotinine levels (SCLs) and pregnancy outcomes among black smokers. METHODS: In a randomized, controlled trial conducted in 2001-2004 in Washington, DC, 714 women (126 active smokers [18%]) were tested for SCLs at the time of recruitment and later in pregnancy. Sociodemographic health risks and pregnancy outcomes were recorded. RESULTS: Birth weights were significantly lower for infants born to mothers with baseline SCLs of >= 20 ng/mL in comparison with <20 ng/mL (P = .024), >= 50 ng/mL in comparison with <50 ng/mL (P = .002), and >= 100 ng/mL in comparison with <100 ng/mL (P = .002), in bivariate analyses. In linear regression analyses adjusting for sociodemographic and medical factors, SCLs of >= 20 ng/mL were associated with a reduction in birth weight of 88 g when SCLs were measured at baseline (P = .042) and 205 g when SCLs were measured immediately before delivery (P < .001). Corresponding results were 129 g (P = .006) and 202 g (P < .001) for >= 50 ng/mL and 139 g (P = .007) and 205 g (P = 0.001) for >= 100 ng/mL. Gestational age was not affected significantly at any SCL, regardless of when SCLs were measured. CONCLUSIONS: Elevated SCLs early in pregnancy or before delivery were associated with reductions in birth weight. At any cutoff level, birth weight reduction was more significant for the same SCL measured in late pregnancy. Maintaining lower levels of smoking for women who are unable to quit may be beneficial. Pediatrics 2009; 124: e671-e680 C1 [El-Mohandes, Ayman A. E.] George Washington Univ, Dept Prevent & Community Hlth, Sch Publ Hlth & Hlth Serv, Med Ctr, Washington, DC 20037 USA. [Kiely, Michele] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Gantz, Marie G.; El-Khorazaty, M. Nabil] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. RP El-Mohandes, AAE (reprint author), George Washington Univ, Dept Prevent & Community Hlth, Sch Publ Hlth & Hlth Serv, Med Ctr, 2175 K St NW,Suite 700, Washington, DC 20037 USA. EM sphaxe@gwumc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [3U18HD030445, 3U18HD030447, 5U18HD31206, 3U18HD03919, 5U18HD036104]; National Center on Minority Health and Health Disparities FX This study was supported by grants 3U18HD030445, 3U18HD030447, 5U18HD31206, 3U18HD03919, and 5U18HD036104 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the National Center on Minority Health and Health Disparities. NR 33 TC 3 Z9 3 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2009 VL 124 IS 4 BP E671 EP E680 DI 10.1542/peds.2008-3784 PG 10 WC Pediatrics SC Pediatrics GA 500CI UT WOS:000270274300049 PM 19786427 ER PT J AU Traupman, EK Smith, TW Uchino, BN Berg, CA Trobst, KK Costa, PT AF Traupman, Emily K. Smith, Timothy W. Uchino, Bert N. Berg, Cynthia A. Trobst, Krista K. Costa, Paul T., Jr. TI Interpersonal circumplex octant, control, and affiliation scales for the NEO-PI-R SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE Interpersonal circumplex; NEO-PI-R; Control; Dominance; Affiliation ID PERSONALITY; HOSTILITY; TAXONOMY; DISEASE; HEALTH AB The Five Factor Model (FFM) traits of agreeableness and extraversion are rotational equivalents of the interpersonal circumplex (IPC) dimensions of affiliation and control. Given that the NEO-PI-R is a widely used measure of the FFM, availability of IPC dimension scales within this inventory could facilitate integration of FFM and interpersonal perspectives. In a study of 301 married couples, we evaluated an IPC scoring system for the NEO-PI-R (Wiggins & Trobst, 1998) comprising 6-item octant scales and composites representing control and affiliation. The octant scales demonstrated expected circular structure. Octant and dimension scales demonstrated convergent and discriminant validity, in analyses of self-report and spouse-rating versions of this IPC measure and the Impact Message Inventory. Further, extraversion corresponded to friendly dominance in the IPC and agreeableness to submissive friendliness. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Traupman, Emily K.; Smith, Timothy W.; Uchino, Bert N.; Berg, Cynthia A.] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. [Trobst, Krista K.] York Univ, Dept Psychol, N York, ON M3J 1P3, Canada. [Costa, Paul T., Jr.] NIA, Lab Personal & Cognit, IRP, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Smith, TW (reprint author), Univ Utah, Dept Psychol, 380 South 1530 East Room 502,Behav Sci Bldg, Salt Lake City, UT 84112 USA. EM tim.smith@psych.utah.edu OI Costa, Paul/0000-0003-4375-1712 FU NIA NIH HHS [R01 AG018903] NR 21 TC 18 Z9 18 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD OCT PY 2009 VL 47 IS 5 BP 457 EP 463 DI 10.1016/j.paid.2009.04.018 PG 7 WC Psychology, Social SC Psychology GA 468SU UT WOS:000267842200013 PM 27840466 ER PT J AU Gill, JM Saligan, L Woods, S Page, G AF Gill, Jessica M. Saligan, Leo Woods, Stephanie Page, Gayle TI PTSD is Associated With an Excess of Inflammatory Immune Activities SO PERSPECTIVES IN PSYCHIATRIC CARE LA English DT Article DE Cortisol; immune; inflammatory; PTSD; trauma ID POSTTRAUMATIC-STRESS-DISORDER; C-REACTIVE PROTEIN; COMBAT VETERANS; CYTOKINE PRODUCTION; PARTNER VIOLENCE; INNATE IMMUNITY; RECEPTOR; CORTISOL; WOMEN; INTERLEUKIN-6 AB PURPOSE. Post-traumatic stress disorder (PTSD) is associated with inflammatory-related medical conditions. This review examines studies of immune function in individuals with PTSD to determine if excessive inflammation is associated with PTSD. CONCLUSIONS. Current studies suggest an excess of inflammatory actions of the immune system in individuals with chronic PTSD. High levels of inflammatory cytokines have also been linked to PTSD vulnerability in traumatized individuals. There is also evidence that excessive inflammation is in part due to insufficient regulation by cortisol. PRACTICE IMPLICATIONS. An excess of inflammatory immune activity may contribute to health declines in individuals with PTSD, and treating PTSD symptoms may reduce these risks. C1 [Gill, Jessica M.] NINR, NIH, Bethesda, MD 20892 USA. [Woods, Stephanie] Univ Akron, Sch Nursing, Akron, OH 44325 USA. [Page, Gayle] Johns Hopkins Univ, Sch Nursing, Bethesda, MD USA. RP Gill, JM (reprint author), NINR, NIH, Bethesda, MD 20892 USA. EM gillj@mail.nih.gov NR 84 TC 87 Z9 89 U1 4 U2 10 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-5990 J9 PERSPECT PSYCHIATR C JI Perspect. Psychiatr. Care PD OCT PY 2009 VL 45 IS 4 BP 262 EP 277 PG 16 WC Nursing; Psychiatry SC Nursing; Psychiatry GA 498YL UT WOS:000270182400004 PM 19780999 ER PT J AU Boudreau, RM Hanlon, JT Roumani, YF Studenski, SA Ruby, CM Wright, RM Hilmer, SN Shorr, RI Bauer, DC Simonsick, EM Newman, AB AF Boudreau, Robert M. Hanlon, Joseph T. Roumani, Yazan F. Studenski, Stephanie A. Ruby, Christine M. Wright, Rollin M. Hilmer, Sarah N. Shorr, Ronald I. Bauer, Douglas C. Simonsick, Eleanor M. Newman, Anne B. TI Central nervous system medication use and incident mobility limitation in community elders: the health, aging, and body composition study SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE aged; mobility; central nervous system drugs ID LOWER-EXTREMITY FUNCTION; BENZODIAZEPINE USE; OLDER-ADULTS; PHYSICAL PERFORMANCE; DISABILITY; ASSOCIATION; MORTALITY; PEOPLE; DRUGS; WOMEN AB Purpose To evaluate whether CNS medication use in older adults was associated with a higher risk of future incident mobility limitation. Methods This 5-year longitudinal cohort study included 3055 participants from the health, aging and body composition (Health ABC) study who were well-functioning at baseline. CNS medication use (benzodiazepine and opioid receptor agonists, antipsychotics, and antidepressants) was determined yearly (except year 4) during in-home or in-clinic interviews. Summated standardized daily doses (low, medium, and high) and duration of CNS drug use were computed. Incident mobility limitation was operationalized as two consecutive self-reports of having any difficulty walking 1/4 mile or climbing 10 steps without resting every 6 months after baseline. Multivariable Cox proportional hazard analyses were conducted adjusting for demographics, health behaviors, health status, and common indications for CNS medications. Results Each year at least 13.9% of participants used a CNS medication. By year 6, overall 49% had developed incident mobility limitation. In multivariable models, CNS medication users compared to never users showed a higher risk for incident mobility limitation (adjusted hazard ratio (Adj. HR) 1.28; 95% confidence interval (CI) 1.12-1.47). Similar findings of increased risk were seen in analyses examining dose- and duration-response relationships. Conclusions CNS medication use is independently associated with an increased risk of future incident mobility limitation in community dwelling elderly. Further studies are needed to determine the impact of reducing CNS medication exposure on mobility problems. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Hanlon, Joseph T.; Roumani, Yazan F.; Studenski, Stephanie A.; Ruby, Christine M.; Wright, Rollin M.; Newman, Anne B.] Univ Pittsburgh, Dept Geriatr Med, Sch Med, Pittsburgh, PA 15213 USA. [Boudreau, Robert M.; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.; Ruby, Christine M.] Univ Pittsburgh, Dept Pharm & Therapeut, Sch Pharm, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.; Studenski, Stephanie A.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res, Pittsburgh, PA USA. [Hanlon, Joseph T.; Studenski, Stephanie A.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. [Hilmer, Sarah N.] Univ Sydney, Sydney, NSW 2006, Australia. [Hilmer, Sarah N.] Royal N Shore Hosp, Sydney, NSW, Australia. [Shorr, Ronald I.] N Florida S Georgia Vet Hlth Syst Geriatr Res Edu, Gainesville, FL USA. [Bauer, Douglas C.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Hanlon, JT (reprint author), Univ Pittsburgh, Dept Geriatr Med, Sch Med, Kaufman Med Bldg Suite 514,3471 5th Ave, Pittsburgh, PA 15213 USA. EM hanlonj@dom.pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Hilmer, Sarah/0000-0002-5970-1501; Boudreau, Robert/0000-0003-0162-5187 FU NIH, National Institute of Aging [R01AG027017, P30AG024827, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX This study was primarily supported by National Institute of Aging grants and contracts (R01AG027017; P30AG024827, N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106). This research was also supported in part by the Intramural Research program of the NIH, National Institute on Aging. Dr Hanlon and Dr Boudreau have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design was done by Bauer, Hanlon, Boudreau, Newman, Shorr, Simonsick, and Studenski. Data were accumulated by Hanlon, Boudreau, and Newman. Analysis and interpretation of the data were done by Hanlon, Boudreau, Newman, Shorr, Simonsick, Bauer, Ruby, Roumani, Studenski, Wright, and Hilmer. The manuscript was drafted by Hanlon, Boudreau, Roumani, Hilmer, Studenski, Wright, and Simonsick. Critical revision of the manuscript for important intellectual content was done by Hanlon, Boudreau, Newman, Roumani, Hilmer, Shorr, Bauer, Studenski, Ruby, Wright, and Simonsick. Statistical analysis was done by Boudreau, Roumani. Funding was obtained by Hanlon and Newman. The study was supervised by Hanlon and Newman. NR 28 TC 26 Z9 26 U1 2 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2009 VL 18 IS 10 BP 916 EP 922 DI 10.1002/pds.1797 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 510GN UT WOS:000271076200006 PM 19585466 ER PT J AU Schindler, CW Panlilio, LV Thorndike, EB AF Schindler, Charles W. Panlilio, Leigh V. Thorndike, Eric B. TI Effect of rate of delivery of intravenous cocaine on self-administration in rats SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Cocaine; Self-administration; Infusion duration; Choice; Rat ID INJECTION SPEED; REINFORCING STRENGTH; SEEKING BEHAVIOR; RHESUS-MONKEYS; HUMANS; INFUSION; CHOICE; AMPHETAMINE; ADDICTION; SCHEDULE AB Many studies of drug self-administration in primates have shown that faster infusions of a drug are more reinforcing than slower infusions. Similar effects have not been shown in rats. We assessed the influence of delivery rate by allowing rats to choose between the same doses of intravenous cocaine delivered over two different infusion speeds. Rats were trained in chambers containing two nose-poke response devices. in Experiment 1, responses in one nose-poke delivered 0.3 mg/kg/injection of cocaine over 10 s, and responses in the other delivered the same dose over 100 s. In Experiment 2, the same procedure was used, but with 1.0 mg/kg/injection dose delivered over 1.7 versus 100 s. During acquisition, most rats preferred the faster infusion. When the delivery rates associated with the nose pokes were reversed, rats trained with 0.3 mg/kg/injection failed to switch nose-poke preference, but half the rats trained with 1.0 mg/kg/injection did switch. In Experiment 3, the choice was between I mg/kg cocaine delivered over 1.7 s and no reinforcement. Here, rats quickly learned to respond in the nose-poke associated with cocaine and quickly switched their choice during reversal. In Experiment 4, two groups of rats were allowed to choose between food delivered with a delay of I versus 5 s or I versus 10 s, respectively. Rats preferred the shorter delay during initial training. In reversal, some rats in the I vs 5 s group failed to reverse, while all the rats in the I vs 10 s group reversed. These results show that faster infusions of cocaine are clearly more reinforcing during acquisition, but delivery rate may not be as important to the maintenance of self-administration once it has been established. The results with food Suggest that these findings represent general principles of behavior and are not unique to drug self-administration. Published by Elsevier Inc. C1 [Schindler, Charles W.; Panlilio, Leigh V.; Thorndike, Eric B.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH,Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM cschindl@helix.nih.gov FU NIH; NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. The authors would like to thank Kevin Thornton, Peter Riley and Reeva Morton for their assistance in conducting the experiments. NR 31 TC 17 Z9 17 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD OCT PY 2009 VL 93 IS 4 BP 375 EP 381 DI 10.1016/j.pbb.2009.05.008 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 491NW UT WOS:000269586800003 PM 19464316 ER PT J AU Davis, CM Rice, KC Riley, AL AF Davis, Catherine M. Rice, Kenner C. Riley, Anthony L. TI Opiate-agonist induced taste aversion learning in the Fischer 344 and Lewis inbred rat strains: Evidence for differential mu opioid receptor activation SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE F344; LEW; Morphine; CTA; Heroin; SNC80; (-)-U50,488H; Opioid ID MORPHINE-TOLERANCE; KNOCKOUT MICE; INDUCED ANTINOCICEPTION; LOCOMOTOR-ACTIVITY; LITHIUM-CHLORIDE; PLACE PREFERENCE; CXBK MICE; DELTA; COCAINE; ANALGESIA AB The Fischer 344 (F344) and Lewis (LEW) inbred rat strains react differently to morphine in a number of behavioral and physiological preparations, including the acquisition of aversions induced by this compound. The present experiment tested the ability of various compounds with relative selectivity at kappa, delta and mu receptor subtypes to assess the relative roles of these subtypes in mediating the differential aversive effects of morphine in the two strains. In the assessment of the role of the kappa receptor in morphine-induced aversions, animals in both strains were given access to saccharin followed by varying doses of the kappa agonist (-)-U50,488H (0.0. 0.28. 0.90 and 1.60 mg/kg). Although (-)-U50.488H induced aversions in both strains, no strain differences emerged. A separate subset of subjects was trained with the selective delta opioid agonist, SNC80 (0.0. 5.6, 10.0 and 18.0 mg/kg), and again although SNC80 induced aversions, there were no strain differences. Finally, a third subset of subjects was trained with heroin (0.0. 3.2, 5.6 and 10.0 mg/kg), a compound with activity at all three opiate receptor subtypes. Although heroin induced aversions in both strains, the aversions were significantly greater in the F344 strain, suggesting that differential activation of the mu opioid receptor likely mediates the reported strain differences in morphine-induced aversion learning. These data were discussed in terms of strain differences in opioid system functioning and the implications of such differences for other morphine-induced behavioral effects reported in F344 and LEW rats. (C) 2009 Elsevier Inc. All rights reserved. C1 [Davis, Catherine M.] American Univ, Psychopharmacol Lab, Dept Psychol, Washington, DC 20016 USA. [Rice, Kenner C.] Natl Inst Drug Abuse, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20852 USA. [Rice, Kenner C.] NIAAA, Bethesda, MD 20852 USA. RP Davis, CM (reprint author), American Univ, Psychopharmacol Lab, Dept Psychol, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM cd2994a@american.edu OI Davis-Takacs, Catherine/0000-0002-2591-6352 FU Mellon Foundation; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by a grant from the Mellon Foundation to Anthony L Riley, and a portion of this work was supported by the intramural research programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. NR 55 TC 16 Z9 16 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD OCT PY 2009 VL 93 IS 4 BP 397 EP 405 DI 10.1016/j.pbb.2009.06.001 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 491NW UT WOS:000269586800006 PM 19508878 ER PT J AU Siber, A Rajter, RF French, RH Ching, WY Parsegian, VA Podgornik, R AF Siber, A. Rajter, R. F. French, R. H. Ching, W. Y. Parsegian, V. A. Podgornik, R. TI Dispersion interactions between optically anisotropic cylinders at all separations: Retardation effects for insulating and semiconducting single-wall carbon nanotubes SO PHYSICAL REVIEW B LA English DT Article ID VANDERWAALS FORCES; RODS AB We derive the complete form of the van der Waals dispersion interaction between two infinitely long anisotropic semiconducting/insulating thin cylinders at all separations. The derivation is based on the general theory of dispersion interactions between anisotropic media as formulated in Munday et al. [Phys. Rev. A 71, 042102 (2005)]. This formulation is then used to calculate the dispersion interactions between a pair of single-walled carbon nanotubes at all separations and all angles. Nonretarded and retarded forms of the interactions are developed separately. The possibility of repulsive dispersion interactions and nonmonotonic dispersion interactions is discussed within the framework of the formulation. C1 [Siber, A.] Univ Zagreb, Inst Phys, Zagreb 10001, Croatia. [Rajter, R. F.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [French, R. H.] DuPont Co Inc, Cent Res, Wilmington, DE 19880 USA. [Ching, W. Y.] Univ Missouri, Dept Phys, Kansas City, MO 64110 USA. [Parsegian, V. A.] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. [Podgornik, R.] NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. [Podgornik, R.] Univ Ljubljana, Fac Math & Phys, Dept Phys, SI-1000 Ljubljana, Slovenia. [Podgornik, R.] Univ Ljubljana, Sch Med, Inst Biophys, SI-1000 Ljubljana, Slovenia. [Podgornik, R.] Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. RP Siber, A (reprint author), Univ Zagreb, Inst Phys, Bijenicka Cesta 46,POB 304, Zagreb 10001, Croatia. RI Ching, Wai-Yim/B-4686-2009; Siber, Antonio/B-8881-2008; French, Roger/E-1986-2011; Podgornik, Rudolf/C-6209-2008 OI Ching, Wai-Yim/0000-0001-7738-8822; Siber, Antonio/0000-0003-1665-6541; French, Roger/0000-0002-6162-0532; Podgornik, Rudolf/0000-0002-3855-4637 FU European Commission [NMP3-CT-2005-013862]; Slovenian Research Agency [J1-0908]; Croatian Ministry of Science [035-0352828-2837]; NSF [CMS-0609050]; Dupont-MIT Alliance; DOE [DE-FG02-84DR45170]; Intramural Research Program of the NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX A. S. and R. P. would like to acknowledge partial financial support for this work by the European Commission under Contract No. NMP3-CT-2005-013862 (INCEMS) and by the Slovenian Research Agency under Contract No. J1-0908 Active Media Nanoactuators with Dispersion Forces). A. S. also acknowledges support by the Croatian Ministry of Science (Project No. 035-0352828-2837). R. R. would like to acknowledge financial support for this work by the NSF under Contract No. CMS-0609050 (NIRT) and the Dupont-MIT Alliance (DMA). W. Y. C. is supported by the DOE under Grant No. DE-FG02-84DR45170. This study was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 25 TC 16 Z9 16 U1 0 U2 4 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1098-0121 J9 PHYS REV B JI Phys. Rev. B PD OCT PY 2009 VL 80 IS 16 AR 165414 DI 10.1103/PhysRevB.80.165414 PG 10 WC Physics, Condensed Matter SC Physics GA 513VL UT WOS:000271352100123 ER PT J AU Agarwala, SS Becker, JC Eggermont, AM Flaherty, KT Garbe, C Goldstein, AM Halpern, A Kashani-Sabet, M Hauschild, A Kirkwood, JM Leachman, S Lorigan, P McMahon, M Messina, J Ribas, A Samlowski, WE Schadendorf, D Sondak, VK AF Agarwala, Sanjiv S. Becker, Jurgen C. Eggermont, Alexander M. Flaherty, Keith T. Garbe, Claus Goldstein, Alisa M. Halpern, Allan Kashani-Sabet, Mohammed Hauschild, Axel Kirkwood, John M. Leachman, Sancy Lorigan, Paul McMahon, Martin Messina, Jane Ribas, Antoni Samlowski, Wolfram E. Schadendorf, Dirk Sondak, Vernon K. TI Meeting report: consensus from the first and second Global Workshops in Melanoma November 19-20, 2008 SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Editorial Material ID STAGE-IV MELANOMA; ADJUVANT THERAPY; PHASE-III; INTERFERON-ALPHA-2B; TRIAL AB This overview of the current state of melanoma research and treatment and directions for moving forward represents the consensus of discussions between expert panelists at the First and Second Global Workshops on Melanoma held in Fajardo, Peurto Rico on November 30-December 1, 2007 and Clearwater Beach, Florida on November 19-20, 2008. C1 [Agarwala, Sanjiv S.] St Lukes Canc Ctr, Bethlehem, PA USA. [Flaherty, Keith T.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Becker, Jurgen C.] Univ Wurzburg, Dept Dermatol Venerol & Allergol, Wurzburg, Germany. [Becker, Jurgen C.] Univ Wurzburg, Dept Dermatol, D-8700 Wurzburg, Germany. [Eggermont, Alexander M.] Erasumus Univ, Med Ctr, Dept Surg Oncol, Rotterdam, Netherlands. [Garbe, Claus] Univ Med Ctr Tubingen, Dept Dermatol, Div Dermatooncol, Tubingen, Germany. [Goldstein, Alisa M.] NCI, Bethesda, MD 20892 USA. [Halpern, Allan] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kashani-Sabet, Mohammed] Univ Calif San Francisco, Melanoma Ctr, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Hauschild, Axel] Univ Kiel, Dept Dermatol, D-2300 Kiel, Germany. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Clin Res Dept Med, Pittsburgh, PA USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Inst Canc, Melanoma & Skin Canc Program, Pittsburgh, PA USA. [Leachman, Sancy] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Melanoma & Cutaneous Oncol Program, Salt Lake City, UT USA. [Lorigan, Paul] Christie Hosp Fdn Trust, Manchester, Lancs, England. [McMahon, Martin] UCSF Comprehens Canc Ctr, Canc Res Inst, San Francisco, CA USA. [Messina, Jane; Sondak, Vernon K.] Univ S Florida, Cutaneous Oncol Program, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Ribas, Antoni] Univ Calif Los Angeles, Div Hematol & Oncol, Los Angeles, CA USA. [Samlowski, Wolfram E.] Nevada Canc Inst, Sect Melanoma Renal Canc & Immunotherapy, Las Vegas, NV USA. [Schadendorf, Dirk] Univ Essen Gesamthsch, Clin Dermatol & Venerol, Essen, Germany. [Sondak, Vernon K.] Univ S Florida, Coll Med, Dept Oncol Sci, Tampa, FL USA. [Sondak, Vernon K.] Univ S Florida, Coll Med, Dept Surg, Tampa, FL 33612 USA. RP Agarwala, SS (reprint author), St Lukes Canc Ctr, Bethlehem, PA USA. EM AgarwaS@slhn.org RI Hauschild, Axel/B-3185-2010; McMahon, Martin/L-3303-2013; Lorigan, Paul/J-6898-2015; OI McMahon, Martin/0000-0003-2812-1042; Lorigan, Paul/0000-0002-8875-2164; Samlowski, Wolfram/0000-0002-0713-914X NR 8 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD OCT PY 2009 VL 22 IS 5 BP 532 EP 543 DI 10.1111/j.1755-148X.2009.00602.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 489AD UT WOS:000269390800009 PM 19659612 ER PT J AU Horvath, A Stratakis, CA AF Horvath, Anelia Stratakis, Constantine A. TI Carney complex and lentiginosis SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE Carney complex; lentiginosis; skin pigmentation ID PEUTZ-JEGHERS-SYNDROME; NODULAR ADRENOCORTICAL DISEASE; DEPENDENT PROTEIN-KINASE; EPITHELIOID BLUE NEVUS; GERMLINE MUTATIONS; ENDOCRINE OVERACTIVITY; ADRENAL-HYPERPLASIA; SPOTTY PIGMENTATION; MELANOCORTIN RECEPTORS; GENETIC-HETEROGENEITY AB P>Initially described as the 'complex of myxomas, spotty skin pigmentation and endocrine overactivity,' Carney complex (CNC) is known as an autosomal dominant multiple neoplasia syndrome involving skin and cardiac myxomas, pigmented skin lesions and endocrine tumors. Pigmented cutaneous manifestations in CNC are important diagnostically because they can be used for the early detection of the disease and, thus, the prevention of life-threatening complications of CNC related to heart myxomas and endocrine abnormalities. Specific for the disease skin lesions are present in more than half of the CNC patients. A major challenge is to distinguish pigmented skin lesions associated with CNC from other skin pathology, and thus accurately estimate the risk of cancer in affected patients; curiously, patients with CNC do not appear to have predisposition to skin cancers whereas this is not the case with other genetic syndromes associated with melanotic and other cutaneous lesions. In this paper, we review the current knowledge on cutaneous pathology associated with CNC and the most recent data on the molecular basis of the disease. C1 [Horvath, Anelia; Stratakis, Constantine A.] NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD); NIH [Z01-HD-000642-04] FX Studies on CNC and related syndromes have been supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), NIH, intramural project Z01-HD-000642-04 (to Dr. C. A. Stratakis). NR 61 TC 24 Z9 26 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD OCT PY 2009 VL 22 IS 5 BP 580 EP 587 DI 10.1111/j.1755-148X.2009.00613.x PG 8 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 489AD UT WOS:000269390800012 PM 19650827 ER PT J AU Loftus, SK Baxter, LL Buac, K Watkins-Chow, DE Larson, DM Pavan, WJ AF Loftus, Stacie K. Baxter, Laura L. Buac, Kristina Watkins-Chow, Dawn E. Larson, Denise M. Pavan, William J. TI Comparison of melanoblast expression patterns identifies distinct classes of genes SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanoblast; retinal pigmented epithelium; in situ hybridization; MITF; SOX10 ID MELANOCYTE-SPECIFIC EXPRESSION; TRANSCRIPTION FACTOR SOX10; CREST-DERIVED MELANOCYTES; RECEPTOR TYROSINE KINASE; C-KIT RECEPTOR; WAARDENBURG-SYNDROME; NEURAL CREST; DOPACHROME-TAUTOMERASE; HIRSCHSPRUNG-DISEASE; SPOTTED MICE AB P>A full understanding of transcriptional regulation requires integration of information obtained from multiple experimental datasets. These include datasets annotating gene expression within the context of an entire organism under normal and genetically perturbed conditions. Here we describe an expression dataset annotating pigment cell-expressed genes of the developing melanocyte and retinal pigmented epithelium lineages. Expression images are annotated and available at http://research.nhgri.nih.gov/manuscripts/Loftus/March2009/. Data are also summarized in a standardized manner using a universal melanoblast scoring scale that accounts for the embryonic location of cells and regional cell density. This approach allowed us to classify 14 pigment genes into four groupings classified by cell lineage expression, temporal-spatial context, and differential alteration in response to altered MITF and SOX10 status. Significant differences in regional populations were also observed across inbred strain backgrounds, highlighting the value of this approach to identify modifier allele influences on melanoblast number and distributions. This analysis revealed novel features of in vivo expression patterns that are not measurable by in vitro-based assays, providing data that in combination with genomic analyses will allow modeling of pigment cell gene expression in development and disease. C1 [Loftus, Stacie K.; Baxter, Laura L.; Buac, Kristina; Watkins-Chow, Dawn E.; Larson, Denise M.; Pavan, William J.] NHGRI, NIH, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Loftus, SK (reprint author), NHGRI, NIH, Genet Dis Res Branch, Bethesda, MD 20892 USA. EM sloftus@mail.nih.gov OI Watkins-Chow, Dawn/0000-0002-4355-0868 FU NIH; NHGRI FX This work was funded through the NIH intramural program, NHGRI. Experiments were performed in accordance with the NHGRI animal care and use protocol G-94-7. We would like to thank Dr. Lidia Kos for Erbb3 cDNA, Lowell Umayam and Anh-Dao Nguyen (NHGRI Bioinfomatics core) for database design and support, and Darryl Leja (NHGRI) for graphics assistance. NR 58 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD OCT PY 2009 VL 22 IS 5 BP 611 EP 622 DI 10.1111/j.1755-148X.2009.00584.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 489AD UT WOS:000269390800015 PM 19493314 ER PT J AU Hearing, VJ AF Hearing, Vincent J. TI Antibodies specific to melanocyte-specific proteins available from the Hearing Laboratory SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODIES; MAMMALIAN TYROSINASE; LOCUS; IDENTIFICATION; BIOSYNTHESIS; EXPRESSION; PATTERNS; SKIN C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132, Bethesda, MD 20892 USA. EM hearingv@nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD OCT PY 2009 VL 22 IS 5 BP 651 EP 651 DI 10.1111/j.1755-148X.2009.00601.x PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 489AD UT WOS:000269390800021 ER PT J AU Xi, L Moscou, MJ Meng, Y Xu, WH Caldo, RA Shaver, M Nettleton, D Wise, RP AF Xi, Liu Moscou, Matthew J. Meng, Yan Xu, Weihui Caldo, Rico A. Shaver, Miranda Nettleton, Dan Wise, Roger P. TI Transcript-Based Cloning of RRP46, a Regulator of rRNA Processing and R Gene-Independent Cell Death in Barley-Powdery Mildew Interactions SO PLANT CELL LA English DT Article ID F-SP HORDEI; ML-A LOCUS; DISEASE RESISTANCE; HYPERSENSITIVE RESPONSE; ARABIDOPSIS-THALIANA; LEAF SENESCENCE; DEFENSE RESPONSE; PLANT DEFENSE; BASAL DEFENSE; MOSAIC-VIRUS AB Programmed cell death (PCD) plays a pivotal role in plant development and defense. To investigate the interaction between PCD and R gene-mediated defense, we used the 22K Barley1 GeneChip to compare and contrast time-course expression profiles of Blumeria graminis f. sp hordei (Bgh) challenged barley (Hordeum vulgare) cultivar C. I. 16151 (harboring the Mla6 powdery mildew resistance allele) and its fast neutron-derived Bgh-induced tip cell death1 mutant, bcd1. Mixed linear model analysis identified genes associated with the cell death phenotype as opposed to R gene-mediated resistance. One-hundred fifty genes were found at the threshold P value < 0.0001 and a false discovery rate < 0.6%. Of these, 124 were constitutively overexpressed in the bcd1 mutant. Gene Ontology and rice (Oryza sativa) alignment-based annotation indicated that 68 of the 124 overexpressed genes encode ribosomal proteins. A deletion harboring six genes on chromosome 5H cosegregates with bcd1-specified cell death and is associated with misprocessing of rRNAs but segregates independent of R gene-mediated resistance. Barley stripe mosaic virus-induced gene silencing of one of the six deleted genes, RRP46 (rRNA-processing protein 46), phenocopied bcd1-mediated tip cell death. These findings suggest that RRP46, a critical component of the exosome core, mediates RNA processing and degradation involved in cell death initiation as a result of attempted penetration by Bgh during the barley-powdery mildew interaction but is independent of gene-for-gene resistance. C1 [Xi, Liu; Moscou, Matthew J.; Meng, Yan; Xu, Weihui; Caldo, Rico A.; Wise, Roger P.] Iowa State Univ, Dept Plant Pathol, Ames, IA 50011 USA. [Xi, Liu; Moscou, Matthew J.; Meng, Yan; Xu, Weihui; Caldo, Rico A.; Wise, Roger P.] Iowa State Univ, Ctr Plant Responses Environm Stresses, Ames, IA 50011 USA. [Shaver, Miranda; Wise, Roger P.] NIH, Natl Sci Fdn, Bioinformat & Computat Syst Biol Summer Inst, Ames, IA 50011 USA. [Nettleton, Dan] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. [Wise, Roger P.] Iowa State Univ, USDA ARS, Ames, IA 50011 USA. RP Wise, RP (reprint author), Iowa State Univ, Dept Plant Pathol, Ames, IA 50011 USA. EM rpwise@iastate.edu RI Moscou, Matthew/D-5266-2011 OI Moscou, Matthew/0000-0003-2098-6818 FU USDA Initiative for Future Agriculture and Food Systems [2001-52100-11346]; NIH-NSF Bioinformatics and Computational Systems Biology Summer Institute [06-08769]; National Science Foundation Plant Genome [05-00461] FX The authors thank Liz Miller for technical assistance during the mutant isolation, and Greg Fuerst for excellent technical assistance throughout the project. This research was supported by the USDA Initiative for Future Agriculture and Food Systems Grant 2001-52100-11346, NIH-NSF Bioinformatics and Computational Systems Biology Summer Institute grant 06-08769, and National Science Foundation Plant Genome grant 05-00461. This article is a joint contribution of the Iowa Agriculture and Home Economics Experiment Station and the Corn Insects and Crop Genetics Research Unit, USDA-Agricultural Research Service. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U. S. Department of Agriculture. NR 66 TC 18 Z9 20 U1 0 U2 9 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 J9 PLANT CELL JI Plant Cell PD OCT PY 2009 VL 21 IS 10 BP 3280 EP 3295 DI 10.1105/tpc.109.066167 PG 16 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 525XW UT WOS:000272252100023 PM 19861556 ER PT J AU Holmes, EC Grenfell, BT AF Holmes, Edward C. Grenfell, Bryan T. TI Discovering the Phylodynamics of RNA Viruses SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID INFLUENZA-A VIRUS; POPULATION-DYNAMICS; MEASLES EPIDEMICS; H3N2 VIRUSES; EVOLUTION; TRANSMISSION; HUMANS; PHYLOGEOGRAPHY; DIVERSITY; EMERGENCE C1 [Holmes, Edward C.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, Mueller Lab, University Pk, PA 16802 USA. [Holmes, Edward C.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. RP Holmes, EC (reprint author), Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, Mueller Lab, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 FU NIGMS NIH HHS [GM080533, R01 GM080533] NR 43 TC 57 Z9 57 U1 1 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2009 VL 5 IS 10 AR e1000505 DI 10.1371/journal.pcbi.1000505 PG 6 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 522XI UT WOS:000272033100002 PM 19855824 ER PT J AU Liu, J Nussinov, R AF Liu, Jin Nussinov, Ruth TI The Mechanism of Ubiquitination in the Cullin-RING E3 Ligase Machinery: Conformational Control of Substrate Orientation SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; STRUCTURAL BASIS; FOLDING FUNNELS; BINDING CASCADES; COMPLEX; INSIGHTS; RECOGNITION; DYNAMICS; ACTIVATION; ALLOSTERY AB In cullin-RING E3 ubiquitin ligases, substrate binding proteins, such as VHL-box, SOCS-box or the F-box proteins, recruit substrates for ubiquitination, accurately positioning and orienting the substrates for ubiquitin transfer. Yet, how the E3 machinery precisely positions the substrate is unknown. Here, we simulated nine substrate binding proteins: Skp2, Fbw7, beta-TrCP1, Cdc4, Fbs1, TIR1, pVHL, SOCS2, and SOCS4, in the unbound form and bound to Skp1, ASK1 or Elongin C. All nine proteins have two domains: one binds to the substrate; the other to E3 ligase modules Skp1/ASK1/Elongin C. We discovered that in all cases the flexible inter-domain linker serves as a hinge, rotating the substrate binding domain, optimally and accurately positioning it for ubiquitin transfer. We observed a conserved proline in the linker of all nine proteins. In all cases, the prolines pucker substantially and the pucker is associated with the backbone rotation toward the E2/ubiquitin. We further observed that the linker flexibility could be regulated allosterically by binding events associated with either domain. We conclude that the flexible linker in the substrate binding proteins orients the substrate for the ubiquitin transfer. Our findings provide a mechanism for ubiquitination and polyubiquitination, illustrating that these processes are under conformational control. C1 [Liu, Jin; Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Liu, J (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM ruthnu@helix.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; Intramural Research Program of the 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 number N01-CO-12400. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 34 Z9 34 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2009 VL 5 IS 10 AR e1000527 DI 10.1371/journal.pcbi.1000527 PG 10 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 522XI UT WOS:000272033100007 PM 19798438 ER PT J AU Averdam, A Petersen, B Rosner, C Neff, J Roos, C Eberle, M Aujard, F Munich, C Schempp, W Carrington, M Shiina, T Inoko, H Knaust, F Coggill, P Sehra, H Beck, S Abi-Rached, L Reinhardt, R Walter, L AF Averdam, Anne Petersen, Beatrix Rosner, Cornelia Neff, Jennifer Roos, Christian Eberle, Manfred Aujard, Fabienne Muenich, Claudia Schempp, Werner Carrington, Mary Shiina, Takashi Inoko, Hidetoshi Knaust, Florian Coggill, Penny Sehra, Harminder Beck, Stephan Abi-Rached, Laurent Reinhardt, Richard Walter, Lutz TI A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates SO PLOS GENETICS LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-I MOLECULES; NATURAL-KILLER-CELLS; HLA-E BINDS; MAXIMUM-LIKELIHOOD; MICROCEBUS-MURINUS; SEQUENCE ALIGNMENT; GENE-COMPLEX; MIXED MODELS; EVOLUTION AB There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of nonpolymorphic KLR in "higher" primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire. C1 [Averdam, Anne; Petersen, Beatrix; Rosner, Cornelia; Neff, Jennifer; Roos, Christian; Walter, Lutz] German Primate Ctr, Dept Primate Genet, Gottingen, Germany. [Roos, Christian; Walter, Lutz] German Primate Ctr, Gene Bank Primates, Gottingen, Germany. [Eberle, Manfred] German Primate Ctr, Dept Behav Ecol & Sociobiol, Gottingen, Germany. [Aujard, Fabienne] CNRS, UMR MNHN 7179, Brunoy, France. [Muenich, Claudia; Schempp, Werner] Univ Freiburg, Inst Human Genet, Freiburg, Germany. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Shiina, Takashi; Inoko, Hidetoshi] Tokai Univ, Sch Med, Isehara, Kanagawa 25911, Japan. [Knaust, Florian; Reinhardt, Richard] Max Planck Inst Mol Genet, Berlin, Germany. [Coggill, Penny; Sehra, Harminder] Wellcome Trust Sanger Inst, Hinxton, England. [Beck, Stephan] UCL, Inst Canc, London, England. [Abi-Rached, Laurent] Stanford Univ, Dept Biol Struct, Sch Med, Stanford, CA 94305 USA. RP Averdam, A (reprint author), German Primate Ctr, Dept Primate Genet, Gottingen, Germany. EM lwalter@gwdg.de RI Abi-Rached, Laurent/H-7236-2012; OI Walter, Lutz/0000-0001-9408-3131 FU Deutsche Forschungsgemeinschaft [GRK 289]; Nationales Genomforschungsnetz (NGFN); European Commission [28594]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; National Institutes of Health [AI 31168] FX This study was supported by grants from the Deutsche Forschungsgemeinschaft (GRK 289) to JN and LW and by the Nationales Genomforschungsnetz (NGFN) to RR. AA was in part supported by the European Commission (contract 28594). PC, HS, and SB were supported by the Wellcome Trust. The contribution of MC was funded 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 Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. LAR was supported by National Institutes of Health Grant AI 31168 to Peter Parham. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 35 Z9 35 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2009 VL 5 IS 10 AR e1000688 DI 10.1371/journal.pgen.1000688 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 522WZ UT WOS:000272032100026 PM 19834558 ER PT J AU Braun, R Rowe, W Schaefer, C Zhang, JH Buetow, K AF Braun, Rosemary Rowe, William Schaefer, Carl Zhang, Jinghui Buetow, Kenneth TI Needles in the Haystack: Identifying Individuals Present in Pooled Genomic Data SO PLOS GENETICS LA English DT Article AB Recent publications have described and applied a novel metric that quantifies the genetic distance of an individual with respect to two population samples, and have suggested that the metric makes it possible to infer the presence of an individual of known genotype in a sample for which only the marginal allele frequencies are known. However, the assumptions, limitations, and utility of this metric remained incompletely characterized. Here we present empirical tests of the method using publicly accessible genotypes, as well as analytical investigations of the method's strengths and limitations. The results reveal that the null distribution is sensitive to the underlying assumptions, making it difficult to accurately calibrate thresholds for classifying an individual as a member of the population samples. As a result, the false-positive rates obtained in practice are considerably higher than previously believed. However, despite the metric's inadequacies for identifying the presence of an individual in a sample, our results suggest potential avenues for future research on tuning this method to problems of ancestry inference or disease prediction. By revealing both the strengths and limitations of the proposed method, we hope to elucidate situations in which this distance metric may be used in an appropriate manner. We also discuss the implications of our findings in forensics applications and in the protection of GWAS participant privacy. C1 [Braun, Rosemary; Rowe, William; Zhang, Jinghui; Buetow, Kenneth] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Schaefer, Carl; Buetow, Kenneth] NCI, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. RP Braun, R (reprint author), NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. EM braunr@mail.nih.gov OI Braun, Rosemary/0000-0001-9668-9866 FU National Cancer Institute, National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD. RB was supported by the Cancer Prevention Fellowship Program, National Cancer Institute, National Institutes of Health, Bethesda, MD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 4 TC 24 Z9 25 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2009 VL 5 IS 10 AR e1000668 DI 10.1371/journal.pgen.1000668 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 522WZ UT WOS:000272032100006 PM 19798441 ER PT J AU Wheeler, HE Metter, EJ Tanaka, T Absher, D Higgins, J Zahn, JM Wilhelmy, J Davis, RW Singleton, A Myers, RM Ferrucci, L Kim, SK AF Wheeler, Heather E. Metter, E. Jeffrey Tanaka, Toshiko Absher, Devin Higgins, John Zahn, Jacob M. Wilhelmy, Julie Davis, Ronald W. Singleton, Andrew Myers, Richard M. Ferrucci, Luigi Kim, Stuart K. TI Sequential Use of Transcriptional Profiling, Expression Quantitative Trait Mapping, and Gene Association Implicates MMP20 in Human Kidney Aging SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CANDIDATE GENES; PARKINSON-DISEASE; ALZHEIMER-DISEASE; ALLELIC VARIATION; HUMAN LONGEVITY; RENAL-FUNCTION; HUMAN HOMOLOG; HUMAN BRAIN; AGE AB Kidneys age at different rates, such that some people show little or no effects of aging whereas others show rapid functional decline. We sequentially used transcriptional profiling and expression quantitative trait loci (eQTL) mapping to narrow down which genes to test for association with kidney aging. We first performed whole-genome transcriptional profiling to find 630 genes that change expression with age in the kidney. Using two methods to detect eQTLs, we found 101 of these age-regulated genes contain expression-associated SNPs. We tested the eQTLs for association with kidney aging, measured by glomerular filtration rate (GFR) using combined data from the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI study. We found a SNP association (rs1711437 in MMP20) with kidney aging (uncorrected p = 3.6 x 10(-5), empirical p = 0.01) that explains 1%-2% of the variance in GFR among individuals. The results of this sequential analysis may provide the first evidence for a gene association with kidney aging in humans. C1 [Wheeler, Heather E.; Kim, Stuart K.] Stanford Univ, Med Ctr, Dept Genet, Stanford, CA 94305 USA. [Metter, E. Jeffrey; Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Metter, E. Jeffrey; Tanaka, Toshiko; Ferrucci, Luigi] Medstar Res Inst, Baltimore, MD USA. [Absher, Devin; Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Higgins, John] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA. [Zahn, Jacob M.; Wilhelmy, Julie; Davis, Ronald W.] Stanford Genome Technol Ctr, Palo Alto, CA USA. [Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Kim, Stuart K.] Stanford Univ, Med Ctr, Dept Dev Biol, Stanford, CA 94305 USA. RP Wheeler, HE (reprint author), Stanford Univ, Med Ctr, Dept Genet, Stanford, CA 94305 USA. EM kim@cmgm.stanford.edu RI Singleton, Andrew/C-3010-2009; OI Wheeler, Heather/0000-0003-1365-9667 FU National Institutes of Health [R01 AG025941-01A2]; Ellison Medical Foundation; NIH, National Institute on Aging; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336] FX This work was supported by the National Institutes of Health (R01 AG025941-01A2) and the Ellison Medical Foundation. The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through an R&D contract with MedStar Research Institute. The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). HEW was funded by a NIH grant to the Stanford Genetics and Developmental Biology Training Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 37 Z9 37 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2009 VL 5 IS 10 AR e1000685 DI 10.1371/journal.pgen.1000685 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 522WZ UT WOS:000272032100023 PM 19834535 ER PT J AU Gordon, I Paoloni, M Mazcko, C Khanna, C AF Gordon, Ira Paoloni, Melissa Mazcko, Christina Khanna, Chand TI The Comparative Oncology Trials Consortium: Using Spontaneously Occurring Cancers in Dogs to Inform the Cancer Drug Development Pathway SO PLOS MEDICINE LA English DT Editorial Material ID TYROSINE KINASE INHIBITOR; CANINE OSTEOSARCOMA; MURAMYL TRIPEPTIDE; COMPANION ANIMALS; CLINICAL-TRIALS; CISPLATIN; HUMANS; HYPERTHERMIA; MALIGNANCIES; TRANSLATION C1 [Gordon, Ira] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Paoloni, Melissa; Mazcko, Christina; Khanna, Chand] NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gordon, I (reprint author), NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov NR 30 TC 56 Z9 56 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD OCT PY 2009 VL 6 IS 10 AR e1000161 DI 10.1371/journal.pmed.1000161 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 522XB UT WOS:000272032300005 PM 19823573 ER PT J AU Schwarz, A Helling, S Collin, N Teixeira, CR Medrano-Mercado, N Hume, JCC Assumpcao, TC Marcus, K Stephan, C Meyer, HE Ribeiro, JMC Billingsley, PF Valenzuela, JG Sternberg, JM Schaub, GA AF Schwarz, Alexandra Helling, Stefan Collin, Nicolas Teixeira, Clarissa R. Medrano-Mercado, Nora Hume, Jen C. C. Assumpcao, Teresa C. Marcus, Katrin Stephan, Christian Meyer, Helmut E. Ribeiro, Jose M. C. Billingsley, Peter F. Valenzuela, Jesus G. Sternberg, Jeremy M. Schaub, Guenter A. TI Immunogenic Salivary Proteins of Triatoma infestans: Development of a Recombinant Antigen for the Detection of Low-Level Infestation of Triatomines SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID RURAL NORTHWESTERN ARGENTINA; MOSQUITO ANOPHELES-GAMBIAE; RHODNIUS-PROLIXUS STAL; CHAGAS-DISEASE CONTROL; ANTIBODY-RESPONSE; BLOODSUCKING BUG; LUTZOMYIA-LONGIPALPIS; 2-DIMENSIONAL ELECTROPHORESIS; TRYPANOSOMA-CRUZI; ARTHROPOD SALIVA AB Background: Triatomines are vectors of Trypanosoma cruzi, the etiological agent of Chagas disease in Latin America. The most effective vector, Triatoma infestans, has been controlled successfully in much of Latin America using insecticide spraying. Though rarely undertaken, surveillance programs are necessary in order to identify new infestations and estimate the intensity of triatomine bug infestations in domestic and peridomestic habitats. Since hosts exposed to triatomines develop immune responses to salivary antigens, these responses can be evaluated for their usefulness as epidemiological markers to detect infestations of T. infestans. Methodology/Principal Findings: T. infestans salivary proteins were separated by 2D-gel electrophoresis and tested for their immunogenicity by Western blotting using sera from chickens and guinea pigs experimentally exposed to T. infestans. From five highly immunogenic protein spots, eight salivary proteins were identified by nano liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoLC-ESI-MS/MS) and comparison to the protein sequences of the National Center for Biotechnology Information (NCBI) database and expressed sequence tags of a unidirectionally cloned salivary gland cDNA library from T. infestans combined with the NCBI yeast protein sub-database. The 14.6 kDa salivary protein [gi vertical bar 149689094] was produced as recombinant protein (rTiSP14.6) in a mammalian cell expression system and recognized by all animal sera. The specificity of rTiSP14.6 was confirmed by the lack of reactivity to anti-mosquito and anti-sand fly saliva antibodies. However, rTiSP14.6 was recognized by sera from chickens exposed to four other triatomine species, Triatoma brasiliensis, T. sordida, Rhodnius prolixus, and Panstrongylus megistus and by sera of chickens from an endemic area of T. infestans and Chagas disease in Bolivia. Conclusions/Significance: The recombinant rTiSP14.6 is a suitable and promising epidemiological marker for detecting the presence of small numbers of different species of triatomines and could be developed for use as a new tool in surveillance programs, especially to corroborate vector elimination in Chagas disease vector control campaigns. C1 [Schwarz, Alexandra; Billingsley, Peter F.; Sternberg, Jeremy M.] Univ Aberdeen, Sch Biol Sci, Aberdeen, Scotland. [Schwarz, Alexandra; Schaub, Guenter A.] Ruhr Univ Bochum, Grp Zool Parasitol, Bochum, Germany. [Helling, Stefan; Marcus, Katrin; Stephan, Christian; Meyer, Helmut E.] Ruhr Univ Bochum, Med Proteom Ctr, Bochum, Germany. [Collin, Nicolas; Teixeira, Clarissa R.; Ribeiro, Jose M. C.; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Medrano-Mercado, Nora] Univ Mayor San Simon, Dept Biol, Fac Ciencias & Tecnol, Lab Chagas Dis & Immunoparasitol, Cochabamba, Bolivia. [Hume, Jen C. C.] NIAID, Int Studies & Entomol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Assumpcao, Teresa C.] Univ Brasilia, Lab Host Parasite Interface, Brasilia, DF, Brazil. [Billingsley, Peter F.] Sanaria, Rockville, MD USA. RP Schwarz, A (reprint author), Univ Aberdeen, Sch Biol Sci, Zool Bldg, Aberdeen, Scotland. EM alexandraschwarz@arcor.de OI Sternberg, Jeremy/0000-0002-1596-3622; Ribeiro, Jose/0000-0002-9107-0818 FU German Academic Exchange Service (DAAD), Bonn, Germany; the Boehringer Ingelheim Fonds (BIF); Deutsche Forschungsgemeinschaft [Scha 339/ 13- 1]; Humboldt Foundation; University of Aberdeen, Scotland FX This work was supported by grants from the German Academic Exchange Service (DAAD), Bonn, Germany (short- term scholarship), the Boehringer Ingelheim Fonds (BIF), Heidesheim, Germany (travel award), and the ` Deutsche Forschungsgemeinschaft' (project Scha 339/ 13- 1). The support by the Humboldt Foundation to NMM is gratefully acknowledged, and AS was funded by the University of Aberdeen, Scotland (Sixth Century Scholarship). This work was also in part supported by the Intramural Research Program of the Division of Intramural Research, 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 78 TC 20 Z9 21 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD OCT PY 2009 VL 3 IS 10 AR e532 DI 10.1371/journal.pntd.0000532 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 522XF UT WOS:000272032800009 PM 19841746 ER PT J AU Bossart, KN Zhu, ZY Middleton, D Klippel, J Crameri, G Bingham, J McEachern, JA Green, D Hancock, TJ Chan, YP Hickey, AC Dimitrov, DS Wang, LF Broder, CC AF Bossart, Katharine N. Zhu, Zhongyu Middleton, Deborah Klippel, Jessica Crameri, Gary Bingham, John McEachern, Jennifer A. Green, Diane Hancock, Timothy J. Chan, Yee-Peng Hickey, Andrew C. Dimitrov, Dimiter S. Wang, Lin-Fa Broder, Christopher C. TI A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection SO PLOS PATHOGENS LA English DT Article ID HENDRA VIRUS; SUBUNIT VACCINE; HAMSTER MODEL; TRANSMISSION; GLYCOPROTEIN; BANGLADESH; RECEPTOR; CATS; BATS; MORBILLIVIRUS AB Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 TCID(50) within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody. C1 [Bossart, Katharine N.; Middleton, Deborah; Klippel, Jessica; Crameri, Gary; Bingham, John; McEachern, Jennifer A.; Green, Diane; Hancock, Timothy J.; Wang, Lin-Fa] Australian Anim Hlth Lab, CSIRO Livestock Ind, Geelong, Vic, Australia. [Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, CCRNP, CCR,NIH, Frederick, MD 21701 USA. [Zhu, Zhongyu] NCI, BRP, SAIC Frederick Inc, Frederick, MD 21701 USA. [Chan, Yee-Peng; Hickey, Andrew C.; Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. RP Bossart, KN (reprint author), Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. EM kbossart@bu.edu; cbroder@usuhs.mil RI Crameri, Gary/H-8441-2013; Barr, Jennifer/H-9254-2013; Bingham, John/H-8591-2013; OI Bossart, Katharine/0000-0001-6886-6896 FU Jack Brockhoff Foundation; NIH [AI056423, AI054715, AI077995] FX This study was supported by a Jack Brockhoff Foundation grant to KNB and NIH grants AI056423, AI054715 and AI077995 to CCB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 101 Z9 102 U1 0 U2 11 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 OCT PY 2009 VL 5 IS 10 AR e1000642 DI 10.1371/journal.ppat.1000642 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 522XK UT WOS:000272033300046 PM 19888339 ER PT J AU Casazza, JP Brenchley, JM Hill, BJ Ayana, R Ambrozak, D Roederer, M Douek, DC Betts, MR Koup, RA AF Casazza, Joseph P. Brenchley, Jason M. Hill, Brenna J. Ayana, Ribka Ambrozak, David Roederer, Mario Douek, Daniel C. Betts, Michael R. Koup, Richard A. TI Autocrine Production of beta-Chemokines Protects CMV-Specific CD4(+) T Cells from HIV Infection SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MACROPHAGE INFLAMMATORY PROTEIN-1; CYTOMEGALOVIRUS RETINITIS; HIV-1-INFECTED SUBJECTS; ANTIRETROVIRAL THERAPY; RESPONSES REVEALS; NONHUMAN-PRIMATES; RECEPTOR CCR5; IN-VIVO; IDENTIFICATION AB Induction of a functional subset of HIV-specific CD4(+) T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4(+) T cells, which are less frequently infected than HIV-specific CD4(+) T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4(+) T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4(+) T cells rapidly up-regulated production of MIP-1 alpha and MIP-1 beta mRNA, resulting in a rapid increase in production of MIP-1 alpha and MIP-1 beta after cognate antigen stimulation. Production of beta-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4(+) T cells. To test whether production of beta-chemokines by CD4(+) T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4(+) T cells. We found that CMV-specific CD4(+) T cells which produced MIP-1 beta contained 10 times less Gag DNA than did those which failed to produce MIP-1 beta. These data suggest that CD4(+) T cells which produce MIP-1 alpha and MIP-1 beta bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection. C1 [Casazza, Joseph P.; Ayana, Ribka; Ambrozak, David; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.; Hill, Brenna J.] NIAID, Immunopathogenesis Unit, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Betts, Michael R.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. RP Casazza, JP (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jcasazza@mail.nih.gov FU Intramural NIH/NIAID funding FX This work was supported by Intramural NIH/NIAID funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 38 Z9 38 U1 0 U2 2 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 OCT PY 2009 VL 5 IS 10 AR e1000646 DI 10.1371/journal.ppat.1000646 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 522XK UT WOS:000272033300050 PM 19876388 ER PT J AU McDonald, SM Matthijnssens, J McAllen, JK Hine, E Overton, L Wang, SL Lemey, P Zeller, M Van Ranst, M Spiro, DJ Patton, JT AF McDonald, Sarah M. Matthijnssens, Jelle McAllen, John K. Hine, Erin Overton, Larry Wang, Shiliang Lemey, Philippe Zeller, Mark Van Ranst, Marc Spiro, David J. Patton, John T. TI Evolutionary Dynamics of Human Rotaviruses: Balancing Reassortment with Preferred Genome Constellations SO PLOS PATHOGENS LA English DT Article ID GROUP-A ROTAVIRUS; LINKED-IMMUNOSORBENT-ASSAY; G-GENOTYPE; STRAINS; VACCINE; GASTROENTERITIS; VIRUS; SEROTYPES; CHILDREN; PROTEIN AB Group A human rotaviruses (RVs) are a major cause of severe gastroenteritis in infants and young children. Yet, aside from the genes encoding serotype antigens (VP7; G-type and VP4; P-type), little is known about the genetic make-up of emerging and endemic human RV strains. To gain insight into the diversity and evolution of RVs circulating at a single location over a period of time, we sequenced the eleven-segmented, double-stranded RNA genomes of fifty-one G3P[8] strains collected from 1974 to 1991 at Children's Hospital National Medical Center, Washington, D. C. During this period, G1P[8] strains typically dominated, comprising on average 56% of RV infections each year in hospitalized children. A notable exception was in the 1976 and 1991 winter seasons when the incidence of G1P[8] infections decreased dramatically, a trend that correlated with a significant increase in G3P[8] infections. Our sequence analysis indicates that the 1976 season was characterized by the presence of several genetically distinct, co-circulating clades of G3P[8] viruses, which contained minor but significant differences in their encoded proteins. These 1976 lineages did not readily exchange gene segments with each other, but instead remained stable over the course of the season. In contrast, the 1991 season contained a single major clade, whose genome constellation was similar to one of the 1976 clades. The 1991 clade may have gained a fitness advantage after reassorting with as of yet unidentified RV strain(s). This study reveals for the first time that genetically distinct RV clades of the same G/P-type can co-circulate and cause disease. The findings from this study also suggest that, although gene segment exchange occurs, most reassortant strains are replaced over time by lineages with preferred genome constellations. Elucidation of the selective pressures that favor maintenance of RVs with certain sets of genes may be necessary to anticipate future vaccine needs. C1 [McDonald, Sarah M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Matthijnssens, Jelle; Lemey, Philippe; Zeller, Mark; Van Ranst, Marc] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Lab Clin & Epidemiol Virol, Louvain, Belgium. [McAllen, John K.; Hine, Erin; Overton, Larry; Wang, Shiliang; Spiro, David J.] J Craig Venter Inst, Rockville, MD USA. RP McDonald, SM (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014; Matthijnssens, Jelle/A-6770-2015; Matthijnssens, Jelle/B-8634-2016; OI Van Ranst, Marc/0000-0002-1674-4157 FU Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases; Research Fund K.U. Leuven FX SMM and JTP are supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. JM is supported by a postdoctoral fellowship of the Research Fund K.U. Leuven. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 82 Z9 83 U1 1 U2 5 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 OCT PY 2009 VL 5 IS 10 AR e1000634 DI 10.1371/journal.ppat.1000634 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 522XK UT WOS:000272033300038 PM 19851457 ER PT J AU Moore, MD Nikolaitchik, OA Chen, JB Hammarskjold, ML Rekosh, D Hu, WS AF Moore, Michael D. Nikolaitchik, Olga A. Chen, Jianbo Hammarskjoeld, Marie-Louise Rekosh, David Hu, Wei-Shau TI Probing the HIV-1 Genomic RNA Trafficking Pathway and Dimerization by Genetic Recombination and Single Virion Analyses SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; NUCLEAR EXPORT; MESSENGER-RNA; VIRAL REPLICATION; CELLS; DISTANCE; RATES; EXPRESSION; MUTATIONS AB Once transcribed, the nascent full-length RNA of HIV-1 must travel to the appropriate host cell sites to be translated or to find a partner RNA for copackaging to form newly generated viruses. In this report, we sought to delineate the location where HIV-1 RNA initiates dimerization and the influence of the RNA transport pathway used by the virus on downstream events essential to viral replication. Using a cell-fusion-dependent recombination assay, we demonstrate that the two RNAs destined for copackaging into the same virion select each other mostly within the cytoplasm. Moreover, by manipulating the RNA export element in the viral genome, we show that the export pathway taken is important for the ability of RNA molecules derived from two viruses to interact and be copackaged. These results further illustrate that at the point of dimerization the two main cellular export pathways are partially distinct. Lastly, by providing Gag in trans, we have demonstrated that Gag is able to package RNA from either export pathway, irrespective of the transport pathway used by the gag mRNA. These findings provide unique insights into the process of RNA export in general, and more specifically, of HIV-1 genomic RNA trafficking. C1 [Moore, Michael D.; Nikolaitchik, Olga A.; Chen, Jianbo; Hu, Wei-Shau] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Hammarskjoeld, Marie-Louise; Rekosh, David] Univ Virginia, Myles H Thaler Ctr AIDS Res, Charlottesville, VA USA. RP Moore, MD (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM whu@ncifcrf.gov RI Chen, Jianbo/N-3737-2014 OI Chen, Jianbo/0000-0001-6491-6577 FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute, Center for Cancer Research; NIH [AI068501, CA097095] FX This work is supported in part by the Intramural Research Program of the National Institutes of Health (NIH, www.nih.gov), National Cancer Institute, Center for Cancer Research (MDM, OAR, and WSH), and in part by NIH grants AI068501 (to DR), CA097095 (to MLH) and AI068501 (to MLH). Partial salary support for DR and MLH was provided by the Myles H. Thaler and Charles H. Ross Jr. professorships at UVA (www.virginia.edu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 53 Z9 53 U1 1 U2 3 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 OCT PY 2009 VL 5 IS 10 AR e1000627 DI 10.1371/journal.ppat.1000627 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 522XK UT WOS:000272033300031 PM 19834549 ER PT J AU Wearing, HJ Rohani, P AF Wearing, Helen J. Rohani, Pejman TI Estimating the Duration of Pertussis Immunity Using Epidemiological Signatures SO PLOS PATHOGENS LA English DT Article ID BORDETELLA-PERTUSSIS; STOCHASTIC SIMULATION; HOUSEHOLD EXPOSURE; WANING IMMUNITY; VACCINATION; TRANSMISSION; DISEASE; IMMUNIZATION; INFECTION; ENGLAND AB Case notifications of pertussis have shown an increase in a number of countries with high rates of routine pediatric immunization. This has led to significant public health concerns over a possible pertussis re-emergence. A leading proposed explanation for the observed increase in incidence is the loss of immunity to pertussis, which is known to occur after both natural infection and vaccination. Little is known, however, about the typical duration of immunity and its epidemiological implications. Here, we analyze a simple mathematical model, exploring specifically the inter-epidemic period and fade-out frequency. These predictions are then contrasted with detailed incidence data for England and Wales. We find model output to be most sensitive to assumptions concerning naturally acquired immunity, which allows us to estimate the average duration of immunity. Our results support a period of natural immunity that is, on average, long-lasting (at least 30 years) but inherently variable. C1 [Wearing, Helen J.] Univ New Mexico, Dept Biol, Albuquerque, NM 87131 USA. [Wearing, Helen J.] Univ New Mexico, Dept Math & Stat, Albuquerque, NM 87131 USA. [Rohani, Pejman] Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA. [Rohani, Pejman] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Wearing, HJ (reprint author), Univ New Mexico, Dept Biol, Albuquerque, NM 87131 USA. EM hwearing@unm.edu FU National Institutes of Health [R01 GM69111]; National Science Foundation [DEB 0343176]; Ellison Medical Foundation; University of New Mexico FX This work was supported by the National Institutes of Health (R01 GM69111), the National Science Foundation (DEB 0343176) and a New Scholar Award in Global Infectious Disease from the Ellison Medical Foundation to PR. HJW was supported, in part, by start-up funds from the University of New Mexico. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 57 Z9 58 U1 1 U2 5 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 OCT PY 2009 VL 5 IS 10 AR e1000647 DI 10.1371/journal.ppat.1000647 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 522XK UT WOS:000272033300051 PM 19876392 ER PT J AU Xu, S Shen, J AF Xu, Su Shen, Jun TI Studying enzymes by in vivo C-13 magnetic resonance spectroscopy SO PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY LA English DT Review DE Fast chemical exchange; Enzyme-catalyzed reactions; Enzyme kinetics; In vivo C-13 magnetization transfer effect; Magnetic resonance spectroscopy ID CREATINE-KINASE REACTION; RAT SKELETAL-MUSCLE; LACTATE-DEHYDROGENASE ISOENZYMES; KETOGLUTARATE GLUTAMATE EXCHANGE; TRANSFER KINETIC MEASUREMENTS; CHLORALOSE-ANESTHETIZED RATS; TRICARBOXYLIC-ACID CYCLE; ANHYDRASE-II DEFICIENCY; RENAL TUBULAR-ACIDOSIS; CARBONIC-ANHYDRASE C1 [Xu, Su; Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU NIMH; NIH FX This work was supported by the Intramural Research Program of the NIMH, NIH. The authors thank Ms. Ioline Henter for help with manuscript preparation. NR 166 TC 4 Z9 4 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6565 J9 PROG NUCL MAG RES SP JI Prog. Nucl. Magn. Reson. Spectrosc. PD OCT PY 2009 VL 55 IS 3 BP 266 EP 283 DI 10.1016/j.pnmrs.2009.06.002 PG 18 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Chemistry; Physics; Spectroscopy GA 489EM UT WOS:000269402800005 PM 20161496 ER PT J AU Xu, JF Sun, JEL Kader, AK Lindstrom, S Wiklund, F Hsu, FC Johansson, JE Zheng, SL Thomas, G Hayes, RB Kraft, P Hunter, DJ Chanock, SJ Isaacs, WB Gronberg, H AF Xu, Jianfeng Sun, Jielin Kader, A. Karim Lindstrom, Sara Wiklund, Fredrik Hsu, Fang-Chi Johansson, Jan-Erik Zheng, S. Lilly Thomas, Gilles Hayes, Richard B. Kraft, Peter Hunter, David J. Chanock, Stephen J. Isaacs, William B. Gronberg, Henrik TI Estimation of Absolute Risk for Prostate Cancer Using Genetic Markers and Family History SO PROSTATE LA English DT Article DE SNPs; association; early detection; chemoprevention ID GENOME-WIDE ASSOCIATION; SEQUENCE VARIANTS; MULTIPLE; POPULATIONS; LOCI; SUSCEPTIBILITY; FINASTERIDE; PREDICTION AB BACKGROUND. Multiple DNA sequence variants in the form of single-nucleotide polymorphisms (SNPs) have been found to be reproducibly associated with prostate cancer (PCa) risk. METHODS. Absolute risk for PCa among men with various numbers of inherited risk alleles and family history of PCa was estimated in a population-based case-control study in Sweden (2,893 cases and 1,781 controls), and a nested case-control study from the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening Trial in the U.S. (1,172 cases and 1,157 controls). RESULTS. Increased number of risk alleles and positive family history were independently associated with PCa risk. Considering men with 11 risk alleles (mode) and negative family history as having baseline risk, men who had >= 14 risk alleles and positive family history had an odds ratio (OR) of 4.92 [95% confidence interval (CI): 3.64-6.64] in the Swedish study. These associations were confirmed in the U.S. population. Once a man's SNP genotypes and family history are known, his absolute risk for PCa can be readily calculated and easily interpreted. For example, 55-year-old men with a family history and >= 14 risk alleles have a 52% and 41% risk of being diagnosed with PCa in the next 20 years in the Swedish and U.S. populations, respectively. In comparison, without knowledge of genotype and family history, these men had an average population absolute risk of 13%. CONCLUSION. This risk prediction model may be used to identify men at considerably elevated PCa risk who may be selected for chemoprevention. Prostate 69: 1565-1572, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Xu, Jianfeng; Sun, Jielin; Kader, A. Karim; Hsu, Fang-Chi; Zheng, S. Lilly] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC 27157 USA. [Xu, Jianfeng; Sun, Jielin; Hsu, Fang-Chi; Zheng, S. Lilly] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA. [Kader, A. Karim] Wake Forest Univ, Bowman Gray Sch Med, Dept Urol, Winston Salem, NC 27157 USA. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hsu, Fang-Chi] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Johansson, Jan-Erik] Orebro Univ Hosp, Dept Urol, Orebro, Sweden. [Thomas, Gilles; Hayes, Richard B.; Kraft, Peter; Hunter, David J.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Isaacs, William B.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. RP Xu, JF (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jxu@wfubmc.edu; wisaacs@jhmi.edu OI Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute [CA105055, CA106523, CA95052]; Department of Defense [PC051264]; Swedish Cancer Society (Cancerfonden); Swedish Academy of Sciences (Vetenskapsradet) FX Grant sponsor: National Cancer Institute; Grant numbers: CA105055, CA106523, CA95052; Grant sponsor: Department of Defense; Grant number: PC051264; Grant sponsor: Swedish Cancer Society (Cancerfonden); Grant sponsor: Swedish Academy of Sciences (Vetenskapsradet). NR 29 TC 53 Z9 55 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD OCT 1 PY 2009 VL 69 IS 14 BP 1565 EP 1572 DI 10.1002/pros.21002 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 497OV UT WOS:000270070300009 PM 19562736 ER PT J AU Remmert, K Uruno, T Hammer, JA AF Remmert, Kirsten Uruno, Takehito Hammer, John A., III TI Purification of capping protein using the capping protein binding site of CARMIL as an affinity matrix SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Capping protein; CARMIL; Affinity matrix; CAH3 domain ID ACTIN-BASED MOTILITY; ARP2/3 COMPLEX; BARBED END; MYOSIN-I; FILAMENT; POLYMERIZATION; IDENTIFICATION; DICTYOSTELIUM; MECHANISM; INSIGHTS AB Capping protein (CP) is a ubiquitously expressed, heterodimeric actin binding protein that is essential for normal actin dynamics in cells. The existing methods for purifying native CP from tissues and recombinant CP from bacteria are time-consuming processes that involve numerous conventional chromatographic steps and functional assays to achieve a homogeneous preparation of the protein. Here, we report the rapid purification of Acanthamoeba CP from amoeba extracts and recombinant mouse CP from E. coli extracts using as an affinity matrix GST-fusion proteins containing the CP binding site from Acanthamoeba CARMIL and mouse CARMIL-1, respectively. This improved method for CP purification should facilitate the in vitro analysis of CP structure, function, and regulation. Published by Elsevier Inc. C1 [Remmert, Kirsten; Uruno, Takehito; Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Room 2523,9000 Rockville Pike, Rockville, MD USA. EM hammerj@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 20 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD OCT PY 2009 VL 67 IS 2 BP 113 EP 119 DI 10.1016/j.pep.2009.05.002 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 541LJ UT WOS:000273416900008 PM 19427903 ER PT J AU Post, RM AF Post, Robert M. TI Bipolar Disorder, with a Focus on Childhood-onset Bipolar Disorder SO PSYCHIATRIC ANNALS LA English DT Editorial Material ID ADOLESCENTS; CHILDREN C1 [Post, Robert M.] George Washington Univ, Washington, DC 20052 USA. [Post, Robert M.] Bipolar Collaborat Network, Bethesda, MD USA. [Post, Robert M.] NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Post, RM (reprint author), George Washington Univ, Washington, DC 20052 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD OCT PY 2009 VL 39 IS 10 BP 874 EP + DI 10.3928/00485718-20090924-04 PG 2 WC Psychiatry SC Psychiatry GA 507IY UT WOS:000270847300002 ER PT J AU Gillum, RF Santibanez, S Bennett, G Donahue, M AF Gillum, R. F. Santibanez, Scott Bennett, Glen Donahue, Michael TI ASSOCIATIONS OF PRAYER, MIND-BODY THERAPY, AND SMOKING CESSATION IN A NATIONAL SURVEY SO PSYCHOLOGICAL REPORTS LA English DT Article ID CIGARETTE-SMOKING; AFRICAN-AMERICANS; INTERVENTIONS; RELAXATION; PROGRAM; ADULTS; HEART; SOUL AB Smoking is the leading preventable cause of death. Many people use mind-body therapies and/or prayer to assist them in smoking cessation, but more information on their effectiveness is needed. In the 2002 National Health Interview Survey, 5,864 persons aged 18 or older reported smoking in the prior 12 mo.; among these, users of any of 10 mind-body therapies or prayer were compared to nonusers to assess smoking cessation attempts and smoking cessation over a 1-yr. period. Weighted logistic regression showed that the adjusted odds of reporting quit attempts during the year prior to interview or of reporting no longer smoking at interview were significantly higher in those using prayer alone, ally mind-body therapy alone, or both, compared with those who used neither. In the Subset of 2,839 persons who reported smoking 12 mo. prior to interview and attempting to quit during the year prior to interview, the odds of reporting no longer smoking at interview were no greater for those who used prayer, any mind-body therapy, or both, than in those using neither. C1 [Gillum, R. F.] Howard Univ, Sch Divin, Washington, DC 20017 USA. [Gillum, R. F.] Howard Univ, Coll Med, Washington, DC 20017 USA. [Santibanez, Scott] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Bennett, Glen] Natl Inst Hlth, Bethesda, MD 20892 USA. [Donahue, Michael] Inst Psychol Sci, Alexandria, VA USA. RP Gillum, RF (reprint author), Howard Univ, Sch Divin, Washington, DC 20017 USA. EM frank.gillum@gmail.com NR 26 TC 2 Z9 2 U1 1 U2 5 PU AMMONS SCIENTIFIC, LTD PI MISSOULA PA PO BOX 9229, MISSOULA, MT 59807-9229 USA SN 0033-2941 J9 PSYCHOL REP JI Psychol. Rep. PD OCT PY 2009 VL 105 IS 2 BP 593 EP 604 DI 10.2466/PR0.105.2.593-604 PG 12 WC Psychology, Multidisciplinary SC Psychology GA 508TM UT WOS:000270959200029 PM 19928621 ER PT J AU Fortune-Greeley, AK Flynn, KE Jeffery, DD Williams, MS Keefe, FJ Reeve, BB Willis, GB Weinfurt, KP AF Fortune-Greeley, Alice K. Flynn, Kathryn E. Jeffery, Diana D. Williams, Megan S. Keefe, Francis J. Reeve, Bryce B. Willis, Gordon B. Weinfurt, Kevin P. TI Using cognitive interviews to evaluate items for measuring sexual functioning across cancer populations: improvements and remaining challenges SO QUALITY OF LIFE RESEARCH LA English DT Article DE Clinical trials as topic; Neoplasms; Patient satisfaction; Psychometrics; Quality indicators; Quality of life; Sexuality; Treatment outcome ID QUALITY-OF-LIFE; INFORMATION-SYSTEM PROMIS; INTIMACY; INDEX AB One goal of the Patient-Reported Outcomes Measurement Information System (TM) (PROMIS (TM)) is to develop a measure of sexual functioning that broadens the definition of sexual activity and incorporates items that reflect constructs identified as important by patients with cancer. We describe how cognitive interviews improved the quality of the items and discuss remaining challenges to assessing sexual functioning in research with cancer populations. We conducted 39 cognitive interviews of patients with cancer and survivors on the topic of sexual experience. Each of the 83 candidate items was seen by 5-24 participants. Participants included both men and women and varied by cancer type, treatment trajectory, race, and literacy level. Significantly revised items were retested in subsequent interviews. Cognitive interviews provided useful feedback about the relevance, sensitivity, appropriateness, and clarity of the items. Participants identified broad terms (e.g., "sex life") to assess sexual experience and exposed the challenges of measuring sexual functioning consistently, considering both adjusted and unadjusted sexual experiences. Cognitive interviews were critical for item refinement in the development of the PROMIS measure of sexual function. Efforts are underway to validate the measure in larger cancer populations. C1 [Fortune-Greeley, Alice K.; Flynn, Kathryn E.; Weinfurt, Kevin P.] Duke Clin Res Inst, Ctr Clin & Genet Econ, Durham, NC 27715 USA. [Flynn, Kathryn E.; Keefe, Francis J.; Weinfurt, Kevin P.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [Williams, Megan S.] Duke Univ, Sch Nursing, Durham, NC USA. [Jeffery, Diana D.; Reeve, Bryce B.; Willis, Gordon B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Weinfurt, KP (reprint author), Duke Clin Res Inst, Ctr Clin & Genet Econ, POB 17969, Durham, NC 27715 USA. EM kevin.weinfurt@duke.edu RI Flynn, Kathryn/M-5346-2013; OI Flynn, Kathryn/0000-0002-4427-3583; Fortune-Greeley, Alice/0000-0001-9004-571X FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [U01AR052186]; National Cancer Institute FX Funding/Support: This work was funded by grant U01AR052186 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, with additional support from the National Cancer Institute. Disclaimer: The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Cancer Institute, or the National Institutes of Health. PROMIS Sexual Function Domain Committee: Maria R. Fawzy, Kathryn E. Flynn, Tracey L. Krupski, Laura S. Porter, Rebecca Shelby, and Kevin P. Weinfurt (Duke University); Elizabeth A. Hahn (Northwestern University); and Diana D. Jeffery and Bryce B. Reeve (National Cancer Institute). Additional Contributions: We thank Elizabeth Clipp of Duke University and Wendy Demark-Wahnefried of MD Anderson Cancer Center for assistance with PROMIS grant development; Denise Snyder of Duke University for assistance with data collection; Justin Levens and Chantelle Hardy of Duke University for conducting the cognitive interviews; Janice Tzeng of Duke University for research assistance; and Damon Seils of Duke University for editorial assistance and manuscript preparation. NR 21 TC 20 Z9 20 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2009 VL 18 IS 8 BP 1085 EP 1093 DI 10.1007/s11136-009-9523-x PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 495IU UT WOS:000269885400014 PM 19672697 ER PT J AU Lushchak, OV Bayliak, MM Korobova, OV Levine, RL Lushchak, VI AF Lushchak, Oleh V. Bayliak, Maria M. Korobova, Olha V. Levine, Rodney L. Lushchak, Volodymyr I. TI Buffer modulation of menadione-induced oxidative stress in Saccharomyces cerevisiae SO REDOX REPORT LA English DT Article DE aconitase; antioxidant enzymes; glutathione; protein carbonyls; reactive oxygen species; Saccharomyces cerevisiae ID REDOX-DEPENDENT MODULATION; CARBONATE RADICAL-ANION; AMINO-ACID OXIDATION; CU,ZN-SUPEROXIDE DISMUTASE; HYDROGEN-PEROXIDE; SUPEROXIDE-DISMUTASE; MITOCHONDRIAL ACONITASE; BICARBONATE BUFFER; CHEMISTRY; PROTEINS AB The objective of this study was to compare, in vivo, the effects of bicarbonate and phosphate buffers on survival and menadione-induced oxidative stress in yeast cells. The latter were treated with different concentrations of menadione in the presence of these two buffers. At 25 mM concentration of buffers, menadione only slightly reduced yeast surviving; at up mM concentration, cell killing by menadione was much more pronounced in bicarbonate than in phosphate buffer. Although the content of protein carbonyl groups did not show development of oxidative stress under menadione-induced stress, inactivation of aconitase and decrease in glutathione level mirrored its induction. However, cellular glutathione and aconitase activity decrease did not correlate with yeast survival. In vitro, aconitase was more quickly inactivated in up mM carbonate, than in up mM phosphate buffer. The possible involvement of the carbonate radical in these processes is discussed. C1 [Lushchak, Oleh V.; Bayliak, Maria M.; Korobova, Olha V.; Lushchak, Volodymyr I.] Vassyl Stefanyk Precarpathian Natl Univ, Dept Biochem, UA-76025 Ivano Frankivsk, Ukraine. [Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Lushchak, VI (reprint author), Vassyl Stefanyk Precarpathian Natl Univ, Dept Biochem, 57 Shevchenko Str, UA-76025 Ivano Frankivsk, Ukraine. EM lushchak@pu.if.ua RI Lushchak, Oleh/A-8772-2015; Bayliak, Maria/P-8950-2015; Levine, Rodney/D-9885-2011 OI Lushchak, Oleh/0000-0002-4627-1987; Bayliak, Maria/0000-0001-6268-8910; FU Intramural NIH HHS [ZIA HL000225-32] NR 40 TC 7 Z9 7 U1 0 U2 3 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1351-0002 J9 REDOX REP JI Redox Rep. PD OCT PY 2009 VL 14 IS 5 BP 214 EP 220 DI 10.1179/135100009X12525712409454 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 517OL UT WOS:000271625100004 PM 19843376 ER PT J AU Prause, AS Stoffel, MH Portier, CJ Mevissen, M AF Prause, Andrea S. Stoffel, Michael H. Portier, Christopher J. Mevissen, Meike TI Expression and function of 5-HT7 receptors in smooth muscle preparations from equine duodenum, ileum, and pelvic flexure SO RESEARCH IN VETERINARY SCIENCE LA English DT Article DE 5-HT7 receptor; Interstitial cells of Cajal; c-Kit; Equine; Intestine; Motility ID GUINEA-PIG ILEUM; GASTROINTESTINAL-TRACT; INTERSTITIAL-CELLS; SMALL-INTESTINE; PHARMACOLOGICAL CHARACTERIZATION; 5-HYDROXYTRYPTAMINE(4) RECEPTOR; MEDIATING CONTRACTION; LONGITUDINAL MUSCLE; HORSES; SEROTONIN AB In horses, gastrointestinal (GI) disorders occur frequently and cause a considerable demand for efficient medication. 5-Hydroxytryptamine receptors (5-HT) have been reported to be involved in GI tract motility and thus, are potential targets for treating functional bowel disorders. Our studies extend current knowledge on the 5-HT7 receptor in equine duodenum, ileum and pelvic flexure by studying its expression throughout the intestine and its role in modulating contractility in vitro by immunofluorescence and organ bath experiments, respectively. 5-HT7 immunoreactivity was demonstrated in both smooth muscle layers, particularly in the circular one, and within the myenteric plexus. Interstitial cells of Cajal (ICC), identified by c-Kit labeling, show a staining pattern similar to that of 5-HT7 immunoreactivity. The selective 5-HT7 receptor antagonist SB-269970 increased the amplitude of contractions in spontaneous contracting specimens of the ileum and in electrical field-stimulated specimens of the pelvic flexure concentration-dependently. Our in vitro experiments suggest an involvement of the 5-HT7 receptor subtype in contractility of equine intestine. While the 5-HT7 receptor has been established to be constitutively active and inhibits smooth muscle contractility, our experiments demonstrate an increase in contractility by the 5-HT7 receptor ligand SB-269970, suggesting it exerting inverse agonist properties. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Prause, Andrea S.; Mevissen, Meike] Univ Bern, Div Vet Pharmacol & Toxicol, CH-3012 Bern, Switzerland. [Stoffel, Michael H.] Univ Bern, Div Vet Anat, CH-3012 Bern, Switzerland. [Portier, Christopher J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Mevissen, M (reprint author), Univ Bern, Div Vet Pharmacol & Toxicol, CH-3012 Bern, Switzerland. EM meike.mevissen@vpi.unibe.ch RI Portier, Christopher/A-3160-2010; Stoffel, Michael/I-6939-2015 OI Portier, Christopher/0000-0002-0954-0279; Stoffel, Michael/0000-0002-4699-5125 FU Vetsuisse and the Berne University Research Foundation; Intramural Research Program of the NIH; NIEHS FX This study was funded by Vetsuisse and the Berne University Research Foundation. This research was supported [in part] by the Intramural Research Program of the NIH, and NIEHS. NR 44 TC 7 Z9 9 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0034-5288 J9 RES VET SCI JI Res. Vet. Sci. PD OCT PY 2009 VL 87 IS 2 BP 292 EP 299 DI 10.1016/j.rvsc.2009.03.009 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 482PH UT WOS:000268900700029 PM 19364615 ER PT J AU Ballarino, GJ Olivier, KN Claypool, RJ Holland, SM Prevots, DR AF Ballarino, Guillermo J. Olivier, Kenneth N. Claypool, Reginald J. Holland, Steven M. Prevots, D. Rebecca TI Pulmonary nontuberculous mycobacterial infections: Antibiotic treatment and associated costs SO RESPIRATORY MEDICINE LA English DT Article DE Mycobacteria, atypical; Nontuberculous mycobacteria; Anti mycobacterial. agents; Health-care costs; Drug toxicity; Mycobacterium avium complex ID UNITED-STATES; DISEASES; HIV; EPIDEMIOLOGY; SPECIMENS; DIAGNOSIS; CARE AB Recent studies suggest an increasing prevalence of pulmonary nontuberculous mycobacteria (NTM) disease. In the absence of prevalence and cost data, the public health burden of pulmonary NTM disease is difficult to assess. The goal of this study was to assess costs associated with NTM disease treatment and to identify risk factors associated with increased costs. Records from subjects with pulmonary NTM disease enrolled in a natural history protocol were abstracted for presenting symptoms, comorbidities, microbiology, and treatment histories. Antibiotic frequency, duration, adverse reaction, and costs were noted, the total antibiotic burden and cost were calculated, and risk factors associated with high costs were analyzed. From Jan 2004 to Dec 2005, 33 subjects were enrolled; 27 met disease criteria and had sufficient data to assess antibiotic use. Mycobacterium avium complex was present in 89% and Mycobacterium abscessus was present in 21% of subjects. Subjects received a median of 5 (1-10) antibiotics. Adverse effects were common seen in up to 50% with common antibiotics and up to 100% with uncommonly used antibiotics. Median burden of treatment was 2638 (84-7689) drug-days and the median total cost per patient was $19,876 ($398-70,917). Subjects with high treatment costs had an adjusted 9.5 fold (95% CI 1.5-97.2) likelihood of having M. abscessus and a 4.2 fold (95% CI 0.6-59.3) increased likelihood of having more extensive disease. Pulmonary NTM represent an underappreciated disease burden in the US population, with an associated treatment cost comparable to that for other chronic diseases of infectious origin such as HIV/AIDS. Published by Elsevier Ltd. C1 [Prevots, D. Rebecca] NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Ballarino, Guillermo J.] George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. RP Prevots, DR (reprint author), NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH,US Dept HHS, Qrtrs 15B-1,8 W Dr,MSC 2665, Bethesda, MD 20892 USA. EM rprevots@niaid.nih.gov FU NIAID; NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 18 TC 25 Z9 28 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD OCT PY 2009 VL 103 IS 10 BP 1448 EP 1455 DI 10.1016/j.rmed.2009.04.026 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 497IT UT WOS:000270053200009 PM 19467851 ER PT J AU Shah, V Pohida, T Turkbey, B Mani, H Merino, M Pinto, PA Choyke, P Bernardo, M AF Shah, Vijay Pohida, Thomas Turkbey, Baris Mani, Haresh Merino, Maria Pinto, Peter A. Choyke, Peter Bernardo, Marcelino TI A method for correlating in vivo prostate magnetic resonance imaging and histopathology using individualized magnetic resonance -based molds SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID DIFFUSION-WEIGHTED MRI; CONTRAST-ENHANCED MRI; TISSUE-SHRINKAGE; CANCER; LOCALIZATION; SPECIMENS; 3-T AB A method for the design and rapid manufacture of a patient specific tissue slicing device based on in vivo images in order to facilitate the process of correlating the images with histopathology is presented. The method is applied to radical prostatectomy specimens where the customized mold is designed using magnetic resonance (MR) images of each patient obtained prior to surgery. In this case, the mold holds the prostate in place while a knife with a single blade or multiple blades is inserted in slots which are positioned to obtain tissue blocks corresponding to the slices in the MR images. The resulting histological specimens demonstrate good anatomical correlation with the MR images. (C) 2009 American Institute of Physics. [doi:10.1063/1.3242697] C1 [Shah, Vijay; Bernardo, Marcelino] NCI, SAIC Frederick Inc, Frederick, MD 20892 USA. [Shah, Vijay; Turkbey, Baris; Choyke, Peter; Bernardo, Marcelino] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Pohida, Thomas] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Mani, Haresh; Merino, Maria] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Bernardo, M (reprint author), NCI, SAIC Frederick Inc, Frederick, MD 20892 USA. EM bernardom@mail.nih.gov RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project was funded 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 Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 22 TC 35 Z9 35 U1 1 U2 1 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0034-6748 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD OCT PY 2009 VL 80 IS 10 AR 104301 DI 10.1063/1.3242697 PG 6 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 513YE UT WOS:000271359300030 PM 19895076 ER PT J AU Calvo, F AF Calvo, Fabien TI 10(th) anniversary of the French-language Thoracic Oncology Intergroup Meetings Paris, the 18(th) and 19(th) of June 2009 Introduction SO REVUE DE PNEUMOLOGIE CLINIQUE LA French DT Editorial Material C1 Natl Canc Inst, Bethesda, MD 20892 USA. RP Calvo, F (reprint author), Natl Canc Inst, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0761-8417 J9 REV PNEUMOL CLIN JI Rev. Pneumol. Clin. PD OCT PY 2009 VL 65 BP S2 EP S2 PG 1 WC Respiratory System SC Respiratory System GA 527OS UT WOS:000272377000002 ER PT J AU Patterson, GH AF Patterson, George H. TI Fluorescence microscopy below the diffraction limit SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE STED; SPIM; DLSM; SIM; PALM; STORM; Photoactivation; Photoswitching ID STRUCTURED-ILLUMINATION MICROSCOPY; PHOTOACTIVATED LOCALIZATION MICROSCOPY; OPTICAL RECONSTRUCTION MICROSCOPY; FIELD LIGHT-MICROSCOPY; PLASMA-MEMBRANE; SUPERRESOLUTION MICROSCOPY; 3-DIMENSIONAL RESOLUTION; STIMULATED-EMISSION; ELECTRON-MICROSCOPY; AXIAL RESOLUTION AB Fluorescence imaging with conventional microscopy has experienced numerous advances in almost every limiting factor from sensitivity to speed. But improved resolution beyond the fundamental limitation of light diffraction has been elusive until recent years. Now, techniques are available that surpass this barrier and improve resolution up to 10 times over that of conventional microscopy. This chapter provides an overview of these new "super-resolution" imaging methods. Published by Elsevier Ltd. C1 Natl Inst Biomed Imaging & Bioengn, Biophoton Sect, NIH, Bethesda, MD USA. RP Patterson, GH (reprint author), Natl Inst Biomed Imaging & Bioengn, Biophoton Sect, NIH, Bethesda, MD USA. EM pattersg@mail.nih.gov FU Intramural NIH HHS [Z99 EB999999] NR 69 TC 19 Z9 19 U1 4 U2 37 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD OCT PY 2009 VL 20 IS 8 BP 886 EP 893 DI 10.1016/j.semcdb.2009.08.006 PG 8 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 552OA UT WOS:000274300800002 PM 19698798 ER PT J AU Lynch, JK AF Lynch, John Kylan TI Epidemiology and classification of perinatal stroke SO SEMINARS IN FETAL & NEONATAL MEDICINE LA English DT Article DE Epidemiology; Ischemic stroke; Outcome; Perinatal stroke; Risk factors ID ARTERIAL ISCHEMIC-STROKE; NEONATAL CEREBRAL INFARCTION; FACTOR-V-LEIDEN; SINOVENOUS THROMBOSIS; CARDIAC-SURGERY; PRETERM INFANT; RISK-FACTORS; SCHOOL-AGE; FOLLOW-UP; CHILDREN AB Stroke is an important cause of mortality and chronic morbidity in infants and children. Case definitions for perinatal stroke have varied among studies by clinical and laboratory criteria. A recent US National Institutes of Health workshop on perinatal stroke provided consensus recommendations on the definition and classification of perinatal stroke. The incidence of perinatal stroke has been estimated at 1 in 1600 to 5000 births. The clinical presentation of perinatal stroke depends on the time of diagnosis, acute or delayed, but most will present with seizures. Risk factors for perinatal stroke have not been well studied. Several maternal and neonatal disorders have been reported in infants with perinatal stroke. Children who suffer perinatal stroke typically develop long-term disabilities including motor deficits, cognitive and behavioral disorders, and epilepsy. More than half will develop long-term motor or cognitive problems and the recurrence rate after perinatal stroke is very low. (c) 2009 Published by Elsevier Ltd. C1 Natl Inst Neurol Disorders & Stroke, Div Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Lynch, JK (reprint author), Natl Inst Neurol Disorders & Stroke, Div Stroke Diagnost & Therapeut, 10 Ctr Dr,MSC 1447, Bethesda, MD 20892 USA. EM lynchj@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX Dr. Lynch is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 48 TC 43 Z9 48 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1744-165X J9 SEMIN FETAL NEONAT M JI Semin. Fetal Neonatal Med. PD OCT PY 2009 VL 14 IS 5 BP 245 EP 249 DI 10.1016/j.siny.2009.07.001 PG 5 WC Pediatrics SC Pediatrics GA 504UF UT WOS:000270642500002 PM 19664976 ER PT J AU Zebrack, B Hamilton, R Smith, AW AF Zebrack, Brad Hamilton, Rachel Smith, Ashley Wilder TI Psychosocial Outcomes and Service Use Among Young Adults With Cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID QUALITY-OF-LIFE; LONG-TERM SURVIVORS; SUPPORT GROUP PARTICIPATION; SOCIAL-WORK SERVICES; BREAST-CANCER; SELF-EFFICACY; TESTICULAR CANCER; CHILDHOOD-CANCER; HEALTH-CARE; PSYCHOLOGICAL DISTRESS C1 [Zebrack, Brad; Hamilton, Rachel] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, Bethesda, MD 20892 USA. RP Zebrack, B (reprint author), 1080 S Univ, Ann Arbor, MI 48109 USA. NR 143 TC 32 Z9 32 U1 4 U2 16 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2009 VL 36 IS 5 BP 468 EP 477 DI 10.1053/j.seminoncol.2009.07.003 PG 10 WC Oncology SC Oncology GA 510KF UT WOS:000271086700010 PM 19835742 ER PT J AU Gaydos, C Maldeis, NE Hardick, A Hardick, J Quinn, TC AF Gaydos, Charlotte Maldeis, Nancy E. Hardick, Andrew Hardick, Justin Quinn, Thomas C. TI Mycoplasma genitalium as a Contributor to the Multiple Etiologies of Cervicitis in Women Attending Sexually Transmitted Disease Clinics SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID REAL-TIME PCR; PELVIC-INFLAMMATORY-DISEASE; TRANSCRIPTION-MEDIATED AMPLIFICATION; CHLAMYDIA-TRACHOMATIS INFECTION; ROCHE LIGHTCYCLER INSTRUMENT; POLYMERASE-CHAIN-REACTION; VAGINAL SWAB SAMPLES; TRICHOMONAS-VAGINALIS; MUCOPURULENT CERVICITIS; NEISSERIA-GONORRHOEAE AB Objectives: The purpose of this study was to investigate the prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium, in women attending a sexually transmitted disease (STD) clinic, as well as the frequency of coinfections, and relationship of each organism to cervicitis. Methods: In this cross-sectional study of 324 women attending Baltimore City STD Clinics, C. trachomatis, N. gonorrhoeae, T vaginalis, and M. genitalium were detected using nucleic acid amplification tests. Demographic characteristics and risk factors were ascertained. Results: Overall prevalence of infection with C. trachomatis, N. gonorrhoeae, T. vaginalis, and M. genitalium was found to be 11.1%, 4.6%, 15.3%, and 19.2%, respectively. Prevalence in women with cervicitis was 15.8%, 6%, 18.9%, and 28.6% for C. trachomatis, N. gonorrhoeae, T. vaginalis, and M. genitalium, respectively. Percentages of coinfections were high. C. trachomatis and M. genitalium were significantly associated with cervicitis in univariate analysis, but only M. genitalium was significantly associated with cervicitis (AOR: 2.5) in multiple logistic regression models. Conclusion: Knowledge of the statistical association of M. genitalium with cervicitis in this study increases the need for further confirmation of the etiologic significance of this organism with cervicitis in more diverse populations. The high prevalence merits more study and may have implications for diagnosis and treatment of cervicitis. C1 [Gaydos, Charlotte; Hardick, Andrew; Hardick, Justin; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Maldeis, Nancy E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Gaydos, C (reprint author), 530 Rangos Bldg,855 N Wolfe St, Baltimore, MD 21205 USA. EM cgaydos@jhmi.edu RI Gaydos, Charlotte/E-9937-2010 FU The HIV Prevention Trials Network (HPTN); NIAID; National Institutes of Child Health and Human Development (NICH/HD); National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research; NIH; DHHS [U01-AI-068613]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD FX The tests per-formed for Transcription Mediated Amplifications Tests were conducted using APTIMA reagents provided by GenProbe, Inc, San Diego, CA, and supported in part by The HIV Prevention Trials Network (HPTN) sponsored by the NIAID, National Institutes of Child Health and Human Development (NICH/HD), National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, DHHS (U01-AI-068613), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. NR 45 TC 49 Z9 53 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 2009 VL 36 IS 10 BP 598 EP 606 DI 10.1097/OLQ.0b013e3181b01948 PG 9 WC Infectious Diseases SC Infectious Diseases GA 500GN UT WOS:000270286900001 PM 19704398 ER PT J AU Gaydos, C Maldeis, NE Hardick, A Hardick, J Quinn, TC AF Gaydos, C. Maldeis, N. E. Hardick, A. Hardick, J. Quinn, T. C. TI Mycoplasma genitalium compared to chlamydia, gonorrhoea and trichomonas as an aetiological agent of urethritis in men attending STD clinics SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article ID REAL-TIME PCR; SEXUALLY-TRANSMITTED-DISEASES; NONGONOCOCCAL URETHRITIS; ASYMPTOMATIC MEN; URINE; AMPLIFICATION; TRANSMISSION; ASSOCIATION; PERFORMANCE; PREVALENCE AB Objectives: To investigate prevalence of Mycoplasma genitalium, Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis in men, frequency of co-infections, and association of organisms with urethritis in men. Methods: This was a cross-sectional study of 290 men (age range 19-34 years) attending Baltimore City STD clinics. M genitalium, C trachomatis, N gonorrhoeae and T vaginalis, during 2004 were detected using nucleic acid amplification tests (NAATs) (153 with urethritis and 137 without urethritis). Demographic characteristics and risk factors were ascertained. Results: The overall prevalences of infection with C trachomatis, N gonorrhoeae, T vaginalis and M genitalium were 20.3%, 12.8%, 3.4% and 15.2%, respectively. Prevalences in men with urethritis were 32.7%, 24.2%, 5.2% and 22.2% for C trachomatis, N gonorrhoeae, T vaginalis and M genitalium, respectively. Percentages of co- infections were high. All men with N gonorrhoeae had urethritis. C trachomatis and M genitalium were found to be significantly associated with urethritis in univariate analysis and in multiple logistic regression analysis. Conclusion: The association of M genitalium with urethritis in this study provides confirmation of the importance of screening men for M genitalium as a cause of non-gonococcal urethritis and supports treatment considerations for urethritis for agents other than gonococci and chlamydia. C1 [Gaydos, C.; Hardick, A.; Hardick, J.; Quinn, T. C.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Maldeis, N. E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Quinn, T. C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Gaydos, C (reprint author), 530 Rangos Bldg,855 N Wolfe St, Baltimore, MD 21205 USA. EM cgaydos@jhmi.edu RI Gaydos, Charlotte/E-9937-2010 FU GenProbe, InC; NIAID; National Institutes of Child Health and Human Development (NICH/HD); National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research, of the NIH, DHHS [U01-AI-068613]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD FX This work was conducted using Aptima reagents provided by GenProbe, InC and supported in part by the HIV Prevention Trials Network (HPTN) sponsored by the NIAID, National Institutes of Child Health and Human Development (NICH/HD), National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, DHHS (U01-AI-068613), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. NR 15 TC 29 Z9 34 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD OCT PY 2009 VL 85 IS 6 BP 438 EP 440 DI 10.1136/sti.2008.035477 PG 3 WC Infectious Diseases SC Infectious Diseases GA 505VA UT WOS:000270725200009 PM 19383597 ER PT J AU Yuan, M Yang, YN Zheng, G AF Yuan, Min Yang, Yaning Zheng, Gang TI TWO-STAGE GENOME-WIDE ASSOCIATION STUDIES WITH DNA POOLING AND GENETIC MODEL SELECTION SO STATISTICA SINICA LA English DT Article DE Cost-effective design; DNA pooling; genetic model selection; joint analysis; robustness; trend tests; two-stage ID HARDY-WEINBERG EQUILIBRIUM; LARGE-SCALE ASSOCIATION; SAMPLE-SIZE; DISEASE ASSOCIATION; TREND TESTS; DESIGNS; DISEQUILIBRIUM; EFFICIENT; SCANS; POWER AB The two-stage design is a common cost-effective approach for genome-wide association studies. The first stage serves as a screening to identify a subset of single-nucleotide polymorphisms (SNPs) from 100,000 to 500,000 SNPs using a fraction of case-control samples. In the second stage, only the selected SNPs are genotyped using the remaining case-control samples. On the other hand, DNA pooling is another common strategy to save genotyping cost. In this article, we propose a method using DNA pooling in the first stage and genotype-based analysis in the second stage. A joint analysis to combine both stages is applied to a two-stage design with DNA pooling when the underlying genetic model is known. When the genetic model is unknown, we use a robust procedure in the joint analysis by applying genetic model selection in the second stage based on the difference of Hardy-Weinberg disequilibrium coefficients between cases and controls. Performance of our method and comparison with other approaches are investigated by simulation studies. C1 [Yuan, Min; Yang, Yaning] Univ Sci & Technol China, Dept Stat & Finance, Hefei, Anhui, Peoples R China. [Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Yuan, M (reprint author), Univ Sci & Technol China, Dept Stat & Finance, Hefei, Anhui, Peoples R China. EM myuan@mail.ustc.edu.cn; ynyang@ustc.edu.cn; zhengg@nhlbi.nih.gov FU Chinese Council of Scholarship; China NSF; Chinese Academy of Science FX The work of Yuan was completed while she was visiting Department of Statistics, Columbia University, partially supported by the Chinese Council of Scholarship. She also thanks Dr. Zhiliang Ying for his encouragement and support during her visit. The work of Yuan and Yang was also partially supported by a China NSF Grant and a grant from the Chinese Academy of Science. We would like to thank two reviewers for their insightful suggestions and comments which have greatly improved our presentation. NR 32 TC 0 Z9 1 U1 0 U2 3 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD OCT PY 2009 VL 19 IS 4 BP 1769 EP 1786 PG 18 WC Statistics & Probability SC Mathematics GA 521ZT UT WOS:000271966500027 ER PT J AU Nasonkin, I Mahairaki, V Xu, LY Hatfield, G Cummings, BJ Eberhart, C Ryugo, DK Maric, D Bar, E Koliatsos, VE AF Nasonkin, Igor Mahairaki, Vasiliki Xu, Leyan Hatfield, Glen Cummings, Brian J. Eberhart, Charles Ryugo, David K. Maric, Dragan Bar, Eli Koliatsos, Vassilis E. TI Long-Term, Stable Differentiation of Human Embryonic Stem Cell-Derived Neural Precursors Grafted into the Adult Mammalian Neostriatum SO STEM CELLS LA English DT Article DE Cellular therapy; Embryonic stem cells; Neural differentiation; Neural induction; Neural stem cells; Pluripotent stem cells; Stem cell plasticity; Stem cell transplantation ID CENTRAL-NERVOUS-SYSTEM; LATERAL GANGLIONIC EMINENCE; IN-VITRO DIFFERENTIATION; DOUBLECORTIN-LIKE-KINASE; SPINAL-CORD; RAT-BRAIN; STRIATAL PROGENITORS; DOPAMINERGIC-NEURONS; ADHERENT CULTURE; PRONEURAL BHLH AB Stem cell grafts have been advocated as experimental treatments for neurological diseases by virtue of their ability to offer trophic support for injured neurons and, theoretically, to replace dead neurons. Human embryonic stem cells (HESCs) are a rich source of neural precursors (NPs) for grafting, but have been questioned for their tendency to form tumors. Here we studied the ability of HESC-derived NP grafts optimized for cell number and differentiation stage prior to transplantation, to survive and stably differentiate and integrate in the basal forebrain (neostriatum) of young adult nude rats over long periods of time (6 months). NPs were derived from adherent monolayer cultures of HESCs exposed to noggin. After transplantation, NPs showed a drastic reduction in mitotic activity and an avid differentiation into neurons that projected via major white matter tracts to a variety of forebrain targets. A third of NP-derived neurons expressed the basal forebrain-neostriatal marker dopamine-regulated and cyclic AMP-regulated phosphoprotein. Graft-derived neurons formed mature synapses with host postsynaptic structures, including dendrite shafts and spines. NPs inoculated in white matter tracts showed a tendency toward glial (primarily astrocytic) differentiation, whereas NPs inoculated in the ventricular epithelium persisted as nestin(+) precursors. Our findings demonstrate the long-term ability of noggin-derived human NPs to structurally integrate tumor-free into the mature mammalian forebrain, while maintaining some cell fate plasticity that is strongly influenced by particular central nervous system (CNS) niches. STEM CELLS 2009;27:2414-2426 C1 [Nasonkin, Igor; Mahairaki, Vasiliki; Xu, Leyan; Hatfield, Glen; Bar, Eli; Koliatsos, Vassilis E.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. [Koliatsos, Vassilis E.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Koliatsos, Vassilis E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Cummings, Brian J.] Univ Calif Irvine, Reeve Irvine Res Ctr, Irvine, CA USA. [Eberhart, Charles] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Eberhart, Charles] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Ryugo, David K.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, Flow Cytometry Core Facil, NIH, Bethesda, MD USA. RP Nasonkin, I (reprint author), NEI, NIH, Neurobiol Neurodegenerat & Repair Lab, 9000 Rockville Pike,Bldg 6,Rm 341, Bethesda, MD 20892 USA. EM nasonkini@mail.nih.gov; koliat@jhmi.edu RI Cummings, Brian/C-9180-2012; Ryugo, David/G-1940-2012 OI Cummings, Brian/0000-0003-3628-5290; Ryugo, David/0000-0002-5250-7503 FU National Institutes of Health [NS45140-03, NIDCD DC000232, NIDCD P30 DC005211, EY01765]; Robert Packard Center; Muscular Dystrophy Association FX We thank Alex Kecojevic, Annie Welsh, Tan Pongstaporn, and Christa Baker for their technical help and StemCells Inc. and Dr. Christopher Walsh for their generous gifts of the SC121 and DCAMKL1 antibodies, respectively. This work was supported by the National Institutes of Health grants NS45140-03, NIDCD DC000232, NIDCD P30 DC005211, and EY01765, the Robert Packard Center for ALS Research at Johns Hopkins, and the Muscular Dystrophy Association. NR 58 TC 32 Z9 32 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD OCT PY 2009 VL 27 IS 10 BP 2414 EP 2426 DI 10.1002/stem.177 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 520GP UT WOS:000271830200005 PM 19609935 ER PT J AU Wendell, CR Zonderman, AB Metter, EJ Najjar, SS Waldstein, SR AF Wendell, Carrington Rice Zonderman, Alan B. Metter, E. Jeffrey Najjar, Samer S. Waldstein, Shari R. TI Carotid Intimal Medial Thickness Predicts Cognitive Decline Among Adults Without Clinical Vascular Disease SO STROKE LA English DT Article DE carotid intimal medial thickness; subclinical vascular disease; atherosclerosis; cognitive function; neuropsychology ID CARDIOVASCULAR RISK-FACTORS; CEREBROVASCULAR-DISEASE; ALZHEIMERS-DISEASE; IMPAIRMENT; ATHEROSCLEROSIS; ASSOCIATIONS; PERFORMANCE; DEMENTIA; LESIONS; HEALTH AB Background and Purpose-Though clinical cardiovascular and cerebrovascular diseases are established risk factors for cognitive decline and dementia, less is known about the relations between vascular health and cognition among individuals without these diseases. Carotid intimal medial thickness (IMT), a measure of subclinical vascular disease, is associated with concurrent decrements in cognitive function, but relatively little research has examined longitudinal relations between carotid IMT and prospective cognitive decline. Methods-We examined relations of carotid IMT to prospective trajectories of cognitive function among 538 (aged 20 to 93, 39% male, 66% white) participants in the Baltimore Longitudinal Study of Aging (BLSA) free of known cardiovascular, cerebrovascular, and neurological disease. Participants underwent initial carotid ultrasonography and repeat neuropsychological testing on up to 8 occasions over up to 11 years of follow-up. Mixed-effects regression analyses were adjusted for age, gender, race, education, mean arterial pressure, body mass index, total cholesterol, smoking, depressive symptoms, and cardiovascular medication use. Results-Individuals with greater carotid IMT displayed accelerated decline in performance over time on multiple tests of verbal and nonverbal memory, as well as a test of semantic association fluency and executive function. Conclusions-Carotid IMT predicts accelerated cognitive decline, particularly in the domain of memory, among community-dwelling individuals free of vascular and neurological disease. (Stroke. 2009;40:3180-3185.) C1 [Wendell, Carrington Rice; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21250 USA. [Wendell, Carrington Rice; Zonderman, Alan B.; Metter, E. Jeffrey; Najjar, Samer S.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Waldstein, Shari R.] Univ Maryland, Sch Med, Div Gerontol, Dept Med, Baltimore, MD 21201 USA. Baltimore VA Med Center, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. RP Wendell, CR (reprint author), Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM rice3@umbc.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health; National Institute on Aging. FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 35 TC 72 Z9 72 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD OCT PY 2009 VL 40 IS 10 BP 3180 EP 3185 DI 10.1161/STROKEAHA.109.557280 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 499NV UT WOS:000270229800004 PM 19644063 ER PT J AU Mathur, A Gorden, P Libutti, SK AF Mathur, Aarti Gorden, Philip Libutti, Steven K. TI Insulinoma SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Insulinoma; Pancreatic neuroendocrine tumor; Metastatic insulinoma; Management; Surgery ID ISOLATED HEPATIC PERFUSION; ENDOCRINE GASTROENTEROPANCREATIC TUMORS; GASTROINTESTINAL NEUROENDOCRINE TUMORS; INTRAARTERIAL CALCIUM STIMULATION; ISLET-CELL CARCINOMA; NEOPLASIA TYPE-I; LIVER METASTASES; SURGICAL-MANAGEMENT; 25-YEAR EXPERIENCE; PHASE-I AB Insulinoma is a rare neuroendocrine tumor with an incidence of 4 per 1 million persons per year, which may occur as a unifocal sporadic event in patients without an inherited syndrome or as a part of multiple endocrine neoplasia type 1. Key neuroglycopenic and hypoglycemic symptoms in conjunction with biochemical proof establish the diagnosis. Once the diagnosis is established, the insulinoma is preoperatively localized within the pancreas with the goal of surgical excision for cure. This review discusses the historical background, diagnosis, and management of sporadic insulinoma. C1 [Libutti, Steven K.] Montefiore Einstein Ctr Canc Care, Bronx, NY 10467 USA. [Mathur, Aarti] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Gorden, Philip] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Libutti, Steven K.] Albert Einstein Canc Ctr, Bronx, NY 10467 USA. [Libutti, Steven K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. RP Libutti, SK (reprint author), Montefiore Einstein Ctr Canc Care, 3400 Bainbridge Ave, Bronx, NY 10467 USA. EM slibutti@montefiore.org FU Intramural NIH HHS [Z99 DK999999] NR 68 TC 27 Z9 29 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD OCT PY 2009 VL 89 IS 5 BP 1105 EP + DI 10.1016/j.suc.2009.06.009 PG 18 WC Surgery SC Surgery GA 519QN UT WOS:000271782300006 PM 19836487 ER PT J AU Siegenthaler, MP Beyersdorf, F AF Siegenthaler, Michael P. Beyersdorf, Friedhelm TI Endovascular Repair of Thoracoabdominal Aortic Aneurysms SO TEXAS HEART INSTITUTE JOURNAL LA English DT Article DE Aortic aneurysm, abdominal/surgery; aortic aneurysm, thoracic/surgery; blood vessel prosthesis implantation/methods; mortality/trends; paraplegia/etiology; stents; surgical procedures, minimally invasive/methods; tomography, X-ray computed; treatment outcome ID MORTALITY AB Results of conventional open surgery for thoracoabdominal aortic aneurysm (TAAA) have shown 10% to 20% mortality rates in real-life series, such as R state registries,(1) but a few specialized centers report better data.(2) The role of endovascular repair in patients with TAAAs is uncertain. In endovascular TAAA cases, in which complete covering of the visceral and renal aortic segment is necessary, a branched or a fenestrated endograft(3)-or a hybrid open surgical revascularization followed by stent-graft repair-is required.(4) Branched grafts are available only for elective cases, because the Current grafts have to be custom-made. This presentation focuses on our experience between 2000 and 2008 with endovascular treatment of TAAA, with selective open Surgical visceral and renal bypasses performed only if necessary, followed by immediate endovascular stent-graft therapy of the aneurysm.(5) Our surgical technique IS illustrated, and the pitfalls associated with this method discussed. C1 [Siegenthaler, Michael P.; Beyersdorf, Friedhelm] Univ Freiburg, Dept Cardiovasc Surg, D-79106 Freiburg, Germany. RP Siegenthaler, MP (reprint author), Suburban Hosp, NIH Heart Ctr, 8600 Old Georgetown Rd, Bethesda, MD 20814 USA. EM siegenthalermp@nhlbi.nih.gov NR 6 TC 1 Z9 1 U1 1 U2 1 PU TEXAS HEART INST PI HOUSTON PA PO BOX 20345, HOUSTON, TX 77225-0345 USA SN 0730-2347 J9 TEX HEART I J JI Tex. Heart Inst. J. PD OCT PY 2009 VL 36 IS 5 BP 446 EP 448 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 505JD UT WOS:000270688600018 PM 19876425 ER PT J AU McCrae, RR AF McCrae, Robert R. TI The Physics and Chemistry of Personality SO THEORY & PSYCHOLOGY LA English DT Article DE Five-Factor Model; philosophy of science; processes; social-cognitive approaches; traits ID 5-FACTOR MODEL; INDIVIDUAL-DIFFERENCES; TRAIT; PSYCHOLOGY; SELF; AGE; CONSISTENCY; MOTIVATION; UNIVERSAL; CRITERIA AB Physics and chemistry, two basic natural sciences, are today seamlessly integrated, but for much of their history they were separate enterprises with distinct methods and goals. Physicists have consistently sought simplicity and mathematical rigor, whereas chemists seem to have been fascinated by the challenges of complexity. Parallels between these two sciences and the two major branches of contemporary personality psychology are described in an attempt to put in perspective the daunting enterprise of constructing a unified science of human nature. C1 [McCrae, Robert R.] NIA, NIH, DHHS, Bethesda, MD 20892 USA. RP McCrae, RR (reprint author), 809 Evesham Ave, Baltimore, MD 21212 USA. EM RRMcCrae@gmail.com NR 67 TC 10 Z9 10 U1 3 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0959-3543 J9 THEOR PSYCHOL JI Theory Psychol. PD OCT PY 2009 VL 19 IS 5 BP 670 EP 687 DI 10.1177/0959354309341928 PG 18 WC Psychology, Multidisciplinary SC Psychology GA 507BQ UT WOS:000270825400005 ER PT J AU Karschner, EL Schwope, DM Schwilke, EW Gorelick, DA Goodwin, RS Lowe, RH Kelly, DL Huestis, MA AF Karschner, Erin L. Schwope, David M. Schwilke, Eugene W. Gorelick, David A. Goodwin, Robert S. Lowe, Ross H. Kelly, Deanna L. Huestis, Marilyn A. TI Whole Blood/Plasma Ratios in Ten Chronic Cannabis Users after Frequent Oral THC Administration SO THERAPEUTIC DRUG MONITORING LA English DT Meeting Abstract CT 11th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology CY OCT 03-08, 2009 CL Montreal, CANADA C1 [Gorelick, David A.] Natl Inst Drug Abuse, Off Sci Director, Intramural Res Program, NIH, Baltimore, MD USA. [Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD OCT PY 2009 VL 31 IS 5 MA 8 BP 606 EP 606 PG 1 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 502UB UT WOS:000270484600021 ER PT J AU Concheiro, M Jones, HE Johnson, RE Shakleya, DM Huestis, MA AF Concheiro, Marta Jones, Hendree E. Johnson, Rolley E. Shakleya, Diaa M. Huestis, Marilyn A. TI Placenta for Monitoring in utero Drug Exposure to Buprenorphine and Correlation with Neonatal Outcomes SO THERAPEUTIC DRUG MONITORING LA English DT Meeting Abstract CT 11th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology CY OCT 03-08, 2009 CL Montreal, CANADA C1 [Concheiro, Marta; Shakleya, Diaa M.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Jones, Hendree E.; Johnson, Rolley E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD OCT PY 2009 VL 31 IS 5 MA 11 BP 607 EP 607 PG 1 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 502UB UT WOS:000270484600024 ER PT J AU Schwope, DM Schwilke, EW Karschner, EL Gorelick, DA Goodwin, RS Lowe, RH Kelly, DL Huestis, MA AF Schwope, David M. Schwilke, Eugene W. Karschner, Erin L. Gorelick, David A. Goodwin, Robert S. Lowe, Ross H. Kelly, Deanna L. Huestis, Marilyn A. TI Whole Blood Total Cannabinoids during Multiple Daily Oral THC Dosing SO THERAPEUTIC DRUG MONITORING LA English DT Meeting Abstract CT 11th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology CY OCT 03-08, 2009 CL Montreal, CANADA C1 [Gorelick, David A.] Natl Inst Drug Abuse, Off Sci Director, IRP, NIH, Baltimore, MD USA. [Kelly, Deanna L.] Univ Maryland, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD OCT PY 2009 VL 31 IS 5 MA 40 BP 615 EP 615 PG 1 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 502UB UT WOS:000270484600053 ER PT J AU Ross, DS Litofsky, D Ain, KB Bigos, T Brierley, JD Cooper, DS Haugen, BR Jonklaas, J Ladenson, PW Magner, J Robbins, J Skarulis, MC Steward, DL Maxon, HR Sherman, SI AF Ross, Douglas S. Litofsky, Danielle Ain, Kenneth B. Bigos, Thomas Brierley, James D. Cooper, David S. Haugen, Bryan R. Jonklaas, Jacqueline Ladenson, Paul W. Magner, James Robbins, Jacob Skarulis, Monica C. Steward, David L. Maxon, Harry R. Sherman, Steven I. TI Recurrence After Treatment of Micropapillary Thyroid Cancer SO THYROID LA English DT Article ID LYMPH-NODE METASTASIS; PAPILLARY; CARCINOMA; MICROCARCINOMA; DISEASE; EXPERIENCE; MANAGEMENT; INSTITUTE AB Background: Despite very low mortality associated with micropapillary thyroid cancer, locoregional recurrence is common and controversy exists regarding optimal surgical treatment and the role of adjunctive radioiodine. Methods: The National Thyroid Cancer Treatment Cooperative Study Group Registry was analyzed for recurrences in patients with unifocal versus multifocalmicropapillary cancer, with or without nodal disease, depending upon the extent of surgery and the use of adjunctive radioiodine. Six hundred eleven patients considered disease-free after initial therapy were followed for 2572 person-years. Results: Thirty patients (6.2%) had recurrences detected at a mean 2.8 years after primary treatment. Recurrences did not differ between patients with unifocal and multifocal disease overall; however, among patients who received less than a near-total thyroidectomy (NTT), those with multifocal disease had more recurrences than those with unifocal disease (18% vs. 4%, p = 0.01). Patients with multifocal disease who had a total (T) or NTT trended toward fewer recurrences than those undergoing less than an NTT (6% vs. 18%, p = 0.058). In patients who did not receive radioiodine therapy, recurrence was more common in patients with multifocal disease versus unifocal disease (7% vs. 2%, p - 0.02). However, radioiodine did not reduce recurrences in patients with multifocal disease or patients with positive nodes. Patients with positive nodes had more recurrences than node-negative patients regardless of surgical extent or use of radioiodine. Conclusions: Patients with micropapillary multifocal disease have a reduced risk of recurrence after a T/NTT compared with less surgery. A randomized, controlled trial is necessary and feasible to determine if radioiodine ablation of thyroid remnants is advantageous in patients with intrathyroidal micropapillary cancer. C1 [Ross, Douglas S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Litofsky, Danielle; Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ain, Kenneth B.] Univ Kentucky, Med Ctr, VA Med Ctr, Lexington, KY USA. [Bigos, Thomas] Maine Med Ctr, Portland, ME 04102 USA. [Brierley, James D.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Cooper, David S.; Ladenson, Paul W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Haugen, Bryan R.] Univ Colorado Denver, Aurora, CO USA. [Haugen, Bryan R.] Hlth Sci Ctr, Aurora, CO USA. [Jonklaas, Jacqueline] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Magner, James] Genzyme Corp, Cambridge, MA USA. [Robbins, Jacob; Skarulis, Monica C.] NIH, Bethesda, MD 20892 USA. [Steward, David L.; Maxon, Harry R.] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. RP Ross, DS (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dross@partners.org RI Jonklaas, Jacqueline/G-2807-2010; OI Jonklaas, Jacqueline/0000-0002-2238-2666; Ain, Kenneth/0000-0002-2668-934X; Sherman, Steven/0000-0002-3079-5153 NR 21 TC 82 Z9 88 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD OCT PY 2009 VL 19 IS 10 BP 1043 EP U3 DI 10.1089/thy.2008.0407 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 512VR UT WOS:000271279900004 PM 19772419 ER PT J AU Djouad, F Rackwitz, L Song, YJ Janjanin, S Tuan, RS AF Djouad, Farida Rackwitz, Lars Song, Yingjie Janjanin, Sasa Tuan, Rocky S. TI ERK1/2 Activation Induced by Inflammatory Cytokines Compromises Effective Host Tissue Integration of Engineered Cartilage SO TISSUE ENGINEERING PART A LA English DT Article ID NF-KAPPA-B; MESENCHYMAL STEM-CELLS; NECROSIS-FACTOR-ALPHA; GROWTH-FACTOR-BETA; ARTICULAR-CARTILAGE; TNF-ALPHA; GENE-EXPRESSION; MESSENGER-RNA; MATRIX; CHONDROCYTES AB Objective: Proinflammatory cytokines are known to provoke degradative signaling cascades that promote extracellular matrix disintegration in articular cartilage. Because integration of the repair tissue into the surrounding native cartilage to produce a mechanically stable interface has a profound impact on the viability and functionality of the restored joint surface, this study examined the effects of proinflammatory cytokines on the properties of tissue-engineered cartilage in the context of integration. Methods: Using an established in vitro cartilage defect model, we examined the integration of chondrocyte-laden agarose constructs into native articular cartilage and the biochemical and biomechanical alterations of these implants upon treatment with interleukin 1-beta (IL1-beta) and tumor necrosis factor-alpha (TNF-alpha). Additionally, we probed extracellular regulated kinase (ERK) signaling involvement in response to proinflammatory cytokines. Results: The time-dependent accumulation of extracellular matrix and concomitant increase in Young's modulus observed in the absence of cytokines was significantly decreased upon IL1-beta and TNF-alpha treatment. Push-out test showed the highest interface strength in hybrid cultures maintained without cytokines, which was significantly lowered with IL1-beta and TNF-alpha treatment. Histological characteristics of the interface region are consistent with the biochemical findings. Treatment with an inhibitor of ERK pathway antagonized the deleterious effects caused by both cytokines. Conclusion: This study is the first to show the functional catastrophic effects of IL1-beta and TNF-alpha on the biochemical, structural, and integrative properties of tissue-engineered cartilage and their significant counteraction by the blockade of ERK signaling pathway. With the discovery of new potential chemical entities, ERK inhibitor may emerge as a new therapeutic approach for functional integration and mechanical integrity of an engineered cartilage to the host tissue and, therefore, enhance long-term viability and functionality of the restored joint surface. C1 [Djouad, Farida; Rackwitz, Lars; Song, Yingjie; Janjanin, Sasa; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, 50 South Dr,Room 1140,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov OI Djouad, Farida/0000-0001-8248-6822 FU Intramural NIH HHS NR 32 TC 14 Z9 14 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD OCT PY 2009 VL 15 IS 10 BP 2825 EP 2835 DI 10.1089/ten.tea.2008.0663 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 503QG UT WOS:000270553200007 PM 19243242 ER PT J AU Hallett, M Benecke, R Blitzer, A Comella, CL AF Hallett, Mark Benecke, Reiner Blitzer, Andrew Comella, Cynthia L. TI Treatment of focal dystonias with botulinum neurotoxin SO TOXICON LA English DT Article; Proceedings Paper CT 6th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins CY JUN 12-15, 2008 CL Baveno, ITALY DE Botulinum toxin; Focal dystonia; Cranial dystonia; Cervical dystonia; Spasmodic dysphonia; Focal hand dystonia ID TRANSCRANIAL MAGNETIC STIMULATION; ADDUCTOR SPASMODIC DYSPHONIA; LARYNGEAL NERVE-SECTION; 1-YEAR FOLLOW-UP; WRITERS CRAMP; HAND DYSTONIA; CERVICAL DYSTONIA; DOUBLE-BLIND; SPASTIC DYSPHONIA; TOXIN MANAGEMENT AB This is a review on the use of injections of botulinum toxin for the treatment of focal dystonias. Disorders covered include cranial dystonia, cervical dystonia, spasmodic dysphonia, and focal hand dystonia. Considered are clinical aspects, alternative treatment strategies and principles of use of botulinum toxin injections. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Benecke, Reiner] Univ Rostock, Dept Neurol, Rostock, Germany. [Blitzer, Andrew] Columbia Univ Coll Phys & Surg, Dept Otolaryngol, Ctr Voice & Swallowing Disorders, New York, NY 10032 USA. [Comella, Cynthia L.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D37,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003032-05] NR 31 TC 26 Z9 27 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD OCT PY 2009 VL 54 IS 5 BP 628 EP 633 DI 10.1016/j.toxicon.2008.12.008 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 496IW UT WOS:000269965400013 PM 19103214 ER PT J AU Seltsam, A Grueger, D Blasczyk, R Flegel, WA AF Seltsam, Axel Grueger, Daniela Blasczyk, Rainer Flegel, Willy A. TI Easy identification of antibodies to high-prevalence Scianna antigens and detection of admixed alloantibodies using soluble recombinant Scianna protein SO TRANSFUSION LA English DT Article ID BLOOD-GROUP ANTIGEN; PARTICLE GEL IMMUNOASSAY; RAPID DETECTION; GROUP SYSTEM; HUMAN ERMAP; SUBSTANCE; SEMA7A; DUFFY AB BACKGROUND: Identification of antibodies against high-prevalence Scianna (Sc; ERMAP) antigens, like Sc1 and Sc5, is difficult and may incur delays in blood procurement and costs. The detection of additional clinically significant alloantibodies is hampered in the presence of anti-Scianna. Soluble recombinant Scianna protein is demonstrated to facilitate antibody diagnostics in both cases. STUDY DESIGN AND METHODS: Soluble recombinant Scianna protein (Sc:1,-2,3,-4,5,6,7) was produced comprising the antigenic extracellular domain fused to a V5-His tag. The protein was isolated from eukaryotic cell culture supernatants of stably transfected HEK293 cells. Seven serum samples with anti-Sc1, anti-Sc2, and anti-Sc5 and 30 serum samples with antibodies to other blood group antigens were evaluated in hemagglutination inhibition assays. Antisera with mixed antibody specificities and autoantibodies were also tested. RESULTS: Soluble Scianna protein inhibited specifically antibodies to the high-prevalence Scianna antigens Sc1 and Sc5. No antibodies were neutralized that were directed to the low-prevalence Sc2 antigen or to a large representative set of antigens from other blood group systems. Clinically relevant antibodies could be identified despite being masked by anti-Sc1 and anti-Sc5. A mixture of Scianna and JMH proteins allowed detecting a common antibody despite the presence of antibodies to high-prevalence antigens of the Scianna or JMH blood group systems. CONCLUSION: Antibody detection systems comprising soluble recombinant Scianna protein provide an easy single-step method for detection and identification of antibodies to high-prevalence Scianna antigens. Reagents with Scianna and other recombinant blood group proteins and mixtures of such proteins would be useful routine reagents in immunohematology. C1 Inst Springe, German Red Cross Blood Donor Serv NSTOB, Springe, Germany. Hannover Med Sch, Inst Transfus Med, D-3000 Hannover, Germany. Inst Ulm, German Red Cross Blood Donor Serv Baden Wurttembe, Ulm, Germany. Univ Hosp Ulm, Inst Transfus Med, Ulm, Germany. RP Flegel, WA (reprint author), Natl Inst Hlth, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM flegelwa@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 26 TC 2 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2009 VL 49 IS 10 BP 2090 EP 2096 DI 10.1111/j.1537-2995.2009.02255.x PG 7 WC Hematology SC Hematology GA 502BW UT WOS:000270430100015 PM 19555420 ER PT J AU Klein, HG AF Klein, Harvey G. TI In Memoriam-Robert M. Winslow (1941-2009) OBITUARY SO TRANSFUSION LA English DT Biographical-Item C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM hklein@dtm.cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2009 VL 49 IS 10 BP 2243 EP 2244 PG 2 WC Hematology SC Hematology GA 502BW UT WOS:000270430100036 ER PT J AU Tounkara, A Diakite, M Noumsi, GT Sarro, YDS Siddiqui, S Parta, M AF Tounkara, A. Diakite, M. Noumsi, G. T. Sarro, Y. D. S. Siddiqui, S. Parta, M. TI Retrospective surveillance of HIV prevalence in blood donors can help in the selection of the best social group for blood donation in Mali SO TRANSFUSION MEDICINE LA English DT Article DE blood donors; HIV; Mali; West Africa ID ESTIMATING HIV/AIDS; RISK; INFECTION; TRANSFUSION; AFRICA AB The National Centre for Blood Transfusion, Bamako, Mali has collected data that characterizes trend in HIV prevalence over 10 years by gender, age, occupation, marital status and donor category. These data help to describe national HIV prevalence and assist in formulating blood donation policies. Donations from 1993 to 2002 were categorized by donor age (decade), occupation (student, military and other), marital status (single, married and other), gender and donor status (volunteer, occasional and family). Comparisons were made using conservative estimates of donation frequency/donor category. Donations increased by more than 400%. By 1999, increased HIV prevalence in donations from women was consistently present. Donations from the age group of 30-39 years showed an increased prevalence beginning in 2000, which by 2002 was almost 10 times greater than in the low-prevalence (< 20 years) group (5.9 vs. 0.6%). By 2000, both categories - students and military were less likely to be HIV positive than those from other occupational categories, and donations from married persons were less likely to be HIV positive by 1997. The highest prevalence was observed in the 'occasional' donor category, which increased to > 14% by 2001; volunteer donation HIV positive peaked at 2.3% in 1999. HIV prevalence in blood donations in Bamako, Mali, demonstrates important trends from 1993 to 2002. The prevalence of > 14% in donations from occasional donors and significant trends by decade, gender, marital status and occupation argue for increased analysis of the blood donor population to improve blood safety and to understand the demographics of HIV infection in Mali. C1 [Tounkara, A.; Sarro, Y. D. S.; Siddiqui, S.] Univ Bamako, FMPOS NIAID HIV TB Res Initiat, Bamako, Mali. [Tounkara, A.; Sarro, Y. D. S.; Siddiqui, S.; Parta, M.] Ctr Natl Transfus Sanguine, Bamako, Mali. [Diakite, M.] Mali NIH Int Ctr Excellence Res MRTC ICER, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Noumsi, G. T.; Parta, M.] NIAID, NIH, Bethesda, MD 20892 USA. RP Tounkara, A (reprint author), Univ Bamako, FMPOS NIAID HIV TB Res Initiat, BP 1805, Bamako, Mali. EM anatol@mrtcbko.org FU National Blood Bank of Mali; Government of Mali FX We thank the blood donor groups, colleagues at the National Blood Bank of Mali for their support and participation and the Government of Mali for financial support. We thank two anonymous reviewers for a critical review and helpful suggestions. NR 16 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0958-7578 J9 TRANSFUSION MED JI Transfus. Med. PD OCT PY 2009 VL 19 IS 5 BP 252 EP 259 DI 10.1111/j.1365-3148.2009.00950.x PG 8 WC Hematology SC Hematology GA 491OU UT WOS:000269589400005 PM 19747288 ER PT J AU Berger, VW AF Berger, Vance W. TI The (lack of) quality in assessing the quality of transplantation trials SO TRANSPLANT INTERNATIONAL LA English DT Letter C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 5 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0934-0874 EI 1432-2277 J9 TRANSPL INT JI Transpl. Int. PD OCT PY 2009 VL 22 IS 10 BP 1029 EP 1029 DI 10.1111/j.1432-2277.2009.00899.x PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 490YG UT WOS:000269543400014 PM 19497066 ER PT J AU Helming, L Gordon, S AF Helming, Laura Gordon, Siamon TI Molecular mediators of macrophage fusion SO TRENDS IN CELL BIOLOGY LA English DT Review ID GIANT-CELL FORMATION; TETRASPANINS CD9; APOPTOTIC CELLS; DC-STAMP; IN-VIVO; ALTERNATIVE ACTIVATION; CUTTING EDGE; OSTEOCLAST; CD81; PHAGOCYTOSIS AB Fusion of macrophages leads to the formation of osteoclasts in bone and of multinucleated giant cells in granulomas. The precise function of granuloma-associated multinucleates giant cells is not clear but substantial progress has recently been made in identifying the molecular machinery involved in macrophage fusion. Signaling processes mediated by DAP12 and STAT6 induce a fusion-competent status. Chemotaxis through CCL2, cell-cell adhesion mediated by E-cadherin, exposure of phosphatidylserine, lipid recognition by CD36 and cytoskeletal rearrangements depending on RAC1 are prerequisites for successful macrophage fusion. We review current knowledge on the molecular mediators of giant cell formation, compare giant cells with osteoclasts and highlight key target areas for future research and medical relevance. C1 [Helming, Laura] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, Munich, Germany. [Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Gordon, Siamon] NCI, NIH, Frederick, MD 21701 USA. RP Helming, L (reprint author), Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, Munich, Germany. EM laura.helming@lrz.tum.de FU Medical Research Council [G0600727] NR 54 TC 119 Z9 121 U1 0 U2 18 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD OCT PY 2009 VL 19 IS 10 BP 514 EP 522 DI 10.1016/j.tcb.2009.07.005 PG 9 WC Cell Biology SC Cell Biology GA 511EU UT WOS:000271147500004 PM 19733078 ER PT J AU Cizza, G Primma, S Csako, G AF Cizza, Giovanni Primma, Svetlana Csako, Gyorgy TI Depression as a risk factor for osteoporosis SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID BONE-MINERAL DENSITY; SEROTONIN REUPTAKE INHIBITORS; BODY-MASS INDEX; PREMENOPAUSAL WOMEN; MAJOR DEPRESSION; POSTMENOPAUSAL WOMEN; HIP FRACTURE; OLDER WOMEN; ANOREXIA-NERVOSA; MENTAL DISTRESS AB Osteoporosis is a major public health threat. Multiple studies have reported an association between depression and low bone mineral density, but a causal link between these two conditions is disputed. Here we review the endocrine and immune alterations secondary to depression that might affect bone mass. We also discuss the possible role of poor lifestyle in the etiology of osteoporosis in subjects with depression and the potential effect of antidepressants on bone loss. We propose that depression induces bone loss and osteoporotic fractures, primarily via specific immune and endocrine mechanisms, while poor lifestyle habits and use of specific antidepressants are potential contributory factors. C1 [Cizza, Giovanni; Primma, Svetlana] NIDDK, Clin Endocrine Sect, Clin Endocrinol Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Csako, Gyorgy] NIH, Dept Lab Med, Ctr Clin, DHHS, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), NIDDK, Clin Endocrine Sect, Clin Endocrinol Branch, NIH,DHHS, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov FU National Institute of Diabetes, Digestive and Kidney Diseases; Clinical Center, NIH FX This research was supported by the Intramural Research Programs of the National Institute of Diabetes, Digestive and Kidney Diseases and the Clinical Center, NIH. NR 60 TC 45 Z9 50 U1 0 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD OCT PY 2009 VL 20 IS 8 BP 367 EP 373 DI 10.1016/j.tem.2009.05.003 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 506GX UT WOS:000270764200001 PM 19747841 ER PT J AU Krsmanovic, LZ Hu, L Leung, PK Feng, H Catt, KJ AF Krsmanovic, Lazar Z. Hu, Lian Leung, Po-Ki Feng, Hao Catt, Kevin J. TI The hypothalamic GnRH pulse generator: multiple regulatory mechanisms SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID GONADOTROPIN-RELEASING-HORMONE; ESTROGEN-RECEPTOR-ALPHA; HUMAN CHORIONIC-GONADOTROPIN; MESSENGER RIBONUCLEIC-ACIDS; PROTEIN-COUPLED-RECEPTOR; RAT ANTERIOR-PITUITARY; GENE-EXPRESSION; RHESUS-MONKEY; IN-VITRO; NEUROPEPTIDE RELEASE AB Pulsatile secretion of gonadotropin-releasing hormone (GnRH) release is an intrinsic property of hypothalamic GnRH neurons. Pulse generation has been attributed to multiple specific mechanisms, including spontaneous electrical activity of GnRH neurons, calcium and cAMP signaling, a GnRH receptor autocrine regulatory component, a GnRH concentration-dependent switch in GnRH receptor (GnRH-R) coupling to specific G proteins, the expression of G protein-coupled receptors (GPCRs) and steroid receptors, and homologous and heterologous interactions between cell membrane receptors expressed in GnRH neurons. The coexistence of multiple regulatory mechanisms for pulsatile GnRH secretion provides a high degree of redundancy in maintaining this crucial component of the mammalian reproductive process. These studies provide insights into the basic cellular and molecular mechanisms involved in GnRH neuronal function. C1 [Krsmanovic, Lazar Z.; Hu, Lian; Leung, Po-Ki; Feng, Hao; Catt, Kevin J.] NICHHD, Sect Hormonal Regulat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, Sect Hormonal Regulat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM kcatt@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 67 TC 27 Z9 28 U1 0 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD OCT PY 2009 VL 20 IS 8 BP 402 EP 408 DI 10.1016/j.tem.2009.05.002 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 506GX UT WOS:000270764200006 PM 19740674 ER PT J AU Wise, RA AF Wise, Roy A. TI Roles for nigrostriatal-not just mesocorticolimbic-dopamine in reward and addiction SO TRENDS IN NEUROSCIENCES LA English DT Review ID VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION; BRAIN-STIMULATION REWARD; NUCLEUS-ACCUMBENS DOPAMINE; SYNAPTIC PLASTICITY; COCAINE-SEEKING; SELF-STIMULATION; SUBSTANTIA-NIGRA; CAUDATE-NUCLEUS; DORSAL STRIATUM AB Forebrain dopamine circuitry has traditionally been studied by two largely independent specialist groups: students of Parkinson's disease who study the nigrostriatal dopamine system that originates in the substantial nigra (SN) and students of motivation and addiction who study the role of the mesolimbic and mesocortical dopamine systems that originate in the ventral tegmental area (VTA). The anatomical evidence for independent nigrostriatal and mesolimbic dopamine systems has, however, long been obsolete. There is now compelling evidence that both nominal "systems" participate in reward function and addiction. Electrical stimulation of both SN and VTA is rewarding, blockade of glutamatergic or cholinergic input to either SN or VTA attenuates the habit-forming effects of intravenous cocaine, and dopamine in both nigrostriatal and mesocorticolimbic terminal fields participates in the defining property of rewarding events: the reinforcement of memory consolidation. Thus, the similarities between nigrostriatal and mesolimbic dopamine systems can be as important as their differences. C1 Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD USA. RP Wise, RA (reprint author), Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD USA. EM rwise@intra.nida.nih.gov RI Wise, Roy/A-6465-2012 FU Intramural Research Program; National Institute on Drug Abuse; National Institutes of Health; Department of Health and Human Services FX Supported by funding from the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. I thank Yavin Shabam, Stefanie Geisler and Maria Flavia Barbano for constructive comments on an earlier draft of the paper. NR 94 TC 182 Z9 188 U1 3 U2 32 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2009 VL 32 IS 10 BP 517 EP 524 DI 10.1016/j.tins.2009.06.004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 509GQ UT WOS:000271003400001 PM 19758714 ER PT J AU Hall, MD Handley, MD Gottesman, MM AF Hall, Matthew D. Handley, Misty D. Gottesman, Michael M. TI Is resistance useless? Multidrug resistance and collateral sensitivity SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID HAMSTER OVARY CELLS; BREAST-CANCER-CELLS; MAGNETIC-RESONANCE SPECTROSCOPY; MDR1 GENE-EXPRESSION; K562 LEUKEMIC-CELLS; P-GLYCOPROTEIN; CROSS-RESISTANCE; DRUG-RESISTANCE; TUMOR-CELLS; IRON CHELATORS AB When cancer cells develop resistance to chemotherapeutics, it is frequently conferred by the ATP-dependent efflux pump P-glycoprotein (MDR1, P-gp, ABCB1). P-gp can efflux a wide range of cancer drugs; its expression confers cross-resistance, termed "multidrug resistance" (MDR), to a wide range of drugs. Strategies to overcome this resistance have been actively sought for more than 30 years, yet clinical solutions do not exist. A less understood aspect of MDR is the hypersensitivity of resistant cancer cells to other drugs, a phenomenon known as "collateral sensitivity" (CS). This review highlights the extent of this effect for the first time, and discusses hypotheses (e.g. generation of reactive oxygen species) to account for the underlying generality of this phenomenon, and proposes exploitation of CS as a strategy to improve response to chemotherapy. C1 [Hall, Matthew D.; Handley, Misty D.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM gottesmm@mail.nih.gov RI Hall, Matthew/B-2132-2010 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The authors would like to acknowledge Dr. Gergely Szakaes, who began the work on CS in our laboratory, and Dr. Elias Georges, who has worked extensively on verapamil CS and first reported the ROS hypothesis for CS. We thank members of the Laboratory of Cell Biology for helpful discussions, and George Leiman and Kyle R. Brimacombe for editorial assistance. The authors also acknowledge the contributions from the referees, whose critical comments enhanced this review. NR 127 TC 115 Z9 121 U1 1 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD OCT PY 2009 VL 30 IS 10 BP 546 EP 556 DI 10.1016/j.tips.2009.07.003 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 509XZ UT WOS:000271053900005 PM 19762091 ER PT J AU Kimani, JW Yoshiura, K Shi, M Jugessur, A Moretti-Ferreira, D Christensen, K Murray, JC AF Kimani, Jane W. Yoshiura, Koh-ichiro Shi, Min Jugessur, Astanand Moretti-Ferreira, Danilo Christensen, Kaare Murray, Jeffrey C. TI Search for Genomic Alterations in Monozygotic Twins Discordant for Cleft Lip and/or Palate SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Article DE monozygotic twins; discordant; cleft lip and palate; genome-wide ID FEMALE; HYBRIDIZATION; CONCORDANT; FREQUENCY; MUTATION; GENES AB Phenotypically discordant monozygotic twins offer the possibility of gene discovery through delineation of molecular abnormalities in one member of the twin pair. One proposed mechanism of discordance is postzygotically occurring genomic alterations resulting from mitotic recombination and other somatic changes. Detection of altered genomic fragments can reveal candidate gene loci that can be verified through additional analyses. We investigated this hypothesis using array comparative genomic hybridization; the 50K and 250K Affymetrix GeneChip (R) SNP arrays and an Illumina custom array consisting of 1,536 SNPs, to scan for genomic alterations in a sample of monozygotic twin pairs with discordant cleft lip and/or palate phenotypes. Paired analysis for deletions, amplifications and loss of heterozygosity, along with sequence verification of SNPs with discordant genotype calls did not reveal any genomic discordance between twin pairs in lymphocyte DNA samples. Our results demonstrate that postzygotic genomic alterations are not a common cause of monozygotic twin discordance for isolated cleft lip and/or palate. However, rare or balanced genomic alterations, tissue-specific events and small aberrations beyond the detection level of our experimental approach cannot be ruled out. The stability of genomes we observed in our study samples also suggests that detection of discordant events in other monozygotic twin pairs would be remarkable and of potential disease significance. C1 [Kimani, Jane W.; Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Yoshiura, Koh-ichiro] Nagasaki Univ, Grad Sch Biomed Sci, Dept Human Genet, Nagasaki 852, Japan. [Shi, Min] NIEHS, Biostat Branch, Bethesda, MD USA. [Jugessur, Astanand] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Moretti-Ferreira, Danilo] Genet Univ Estadual Paulista, Serv Aconselhamento, Botucatu, SP, Brazil. [Christensen, Kaare] Univ So Denmark, Inst Publ Hlth, Dept Epidemiol, Odense, Denmark. RP Murray, JC (reprint author), Univ Iowa, Dept Pediat, S Grand Ave,2182 ML, Iowa City, IA 52242 USA. EM jeff-murray@uiowa.edu RI Christensen, Kaare/C-2360-2009; Moretti-Ferreira, Danilo/F-9565-2012 OI Christensen, Kaare/0000-0002-5429-5292; FU NIH; National Institute of Environmental Health Sciences [Z01ES04007-12]; [R37DE008S59]; [P50DE016215]; [R01DE015197] FX We would like to thank the patients and families who contributed samples and information for this study. We are also grateful to Maria Johnson for technical assistance. This study was supported by the following grants: R37DE008S59, P50DE016215, R01DE015197, and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01ES04007-12). NR 29 TC 12 Z9 12 U1 0 U2 1 PU AUSTRALIAN ACAD PRESS PI BOWEN HILLS PA 32 JEAYS ST, BOWEN HILLS, QLD 4006, AUSTRALIA SN 1832-4274 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD OCT PY 2009 VL 12 IS 5 BP 462 EP 468 PG 7 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 507NW UT WOS:000270862300007 PM 19803774 ER PT J AU Hancock, HA Smith, LH Cuesta, J Durrani, AK Angstadt, M Palmeri, ML Kimmel, E Frenkel, V AF Hancock, Hilary A. Smith, Lauren H. Cuesta, Julian Durrani, Amir K. Angstadt, Mary Palmeri, Mark L. Kimmel, Eitan Frenkel, Victor TI INVESTIGATIONS INTO PULSED HIGH-INTENSITY FOCUSED ULTRASOUND-ENHANCED DELIVERY: PRELIMINARY EVIDENCE FOR A NOVEL MECHANISM SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE Pulsed high-intensity focused ultrasound; Muscle; Extravasation; Interstitial transport; Radiation force displacements; Shear strain ID ACOUSTIC RADIATION FORCE; STRETCH-SHORTENING CYCLES; BRAIN-BARRIER DISRUPTION; ECCENTRIC EXERCISE; IN-VITRO; MONOCLONAL-ANTIBODY; SKELETAL-MUSCLE; DRUG-DELIVERY; SOLID TUMORS; FISH SKIN AB Pulsed high-intensity focused ultrasound (HIFU) exposures without ultrasound contrast agents have been used for noninvasively enhancing the delivery of various agents to improve their therapeutic efficacy in a variety of tissue models in a nondestructive manner. Despite the versatility of these exposures, little is known about the mechanisms by which their effects are produced. In this study, pulsed-HIFU exposures were given in the calf muscle of mice, followed by the administration of a variety of fluorophores, both soluble and particulate, by local or systemic injection. In vivo imaging (whole animal and microscopic) was used to quantify observations of increased extravasation and interstitial transport of the fluorophores as a result of the exposures. Histological analysis indicated that the exposures caused some structural alterations such as enlarged gaps between muscle fiber bundles. These effects were consistent with increasing the permeability of the tissues; however, they were found to be transient and reversed themselves gradually within 72 h. Simulations of radiation force-induced displacements and the resulting local shear strain they produced were carried out to potentially explain the manner by which these effects occurred. A better understanding of the mechanisms involved with pulsed HIFU exposures for noninvasively enhancing delivery will facilitate the process for optimizing their use. (E-mail: vfrenkel@cc.nih.gov) Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. C1 [Hancock, Hilary A.; Smith, Lauren H.; Cuesta, Julian; Durrani, Amir K.; Angstadt, Mary; Frenkel, Victor] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Palmeri, Mark L.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. [Kimmel, Eitan] Technion Israel Inst Technol, Dept Biomed Engn, IL-32000 Haifa, Israel. RP Frenkel, V (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10,Room 1N306A,10 Ctr Dr, Bethesda, MD 20892 USA. EM vfrenkel@cc.nih.gov RI Palmeri, Mark/B-7167-2015 OI Palmeri, Mark/0000-0001-8995-0050 FU NIH, National Institutes of Health [CA114075] FX The authors would like to thank Dr. Stuart J. Warden and Dr. Matthew R. Dreher for their thoughtful consultations and discussions. This research was supported in part by NIH R01 grant number CA114075 and the intramural research program of the Clinical Center, National Institutes of Health. NR 53 TC 68 Z9 71 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-5629 J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD OCT PY 2009 VL 35 IS 10 BP 1722 EP 1736 DI 10.1016/j.ultrasmedbio.2009.04.020 PG 15 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 600TN UT WOS:000278011900016 PM 19616368 ER PT J AU Ramsey, SD McDermott, CL Zeliadt, SB Blough, DK Fedorenko, CR Arora, NK Penson, DF Oakley-Girvan, I Hamilton, AS Van den Eeden, SK Potosky, AL AF Ramsey, S. D. McDermott, C. L. Zeliadt, S. B. Blough, D. K. Fedorenko, C. R. Arora, N. K. Penson, D. F. Oakley-Girvan, I Hamilton, A. S. Van den Eeden, S. K. Potosky, A. L. TI COMPLEMENTARY AND ALTERNATIVE MEDICINE (CAM) USE AMONG LOCAL STAGE PROSTATE CANCER PATIENTS: TYPES, FACTORS ASSOCIATED WITH USE AND PERCEIVED BENEFITS SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Ramsey, S. D.; McDermott, C. L.; Fedorenko, C. R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Zeliadt, S. B.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Blough, D. K.] Univ Washington, Seattle, WA 98195 USA. [Arora, N. K.] NCI, Bethesda, MD 20892 USA. [Penson, D. F.] Univ So Calif, Norris Canc Ctr, Los Angeles, CA USA. [Oakley-Girvan, I] No Calif Canc Ctr, Fremont, CA USA. [Hamilton, A. S.] USC, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA USA. [Van den Eeden, S. K.] Kaiser Permanente, Oakland, CA USA. [Potosky, A. L.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD OCT PY 2009 VL 12 IS 7 BP A283 EP A283 DI 10.1016/S1098-3015(10)74386-2 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 495GH UT WOS:000269878100311 ER PT J AU Reed, SD Whellan, DJ Li, Y Friedman, JY Pina, IL Settles, SJ Davidson-Ray, L Johnson, J Cooper, LS O'Connor, CM Schulman, KA AF Reed, S. D. Whellan, D. J. Li, Y. Friedman, J. Y. Pina, I. L. Settles, S. J. Davidson-Ray, L. Johnson, J. Cooper, L. S. O'Connor, C. M. Schulman, K. A. TI COST OF EXERCISE TRAINING AND ITS IMPACT ON MEDICAL RESOURCE USE AND COSTS: RESULTS OF HF-ACTION TRIAL SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Reed, S. D.; Li, Y.; Friedman, J. Y.; Settles, S. J.; Johnson, J.; O'Connor, C. M.; Schulman, K. A.] Duke Clin Res Inst, Durham, NC USA. [Whellan, D. J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Pina, I. L.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Davidson-Ray, L.] Duke Univ, Durham, NC USA. [Cooper, L. S.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD OCT PY 2009 VL 12 IS 7 BP A323 EP A323 DI 10.1016/S1098-3015(10)74588-5 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 495GH UT WOS:000269878100513 ER PT J AU Xiao, S Paldurai, A Nayak, B Subbiah, M Collins, PL Samal, SK AF Xiao, Sa Paldurai, Anandan Nayak, Baibaswata Subbiah, Madhuri Collins, Peter L. Samal, Siba K. TI Complete genome sequence of avian paramyxovirus type 7 (strain Tennessee) and comparison with other paramyxoviruses SO VIRUS RESEARCH LA English DT Article DE Avian paramyxovirus; Genome sequence; APMV-7; Strain Tennessee ID NEWCASTLE-DISEASE-VIRUS; HEMAGGLUTININ-NEURAMINIDASE GLYCOPROTEIN; COMPLETE NUCLEOTIDE-SEQUENCE; FUSION PROTEIN; RNA VIRUSES; UNTRANSLATED REGIONS; MATRIX PROTEIN; AMINO-ACID; REPLICATION; CLEAVAGE AB The complete genome sequence of avian paramyxovirus serotype 7 (APMV-7) prototype strain dove/Tennessee/4/75 was determined. The genome size is 15,480 nucleotides (nt) long and follows the "rule of six". The genome contains six non-overlapping genes in the order of 3'-N-P/V/W-M-F-HN-L-5'. The T-leader and 5'-trailer sequences of the genome are 55 and 127 nt long, respectively. The first 12 nt of the leader and trailer sequences are complementary to each other. The viral genes are flanked by highly conserved gene-start (GS) and gene-end (GE) transcription signals, and in addition the T-leader sequence contains a sequence ((35)AAUUAUUUUUU(45)) that is identical to the GE signal present at two of the genes. The genes are separated by intergenic sequences (IGS) ranging between 11 and 70 nt. The phosphoprotein (P) gene contains a conserved RNA editing site (3'-UUUUUCCC-5') presumed to be involved in the production of V and W proteins. The viral fusion (F) protein has a single basic amino acid at the putative cleavage site ((101)TLPSS (R) under bar down arrow F(107)); however, the virus did not require exogenous protease for in vitro replication. The virus grew in only a few established cell lines, indicating a restricted host range. Sequence alignment and phylogenetic analysis of the predicted amino acid sequence of APMV-7 proteins with the cognate proteins of the viruses of all five genera of the family Paramyxoviridue showed that APMV-7 is more closely related to APMV-2, -6, -8 than to APMV-1, -3, -4 and -9. The mean death time in embryonated chicken eggs was found to be more than 144 h, indicating APMV-7 to be avirulent for chickens. Crown Copyright (C) 2009 Published by Elsevier B.V. All rights reserved. C1 [Xiao, Sa; Paldurai, Anandan; Nayak, Baibaswata; Subbiah, Madhuri; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU MAID [NOIA060009]; NIH; U.S. Government FX We thank Sachin Kumar for helpful suggestions in the present complete genome sequencing experiment. We thank Dianel Rockemann, Flavia Dias and all our laboratory members for their excellent technical assistance and help. We also thank Ireen Dryburgh-Barry for proofreading the manuscript. "This research was supported by MAID contract no. NOIA060009 (85% support) and MAID, NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government." NR 53 TC 32 Z9 32 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD OCT PY 2009 VL 145 IS 1 BP 80 EP 91 DI 10.1016/j.virusres.2009.06.003 PG 12 WC Virology SC Virology GA 503JY UT WOS:000270531600011 PM 19540277 ER PT J AU Chattopadhyay, MK Chen, WP Poy, G Cam, M Stiles, D Tabor, H AF Chattopadhyay, Manas K. Chen, Weiping Poy, George Cam, Margaret Stiles, David Tabor, Herbert TI Microarray studies on the genes responsive to the addition of spermidine or spermine to a Saccharomyces cerevisiae spermidine synthase mutant SO YEAST LA English DT Article DE microarray; polyamines; spermidine; spermine; yeast ID AMINO-ACID-METABOLISM; TRANSCRIPTIONAL REGULATION; POLYAMINE MODULON; NEUROSPORA-CRASSA; SPE2-DELTA MUTANT; CELL-GROWTH; YEAST-CELLS; EXPRESSION; BIOSYNTHESIS; HYPUSINE AB The naturally occurring polyamines putrescine, spermidine or spermine are ubiquitous in all cells. Although polyamines have prominent regulatory roles in cell division and growth, precise molecular and cellular functions are not well-established in vivo. In this work we have performed microarray experiments with a spermidine synthase, spermine oxidase mutant (Delta spe3 Delta fms1) strain to investigate the responsiveness of yeast genes to supplementation with spermidine or spermine. Expression analysis identified genes responsive to the addition of either excess spermidine (10(-5) (M)) or spermine (10-5 m) compared to a control culture containing 10(-8) (M) spermidine. 247 genes were upregulated > two-fold and 11 genes were upregulated > 10-fold after spermidine addition. Functional categorization of the genes showed induction of transport-related genes and genes involved in methionine, arginine, lysine, NAD and biotin biosynthesis. 268 genes were downregulated more than two-fold, and six genes were downregulated > eight-fold after spermidine addition. A majority of the downregulated genes are involved in nucleic acid metabolism and various stress responses. In contrast, only a few genes (18) were significantly responsive to spermine. Thus, results from global gene expression profiling demonstrate a more major role for spermidine in modulating gene expression in yeast than spermine. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Chattopadhyay, Manas K.; Tabor, Herbert] NIDDK, NIH, Lab Biochem & Genet, Bethesda, MD 20892 USA. [Chen, Weiping; Poy, George; Cam, Margaret; Stiles, David] NIDDK, NIH, Microarray Core Facil, Bethesda, MD 20892 USA. RP Chattopadhyay, MK (reprint author), NIDDK, NIH, Lab Biochem & Genet, 8 Ctr Dr,Bldg 8,Room 219, Bethesda, MD 20892 USA. EM manasc@intra.niddk.nih.gov FU NIH (National Institute of Diabetes, Digestive and Kidney Diseases). FX This research was supported by the Intramural Research Programme of the NIH (National Institute of Diabetes, Digestive and Kidney Diseases). NR 39 TC 15 Z9 15 U1 1 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD OCT PY 2009 VL 26 IS 10 BP 531 EP 544 DI 10.1002/yea.1703 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 507MY UT WOS:000270859500001 PM 19688718 ER PT J AU Nagata, S Pastan, I AF Nagata, Satoshi Pastan, Ira TI Removal of B cell epitopes as a practical approach for reducing the immunogenicity of foreign protein-based therapeutics SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Deimmunization; Mutagenesis; Antigen; Antigenicity; Antibody; Biopharmaceutical ID RECOMBINANT STAPHYLOKINASE VARIANTS; BOTULINUM NEUROTOXIN-A; IMMUNE-RESPONSES; HUMAN-ANTIBODY; T-CELL; ANTIGENIC DETERMINANTS; MONOCLONAL-ANTIBODIES; CYTOCHROME-C; IMMUNOTOXIN; PREDICTION AB Immunogenicity of non-human proteins with useful therapeutic properties has prevented their development for use in the therapy of disease. However, this class of proteins could be very useful, if their immunogenicity could be markedly reduced so that many treatment cycles could be administered. One approach to reduce the immunogenicity of foreign proteins is to identify B cell epitopes on the protein and eliminate them by mutagenesis. In this article, theoretical aspects and experimental evidence for the feasibility of B cell epitope removal is reviewed. A special focus is given to our results with deimmunization of recombinant immunotoxins in which Fvs are fused to a 38 kDa portion of the bacterial protein, Pseudomonas exotoxin A (PE38). Immunotoxins targeting CD22 and CD25 have produced complete remissions in many patients with drug resistant Hairy Cell Leukemia and are being evaluated in other malignancies. Experimental data summarized in this review indicates that removal of B cell epitopes is a practical approach for making less immunogenic protein therapeutics from non-human functional proteins. This approach requires grouping of the epitopes to identify targets for deimmunization followed by quantitative analysis of the decrease in affinity produced by the mutations in B cell epitopes. Published by Elsevier B.V. C1 [Nagata, Satoshi] Sanford Res USD, Canc Biol Res Ctr, Sioux Falls, SD 57105 USA. [Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Nagata, S (reprint author), Sanford Res USD, Canc Biol Res Ctr, 1400 W 22nd St, Sioux Falls, SD 57105 USA. EM nagatas@sanfordhealth.org; pastani@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 101 TC 34 Z9 36 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD SEP 30 PY 2009 VL 61 IS 11 BP 977 EP 985 DI 10.1016/j.addr.2009.07.014 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 511BC UT WOS:000271137600009 PM 19679153 ER PT J AU Lee, JY Yang, ST Kim, HJ Lee, SK Jung, HH Shin, SY Kim, JI AF Lee, Ju Yeon Yang, Sung-Tae Kim, Hyo Jeong Lee, Seung Kyu Jung, Hyun Ho Shin, Song Yub Kim, Jae Il TI Different modes of antibiotic action of homodimeric and monomeric bactenecin, a cathelicidin-derived antibacterial peptide SO BMB REPORTS LA English DT Article DE Antibacterial activity; Homodimeric bactenecin; Model membrane; Monomeric bactenecin; Oligomerization ID ANTIMICROBIAL CATIONIC PEPTIDE; CELL-PENETRATING PEPTIDE; CYTOPLASMIC MEMBRANE; BACTERICIDAL ACTION; BOVINE NEUTROPHILS; FLUORESCENCE; PURIFICATION; LIPOSOMES; MECHANISM; RICH AB The bactenecin is an antibacterial peptide with an intramolecular disulfide bond. We recently found that homodimeric bactenecin exhibits more potent antibacterial activity than the monomeric form and retains its activity at physiological conditions. Here we assess the difference in the modes of antibiotic action of homodimeric and monomeric bactenecins. Both monomeric and dimeric bactenecins almost completely killed both Staphylococcus aureus and E. coli within 10-30 min at concentrations of 8-16 mu M. However, exposure to liposomes elicited an increase in the fluorescence quantum yield from a tryptophan-containing monomeric analog, while the homodimeric analog showed a significant reduction in fluorescence intensity. Moreover, unlike the monomer, the homodimer displayed apparent membrane-lytic activity enabling release of various sized dyes from liposomes, and rapidly and fully depolarized the S. aureus membrane. Together, our results suggest that homodimeric bactenecin forms pores in the bacterial membrane, while monomeric one penetrates through the membrane to target intracellular molecules/organelles. [BMB reports 2009; 42(9): 586-592] C1 [Lee, Ju Yeon; Yang, Sung-Tae; Kim, Hyo Jeong; Lee, Seung Kyu; Jung, Hyun Ho; Kim, Jae Il] Gwangju Inst Sci & Technol, Dept Life Sci, Res Ctr Bioimaging, Kwangju 500712, South Korea. [Yang, Sung-Tae] NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. [Shin, Song Yub] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea. [Shin, Song Yub] Chosun Univ, Grad Sch, Dept Biomat, Kwangju 501759, South Korea. [Kim, Jae Il] AnyGen Co Ltd, Kwangju 500712, South Korea. RP Kim, JI (reprint author), Gwangju Inst Sci & Technol, Dept Life Sci, Res Ctr Bioimaging, Kwangju 500712, South Korea. EM jikim@gist.ac.kr NR 26 TC 10 Z9 11 U1 2 U2 6 PU KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY PI SEOUL PA KOREA SCIENCE & TECHNOLOGY CENTER, # 801, 635-4 , YEOKSAM-DONG, KANGNAM-KU, SEOUL, 135-703, SOUTH KOREA SN 1976-6696 J9 BMB REP JI BMB Rep. PD SEP 30 PY 2009 VL 42 IS 9 BP 586 EP 592 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 505QH UT WOS:000270708900007 PM 19788860 ER PT J AU Morris, JC Waldmann, TA AF Morris, John C. Waldmann, Thomas A. TI Antibody-based therapy of leukaemia SO EXPERT REVIEWS IN MOLECULAR MEDICINE LA English DT Review ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; ANTI-CD20 MONOCLONAL-ANTIBODY; NON-HODGKINS-LYMPHOMA; T-CELL LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; PHASE-II TRIAL; PREVIOUSLY UNTREATED PATIENTS; DOSE-ESCALATION TRIAL; HUMAN CD52 ANTIBODY AB Over the past decade, monoclonal antibodies have dramatically impacted the treatment of haematological malignancies, as evidenced by the effect of rituximab on the response rate and survival of patients with follicular and diffuse large B cell non-Hodgkin's lymphoma. Currently, only two monoclonal antibodies - the anti-CD33 immunotoxin gemtuzumab ozogamicin and the CD52-directed antibody alemtuzumab - are approved for treatment of relapsed acute myeloid leukaemia in older patients and B cell chronic lymphocytic leukaemia, respectively. Although not approved for such treatment, alemtuzumab is also active against T cell prolymphocytic leukaemia, cutaneous T cell lymphoma and Sezary syndrome, and adult T cell leukaemia and lymphoma. In addition, rituximab has demonstrated activity against B cell chronic lymphocytic and hairy cell leukaemia. Monoclonal antibodies targeting CD4, CD19, CD20, CD22, CD23, CD25, CD45, CD66 and CD122 are now being studied in the clinic for the treatment of leukaemia. Here, we discuss how these new antibodies have been engineered to reduce immunogenicity and improve antibody targeting and binding. Improved interactions with Fc receptors on immune effector cells can enhance destruction of target cells through antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. The antibodies can also be armed with cellular toxins or radionuclides to enhance the destruction of leukaemia cells. C1 [Morris, John C.] NCI, Metab Branch, Ctr Canc Res, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Morris, JC (reprint author), NCI, Metab Branch, Ctr Canc Res, Mark O Hatfield Clin Res Ctr, Room 4-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM jmorris@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors wish to thank the reviewers for their thoughtful and helpful comments on this article. NR 195 TC 19 Z9 20 U1 0 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1462-3994 J9 EXPERT REV MOL MED JI Expert Rev. Mol. Med. PD SEP 30 PY 2009 VL 11 AR e29 DI 10.1017/S1462399409001215 PG 25 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 577UO UT WOS:000276249700001 PM 19788782 ER PT J AU Matveev, V Bertram, R Sherman, A AF Matveev, Victor Bertram, Richard Sherman, Arthur TI Ca2+ Current versus Ca2+ Channel Cooperativity of Exocytosis SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FAST CNS SYNAPSE; TRANSMITTER RELEASE; CALCIUM-CHANNEL; NEUROTRANSMITTER RELEASE; NEUROMUSCULAR-JUNCTION; PRESYNAPTIC CALCIUM; MONTE-CARLO; RAT CALYX; VESICLE; DEPENDENCE AB Recently there has been significant interest and progress in the study of spatiotemporal dynamics of Ca2+ that triggers exocytosis at a fast chemical synapse, which requires understanding the contribution of individual calcium channels to the release of a single vesicle. Experimental protocols provide insight into this question by probing the sensitivity of exocytosis to Ca2+ influx. While varying extracellular or intracellular Ca2+ concentration assesses the intrinsic biochemical Ca2+ cooperativity of neurotransmitter release, varying the number of open Ca2+ channels using pharmacological channel block or the tail current titration probes the cooperativity between individual Ca2+ channels in triggering exocytosis. Despite the wide use of these Ca2+ sensitivity measurements, their interpretation often relies on heuristic arguments. Here we provide a detailed analysis of the Ca2+ sensitivity measures probed by these experimental protocols, present simple expressions for special cases, and demonstrate the distinction between the Ca2+ current cooperativity, defined by the relationship between exocytosis rate and the whole-terminal Ca2+ current magnitude, and the underlying Ca2+ channel cooperativity, defined as the average number of channels involved in the release of a single vesicle. We find simple algebraic expressions that show that the two are different but linearly related. Further, we use three-dimensional computational modeling of buffered Ca2+ diffusion to analyze these distinct Ca2+ cooperativity measures, and demonstrate the role of endogenous Ca2+ buffers on such measures. We show that buffers can either increase or decrease the Ca2+ current cooperativity of exocytosis, depending on their concentration and the single-channel Ca2+ current. C1 [Matveev, Victor] New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. [Bertram, Richard] Florida State Univ, Dept Math, Tallahassee, FL 32306 USA. [Bertram, Richard] Florida State Univ, Program Neurosci, Tallahassee, FL 32306 USA. [Bertram, Richard] Florida State Univ, Program Mol Biophys, Tallahassee, FL 32306 USA. [Sherman, Arthur] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Matveev, V (reprint author), New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. EM matveev@njit.edu FU National Science Foundation [DMS-0817703, DMS-0613179]; Intramural Research Program of the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by National Science Foundation Grants DMS-0817703 (to V.M.) and DMS-0613179 (to R.B.) and by the Intramural Research Program of the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases (A.S.). NR 36 TC 15 Z9 16 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 30 PY 2009 VL 29 IS 39 BP 12196 EP 12209 DI 10.1523/JNEUROSCI.0263-09.2009 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 501EV UT WOS:000270363300019 PM 19793978 ER PT J AU Vullhorst, D Neddens, J Karavanova, I Tricoire, L Petralia, RS McBain, CJ Buonanno, A AF Vullhorst, Detlef Neddens, Joerg Karavanova, Irina Tricoire, Ludovic Petralia, Ronald S. McBain, Chris J. Buonanno, Andres TI Selective Expression of ErbB4 in Interneurons, But Not Pyramidal Cells, of the Rodent Hippocampus SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NEUREGULIN RECEPTOR ERBB4; LONG-TERM POTENTIATION; TYROSINE KINASE; DEVELOPMENTAL PROFILE; NEURAL DEVELOPMENT; CEREBRAL-CORTEX; ADULT-RAT; SYNAPSES; NEURONS AB NRG1 and ERBB4 have emerged as some of the most reproducible schizophrenia risk genes. Moreover, the Neuregulin (NRG)/ErbB4 signaling pathway has been implicated in dendritic spine morphogenesis, glutamatergic synaptic plasticity, and neural network control. However, despite much attention this pathway and its effects on pyramidal cells have received recently, the presence of ErbB4 in these cells is still controversial. As knowledge of the precise locus of receptor expression is crucial to delineating the mechanisms by which NRG signaling elicits its diverse physiological effects, we have undertaken a thorough analysis of ErbB4 distribution in the CA1 area of the rodent hippocampus using newly generated rabbit monoclonal antibodies and ErbB4-mutant mice as negative controls. We detected ErbB4 immunoreactivity in GABAergic interneurons but not in pyramidal neurons, a finding that was further corroborated by the lack of ErbB4 mRNA in electrophysiologically identified pyramidal neurons as determined by single-cell reverse transcription-PCR. Contrary to some previous reports, we also did not detect processed ErbB4 fragments or nuclear ErbB4 immunoreactivity. Ultrastructural analysis in CA1 interneurons using immunoelectron microscopy revealed abundant ErbB4 expression in the somatodendritic compartment in which it accumulates at, and adjacent to, glutamatergic postsynaptic sites. In contrast, we found no evidence for presynaptic expression in cultured GAD67-positive hippocampal interneurons and in CA1 basket cell terminals. Our findings identify ErbB4-expressing interneurons, but not pyramidal neurons, as a primary target of NRG signaling in the hippocampus and, furthermore, implicate ErbB4 as a selective marker for glutamatergic synapses on inhibitory interneurons. C1 [Buonanno, Andres] NIDCD, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Tricoire, Ludovic; McBain, Chris J.] NIDCD, Lab Cellular & Mol Neurophysiol, Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Petralia, Ronald S.] NIDCD, Neurochem Lab, Bethesda, MD 20892 USA. RP Buonanno, A (reprint author), NIDCD, Mol Neurobiol Sect, NIH, Bldg 35,Room 2C-1000,35 Lincoln Dr, Bethesda, MD 20892 USA. EM buonanno@mail.nih.gov FU National Institute of Child Health and Human Development (NICHD); National Institute on Deafness and Other Communication Disorders intramural program FX This work was supported by the National Institute of Child Health and Human Development (NICHD) intramural program (D.V., J.N., I.K., L.T., C.J.M., A.B.) and the National Institute on Deafness and Other Communication Disorders intramural program (R.S.P.). We thank Dr. Ya-Xian Wang for help with immunoelectron microscopy, Dr. Z. Sheng for the SNPH Delta MT-GFP construct, and V. Schram and C. Smith from the NICHD and National Institute of Neurological Disorders and Stroke microscopy core facilities for expert assistance. NR 45 TC 98 Z9 99 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 30 PY 2009 VL 29 IS 39 BP 12255 EP 12264 DI 10.1523/JNEUROSCI.2454-09.2009 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 501EV UT WOS:000270363300025 PM 19793984 ER PT J AU Coddou, C Codocedo, JF Li, S Lillo, JG Acuna-Castillo, C Bull, P Stojilkovic, SS Huidobro-Toro, JP AF Coddou, Claudio Codocedo, Juan F. Li, Shuo Lillo, Juan G. Acuna-Castillo, Claudio Bull, Paulina Stojilkovic, Stanko S. Huidobro-Toro, J. Pablo TI Reactive Oxygen Species Potentiate the P2X(2) Receptor Activity through Intracellular Cys(430) SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GROWING ESCHERICHIA-COLI; SMOOTH-MUSCLE CELLS; HYDROGEN-PEROXIDE; HISTIDINE-RESIDUES; RESPIRATORY-CHAIN; RAT HEPATOCYTES; HEAVY-METALS; MODULATION; CHANNELS; MERCURY AB P2X receptor channels (P2XRs) are allosterically modulated by several compounds, mainly acting at the ectodomain of the receptor. Like copper, mercury, a metal that induces oxidative stress in cells, also stimulates the activity of P2X(2)R and inhibits the activity of P2X(4)R. However, the mercury modulation is not related to the extracellular residues critical for copper modulation. To identify the site(s) for mercury action, we generated two chimeras using the full size P2X(2) subunit, termed P2X(2a), and a splice variant lacking a 69 residue segment in the C terminal, termed P2X(2b), as the donors for intracellular and transmembrane segments and the P2X(4) subunit as the donor for ectodomain segment of chimeras. The potentiating effect of mercury on ATP-induced current was preserved in Xenopus oocytes expressing P2X(4/2a) chimera but was absent in oocytes expressing P2X(4/2b) chimera. Site-directed mutagenesis experiments revealed that the Cys(430) residue mediates effects of mercury on the P2X(2a)R activity. Because mercury could act as an oxidative stress inducer, we also tested whether hydrogen peroxide (H2O2) and mitochondrial stress inducers myxothiazol and rotenone mimicked mercury effects. These experiments, done in both oocytes and human embryonic kidney HEK293 cells, revealed that these compounds potentiated the ATP-evoked P2X(2a)R and P2X(4/2a)R currents but not P2X(2b)R and P2X(2a)-C430A and P2X(2a)-C430S mutant currents, whereas antioxidants dithiothreitrol and N-acetylcysteine prevented the H2O2 potentiation. Alkylation of Cys(430) residue with methylmethane-thiosulfonate also abolished the mercury and H2O2 potentiation. Altogether, these results are consistent with the hypothesis that the Cys(430) residue is an intracellular P2X(2a)R redox sensor. C1 [Coddou, Claudio; Codocedo, Juan F.; Lillo, Juan G.; Bull, Paulina; Huidobro-Toro, J. Pablo] Pontificia Univ Catolica Chile, Dept Fisiol, Fac Ciencias Biol,Inst Milenio Biol Fundamental &, Ctr Regulac Celular & Patol Prof JV Luco, Santiago, Chile. [Coddou, Claudio; Codocedo, Juan F.; Lillo, Juan G.; Bull, Paulina; Huidobro-Toro, J. Pablo] Pontificia Univ Catolica Chile, Dept Fisiol, Dept Mol Genet & Microbiol, Santiago, Chile. [Coddou, Claudio; Li, Shuo; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, Natl Inst Hlth, Bethesda, MD 20892 USA. [Acuna-Castillo, Claudio] Univ Santiago Chile, Fac Quim & Biol, Dept Biol, Santiago, Chile. RP Huidobro-Toro, JP (reprint author), Pontificia Univ Catolica Chile, Dept Fisiol, Fac Ciencias Biol,Inst Milenio Biol Fundamental &, Ctr Regulac Celular & Patol Prof JV Luco, Alameda 340,Casilla 114-D,PC 6513677, Santiago, Chile. EM jphuid@bio.puc.cl OI Codocedo Henriquez, Juan Francisco/0000-0002-9683-2156 FU Fondo de Investigacion Avanzada en Areas Prioritarias [13980001]; National Institute of Child Health and Human Development/National Institutes of Health FX This research was funded by Fondo de Investigacion Avanzada en Areas Prioritarias Grant 13980001 and by the Intramural Research Program of the National Institute of Child Health and Human Development/National Institutes of Health. The Millennium Institute for Fundamental and Applied Biology and Programa de Financiamento Basal Grant 12/2007 also contributed with funds. NR 35 TC 17 Z9 17 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 30 PY 2009 VL 29 IS 39 BP 12284 EP 12291 DI 10.1523/JNEUROSCI.2096-09.2009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 501EV UT WOS:000270363300028 PM 19793987 ER PT J AU Prokunina-Olsson, L Kaplan, LM Schadt, EE Collins, FS AF Prokunina-Olsson, Ludmila Kaplan, Lee M. Schadt, Eric E. Collins, Francis S. TI Alternative Splicing of TCF7L2 Gene in Omental and Subcutaneous Adipose Tissue and Risk of Type 2 Diabetes SO PLOS ONE LA English DT Article AB Background: Single nucleotide polymorphisms (SNPs) rs7903146 and rs12255372 located within TCF7L2 gene have been identified as the strongest common genetic risk factors for development of type 2 diabetes (T2D). We hypothesized that these genetic variants might increase the risk of T2D through regulation of alternative splicing or expression level of TCF7L2 in human adipose tissue. Methodology/Principal Findings: Expression of 13 assays detecting alternatively spliced forms of TCF7L2 was measured by quantitative reverse-transcriptase PCR (qRT-PCR) in paired biopsies of omental and subcutaneous adipose tissue from 159 obese individuals (BMI 54.6+/212.2 kg/m(2)). TCF7L2 expression in both types of adipose tissue was not associated with SNPs rs7903146 and rs12255372, T2D status and blood levels of glucose or glycosylated hemoglobin (HbA1c). Expression of assays "ex12-13", "ex12-14" and "ex13-13a" detecting C-terminal alternative exons of TCF7L2 was higher in subcutaneous compared to omental adipose tissue by 1.46 fold (p=6.5x10(-15)), 1.41 fold (p=1.4x10(-9)) and 1.26 fold (p=4.7x10(-6)) in the control group and by 1.86 fold (p=1.7x10(-4)), 1.77 fold (p=7.3x10(-4)) and 1.58 fold (p=6.1x10(-4)) in the T2D group. A pathway enrichment analysis on transcripts significantly co-expressed with TCF7L2 in a microarray set combined with individual expression assays, suggested tissue-specific roles of TCF7L2 splicing forms in regulation of transcription, signal transduction and cell adhesion. Conclusions: Expression of TCF7L2 alternatively spliced forms may have different functional roles in omental and subcutaneous adipose tissue but is not associated with SNPs rs7903146 and rs12255372 or T2D status. RP Prokunina-Olsson, L (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM prokuninal@mail.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU Intramural NIH HHS; NIDDK NIH HHS [P30 DK040561, P30 DK040561-14] NR 26 TC 22 Z9 22 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 SEP 30 PY 2009 VL 4 IS 9 AR e7231 DI 10.1371/journal.pone.0007231 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 501BO UT WOS:000270354100005 PM 19789636 ER PT J AU Hyun, S Sun, YQ Sundaram, R AF Hyun, Seunggeun Sun, Yanqing Sundaram, Rajeshwari TI Assessing cumulative incidence functions under the semiparametric additive risk model SO STATISTICS IN MEDICINE LA English DT Article DE competing risks; survival analysis; cumulative incidence function; confidence interval; semiparametric model AB In analyzing competing risks data, a quantity of considerable interest is the cumulative incidence function. Often, the effect of covariates on the cumulative incidence function is modeled via the proportional hazards model for the cause-specific hazard function. As the proportionality assumption may be too restrictive in practice, we consider an alternative more flexible semiparametric additive hazards model of (Biometrika 1994; 81:501-514) for the cause-specific hazard. This model specifies the effect of covariates on the cause-specific hazard to be additive as well as allows the effect of some covariates to be fixed and that of others to be time varying. We present an approach for constructing confidence intervals as well as confidence bands for the cause-specific cumulative incidence function of subjects with given values of the covariates. Furthermore, we also present an approach for constructing confidence intervals and confidence bands for comparing two cumulative incidence functions given values of the covariates. The finite sample property of the proposed estimators is investigated through simulations. We conclude our paper with an analysis of the well-known malignant melanoma data using our method. Published in 2009 by John Wiley & Sons, Ltd. C1 [Sundaram, Rajeshwari] NICHHD, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Hyun, Seunggeun] Univ S Carolina Upstate, Div Math & Comp Sci, Spartanburg, SC 29303 USA. [Sun, Yanqing] Univ N Carolina, Dept Math & Stat, Charlotte, NC 28223 USA. RP Sundaram, R (reprint author), NICHHD, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM sundaramr2@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002 FU NSF [DMS-0304922, DMS-0604576]; NIH [2 RO1 A1054165-04]; Intramural research program of Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Contract/grant sponsor: NSF; contract/grant numbers: DMS-0304922, DMS-0604576 Contract/grant sponsor: NIH; contract/grant number: 2 RO1 A1054165-04 Contract/grant sponsor: Intramural research program of Eunice Kennedy Shriver National Institute of Child Health and Human Development NR 12 TC 2 Z9 2 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 30 PY 2009 VL 28 IS 22 BP 2748 EP 2768 DI 10.1002/sim.3640 PG 21 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 498YS UT WOS:000270183400002 PM 19585462 ER PT J AU Jia, L Kropachev, K Ding, SA Van Houten, B Geacintov, NE Broyde, S AF Jia, Lei Kropachev, Konstantin Ding, Shuang Van Houten, Bennett Geacintov, Nicholas E. Broyde, Suse TI Exploring Damage Recognition Models in Prokaryotic Nucleotide Excision Repair with a Benzo[a]pyrene-Derived Lesion in UvrB SO BIOCHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; DNA-DAMAGE; SOLUTION CONFORMATION; STRUCTURAL BASIS; QUALITY-CONTROL; ATPASE ACTIVITY; DIOL EPOXIDES; BINDING; PROTEIN AB The UvrB protein is a central unit for damage recognition in the prokaryotic nucleotide excision repair system, which excises bulky DNA lesions. We have utilized molecular modeling and MD simulations based on crystal structures, mutagenesis, and fluorescence data, to model the 10R-(+)-cis-anti-B[a]P-N(2)-dG lesion, derived from the tumorigenic (+)-anti-B[a]PDE metabolite of benzo[a]pyrene, at different locations on the inner and outer strand in UvrB. Our results suggest that this lesion is accommodated on the inner strand where it might translocate through the tunnel created by the beta-hairpin and UvrB domain 1B and ultimately could be housed in the pocket behind the beta-hairpin prior to excision by UvrC. Lesions that vary in size and shape may be stopped at the gate to the tunnel, within the tunnel, or in the pocket when UvrC initiates excision. Common features of beta-hairpin intrusion between the two DNA strands and nucleotide flipping manifested in structures of prokaryotic and eukaryotic NER lesion recognition proteins are consistent with common recognition mechanisms, based on lesion-induced local thermodynamic distortion/destabilization and nucleotide flipping. C1 [Jia, Lei; Ding, Shuang; Broyde, Suse] NYU, Dept Biol, New York, NY 10003 USA. [Kropachev, Konstantin; Geacintov, Nicholas E.; Broyde, Suse] NYU, Dept Chem, New York, NY 10003 USA. [Van Houten, Bennett] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Broyde, S (reprint author), NYU, Dept Biol, 100 Washington Sq E,Room 1009, New York, NY 10003 USA. EM broyde@nyu.edu FU National Institutes of Health; National Cancer Institute [CA28038, CA099194]; NIEHS; Intramural Research Program; National Science Foundation Partnerships for Advanced Computational Infrastructure; [CA75449] FX This work was supported by the National Institutes of Health, National Cancer Institute Grants CA28038 to S.B. and CA099194 to N.E.G., and the NIEHS, NIH, Intramural Research Program to B.V.H.. Partial support for computational infrastructure and systems management was also provided by Grant CA75449 to S.B. Computational support was provided in part by the National Science Foundation Partnerships for Advanced Computational Infrastructure. NR 61 TC 13 Z9 13 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 29 PY 2009 VL 48 IS 38 BP 8948 EP 8957 DI 10.1021/bi9010072 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 495LE UT WOS:000269892000004 PM 19681599 ER PT J AU Koonin, EV Wolf, YI AF Koonin, Eugene V. Wolf, Yuri I. TI The fundamental units, processes and patterns of evolution, and the Tree of Life conundrum SO BIOLOGY DIRECT LA English DT Editorial Material ID HORIZONTAL GENE-TRANSFER; EUKARYOTIC EVOLUTION; SELFISH OPERONS; ORIGIN; VIRUSES; CELLS; SEQUENCE; REPLICATORS; HYPOTHESIS; GENOMICS AB Background: The elucidation of the dominant role of horizontal gene transfer (HGT) in the evolution of prokaryotes led to a severe crisis of the Tree of Life (TOL) concept and intense debates on this subject. Concept: Prompted by the crisis of the TOL, we attempt to define the primary units and the fundamental patterns and processes of evolution. We posit that replication of the genetic material is the singular fundamental biological process and that replication with an error rate below a certain threshold both enables and necessitates evolution by drift and selection. Starting from this proposition, we outline a general concept of evolution that consists of three major precepts. 1. The primary agency of evolution consists of Fundamental Units of Evolution (FUEs), that is, units of genetic material that possess a substantial degree of evolutionary independence. The FUEs include both bona fide selfish elements such as viruses, viroids, transposons, and plasmids, which encode some of the information required for their own replication, and regular genes that possess quasi-independence owing to their distinct selective value that provides for their transfer between ensembles of FUEs (genomes) and preferential replication along with the rest of the recipient genome. 2. The history of replication of a genetic element without recombination is isomorphously represented by a directed tree graph (an arborescence, in the graph theory language). Recombination within a FUE is common between very closely related sequences where homologous recombination is feasible but becomes negligible for longer evolutionary distances. In contrast, shuffling of FUEs occurs at all evolutionary distances. Thus, a tree is a natural representation of the evolution of an individual FUE on the macro scale, but not of an ensemble of FUEs such as a genome. 3. The history of life is properly represented by the "forest" of evolutionary trees for individual FUEs (Forest of Life, or FOL). Search for trends and patterns in the FOL is a productive direction of study that leads to the delineation of ensembles of FUEs that evolve coherently for a certain time span owing to a shared history of vertical inheritance or horizontal gene transfer; these ensembles are commonly known as genomes, taxa, or clades, depending on the level of analysis. A small set of genes (the universal genetic core of life) might show a (mostly) coherent evolutionary trend that transcends the entire history of cellular life forms. However, it might not be useful to denote this trend "the tree of life", or organismal, or species tree because neither organisms nor species are fundamental units of life. Conclusion: A logical analysis of the units and processes of biological evolution suggests that the natural fundamental unit of evolution is a FUE, that is, a genetic element with an independent evolutionary history. Evolution of a FUE on the macro scale is naturally represented by a tree. Only the full compendium of trees for individual FUEs (the FOL) is an adequate depiction of the evolution of life. Coherent evolution of FUEs over extended evolutionary intervals is a crucial aspect of the history of life but a "species" or "organismal" tree is not a fundamental concept. Reviewers: This articles was reviewed by Valerian Dolja, W. Ford Doolittle, Nicholas Galtier, and William Martin C1 [Koonin, Eugene V.; Wolf, Yuri I.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov; wolf@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 73 TC 37 Z9 38 U1 0 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD SEP 29 PY 2009 VL 4 AR 33 DI 10.1186/1745-6150-4-33 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 510AW UT WOS:000271061400001 PM 19788730 ER PT J AU Joshi, A Nagashima, K Freed, EO AF Joshi, Anjali Nagashima, Kunio Freed, Eric O. TI Defects in cellular sorting and retroviral assembly induced by GGA overexpression SO BMC CELL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTIOUS-ANEMIA VIRUS; TRANS-GOLGI NETWORK; FACTOR-BINDING PROTEINS; GAG-MEMBRANE-BINDING; HIV-1 GAG; INTRACELLULAR TRAFFICKING; LATE DOMAIN; UBIQUITIN BINDING; INCLUSION-BODIES AB Background: We previously demonstrated that overexpression of Golgi-localized, gamma-ear containing, Arf-binding (GGA) proteins inhibits retrovirus assembly and release by disrupting the function of endogenous ADP ribosylation factors (Arfs). GGA overexpression led to the formation of large, swollen vacuolar compartments, which in the case of GGA1 sequestered HIV-1 Gag. Results: In the current study, we extend our previous findings to characterize in depth the GGA-induced compartments and the determinants for retroviral Gag sequestration in these structures. We find that GGA-induced structures are derived from the Golgi and contain aggresome markers. GGA overexpression leads to defects in trafficking of transferrin receptor and recycling of cation-dependent mannose 6-phosphate receptor. Additionally, we find that compartments induced by GGA overexpression sequester Tsg101, poly-ubiquitin, and, in the case of GGA3, Hrs. Interestingly, brefeldin A treatment, which leads to the dissociation of endogenous GGAs from membranes, does not dissociate the GGA-induced compartments. GGA mutants that are defective in Arf binding and hence association with membranes also induce the formation of GGA-induced structures. Overexpression of ubiquitin reverses the formation of GGA-induced structures and partially rescues HIV-1 particle production. We found that in addition to HIV-1 Gag, equine infectious anemia virus Gag is also sequestered in GGA1-induced structures. The determinants in Gag responsible for sequestration map to the matrix domain, and recruitment to these structures is dependent on Gag membrane binding. Conclusion: These data provide insights into the composition of structures induced by GGA overexpression and their ability to disrupt endosomal sorting and retroviral particle production. C1 [Joshi, Anjali; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Nagashima, Kunio] NCI, Image Anal Lab, Adv Technol Program, SAIC Frederick, Frederick, MD 21701 USA. [Joshi, Anjali] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Paul L Foster Sch Med,Ctr Excellence Infect Dis, El Paso, TX 79905 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM ajoshi145@yahoo.com; nagashim@ncifcrf.gov; efreed@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; National Cancer Institute, NIH [N01-CO-12400] FX We thank F. Soheilian and S. Ablan for expert technical assistance and members of the Freed lab for helpful discussion and critical review of the manuscript. We thank J. Bonifacino for kindly providing GGA expression vectors, E. Sztul for the GFP-250 construct, A. Ono for the Fyn10deltaMA and Fyn10fullMA Gag chimeras, R. Kopito for the ubiquitin expression vector pCW7, R. Kahn for the GGA1 antibody, and P. Woodman for the GFP-tagged Vps4EQ expression vector. The HIV-Ig and TZM-bl cells were obtained from the NIH AIDS Research and Reference Reagent Program, EIAV anti-p26 antibody was kindly provided by R. Montelaro and MLV anti-p30 was a gift from A. Rein. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by the Intramural AIDS Targeted Antiviral Program. This project was funded in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400. 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 80 TC 10 Z9 10 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD SEP 29 PY 2009 VL 10 AR 72 DI 10.1186/1471-2121-10-72 PG 14 WC Cell Biology SC Cell Biology GA 511XC UT WOS:000271204000001 PM 19788741 ER PT J AU Vasan, RS Demissie, S Kimura, M Cupples, LA White, C Gardner, JP Cao, XG Levy, D Benjamin, EJ Aviv, A AF Vasan, Ramachandran S. Demissie, Serkalem Kimura, Masayuki Cupples, L. Adrienne White, Charles Gardner, Jeffrey P. Cao, Xiaogian Levy, Daniel Benjamin, Emelia J. Aviv, Abraham TI Association of Leukocyte Telomere Length With Echocardiographic Left Ventricular Mass The Framingham Heart Study SO CIRCULATION LA English DT Article DE telomere; echocardiography; hypertension; epidemiology; hypertrophy ID GROWTH-FACTOR-I; ANGIOTENSIN-ALDOSTERONE SYSTEM; CARDIOVASCULAR RISK-FACTORS; DIABETES-MELLITUS; OXIDATIVE STRESS; INSULIN-RESISTANCE; BLOOD-PRESSURE; HYPERTENSIVE SUBJECTS; GENERAL-POPULATION; PHYSICAL-ACTIVITY AB Background-Leukocyte telomere length (LTL) decreases over the adult life course owing to the cumulative burden of oxidative stress, inflammation, and exposure to vascular risk factors. Left ventricular (LV) mass is a biomarker of long-standing exposure to cardiovascular disease risk factors. We hypothesized that LTL is related inversely to LV mass. Methods and Results-We related LTL (measured by Southern blot analysis) to echocardiographic LV mass and its components (LV diastolic dimension and LV wall thickness) in 850 Framingham Heart Study participants (mean age 58 years, 58% women) using multivariable linear regression with adjustment for age, sex, height, weight, systolic blood pressure, hypertension treatment, and smoking. Overall, multivariable-adjusted LTL was positively related to LV mass (beta-coefficient per SD increase 0.072; P=0.001), LV wall thickness (beta=0.053; P=0.01), and LV diastolic dimension (beta=0.035; P=0.09). We observed effect modification by hypertension status (P for interaction=0.02 for LV mass); LTL was more strongly associated with LV mass and LV wall thickness in individuals with hypertension (beta-coefficient per SD increment of 0.10 and 0.08, respectively; P<0.01 for both). Participants with hypertension who were in the top quartile of LV mass had LTL that was 250 base pairs longer than those in the lowest quartile (P for trend across quartiles=0.009). Conclusions-In contrast to our expectation, in the present community-based sample, LTL was positively associated with LV mass and wall thickness, especially so in participants with hypertension. These data are consistent with the hypothesis that longer LTL may be a marker of propensity to LV hypertrophy. (Circulation. 2009; 120: 1195-1202.) C1 [Vasan, Ramachandran S.; Demissie, Serkalem; Cupples, L. Adrienne; Levy, Daniel; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Prevent Med, Evans Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Evans Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Demissie, Serkalem; Cupples, L. Adrienne; White, Charles] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Kimura, Masayuki; Gardner, Jeffrey P.; Cao, Xiaogian; Aviv, Abraham] Univ Med & Dent New Jersey, Ctr Human Dev & Aging, Newark, NJ 07103 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Cupples, L. Adrienne/0000-0003-0273-7965; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, 2 K24 HL04334, RO1HL080124, 6R01-NS 17950, R01AG021593] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195), 2 K24 HL04334, RO1HL080124 (Dr Vasan), 6R01-NS 17950; and R01AG021593 (Dr Aviv). NR 63 TC 31 Z9 33 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 29 PY 2009 VL 120 IS 13 BP 1195 EP 1202 DI 10.1161/CIRCULATIONAHA.109.853895 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 500AU UT WOS:000270270200006 PM 19752323 ER PT J AU Merz, CNB Alberts, MJ Balady, GJ Ballantyne, CM Berra, K Black, HR Blumenthal, RS Davidson, MH Fazio, SB Ferdinand, KC Fine, LJ Fonseca, V Franklin, BA McBride, PE Mensah, GA Merli, GJ O'Gara, PT Thompson, PD Underberg, JA AF Merz, C. Noel Bairey Alberts, Mark J. Balady, Gary J. Ballantyne, Christie M. Berra, Kathy Black, Henry R. Blumenthal, Roger S. Davidson, Michael H. Fazio, Sara B. Ferdinand, Keith C. Fine, Lawrence J. Fonseca, Vivian Franklin, Barry A. McBride, Patrick E. Mensah, George A. Merli, Geno J. O'Gara, Patrick T. Thompson, Paul D. Underberg, James A. CA ACCF AHA ACP TI ACCF/AHA/ACP 2009 Competence and Training Statement: A Curriculum on Prevention of Cardiovascular Disease A Report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Competence and Training (Writing Committee to Develop a Competence and Training Statement on Prevention of Cardiovascular Disease) SO CIRCULATION LA English DT Editorial Material DE ACCF/AHA Competence and Training Statements; competency; prevention; cardiovascular; training; vascular; cardiac; cardiac rehabilitation ID CORONARY-ARTERY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; HEALTH-CARE PROFESSIONALS; RANDOMIZED CONTROLLED-TRIAL; LIPID-LOWERING THERAPY; HIGH-BLOOD-PRESSURE; INTERDISCIPLINARY WORKING GROUP; STROKE-STATISTICS-SUBCOMMITTEE; 64-SLICE COMPUTED-TOMOGRAPHY; SUSTAINED-RELEASE BUPROPION C1 [Merz, C. Noel Bairey; Ballantyne, Christie M.; Blumenthal, Roger S.; McBride, Patrick E.] Amer Coll, Cardiol Fdn, Bryn Mawr, PA 19010 USA. [Alberts, Mark J.] Amer Acad Neurol, St Paul, MN USA. [Black, Henry R.] Amer Soc Hypertens, New York, NY 10016 USA. [Fazio, Sara B.; Merli, Geno J.] Amer Coll Physicians, Philadelphia, PA 19106 USA. [Ferdinand, Keith C.] Assoc Black Cardiologists, Atlanta, GA 30308 USA. [Fine, Lawrence J.] NHLBI, Bethesda, MD USA. [Fonseca, Vivian] Amer Diabet Assoc, Alexandria, VA USA. [Franklin, Barry A.; O'Gara, Patrick T.] Amer Heart Assoc, Dallas, TX USA. [Fine, Lawrence J.; Mensah, George A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Thompson, Paul D.] Amer Coll Sports Med, Indianapolis, IN USA. [Underberg, James A.] Amer Coll Prevent Med, Washington, DC USA. [Fine, Lawrence J.; Mensah, George A.] NIH, Bethesda, MD USA. RP Merz, CNB (reprint author), Amer Coll, Cardiol Fdn, Bryn Mawr, PA 19010 USA. NR 223 TC 17 Z9 19 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 29 PY 2009 VL 120 IS 13 BP E100 EP E126 DI 10.1161/CIRCULATIONAHA.109.192640 PG 27 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 500AU UT WOS:000270270200021 ER PT J AU McCroskery, S Bailey, A Lin, L Daniels, MP AF McCroskery, S. Bailey, A. Lin, L. Daniels, M. P. TI TRANSMEMBRANE AGRIN REGULATES DENDRITIC FILOPODIA AND SYNAPSE FORMATION IN MATURE HIPPOCAMPAL NEURON CULTURES SO NEUROSCIENCE LA English DT Article DE synapse formation; lenti-virus; shRNA; agrin; filopodia; dendrite ID HEPARAN-SULFATE PROTEOGLYCAN; CENTRAL-NERVOUS-SYSTEM; RAT HIPPOCAMPAL; DEFICIENT MICE; NEURITE OUTGROWTH; RECOMBINANT AGRIN; CORTICAL-NEURONS; SPINE FORMATION; IN-VIVO; RECEPTOR AB The transmembrane isoform of agrin (Tm-agrin) is the predominant form expressed in the brain but its putative roles in brain development are not well understood. Recent reports have implicated Tm-agrin in the formation and stabilization of filopodia on neurites of immature central and peripheral neurons in culture. In maturing central neurons, dendritic filopodia are believed to facilitate synapse formation. In the present study we have investigated the role of Tm-agrin in regulation of dendritic filopodia and synaptogenesis in maturing cultures of rat hippocampal neurons. We did this by infecting the neurons with an RNAi lentivirus to deplete endogenous agrin during the developmental period when filopodia density on the dendritic arbor was high, and synapse formation was rapid. We found that dendritic filopodia density was markedly reduced, as was synapse density along dendrites. Moreover, synapse formation was more sharply reduced on dendrites of infected neurons contacted by uninfected axons than on uninfected dendrites contacted by infected axons. The results are consistent with a physiological role for Tm-agrin in the maturation of hippocampal neurons involving positive regulation of dendritic filopodia and consequent promotion of synaptogenesis, but also suggest a role for axonal agrin in synaptogenesis. Published by Elsevier Ltd on behalf of IBRO. C1 [McCroskery, S.; Bailey, A.; Lin, L.; Daniels, M. P.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [McCroskery, S.] ERMA New Zealand, New Organisms Grp, Wellington, New Zealand. [Lin, L.] NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. [Daniels, M. P.] NHLBI, Electron Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Daniels, MP (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM danielsm2@mail.nih.gov FU National Heart, Lung and Blood Institute, NIH FX This research was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute, NIH. NR 57 TC 21 Z9 23 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD SEP 29 PY 2009 VL 163 IS 1 BP 168 EP 179 DI 10.1016/j.neuroscience.2009.06.012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 489FD UT WOS:000269404600015 PM 19524020 ER PT J AU Leker, RR Toth, ZE Shahar, T Cassiani-Ingoni, R Szalayova, I Key, S Bratincsak, A Mezey, E AF Leker, R. R. Toth, Z. E. Shahar, T. Cassiani-Ingoni, R. Szalayova, I. Key, S. Bratincsak, A. Mezey, E. TI TRANSFORMING GROWTH FACTOR alpha INDUCES ANGIOGENESIS AND NEUROGENESIS FOLLOWING STROKE SO NEUROSCIENCE LA English DT Article DE stroke; transforming growth factor alpha; neurogenesis; angiogenesis ID ADULT HIPPOCAMPAL NEUROGENESIS; TYRAMIDE SIGNAL AMPLIFICATION; CEREBRAL-ARTERY OCCLUSION; REDUCES INFARCT VOLUME; BONE-MARROW; FACTOR RECEPTOR; PERIPHERAL-BLOOD; STEM-CELLS; IN-VIVO; G-CSF AB The cytokine transforming growth factor alpha (TGF alpha) has proangiogenic and proneurogenic effects and can potentially reduce infarct volumes. Therefore, we administered TGF alpha or vehicle directly into the area surrounding the infarct in female mice that received gender-mismatched bone marrow transplants from green fluorescent protein (GFP)-expressing males prior to undergoing permanent middle cerebral artery occlusion. Newborn cells were tracked with bromodeoxyuridine (BrdU) labeling and immunohistochemistry at 90 days after stroke onset. We also studied the ingress of bone marrow-derived cells into the ischemic brain to determine whether such cells contribute to angiogenesis or neurogenesis. Infarct volumes were measured at 90 days poststroke. The results show that TGF alpha led to significant increments in the number of newborn neurons and glia in the ischemic hemisphere. TGF alpha also led to significant increments in the number of bone marrow-derived cells entering into the ischemic hemisphere. Most of these cells did not label with BrdU and represented endothelial cells that incorporated into blood vessels in the infarct border zone. Our results also show that infarct size was significantly reduced in animals treated with TGF alpha compared with controls. These results suggest that TGF alpha can induce angiogenesis, neurogenesis and neuroprotection after stroke. At least part of the pro-angiogenic effect appears to be secondary to the incorporation of bone marrow-derived endothelial cells into blood vessels in the infarct border zone. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Leker, R. R.] Hebrew Univ Jerusalem, Hadassah Med Ctr, Stroke Serv, Dept Neurol,Peritz & Chantal Scheinberg Cerebrova, IL-91120 Jerusalem, Israel. [Leker, R. R.; Toth, Z. E.; Shahar, T.; Cassiani-Ingoni, R.; Szalayova, I.; Key, S.; Bratincsak, A.; Mezey, E.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Toth, Z. E.] Semmelweis Univ, Dept Anat Histol & Embryol, Neuromorphol & Neuroendocrine Res Lab, H-1085 Budapest, Hungary. [Toth, Z. E.] Hungarian Acad Sci, Budapest, Hungary. RP Leker, RR (reprint author), Hebrew Univ Jerusalem, Hadassah Med Ctr, Stroke Serv, Dept Neurol,Peritz & Chantal Scheinberg Cerebrova, Hadassah Kerem POB 12000, IL-91120 Jerusalem, Israel. EM leker@cc.huji.ac.il FU Chantel and Peritz Scheinberg Cerebrovascular Research Fund; Sol Irwin Juni Trust Fund; NIDCR intramural research program FX Dr. Leker was supported in part by the Chantel and Peritz Scheinberg Cerebrovascular Research Fund and by the Sol Irwin Juni Trust Fund. This study was supported by the NIDCR intramural research program. NR 44 TC 24 Z9 24 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD SEP 29 PY 2009 VL 163 IS 1 BP 233 EP 243 DI 10.1016/j.neuroscience.2009.05.050 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 489FD UT WOS:000269404600021 PM 19481589 ER PT J AU Fritsch, B Qashu, F Figueiredo, TH Aroniadou-Anderjaska, V Rogawski, MA Braga, MFM AF Fritsch, B. Qashu, F. Figueiredo, T. H. Aroniadou-Anderjaska, V. Rogawski, M. A. Braga, M. F. M. TI PATHOLOGICAL ALTERATIONS IN GABAERGIC INTERNEURONS AND REDUCED TONIC INHIBITION IN THE BASOLATERAL AMYGDALA DURING EPILEPTOGENESIS SO NEUROSCIENCE LA English DT Review DE basolateral amygdala; interneurons; epileptogenesis; status epilepticus; kainate receptors; inhibitory synaptic transmission ID TEMPORAL-LOBE EPILEPSY; GLUTAMIC-ACID DECARBOXYLASE; INDUCED STATUS EPILEPTICUS; BENZODIAZEPINE-RECEPTOR BINDING; LIMBIC STATUS EPILEPTICUS; MESSENGER-RNA EXPRESSION; DENTATE GRANULE CELLS; RAT HIPPOCAMPUS; GABA(A) RECEPTOR; KAINATE RECEPTORS AB An acute brain insult such as traumatic head/brain injury, stroke, or an episode of status epilepticus can trigger epileptogenesis, which, after a latent, seizure-free period, leads to epilepsy. The discovery of effective pharmacological interventions that can prevent the development of epilepsy requires knowledge of the alterations that occur during epileptogenesis in brain regions that play a central role in the induction and expression of epilepsy. In the present study, we investigated pathological alterations in GABAergic inter-neurons in the rat basolateral amygdala (BLA), and the functional impact of these alterations on inhibitory synaptic transmission, on days 7 to 10 after status epilepticus induced by kainic acid. Using design-based stereology combined with glutamic acid decarboxylase (GAD) 67 immunohistochemistry, we found a more extensive loss of GABAergic interneurons compared to the loss of principal cells. Fluoro-Jade C staining showed that neuronal degeneration was still ongoing. These alterations were accompanied by an increase in the levels of GAD and the alpha 1 subunit of the GABA(A) receptor, and a reduction in the GluK1 (previously known as GluR5) subunit, as determined by Western blots. Whole-cell recordings from BLA pyramidal neurons showed a significant reduction in the frequency and amplitude of action potential-dependent spontaneous inhibitory postsynaptic currents (IPSCs), a reduced frequency but not amplitude of miniature IPSCs, and impairment in the modulation of IPSCs via GluK1-containing kainate receptors (GluK1Rs). Thus, in the BLA, GABAergic interneurons are more vulnerable to seizure-induced damage than principal cells. Surviving interneurons increase their expression of GAD and the alpha 1 GABA(A) receptor subunit, but this does not compensate for the interneuronal loss; the result is a dramatic reduction of tonic inhibition in the BLA circuitry. As activation of GluK1Rs by ambient levels of glutamate facilitates GABA release, the reduced level and function of these receptors may contribute to the reduction of tonic inhibitory activity. These alterations at a relatively early stage of epileptogenesis may facilitate the progress towards the development of epilepsy. Published by Elsevier Ltd on behalf of IBRO. C1 [Figueiredo, T. H.; Aroniadou-Anderjaska, V.; Braga, M. F. M.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Fritsch, B.; Rogawski, M. A.] NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. [Qashu, F.; Aroniadou-Anderjaska, V.; Braga, M. F. M.] Uniformed Serv Univ Hlth Sci, Neurosci Program, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Rogawski, M. A.] Univ Calif Davis, Sch Med, Dept Neurol, Sacramento, CA 95817 USA. RP Braga, MFM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, F Edward Hebert Sch Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mbraga@usuhs.mil RI Rogawski, Michael/B-6353-2009; OI Rogawski, Michael/0000-0002-3296-8193; Fritsch, Brita/0000-0003-4884-9049 FU National Institutes of Health CounterACT Program [U01 NS058162-01]; Defense Threat Reduction Agency-Joint Science and Technology Office [1.E0021_07-US-C]; NINDS Intramural Research Program FX This work was supported by the National Institutes of Health CounterACT Program (NINDS award U01 NS058162-01 to M.F.M.B.), the Defense Threat Reduction Agency-Joint Science and Technology Office, Medical S&T Division (grant 1.E0021_07-US-C to M.F.M.B.), and the NINDS Intramural Research Program (M.A.R.). NR 101 TC 27 Z9 29 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD SEP 29 PY 2009 VL 163 IS 1 BP 415 EP 429 DI 10.1016/j.neuroscience.2009.06.034 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 489FD UT WOS:000269404600037 PM 19540312 ER PT J AU Sung, MH Salvatore, L De Lorenzi, R Indrawan, A Pasparakis, M Hager, GL Bianchi, ME Agresti, A AF Sung, Myong-Hee Salvatore, Luigi De Lorenzi, Rossana Indrawan, Anindya Pasparakis, Manolis Hager, Gordon L. Bianchi, Marco E. Agresti, Alessandra TI Sustained Oscillations of NF-kappa B Produce Distinct Genome Scanning and Gene Expression Profiles SO PLOS ONE LA English DT Article AB NF-kappa B is a prototypic stress-responsive transcription factor that acts within a complex regulatory network. The signaling dynamics of endogenous NF-kappa B in single cells remain poorly understood. To examine real time dynamics in living cells, we monitored NF-kappa B activities at multiple timescales using GFP-p65 knock-in mouse embryonic fibroblasts. Oscillations in NFkB were sustained in most cells, with several cycles of transient nuclear translocation after TNF-alpha stimulation. Mathematical modeling suggests that NF-kappa B oscillations are selected over other non-oscillatory dynamics by fine-tuning the relative strengths of feedback loops like I kappa B alpha. The ability of NF-kappa B to scan and interact with the genome in vivo remained remarkably constant from early to late cycles, as observed by fluorescence recovery after photobleaching (FRAP). Perturbation of long-term NF-kappa B oscillations interfered with its short-term interaction with chromatin and balanced transcriptional output, as predicted by the mathematical model. We propose that negative feedback loops do not simply terminate signaling, but rather promote oscillations of NF-kappa B in the nucleus, and these oscillations are functionally advantageous. RP Sung, MH (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM sungm@mail.nih.gov; agresti.alessandra@hsr.it RI Agresti, Alessandra/K-5228-2016; OI Agresti, Alessandra/0000-0001-5006-9506; Pasparakis, Manolis/0000-0002-9870-0966 FU Intramural NIH HHS; Associazione Italiana per la Ricerca sul Cancro NR 30 TC 56 Z9 56 U1 1 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 SEP 29 PY 2009 VL 4 IS 9 AR e7163 DI 10.1371/journal.pone.0007163 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 500HR UT WOS:000270290100005 PM 19787057 ER PT J AU Skoko, D Li, M Huang, Y Mizuuchi, M Cai, ML Bradley, CM Pease, PJ Xiao, BT Marko, JF Craigie, R Mizuuchi, K AF Skoko, Dunja Li, Min Huang, Ying Mizuuchi, Michiyo Cai, Mengli Bradley, Christina M. Pease, Paul J. Xiao, Botao Marko, John F. Craigie, Robert Mizuuchi, Kiyoshi TI Barrier-to-autointegration factor (BAF) condenses DNA by looping SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autointegration; BAF (Banf1); DNA condensation; DNA looping; retrovirus ID LEM-DOMAIN PROTEINS; NUCLEAR-ENVELOPE; STRUCTURAL BASIS; RETROVIRAL DNA; CELLULAR FACTOR; BINDING; COMPLEX; EMERIN; LAP2-ALPHA; ROLES AB Barrier-to-autointegration factor (BAF) is a protein that has been proposed to compact retroviral DNA, making it inaccessible as a target for self-destructive integration into itself (autointegration). BAF also plays an important role in nuclear organization. We studied the mechanism of DNA condensation by BAF using total internal reflection fluorescence microscopy. We found that BAF compacts DNA by a looping mechanism. Dissociation of BAF from DNA occurs with multiphasic kinetics; an initial fast phase is followed by a much slower dissociation phase. The mechanistic basis of the broad timescale of dissociation is discussed. This behavior mimics the dissociation of BAF from retroviral DNA within preintegration complexes as monitored by functional assays. Thus the DNA binding properties of BAF may alone be sufficient to account for its association with the preintegration complex. C1 [Skoko, Dunja; Li, Min; Huang, Ying; Mizuuchi, Michiyo; Bradley, Christina M.; Craigie, Robert; Mizuuchi, Kiyoshi] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Cai, Mengli] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Pease, Paul J.] Univ Calif Berkeley, Dept Mol & Cellular Biol, Berkeley, CA 94720 USA. [Xiao, Botao; Marko, John F.] Northwestern Univ, Dept Phys & Astron, Evanston, IL 60208 USA. [Marko, John F.] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. RP Mizuuchi, K (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM kmizu@helix.nih.gov FU National Science Foundation [DMR-0715099, PHY-0852130]; Chicago Biomedical Consortium FX We are grateful to Vassili Ivanov for the help with the microscope system. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases intramural program and by the NIH Intramural Aids Targeted Antiviral Program, National Institutes of Health, Department of Health and Human Services, US Government. The work of B. X. and J. F. M. was supported by National Science Foundation Grants DMR-0715099, PHY-0852130 and by a Catalyst Award from the Chicago Biomedical Consortium. NR 31 TC 34 Z9 34 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 29 PY 2009 VL 106 IS 39 BP 16610 EP 16615 DI 10.1073/pnas.0909077106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 500MH UT WOS:000270305800015 PM 19805345 ER PT J AU Kim, HW Chang, YC Chen, M Rapoport, SI Rao, JS AF Kim, Hyung-Wook Chang, Yunyoung C. Chen, Mei Rapoport, Stanley I. Rao, Jagadeesh S. TI Chronic NMDA administration to rats increases brain pro-apoptotic factors while decreasing anti-Apoptotic factors and causes cell death SO BMC NEUROSCIENCE LA English DT Article ID SPINAL-CORD NEURONS; CYTOSOLIC PHOSPHOLIPASE A(2); D-ASPARTATE RECEPTOR; ARACHIDONIC-ACID; ALZHEIMERS-DISEASE; FRONTAL-CORTEX; UNANESTHETIZED RATS; MOOD STABILIZERS; BIPOLAR DISORDER; PROTEIN AB Background: Chronic N-Methyl-d-aspartate (NMDA) administration to rats is reported to increase arachidonic acid signaling and upregulate neuroinflammatory markers in rat brain. These changes may damage brain cells. In this study, we determined if chronic NMDA administration (25 mg/kg i.p., 21 days) to rats would alter expression of pro-and anti-apoptotic factors in frontal cortex, compared with vehicle control. Results: Using real time RT-PCR and Western blotting, chronic NMDA administration was shown to decrease mRNA and protein levels of anti-apoptotic markers Bcl-2 and BDNF, and of their transcription factor phospho-CREB in the cortex. Expression of pro-apoptotic Bax, Bad, and 14-3-3 zeta was increased, as well as Fluoro-Jade B (FJB) staining, a marker of neuronal loss. Conclusion: This alteration in the balance between pro-and anti-apoptotic factors by chronic NMDA receptor activation in this animal model may contribute to neuronal loss, and further suggests that the model can be used to examine multiple processes involved in excitotoxicity. C1 [Kim, Hyung-Wook; Chang, Yunyoung C.; Chen, Mei; Rapoport, Stanley I.; Rao, Jagadeesh S.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM kimhyung@mail.nih.gov; yunyoung.chang@gmail.com; chenmei@mail.nih.gov; sir@helix.nih.gov; jrao@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We thank Dr Sang-Ho Choi for assistance with florescence microscopy. We thank Kathy Benjamin for critically reading the manuscript. NR 54 TC 7 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD SEP 28 PY 2009 VL 10 AR 123 DI 10.1186/1471-2202-10-123 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 513LK UT WOS:000271323600001 PM 19785755 ER PT J AU Maizels, RM Pearce, EJ Artis, D Yazdanbakhsh, M Wynn, TA AF Maizels, Rick M. Pearce, Edward J. Artis, David Yazdanbakhsh, Maria Wynn, Thomas A. TI Regulation of pathogenesis and immunity in helminth infections SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Review ID EGG-INDUCED IMMUNOPATHOLOGY; FOLLICULAR HELPER-CELLS; CD4(+) T-CELLS; SCHISTOSOMA-MANSONI; MOLECULAR-MECHANISMS; FILARIAL INFECTION; TH2 RESPONSES; MOUSE MODELS; EXPRESSION; INFLAMMATION AB Helminths are multicellular eukaryotic parasites that infect over one quarter of the world's population. Through coevolution with the human immune system, these organisms have learned to exploit immunoregulatory pathways, resulting in asymptomatic tolerance of infections in many individuals. When infections and the resulting immune responses become dysregulated, however, acute and chronic pathologies often develop. A recent international meeting focused on how these parasites modulate host immunity and how control of parasitic and immunopathological disease might be achieved. C1 [Maizels, Rick M.] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. [Maizels, Rick M.] Univ Edinburgh, Inst Immunol & Infect Res, Edinburgh, Midlothian, Scotland. [Pearce, Edward J.] Trudeau Inst, Saranac Lake, NY 12983 USA. [Artis, David] Univ Penn, Dept Pathobiol, Sch Vet Med, Philadelphia, PA 19104 USA. [Yazdanbakhsh, Maria] Leiden Univ, Dept Parasitol, Med Ctr, Leiden, Netherlands. [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Maizels, RM (reprint author), Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. EM rick.maizels@ed.ac.uk RI Wynn, Thomas/C-2797-2011 FU Wellcome Trust NR 44 TC 120 Z9 124 U1 0 U2 36 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 28 PY 2009 VL 206 IS 10 BP 2059 EP 2066 DI 10.1084/jem.20091903 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 500AM UT WOS:000270269300002 PM 19770272 ER PT J AU Nolting, J Daniel, C Reuter, S Stuelten, C Li, P Sucov, H Kim, BG Letterio, JJ Kretschmer, K Kim, HJ von Boehmer, H AF Nolting, Jens Daniel, Carolin Reuter, Sabine Stuelten, Christina Li, Peng Sucov, Henry Kim, Byung-Gyu Letterio, John J. Kretschmer, Karsten Kim, Hye-Jung von Boehmer, Harald TI Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; ORAL TOLERANCE; RECEPTOR; INDUCTION; GROWTH; PROMOTER; GENE; DIFFERENTIATION; BINDING; MICE AB It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor alpha (RAR alpha) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RAR alpha 1 isoform was not essential for RA-dependent enhancement of transforming growth factor beta-driven conversion, suggesting that conversion can also be mediated by RAR alpha 2. Interleukin (IL)-6 strongly reduced RAR alpha expression levels such that a deficiency of the predominant RAR alpha 1 isoform leaves too little RAR alpha 2 for RA to inhibit the generation of Th17 cells in the presence of IL-6. C1 [Nolting, Jens; Daniel, Carolin; Reuter, Sabine; Kretschmer, Karsten; Kim, Hye-Jung; von Boehmer, Harald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Stuelten, Christina] NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Li, Peng; Sucov, Henry] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA. [Kim, Byung-Gyu; Letterio, John J.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Dept Pediat, Cleveland, OH 44106 USA. RP von Boehmer, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu RI Kretschmer, Karsten/E-8174-2010; Daniel, Carolin/M-4624-2014 OI Daniel, Carolin/0000-0003-4698-7069 FU National Institutes of Health [NIH-AI53102]; Leopoldina research fellowship [BMBF-LPD 9901/8-184]; LOEWE (LiFF) program of the federal state of Hessen, Germany FX This report was supported by the National Institutes of Health (grant NIH-AI53102 to H. von Boehmer), and C. Daniel was supported by a Leopoldina research fellowship (BMBF-LPD 9901/8-184) and the LOEWE (LiFF) program of the federal state of Hessen, Germany. NR 29 TC 78 Z9 80 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 28 PY 2009 VL 206 IS 10 BP 2131 EP 2139 DI 10.1084/jem.20090639 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 500AM UT WOS:000270269300009 PM 19737861 ER PT J AU Kapogiannis, D Barbey, AK Su, M Krueger, F Grafman, J AF Kapogiannis, Dimitrios Barbey, Aron K. Su, Michael Krueger, Frank Grafman, Jordan TI Neuroanatomical Variability of Religiosity SO PLOS ONE LA English DT Article ID VOXEL-BASED MORPHOMETRY; CORTICAL THICKNESS; ENVIRONMENTAL MEDIATION; ANTISOCIAL-BEHAVIOR; MEMORY PERFORMANCE; TAXI DRIVERS; NEURAL BASIS; LIFE-SPAN; CORTEX; MATTER AB We hypothesized that religiosity, a set of traits variably expressed in the population, is modulated by neuroanatomical variability. We tested this idea by determining whether aspects of religiosity were predicted by variability in regional cortical volume. We performed structural magnetic resonance imaging of the brain in 40 healthy adult participants who reported different degrees and patterns of religiosity on a survey. We identified four Principal Components of religiosity by Factor Analysis of the survey items and associated them with regional cortical volumes measured by voxel-based morphometry. Experiencing an intimate relationship with God and engaging in religious behavior was associated with increased volume of R middle temporal cortex, BA 21. Experiencing fear of God was associated with decreased volume of L precuneus and L orbitofrontal cortex BA 11. A cluster of traits related with pragmatism and doubting God's existence was associated with increased volume of the R precuneus. Variability in religiosity of upbringing was not associated with variability in cortical volume of any region. Therefore, key aspects of religiosity are associated with cortical volume differences. This conclusion complements our prior functional neuroimaging findings in elucidating the proximate causes of religion in the brain. RP Kapogiannis, D (reprint author), NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. EM grafmanj@ninds.nih.gov RI Barbey, Aron/L-7312-2015; OI Barbey, Aron/0000-0002-6092-0912; Grafman, Jordan H./0000-0001-8645-4457; Lauwereyns, Jan/0000-0003-0551-2550 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000966-03] NR 75 TC 17 Z9 18 U1 0 U2 14 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 SEP 28 PY 2009 VL 4 IS 9 AR e7180 DI 10.1371/journal.pone.0007180 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 500HQ UT WOS:000270290000005 PM 19784372 ER PT J AU Clauser, SB Johnson, MR O'Brien, DM Beveridge, JM Fennell, ML Kaluzny, AD AF Clauser, Steven B. Johnson, Maureen R. O'Brien, Donna M. Beveridge, Joy M. Fennell, Mary L. Kaluzny, Arnold D. TI Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program SO IMPLEMENTATION SCIENCE LA English DT Article ID NETWORKS; TRIALS AB Background: In this article, we describe the National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) pilot and the evaluation designed to assess its role, function, and relevance to the NCI's research mission. In doing so, we describe the evolution of and rationale for the NCCCP concept, participating sites' characteristics, its multi-faceted aims to enhance clinical research and quality of care in community settings, and the role of strategic partnerships, both within and outside of the NCCCP network, in achieving program objectives. Discussion: The evaluation of the NCCCP is conceptualized as a mixed method multi-layered assessment of organizational innovation and performance which includes mapping the evolution of site development as a means of understanding the inter-and intra-organizational change in the pilot, and the application of specific evaluation metrics for assessing the implementation, operations, and performance of the NCCCP pilot. The assessment of the cost of the pilot as an additional means of informing the longer-term feasibility and sustainability of the program is also discussed. Summary: The NCCCP is a major systems-level set of organizational innovations to enhance clinical research and care delivery in diverse communities across the United States. Assessment of the extent to which the program achieves its aims will depend on a full understanding of how individual, organizational, and environmental factors align (or fail to align) to achieve these improvements, and at what cost. C1 [Clauser, Steven B.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Johnson, Maureen R.] NCI, Off Director, Bethesda, MD 20892 USA. [O'Brien, Donna M.] Community Healthcare Strategies LLC, New York, NY USA. [Beveridge, Joy M.] SAIC Frederick Inc, Clin Res Program Directorate, Frederick, MD USA. [Fennell, Mary L.] Brown Univ, Dept Sociol, Providence, RI 02912 USA. [Fennell, Mary L.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Kaluzny, Arnold D.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Clauser, SB (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM clausers@mail.nih.gov; johnsonm@mail.nih.gov; donnamobrien@aol.com; jbeveridge@saic.org; Mary_Fennell@brown.edu; kaluzny@email.unc.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] 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 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 US government. NR 28 TC 14 Z9 14 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD SEP 26 PY 2009 VL 4 AR 63 DI 10.1186/1748-5908-4-63 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 515FP UT WOS:000271453500001 PM 19781094 ER PT J AU Lindstrom, KM Guyer, AE Mogg, K Bradley, BP Fox, NA Ernst, M Nelson, EE Leibenluft, E Britton, JC Monk, CS Pine, DS Bar-Haim, Y AF Lindstrom, Kara M. Guyer, Amanda E. Mogg, Karin Bradley, Brendan P. Fox, Nathan A. Ernst, Monique Nelson, Eric E. Leibenluft, Ellen Britton, Jennifer C. Monk, Christopher S. Pine, Daniel S. Bar-Haim, Yair TI Normative data on development of neural and behavioral mechanisms underlying attention orienting toward social-emotional stimuli: An exploratory study SO BRAIN RESEARCH LA English DT Article DE Face; Emotion; Attention; Development; fMRI; Affect ID GENERALIZED ANXIETY DISORDER; THREATENING FACIAL EXPRESSIONS; PREFRONTAL CORTEX ACTIVATION; ANGRY FACES; VENTRAL STRIATUM; COGNITIVE BIAS; INPUTS DEFINE; CHILDREN; ADOLESCENTS; AMYGDALA AB The ability of positive and negative facial signals to influence attention orienting is crucial to social functioning. Given the dramatic developmental change in neural architecture supporting social function, positive and negative facial cues may influence attention orienting differently in relatively young or old individuals. However, virtually no research examines such age-related differences in the neural circuitry supporting attention orienting to emotional faces. we examined age-related correlations in attention-orienting biases to positive and negative face emotions in a healthy sample (N=37; 9-40 years old) using functional magnetic resonance imaging and a dot-probe task. The dot-probe task in an fMRI setting yields both behavioral and neural indices of attention biases towards or away from an emotional cue (happy or angry face). In the full sample, angry-face attention bias scores did not correlate with age, and age did not correlate with brain activation to angry faces. However, age did positively correlate with attention bias towards happy faces; age also negatively correlated with left cuneus and left caudate activation to a happy bias fMRI contrast. Secondary analyses suggested age-related changes in attention bias to happy faces. The tendency in younger children to direct attention away from happy faces (relative to neutral faces) was diminished in the older age groups, in tandem with increasing neural deactivation. Implications for future work on developmental changes in attention-emotion processing are discussed. Published by Elsevier B.V. C1 [Lindstrom, Kara M.; Guyer, Amanda E.; Ernst, Monique; Nelson, Eric E.; Leibenluft, Ellen; Britton, Jennifer C.; Pine, Daniel S.] NIMH, MAP, NIH, Bethesda, MD 20892 USA. [Lindstrom, Kara M.] Karolinska Inst, Dept Clin Neurosci, S-10401 Stockholm, Sweden. [Lindstrom, Kara M.] Stockholm Brain Inst, Stockholm, Sweden. [Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Dept Psychol, Southampton SO9 5NH, Hants, England. [Fox, Nathan A.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Monk, Christopher S.] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. [Bar-Haim, Yair] Tel Aviv Univ, Dept Psychol, Adler Ctr Res Child Dev & Psychopathol, Tel Aviv, Israel. RP Lindstrom, KM (reprint author), NIMH, MAP, NIH, 15K N Dr,Room 108,MSC 2670, Bethesda, MD 20892 USA. EM lindstrk@mail.nih.gov RI Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; Nelson, Eric/B-8980-2008; Britton, Jennifer/J-4501-2013; Monk, Christopher/J-1805-2014; OI Mogg, Karin/0000-0002-2738-7378; Nelson, Eric/0000-0002-3376-2453; Bradley, Brendan/0000-0003-2801-4271 FU National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 55 TC 15 Z9 15 U1 8 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 25 PY 2009 VL 1292 BP 61 EP 70 DI 10.1016/j.brainres.2009.07.045 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 502TK UT WOS:000270482900006 PM 19631626 ER PT J AU Park, JY Wang, PY Matsumoto, T Sung, HJ Ma, WZ Choi, JW Anderson, SA Leary, SC Balaban, RS Kang, JG Hwang, PM AF Park, Joon-Young Wang, Ping-yuan Matsumoto, Takumi Sung, Ho Joong Ma, Wenzhe Choi, Jeong W. Anderson, Stasia A. Leary, Scot C. Balaban, Robert S. Kang, Ju-Gyeong Hwang, Paul M. TI p53 Improves Aerobic Exercise Capacity and Augments Skeletal Muscle Mitochondrial DNA Content SO CIRCULATION RESEARCH LA English DT Article DE aerobic; exercise; mitochondrial DNA; p53; TFAM ID TRANSCRIPTION FACTOR-A; RIBONUCLEOTIDE REDUCTASE; PHYSICAL-FITNESS; BIOGENESIS; MICE; ACTIVATION; EXPRESSION; MORTALITY; APOPTOSIS; DISEASE AB Rationale: Exercise capacity is a physiological characteristic associated with protection from both cardiovascular and all-cause mortality. p53 regulates mitochondrial function and its deletion markedly diminishes exercise capacity, but the underlying genetic mechanism orchestrating this is unclear. Understanding the biology of how p53 improves exercise capacity may provide useful insights for improving both cardiovascular as well as general health. Objective: The purpose of this study was to understand the genetic mechanism by which p53 regulates aerobic exercise capacity. Methods and Results: Using a variety of physiological, metabolic, and molecular techniques, we further characterized maximum exercise capacity and the effects of training, measured various nonmitochondrial and mitochondrial determinants of exercise capacity, and examined putative regulators of mitochondrial biogenesis. As p53 did not affect baseline cardiac function or inotropic reserve, we focused on the involvement of skeletal muscle and now report a wider role for p53 in modulating skeletal muscle mitochondrial function. p53 interacts with Mitochondrial Transcription Factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA ( mtDNA) transcription and maintenance, and regulates mtDNA content. The increased mtDNA in p53(+/+) compared to p53(-/-) mice was more marked in aerobic versus glycolytic skeletal muscle groups with no significant changes in cardiac tissue. These in vivo observations were further supported by in vitro studies showing overexpression of p53 in mouse myoblasts increases both TFAM and mtDNA levels whereas depletion of TFAM by shRNA decreases mtDNA content. Conclusions: Our current findings indicate that p53 promotes aerobic metabolism and exercise capacity by using different mitochondrial genes and mechanisms in a tissue-specific manner. (Circ Res. 2009; 105: 705-712.) C1 [Park, Joon-Young; Wang, Ping-yuan; Matsumoto, Takumi; Sung, Ho Joong; Ma, Wenzhe; Choi, Jeong W.; Anderson, Stasia A.; Balaban, Robert S.; Kang, Ju-Gyeong; Hwang, Paul M.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Park, Joon-Young] Temple Univ, Philadelphia, PA 19122 USA. [Leary, Scot C.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Leary, Scot C.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. RP Hwang, PM (reprint author), NHLBI, Translat Med Branch, NIH, 10CRC-5-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov RI Leary, Scot/B-3036-2012 FU Division of Intramural Research; National Heart, Lung, and Blood Institute; National Institutes of Health; Japan Society for the Promotion of Science FX This research was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, and a postdoctoral fellowship to T. M. from the Japan Society for the Promotion of Science. NR 51 TC 79 Z9 81 U1 1 U2 8 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 SEP 25 PY 2009 VL 105 IS 7 BP 705 EP U110 DI 10.1161/CIRCRESAHA.109.205310 PG 19 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800013 PM 19696408 ER PT J AU Deschamps, A Sun, JH Murphy, E AF Deschamps, Anne Sun, Junhui Murphy, Elizabeth TI Increased S-Nitrosylation in Rat Hearts Treated with a G-Protein Coupled Estrogen Receptor Agonist SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Deschamps, Anne; Sun, Junhui; Murphy, Elizabeth] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P216 BP E51 EP E51 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800221 ER PT J AU Elrod, JW Wong, R Karch, JM York, AJ Murphy, E Molkentin, JD AF Elrod, John W. Wong, Renee Karch, Jason M. York, Allen J. Murphy, Elizabeth Molkentin, Jeffery D. TI Cyclophilin-D Null Mice Display Progressive Cardiac Hypertrophy and Failure in Response to Both Pathological and Physiological Myocardial Stress SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Elrod, John W.; Karch, Jason M.; York, Allen J.; Molkentin, Jeffery D.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Wong, Renee; Murphy, Elizabeth] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 25 PY 2009 VL 105 IS 7 MA P177 BP E44 EP E44 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800184 ER PT J AU Lagranha, C Aponte, A Steenbergen, C Murphy, E AF Lagranha, Claudia Aponte, Angel Steenbergen, Charles Murphy, Elizabeth TI Posttranslational Modification of alpha-Ketoglutarate Dehydrogenase Results in Decrease of ROS Production SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Lagranha, Claudia; Aponte, Angel; Murphy, Elizabeth] NHLBI, NIH, Bethesda, MD 20892 USA. [Steenbergen, Charles] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P131 BP E35 EP E35 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800141 ER PT J AU Li, Y Sirenko, S Lukyanenko, Y Lyashkov, AE Vinogradova, TM Lakatta, EG AF Li, Yue Sirenko, Syevda Lukyanenko, Yevgeniya Lyashkov, Alexey E. Vinogradova, Tatiana M. Lakatta, Edward G. TI High Basal Phosphorylation of Phospholamban at Ca2+/Calmodulin Kinase II-Dependent Site Modulates Spontaneous Subsarcolemmal Local Ca2+ Releases that Drive Normal Automaticity of Sinoatrial Nodal Cells SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Li, Yue; Sirenko, Syevda; Lukyanenko, Yevgeniya; Lyashkov, Alexey E.; Vinogradova, Tatiana M.; Lakatta, Edward G.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P17 BP E14 EP E14 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800032 ER PT J AU Sun, JH Murphy, E AF Sun, Junhui Murphy, Elizebeth TI Changes of Caveolar Proteome in Ischemic Preconditioned Mouse Hearts SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Sun, Junhui; Murphy, Elizebeth] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P135 BP E36 EP E36 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800145 ER PT J AU Teng, RF Calvert, JW Piknova, B Schechter, AN Lefer, DJ Noguchi, CT AF Teng, Ruifeng Calvert, John W. Piknova, Barbora Schechter, Alan N. Lefer, David J. Noguchi, Constance T. TI Exogenous Erythropoietin Cardioprotection in a Mouse Ischemia/Reperfusion Injury Model Requires Nitric Oxide Synthase and Endothelial Cell Response SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Teng, Ruifeng; Piknova, Barbora; Schechter, Alan N.; Noguchi, Constance T.] NIH, Rockville, MD USA. [Calvert, John W.; Lefer, David J.] Emory Univ, Sch Med, Carlyle Fraser Heart Ctr, Atlanta, GA USA. RI Sun, Junhui/C-3499-2011; Calvert, John/F-4497-2014 OI Calvert, John/0000-0001-6858-6042 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P222 BP E52 EP E52 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800227 ER PT J AU Wong, R Elrod, J Gabel, S Steenbergen, C Molkentin, J Murphy, E AF Wong, Renee Elrod, John Gabel, Scott Steenbergen, Charles Molkentin, Jeff Murphy, Elizabeth TI Oxidative Metabolism Is Elevated in Cyclophilin D-Knockout Mice SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Wong, Renee; Murphy, Elizabeth] NHLBI, NIH, Bethesda, MD 20892 USA. [Elrod, John; Molkentin, Jeff] Univ Cincinnati, Childrens Med Cntr, Cincinnati, OH USA. [Gabel, Scott] Natl Inst Environm Hlth Sci, NIH, Rsch Triangle Pk, NC USA. [Steenbergen, Charles] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 25 PY 2009 VL 105 IS 7 MA P60 BP E22 EP E22 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800073 ER PT J AU Zhou, YF Wang, SN Yu, ZX Hoyt, RF Hunter, T Horvath, KA AF Zhou, Yifu Wang, Suna Yu, Zuxi Hoyt, Robert F., Jr. Hunter, Timothy Horvath, Keith A. TI Vascular Endothelial Growth Factor Promotes Adipogenesis of Bone Marrow-Derived Mesenchymal Stem Cells SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Zhou, Yifu; Wang, Suna; Yu, Zuxi; Hoyt, Robert F., Jr.; Hunter, Timothy; Horvath, Keith A.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P158 BP E40 EP E41 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800167 ER PT J AU Cook, KM Hilton, ST Mecinovic, J Motherwell, WB Figg, WD Schofield, CJ AF Cook, Kristina M. Hilton, Stephen T. Mecinovic, Jasmin Motherwell, William B. Figg, William D. Schofield, Christopher J. TI Epidithiodiketopiperazines Block the Interaction between Hypoxia-inducible Factor-1 alpha (HIF-1 alpha) and p300 by a Zinc Ejection Mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IONIZATION MASS-SPECTROMETRY; STRUCTURAL BASIS; METAL-COMPLEXES; IN-VIVO; GLIOTOXIN; TRANSCRIPTION; SPORIDESMIN; CELLS; INHIBITOR; PATHWAY AB The hypoxic response in humans is regulated by the hypoxia-inducible transcription factor system; inhibition of hypoxia-inducible factor (HIF) activity has potential for the treatment of cancer. Chetomin, a member of the epidithiodiketopiperazine (ETP) family of natural products, inhibits the interaction between HIF-alpha and the transcriptional coactivator p300. Structure-activity studies employing both natural and synthetic ETP derivatives reveal that only the structurally unique ETP core is required and sufficient to block the interaction of HIF-1 alpha and p300. In support of both cell-based and animal work showing that the cytotoxic effect of ETPs is reduced by the addition of Zn2+ through an unknown mechanism, our mechanistic studies reveal that ETPs react with p300, causing zinc ion ejection. Cell studies with both natural and synthetic ETPs demonstrated a decrease in vascular endothelial growth factor and antiproliferative effects that were abrogated by zinc supplementation. The results have implications for the design of selective ETPs and for the interaction of ETPs with other zinc ion-binding protein targets involved in gene expression. C1 [Cook, Kristina M.; Figg, William D.] NCI, NIH, Bethesda, MD 20814 USA. [Cook, Kristina M.; Mecinovic, Jasmin; Schofield, Christopher J.] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England. [Cook, Kristina M.; Mecinovic, Jasmin; Schofield, Christopher J.] Univ Oxford, Oxford Ctr Integrat Syst Biol, Oxford OX1 3TA, England. [Hilton, Stephen T.] Univ London, Sch Pharm, Dept Pharmaceut & Biol Chem, London WC1N 1AX, England. [Motherwell, William B.] UCL, Dept Chem, London WC1H 0AJ, England. RP Figg, WD (reprint author), 10 Ctr Dr,9000 Rockville Pike,Bldg 10,Rm 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Hilton, Stephen/C-2699-2008; Cook, Kristina/B-8012-2008; Mecinovic, Jasmin/F-9694-2015; Figg Sr, William/M-2411-2016; OI Hilton, Stephen/0000-0001-8782-4499; Cook, Kristina/0000-0002-0503-7166; Mecinovic, Jasmin/0000-0002-5559-3822; Schofield, Christopher/0000-0002-0290-6565 FU National Institutes of Health [Z01SC 006538]; Cancer Research UK; The Wellcome Trust; Biochemical and Biotechnology Research Council FX This work was supported, in whole or in part, by the National Institutes of Health Grant Z01SC 006538. This work was also supported by grants from Cancer Research UK, The Wellcome Trust, and the Biochemical and Biotechnology Research Council. NR 40 TC 79 Z9 83 U1 4 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 25 PY 2009 VL 284 IS 39 BP 26831 EP 26838 DI 10.1074/jbc.M109.009498 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 496KC UT WOS:000269969600064 PM 19589782 ER PT J AU Plassmeyer, ML Reiter, K Shimp, RL Kotova, S Smith, PD Hurt, DE House, B Zou, XY Zhang, YL Hickman, M Uchime, O Herrera, R Nguyen, V Glen, J Lebowitz, J Jin, AJ Miller, LH MacDonald, NJ Wu, YM Narum, DL AF Plassmeyer, Matthew L. Reiter, Karine Shimp, Richard L., Jr. Kotova, Svetlana Smith, Paul D. Hurt, Darrell E. House, Brent Zou, Xiaoyan Zhang, Yanling Hickman, Merrit Uchime, Onyinyechukwu Herrera, Raul Nguyen, Vu Glen, Jacqueline Lebowitz, Jacob Jin, Albert J. Miller, Louis H. MacDonald, Nicholas J. Wu, Yimin Narum, David L. TI Structure of the Plasmodium falciparum Circumsporozoite Protein, a Leading Malaria Vaccine Candidate SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SECONDARY STRUCTURE ANALYSES; NPNA-REPEAT MOTIF; CD8+ T-CELLS; STRUCTURE PREDICTION; IMMUNOLOGICAL CHARACTERIZATION; INFECTED HEPATOCYTES; BERGHEI SPOROZOITES; PROTECTIVE ANTIGEN; CRYSTAL-STRUCTURE; HEPARAN-SULFATE AB The Plasmodium falciparum circumsporozoite protein (CSP) is critical for sporozoite function and invasion of hepatocytes. Given its critical nature, a phase III human CSP malaria vaccine trial is ongoing. The CSP is composed of three regions as follows: an N terminus that binds heparin sulfate proteoglycans, a four amino acid repeat region (NANP), and a C terminus that contains a thrombospondin-like type I repeat (TSR) domain. Despite the importance of CSP, little is known about its structure. Therefore, recombinant forms of CSP were produced by expression in both Escherichia coli (Ec) and then refolded (EcCSP) or in the methylotrophic yeast Pichia pastoris (PpCSP) for structural analyses. To analyze the TSR domain of recombinant CSP, conformation-dependent monoclonal antibodies that recognized unfixed P. falciparum sporozoites and inhibited sporozoite invasion of HepG2 cells in vitro were identified. These monoclonal antibodies recognized all recombinant CSPs, indicating the recombinant CSPs contain a properly folded TSR domain structure. Characterization of both EcCSP and PpCSP by dynamic light scattering and velocity sedimentation demonstrated that both forms of CSP appeared as highly extended proteins (R(h) 4.2 and 4.58 nm, respectively). Furthermore, high resolution atomic force microscopy revealed flexible, rod-like structures with a ribbon-like appearance. Using this information, we modeled the NANP repeat and TSR domain of CSP. Consistent with the biochemical and biophysical results, the repeat region formed a rod-like structure about 21-25 nm in length and 1.5 nm in width. Thus native CSP appears as a glycosylphosphatidylinositol-anchored, flexible rod-like protein on the sporozoite surface. C1 [Plassmeyer, Matthew L.; Reiter, Karine; Shimp, Richard L., Jr.; Zhang, Yanling; Hickman, Merrit; Uchime, Onyinyechukwu; Herrera, Raul; Nguyen, Vu; Glen, Jacqueline; Miller, Louis H.; MacDonald, Nicholas J.; Wu, Yimin; Narum, David L.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. [Kotova, Svetlana; Smith, Paul D.; Lebowitz, Jacob; Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. [Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct Computat Biol, NIH, Bethesda, MD 20892 USA. [House, Brent; Zou, Xiaoyan] USN, Naval Med Res Ctr, Silver Spring, MD 20910 USA. RP Narum, DL (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, 5640 Fishers Ln,Twinbrook 1, Rockville, MD 20852 USA. EM dnarum@niaid.nih.gov RI Zou, Xiaoyan/E-5564-2010; Hurt, Darrell/B-5076-2013; OI Hurt, Darrell/0000-0002-9829-8567; Jin, Albert/0000-0003-3826-1081 FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health (Intramural Research Program, including NIAID and National Institute of Biomedical Imaging and Bioengineering). NR 67 TC 57 Z9 60 U1 2 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 25 PY 2009 VL 284 IS 39 BP 26951 EP 26963 DI 10.1074/jbc.M109.013706 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 496KC UT WOS:000269969600075 PM 19633296 ER PT J AU Rokney, A Shagan, M Kessel, M Smith, Y Rosenshine, I Oppenheim, AB AF Rokney, Assaf Shagan, Merav Kessel, Martin Smith, Yoav Rosenshine, Ilan Oppenheim, Amos B. TI E. coli Transports Aggregated Proteins to the Poles by a Specific and Energy-Dependent Process SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein aggregation; protein quality control; bacteria; pole; polar localization ID ESCHERICHIA-COLI; BACILLUS-SUBTILIS; QUALITY-CONTROL; CELL; LOCALIZATION; DNAK; CHAPERONES; PROTEASES; MUTATION; DELETION AB Aggregation of proteins due to failure of quality control mechanisms is deleterious to both eukaryotes and prokaryotes. We found that in Escherichia coli, protein aggregates are delivered to the pole and form a large polar aggregate (LPA). The formation of LPAs involves two steps: the formation of multiple small aggregates and the delivery of these aggregates to the pole to form an LPA. Formation of randomly distributed aggregates, their delivery to the poles, and LPA formation are all energy-dependent processes. The latter steps require the proton motive force, activities of the DnaK and DnaJ chaperones, and MreB. About 90 min after their formation, the LPAs are dissolved in a process that is dependent upon ClpB, DnaK, and energy. Our results confirm and substantiate the notion that the formation of LPAs allows asymmetric inheritance of the aggregated proteins to a small number of daughter cells, enabling their rapid elimination from most of the bacterial population. Moreover, the results show that the processing of aggregated proteins by the protein quality control system is a multi-step process with distinct spatial and temporal controls. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Rokney, Assaf; Shagan, Merav; Rosenshine, Ilan; Oppenheim, Amos B.] Hebrew Univ Jerusalem, Dept Microbiol & Mol Genet, IMRIC, Fac Med, IL-91120 Jerusalem, Israel. [Kessel, Martin] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Smith, Yoav] Hebrew Univ Jerusalem, Genom Data Anal Unit, Sch Med, IL-91120 Jerusalem, Israel. RP Rokney, A (reprint author), Hebrew Univ Jerusalem, Dept Microbiol & Mol Genet, IMRIC, Fac Med, POB 12272, IL-91120 Jerusalem, Israel. EM assaf.rokney@mail.huji.ac.il; ilanr@ekmd.huji.ac.il FU National Institutes of Health [R21 AI071240-01]; the Israel-United States Bi-National Foundation; Israel Science Foundation; Israel Academy of Science and Humanities FX This work was supported by grants from the National Institutes of Health (R21 AI071240-01 to Amos Oppenheim and Marcia Goldberg), the Israel-United States Bi-National Foundation, and the Israel Science Foundation, which was founded by the Israel Academy of Science and Humanities. I.R. is an Etta Rosensohn Professor of Bacteriology. We thank Ariella Oppenheim for her support and insightful comments. We thank Nathalie Balaban and Sivan Pearl for their help with microscopy. NR 33 TC 56 Z9 56 U1 2 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 25 PY 2009 VL 392 IS 3 BP 589 EP 601 DI 10.1016/j.jmb.2009.07.009 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 500QE UT WOS:000270317700004 PM 19596340 ER PT J AU Dev, K Santangelo, TJ Rothenburg, S Neculai, D Dey, M Sicheri, F Dever, TE Reeve, JN Hinnebusch, AG AF Dev, Kamal Santangelo, Thomas J. Rothenburg, Stefan Neculai, Dante Dey, Madhusudan Sicheri, Frank Dever, Thomas E. Reeve, John N. Hinnebusch, Alan G. TI Archaeal aIF2B Interacts with Eukaryotic Translation Initiation Factors eIF2 alpha and eIF2B alpha: Implications for aIF2B Function and eIF2B Regulation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE aIF2B; eIF2; eIF2B; archaea; S. cerevisiae ID GUANINE-NUCLEOTIDE-EXCHANGE; GDP-GTP EXCHANGE; PYROCOCCUS-HORIKOSHII OT3; PROTEIN-KINASE PKR; CRYSTAL-STRUCTURE; THERMOCOCCUS-KODAKARAENSIS; SACCHAROMYCES-CEREVISIAE; FACTOR-II; IN-VITRO; GCN4 AB Translation initiation is down-regulated in eukaryotes by phosphorylation of the alpha-subunit of eIF2 (eukaryotic initiation factor 2), which inhibits its guanine nucleotide exchange factor, eIF2B. The N-terminal S1 domain of phosphorylated eIF2 alpha interacts with a subcomplex of eIF2B formed by the three regulatory subunits alpha/GCN3, beta/GCD7, and delta/GCD2, blocking the GDP-GTP exchange activity of the catalytic epsilon-subunit of eIF2B. These regulatory subunits have related sequences and have sequences in common with many archaeal proteins, some of which are involved in methionine salvage and CO(2) fixation. Our sequence analyses however predicted that members of one phylogenetically distinct and coherent group of these archaeal proteins [designated aIF2Bs (archaeal initiation factor 2Bs)] are functional homologs of the alpha, beta, and delta subunits of eIF2B. Three of these proteins, from different archaea, have been shown to bind in vitro to the alpha-subunit of the archaeal aIF2 from the cognate archaeon. In one case, the aIF2B protein was shown further to bind to the S1 domain of the alpha-subunit of yeast eIF2 in vitro and to interact with eIF2B alpha/GCN3 in vivo in yeast. The aIF2B-eIF2 alpha interaction was however independent of eIF2 alpha phosphorylation. Mass spectrometry has identified several proteins that co-purify with alpha IF2B from Thermococcus kodakaraensis, and these include aIF2 alpha, a sugar-phosphate nucleotidyltransferase with sequence similarity to eIF2B epsilon, and several large-subunit (50S) ribosomal proteins. Based on this evidence that aIF2B has functions in common with eIF2B, the crystal structure established for an aIF2B was used to construct a model of the eIF2B regulatory subcomplex. In this model, the evolutionarily conserved regions and sites of regulatory mutations in the three eIF2B subunits in yeast are juxtaposed in one continuous binding surface for phosphorylated eIF2 alpha. Published by Elsevier Ltd. C1 [Dev, Kamal; Rothenburg, Stefan; Dey, Madhusudan; Dever, Thomas E.; Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. [Santangelo, Thomas J.; Reeve, John N.] Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA. [Neculai, Dante; Sicheri, Frank] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI Rothenburg, Stefan/A-8340-2008; Neculai, Dante/A-9923-2011; Sicheri, Frank/F-8856-2013; Neculai, Dante/M-2884-2013; OI Dever, Thomas/0000-0001-7120-9678 FU Intramural Research Program of the National Institutes oNational Institutes of Health [GM53185]; Canadian Cancer Society FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institutes of Health grant GM53185 to J.N.R., and by the Canadian Cancer Society for ES. and D.N. We thank Ernie Hannig for GCD11 antibodies, Hongfang Qiu and Graham Pavitt for assistance and advice to K.D., and Loubna Tazi for comments on the manuscript. NR 46 TC 14 Z9 15 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 25 PY 2009 VL 392 IS 3 BP 701 EP 722 DI 10.1016/j.jmb.2009.07.030 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 500QE UT WOS:000270317700013 PM 19616556 ER PT J AU Sauder, CJ Zhang, CX Link, MA Duprex, WP Carbone, KM Rubin, SA AF Sauder, Christian J. Zhang, Cheryl X. Link, Malen A. Duprex, W. Paul Carbone, Kathryn M. Rubin, Steven A. TI Presence of lysine at aa 335 of the hemagglutinin-neuraminidase protein of mumps virus vaccine strain Urabe AM9 is not a requirement for neurovirulence SO VACCINE LA English DT Article DE Mumps virus; Urabe AM9 vaccine; Neurovirulence ID NUCLEOTIDE-SEQUENCE; POSITION 1081; SAFETY TEST; IN-VITRO; SH GENE; P-GENE; F-GENE; PARAMYXOVIRUS; TRANSCRIPTION; MUTATIONS AB The recent global resurgence of mumps has drawn attention to the continued need for robust mumps immunization programs. Unfortunately, some vaccines derived from inadequately attenuated vaccine strains of mumps virus have caused meningitis in vaccinees, leading to withdrawal of certain vaccine strains from the market, public resistance to vaccination, or in some cases, cessation of national mumps vaccination programs. The most widely implicated mumps vaccine in cases of postvaccination meningitis is derived from the Urabe AM9 strain, which remains in use in some countries. The Urabe AM9 vaccine virus has been shown to exhibit a considerable degree of nucleotide and amino acid heterogeneity. Some studies have specifically implicated variants containing a lysine residue at amino acid position 335 in the hemagglutinin-neuraminidase (HN) protein with neurotoxicity, whereas a glutamic acid residue at this position was associated with attenuation. To test this hypothesis we generated two modified Urabe AM9 cDNA clones coding either for a lysine or a glutamic acid at position 335 in the HN gene. The two viruses were rescued by reverse genetics and characterized in vitro and in vivo. Both viruses exhibited similar growth kinetics in neuronal and non-neuronal cell lines and were of similar neurotoxicity when tested in rats, suggesting that amino acid 335 is not a crucial determinant of Urabe AM9 growth or neurovirulence. Published by Elsevier Ltd. C1 [Sauder, Christian J.; Zhang, Cheryl X.; Link, Malen A.; Rubin, Steven A.] US FDA, DVP, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Duprex, W. Paul] Queens Univ Belfast, Sch Biomed Sci, Belfast BT9 7BL, Antrim, North Ireland. [Carbone, Kathryn M.] Natl Inst Dent & Craniefacial Res, NIH, Bethesda, MD 20892 USA. RP Sauder, CJ (reprint author), US FDA, DVP, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 8800 Rockville Pike,Bldg 29A,HFM 460,Room 2C20, Bethesda, MD 20892 USA. EM christian.sauder@fda.hhs.gov OI Duprex, W Paul/0000-0003-1716-6376 NR 42 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 25 PY 2009 VL 27 IS 42 BP 5822 EP 5829 DI 10.1016/j.vaccine.2009.07.051 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 502ON UT WOS:000270469900017 PM 19660591 ER PT J AU Santra, S Sun, Y Korioth-Schmitz, B Fitzgerald, J Charbonneau, C Santos, G Seaman, MS Ratcliffe, SJ Monteflori, DC Nabel, GJ Ertl, HCJ Letvin, NL AF Santra, Sampa Sun, Yue Korioth-Schmitz, Birgit Fitzgerald, Julie Charbonneau, Cherie Santos, Giannina Seaman, Michael S. Ratcliffe, Sarah J. Monteflori, David C. Nabel, Gary J. Ertl, Hildegund C. J. Letvin, Norman L. TI Heterologous prime/boost immunizations of rhesus monkeys using chimpanzee adenovirus vectors SO VACCINE LA English DT Article DE Chimpanzee adenovirus; HIV-1 vaccine ID IMMUNODEFICIENCY-VIRUS TYPE-1; IMMUNE-RESPONSES; NEUTRALIZING ANTIBODIES; VACCINE CARRIERS; NONHUMAN-PRIMATES; SIV CHALLENGE; HIV-1 VACCINE; VIREMIA; STEP; IMMUNOGENICITY AB Pre-existing immunity to human adenovirus serotype 5 (AdHu5) has been shown to suppress the immunogenicity of recombinant Ad5 (rAdHu5) vector-based vaccines for human immunodeficiency virus type 1 (HIV-1) in both preclinical studies and clinical trials. As a potential solution to this problem we developed adenovirus vaccine vectors of chimpanzee origin. In the present study we assessed the immunogenicity of various chimpanzee adenovirus vectors in a prime/boost regimen to HIV-1 envelope and SIV Gag-Pol in rhesus monkeys and their ability to protect against pathogenic viral challenge. Although rAdHu5-primed monkeys had higher magnitude T cell responses than rAdC7 or rAdC68 prior to challenge, the rAdC7-rAdC1/C5 and rAdHu5-rAdC1/C5 immunizations resulted in comparable magnitude recall cellular immune responses and comparable level of control of viremia post-challenge. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis,Dept Med, Boston, MA 02215 USA. [Fitzgerald, Julie; Ratcliffe, Sarah J.; Ertl, Hildegund C. J.] Univ Penn, Sch Med, Wistar Inst, Philadelphia, PA 19104 USA. [Monteflori, David C.] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. [Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis,Dept Med, E-CLS-1043,3 Blackfan Circle, Boston, MA 02215 USA. EM nletvin@bidmc.harvard.edu RI Korioth-Schmitz, Birgit/M-7816-2015; OI Korioth-Schmitz, Birgit/0000-0002-5271-9223; Ratcliffe, Sarah/0000-0002-6644-8284 FU NIH [P01-A152271, Al060354]; Harvard University Center for AIDS Research (CFAR) FX This work was supported by NIH grant P01-A152271 and Harvard University Center for AIDS Research (CFAR) program grant NIH Al060354. NR 34 TC 31 Z9 31 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 25 PY 2009 VL 27 IS 42 BP 5837 EP 5845 DI 10.1016/j.vaccine.2009.07.050 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 502ON UT WOS:000270469900019 PM 19660588 ER PT J AU Earl, PL Cotter, C Moss, B VanCott, T Currier, J Eller, LA McCutchan, F Birx, DL Michael, NL Marovich, MA Robb, M Earla, PL AF Earl, Patricia L. Cotter, Catherine Moss, Bernard VanCott, Thomas Currier, Jeffrey Eller, Leigh Anne McCutchan, Francine Birx, Deborah L. Michael, Nelson L. Marovich, Mary A. Robb, Merlin Earla, Patricia L. TI Design and evaluation of multi-gene, multi-clade HIV-1 MVA vaccines SO VACCINE LA English DT Article DE MVA; HIV vaccine; Immune response ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VITRO EXPRESSION; TYPE-1 SUBTYPE-C; T-CELL EPITOPES; ANKARA MVA; ENVELOPE GLYCOPROTEIN; IMMUNE-RESPONSES; RHESUS-MONKEYS; GAG-POL; PROTECTIVE IMMUNITY AB Recombinant modified vaccinia virus Ankara (rMVA) expressing HIV-1 genes are promising vaccine candidates. Toward the goal of conducting clinical trials with one or a cocktail of recombinant viruses, four rMVAs expressing env and gag-pol genes from primary HIV-1 isolates representing predominant subtypes from Kenya, Tanzania, Uganda, and Thailand (A, C, D, and CRF01_AE, respectively) were constructed. Efficient expression, processing, and function of Env and Gag were demonstrated. All inserted genes were shown to be genetically stable after repeated passage in cell culture. Strong HIV-specific cellular and humoral immune responses were elicited in mice immunized with each individual vaccine candidate. The MVA/CMDR vaccine candidate expressing CRF01_AE genes has elicited HIV-specific T-cell responses in two independent Phase I clinical trials. Further testing of the other rMVA is warranted. Published by Elsevier Ltd. C1 [Earl, Patricia L.; Cotter, Catherine; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Cotter, Catherine; VanCott, Thomas; Currier, Jeffrey; Eller, Leigh Anne; McCutchan, Francine; Birx, Deborah L.; Michael, Nelson L.; Marovich, Mary A.; Robb, Merlin; Earla, Patricia L.] Walter Reed Army Inst Res, Mil HIV Res Program, Rockville, MD USA. RP Earl, PL (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. EM pearl@niaid.nih.gov FU Intramural Research Program; National Institute of Allergy and Infectious Diseases; U.S. Army Medical Research and Materiel Command [DAMD17-98-27007] FX This work was supported in part by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health and by the U.S. Army Medical Research and Materiel Command and its Cooperative Agreement (DAMD17-98-27007) with the Henry M. Jackson Foundation for the Advancement of Military Medicine. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guidefor the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. NR 80 TC 34 Z9 36 U1 1 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 SEP 25 PY 2009 VL 27 IS 42 BP 5885 EP 5895 DI 10.1016/j.vaccine.2009.07.039 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 502ON UT WOS:000270469900025 PM 19654066 ER PT J AU Hager, GL McNally, JG Misteli, T AF Hager, Gordon L. McNally, James G. Misteli, Tom TI Transcription Dynamics SO MOLECULAR CELL LA English DT Review ID RNA-POLYMERASE-II; EMBRYONIC STEM-CELLS; ESTROGEN-RECEPTOR-ALPHA; BETA-GLOBIN LOCUS; TATA-BINDING PROTEIN; INTERACTIONS IN-VIVO; GLUCOCORTICOID-RECEPTOR; LIVING CELLS; GENE-EXPRESSION; ANDROGEN RECEPTOR AB All aspects of transcription and its regulation involve dynamic events. The basal transcription machinery and regulatory components are dynamically recruited to their target genes, and dynamic interactions of transcription factors with chromatin-and with each other-play a key role in RNA polymerase assembly, initiation, and elongation. These short-term binding dynamics of transcription factors are superimposed by long-term cyclical behavior of chromatin opening and transcription factor-binding events. Its dynamic nature is not only a fundamental property of the transcription machinery, but it is emerging as an important modulator of physiological processes, particularly in differentiation and development. C1 [Hager, Gordon L.; McNally, James G.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM hagerg@mail.nih.gov; mcnallyj@mail.nih.gov; mistelit@mail.nih.gov FU Intramural NIH HHS [Z01 BC010309-10] NR 110 TC 259 Z9 261 U1 3 U2 37 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 24 PY 2009 VL 35 IS 6 BP 741 EP 753 DI 10.1016/j.molcel.2009.09.005 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 503SE UT WOS:000270559100009 PM 19782025 ER PT J AU Volberding, P Demeter, L Bosch, RJ Aga, E Pettinelli, C Hirsch, M Vogler, M Martinez, A Little, S Connick, E AF Volberding, Paul Demeter, Lisa Bosch, Ronald J. Aga, Evgenia Pettinelli, Carla Hirsch, Martin Vogler, Mary Martinez, Ana Little, Susan Connick, Elizabeth CA ACTG 371 Team TI Antiretroviral therapy in acute and recent HIV infection: a prospective multicenter stratified trial of intentionally interrupted treatment SO AIDS LA English DT Article; Proceedings Paper CT 15th Conference on Retroviruses and Opportunistic Infections CY FEB 03-06, 2008 CL Boston, MA DE acute HIV infection; antiretroviral therapy; primary HIV infection; recent HIV infection; treatment interruption ID STRUCTURED TREATMENT INTERRUPTIONS; NATURAL-HISTORY; VIRAL LOAD; IMMUNE ACTIVATION; LYMPHOID-TISSUE; RNA LEVELS; SET-POINT; T-CELLS; VIRUS; AIDS AB Background: Antiretroviral therapy in early HIV infection may enhance outcome and viral control may be better in acute versus recent infection 24 weeks after treatment interruption. Methods: A prospective trial of treatment stratified by acute versus recent HIV-1 infection. If HIV viral load <50 copies/ml after at least 52 weeks, treatment was interrupted. If viremia rebounded, treatment and interruption were repeated. The primary endpoint was maintaining viral load less than 5000 copies/ml for 24 weeks following treatment interruption. Results: Of the 121 patients enrolled at 15 sites, ninety-five percent were men, median age was 34 years; 69% were white. Median viral load was higher in acute HIV-1 infection (210000 copies/ml) than recent HIV-1 infection (43000 copies/ml). The 73 primary endpoint patients (28 acute HIV-1 infection, 45 recent HIV-1 infection) had significantly higher baseline CD4(+) T-cell Counts (P=0.044) and lower viral load (P=0.016). The primary endpoint was achieved in 29 (40%) of the 73 and in 24% of the 121 enrolled overall. There was no significant outcome difference (P=0.81) between the acute HIV-1 infection [43%, 95% confidence interval (CI) 24-63%] and recent HIV-1 infection (38%, 95% CI 24-53%) groups. Differences after longer follow-up can not be ascertained by this trial. Baseline viral load less than 100000/ml 22/46 (48%) compared with more than 100000/ml, 7/27 (26%) and higher baseline CD4(+) immune activation predicted success. Conclusion: Forty percent of patients treated during acute HIV-1 infection or recent HIV-1 infection sustained a viral load less than 5000 copies/ml after 24 weeks of treatment interruption. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Volberding, Paul] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Demeter, Lisa] Univ Rochester, Rochester, NY USA. [Bosch, Ronald J.; Aga, Evgenia; Hirsch, Martin] Harvard Univ, Boston, MA 02115 USA. [Pettinelli, Carla; Martinez, Ana] NIAID, Bethesda, MD 20892 USA. [Vogler, Mary] Cornell Univ, New York, NY 10021 USA. [Little, Susan] Univ Calif San Diego, San Diego, CA 92103 USA. [Connick, Elizabeth] Univ Colorado, Denver, CO 80202 USA. RP Volberding, P (reprint author), Univ Calif San Francisco, 4150 Clement St, San Francisco, CA 94121 USA. EM Paul.volberding@va.gov FU NIAID NIH HHS [AI-38858, AI-68634, AI 69450, AI-68636, AI-69432, P30 AI027763, P30 AI027763-19, AI-38855, U01 AI038855, U01 AI038858, U01 AI068636, U01 AI069450, UM1 AI068636, UM1 AI069450] NR 27 TC 35 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP 24 PY 2009 VL 23 IS 15 BP 1987 EP 1995 DI 10.1097/QAD.0b013e32832eb285 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 502QP UT WOS:000270475400007 PM 19696651 ER PT J AU Porter, BO Shen, J Kovacs, JA Davey, RT Rehm, C Lozier, J Csako, G Nghiem, K Costello, R Lane, HC Sereti, I AF Porter, Brian O. Shen, Jean Kovacs, Joseph A. Davey, Richard T. Rehm, Catherine Lozier, Jay Csako, Gyorgy Nghiem, Khanh Costello, Rene Lane, Henry Clifford Sereti, Irini TI Interleukin-2 cycling causes transient increases in high-sensitivity C-reactive protein and D-dieter that are not associated with plasma HIV-RNA levels SO AIDS LA English DT Article; Proceedings Paper CT 16th Conference on Retroviruses and Opportunistic Infections CY FEB 08-11, 2009 CL Montreal, CANADA DE C-reactive protein; D-dimer; HIV infections; interleukin-2; randomized controlled trial ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED INTERNATIONAL TRIAL; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; ACUTE-PHASE; IL-2; ACTIVATION; MARKERS; IMMUNOTHERAPY; INTERRUPTION AB Objective: To determine the effects of interleukin (IL)-2 treatment on inflammatory and thrombotic biomarkers in chronically HIV-infected adults receiving antiretroviral therapy. Methods: Cryopreserved plasma was evaluated retrospectively for C-reactive protein (CRP) and D-dieter at baseline, end of an IL-2 cycle, and long-term follow up from two randomized, controlled trials: 57 IL-2-naive adults receiving either three to six cycles of IL-2 as well as antiretroviral therapy (nucleoside analogues) or antiretroviral therapy alone for 12 months, and 40 IL-2-experienced adults on highly active antiretroviral therapy who either interrupted or continued therapy for 6 months after a baseline IL-2 cycle. High-sensitivity CRP (hsCRP) was measured by immunonephelometry (detection limit 0.175 mg/l) and D-dimer by latex agglutination (detection limit 0.20 mg/l). Median within group differences and pre and post-IL-2 changes between groups were assessed via nonparametric Wilcoxon signed-rank and Mann-Whitney U-tests. Spearman's rank test was used to assess correlations between changes in hsCRP, D-dieter, and HIV-RNA viral load. Results: Significant increases in hsCRP (study 1: 138.6 mg/l; study 2: 58.9 mg/l) and D-dieter (study 1: 3.1 mg/l; study 2: 0.4 mg/l, all P < 0.0001) occurred by the end of the initial IL-2 cycle, returning to baseline by the end of study. No correlations were seen between changes in hsCRP or D-dieter and HIV-RNA, CD4 T-cell count, or proliferation (Ki67 expression). No thrombotic or cardiovascular serious adverse events occurred during these study periods. Conclusion: IL-2 dosing caused transient increases in plasma hsCRP and D-dieter levels, regardless of HIV-RNA viral load, suggesting the possibility of increased risk for thrombotic events. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Sereti, Irini] NIAID, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Shen, Jean] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Lozier, Jay; Csako, Gyorgy; Nghiem, Khanh; Costello, Rene] NIH, CC, Dept Lab Med, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, NIH, Ctr Clin, Bldg 10,Room 11B07A,10 Ctr Dr, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000585-18] NR 22 TC 14 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 24 PY 2009 VL 23 IS 15 BP 2015 EP 2019 DI 10.1097/QAD.0b013e32832d72c6 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 502QP UT WOS:000270475400010 PM 19617815 ER PT J AU Pulsipher, MA Chitphakdithai, P Logan, BR Leitman, SF Anderlini, P Klein, JP Horowitz, MM Miller, JP King, RJ Confer, DL AF Pulsipher, Michael A. Chitphakdithai, Pintip Logan, Brent R. Leitman, Susan F. Anderlini, Paolo Klein, John P. Horowitz, Mary M. Miller, John P. King, Roberta J. Confer, Dennis L. TI Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34(+) cell dose SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; BLOOD STEM-CELLS; COLONY-STIMULATING FACTOR; IDENTICAL SIBLING TRANSPLANTATION; ACUTE MYELOCYTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; BONE-MARROW TRANSPLANTS; PERIPHERAL-BLOOD; HEMATOLOGIC MALIGNANCIES; GRAFT-REJECTION AB We report outcomes of 932 recipients of unrelated donor peripheral blood stem cell hematopoietic cell transplantation (URD-PBSC HCT) for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome enrolled on a prospective National Marrow Donor Program trial from 1999 through 2003. Preparative regimens included myeloablative (MA; N = 611), reduced-intensity (RI; N = 160), and nonmyeloablative (NMA; N = 161). For MA recipients, CD34(+) counts greater than 3.8 X 10(6)/kg improved neutrophil and platelet engraftment, whereas improved overall survival (OS) and reduced transplant-related mortality (TRM) were seen for all preparative regimens when CD34(+) cell doses exceeded 4.5 X 10(6)/kg. Higher infused doses of CD34(+) cell dose did not result in increased rates of either acute or chronic graft-versus-host disease (GVHD). Three-year OS and disease-free survival (DFS) of recipients of MA, RI, and NMA approaches were similar (33%, 35%, and 32% OS; 33%, 30%, and 29% DFS, respectively). In summary, recipients of URD-PBSC HCT receiving preparative regimens differing in intensity experienced similar survival. Higher CD34(+) cell doses resulted in more rapid engraftment, less TRM, and better 3-year OS (39% versus 25%, MA, P = .004; 38% versus 21% RI/NMA, P = .004) but did not increase the risk of GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00785525. (Blood. 2009; 114: 2606-2616) C1 [Pulsipher, Michael A.] Univ Utah, Sch Med, Primary Childrens Hosp, Salt Lake City, UT 84132 USA. [Chitphakdithai, Pintip; King, Roberta J.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Logan, Brent R.; Klein, John P.; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Leitman, Susan F.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Miller, John P.; Confer, Dennis L.] Natl Marrow Donor Program, Minneapolis, MN USA. RP Pulsipher, MA (reprint author), Univ Utah, Sch Med, Div Hematol Blood & Marrow Transplant, 30 North,1900 East,Rm 5C402, Salt Lake City, UT 84132 USA. EM michael.pulsipher@hsc.utah.edu FU National Marrow Donor Program and the Health Resources and Services Administration [240-97-0036, 231-02-0007]; National Cancer Institute [U24-CA76518]; National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute; Office of Naval Research; Health Services Research Administration (DHHS); Abbott Laboratories; Aetna; American International Group Inc; American Red Cross; Amgen Inc; AnorMED Inc; Astellas Pharma US Inc; Baxter International Inc; Berlex Laboratories Inc; Biogen IDEC Inc; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bristol-Myers Squibb Company; BRT Laboratories Inc; Cangene Corporation; Celgene Corporation; CellGenix Inc; Cell Therapeutics Inc; CelMed Biosciences; Cylex Inc; Cytonome Inc; CytoTherm; DOR BioPharma Inc; Dynal Biotech, an Invitrogen Company; Enzon Pharmaceuticals Inc; Gambro BCT Inc; Gamida Cell Ltd; Genzyme Corporation; Gift of Life Bone Marrow Foundation; GlaxoSmithKline Inc; Histogenetics Inc; HKS Medical Information Systems; Kirin Brewery Co Ltd; Merck Company; The Medical College of Wisconsin; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; MultiPlan Inc; National Marrow Donor Program; Nature Publishing Group; Novartis Pharmaceuticals Inc; Osiris Therapeutics Inc; Pall Medical; Pfizer Inc; Pharmion Corporation; PDL BioPharma, Inc; Roche Laboratories; Sanofi-aventis; Schering Plough Corporation; StemCyte Inc; StemSoft Software Inc; SuperGen, Inc; Sysmex; The Marrow Foundation; THERAKOS Inc; University of Colorado Cord Blood Bank; ViaCell Inc; University of Colorado Cord Blood Bank; ViaCell Inc; ViraCor Laboratories; Wellpoint Inc; Zelos Therapeutics Inc; Bundesministerium fur Bildung und Forschung (Kompetenznetz "Akute und chronische Leukamien" Germany [01GI9981] FX This work was supported by funding from the National Marrow Donor Program and the Health Resources and Services Administration (contract Nos. 240-97-0036 and 231-02-0007) to the National Marrow Donor Program. The CIBMTR is supported by the National Cancer Institute (Public Health Service grant U24-CA76518), the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; Office of Naval Research; Health Services Research Administration (DHHS); and grants from Abbott Laboratories; Aetna; American International Group Inc; American Red Cross; Amgen Inc; Anonymous donation to the Medical College of Wisconsin; AnorMED Inc; Astellas Pharma US Inc; Baxter International Inc; Berlex Laboratories Inc; Biogen IDEC Inc; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bristol-Myers Squibb Company; BRT Laboratories Inc; Cangene Corporation; Celgene Corporation; CellGenix Inc; Cell Therapeutics Inc; CelMed Biosciences; Cylex Inc; Cytonome Inc; CytoTherm; DOR BioPharma Inc; Dynal Biotech, an Invitrogen Company; Enzon Pharmaceuticals Inc; Gambro BCT Inc; Gamida Cell Ltd; Genzyme Corporation; Gift of Life Bone Marrow Foundation; GlaxoSmithKline Inc; Histogenetics Inc; HKS Medical Information Systems; Kirin Brewery Co Ltd; Merck & Company; The Medical College of Wisconsin; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; MultiPlan Inc; National Marrow Donor Program; Nature Publishing Group; Novartis Pharmaceuticals Inc; Osiris Therapeutics Inc; Pall Medical; Pfizer Inc; Pharmion Corporation; PDL BioPharma, Inc; Roche Laboratories; Sanofi-aventis; Schering Plough Corporation; StemCyte Inc; StemSoft Software Inc; SuperGen, Inc; Sysmex; The Marrow Foundation; THERAKOS Inc; University of Colorado Cord Blood Bank; ViaCell Inc; ViraCor Laboratories; Wellpoint Inc; and Zelos Therapeutics Inc. The German AML Intergroup is supported by the Bundesministerium fur Bildung und Forschung (Kompetenznetz "Akute und chronische Leukamien"; grant 01GI9981), Germany.; The views expressed in this article do not reflect the official policy or position of the Health Resources and Services Administration, the National Marrow Donor Program, the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the US government. NR 46 TC 59 Z9 61 U1 2 U2 6 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 SEP 24 PY 2009 VL 114 IS 13 BP 2606 EP 2616 DI 10.1182/blood-2009-03-208355 PG 11 WC Hematology SC Hematology GA 498KK UT WOS:000270138600011 PM 19608747 ER PT J AU Dyer, KD Percopo, CM Fischer, ER Gabryszewski, SJ Rosenberg, HF AF Dyer, Kimberly D. Percopo, Caroline M. Fischer, Elizabeth R. Gabryszewski, Stanislaw J. Rosenberg, Helene F. TI Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6 SO BLOOD LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; AIRWAY EPITHELIAL-CELLS; INDUCED CHEMOKINE EXPRESSION; PNEUMONIA VIRUS; INTERFERON-GAMMA; HOST-DEFENSE; PULMONARY EOSINOPHILIA; MICE PVM; ASTHMA; DEGRANULATION AB Eosinophils are recruited to the lung in response to infection with pneumovirus pathogens and have been associated with both the pathophysiologic sequelae of infection and, more recently, with accelerated virus clearance. Here, we demonstrate that the pneumovirus pathogens, respiratory syncytial virus (RSV) and pneumonia virus of mice (PVM), can infect human and mouse eosinophils, respectively, and that virus infection of eosinophils elicits the release of disease-related proinflammatory mediators from eosinophils. RSV replication in human eosinophils results in the release of infectious virions and in the release of the proinflammatory mediator, interleukin-6 (IL-6). PVM replication in cultured bone marrow eosinophils (bmEos) likewise results in release of infectious virions and the proinflammatory mediators IL-6, IP-10, CCL2, and CCL3. In contrast to the findings reported in lung tissue of RSV-challenged mice, PVM replication is accelerated in MyD88 gene-deleted bmEos, whereas release of cytokines is diminished. Interestingly, exogenous IL-6 suppresses virus replication in MyD88 gene-deleted bmEos, suggesting a role for a MyD88-dependent cytokine-mediated feedback circuit in modulating this response. Taken together, our findings suggest that eosinophils are targets of virus infection and may have varied and complex contributions to the pathogenesis and resolution of pneumovirus disease. (Blood. 2009; 114: 2649-2656) C1 [Dyer, Kimberly D.; Percopo, Caroline M.; Gabryszewski, Stanislaw J.; Rosenberg, Helene F.] NIAID, Eosinophil Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MN USA. RP Dyer, KD (reprint author), 10 Ctr Dr,Bldg 10 Rm 11C216, Bethesda, MD 20892 USA. EM kdyer@niaid.nih.gov FU Division Intramural Research (DIR); NIAID FX This work is supported by Division Intramural Research (DIR) funding from the NIAID ( H. F. R.). NR 58 TC 36 Z9 38 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 24 PY 2009 VL 114 IS 13 BP 2649 EP 2656 DI 10.1182/blood-2009-01-199497 PG 8 WC Hematology SC Hematology GA 498KK UT WOS:000270138600017 PM 19652202 ER PT J AU Bryceson, YT Ljunggren, HG Long, EO AF Bryceson, Yenan T. Ljunggren, Hans-Gustaf Long, Eric O. TI Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors SO BLOOD LA English DT Article ID LEUKOCYTE ADHESION DEFICIENCY; RESTING NK CELLS; SEQUENCE-DERIVED PEPTIDES; MHC CLASS-I; HLA-E BINDS; KILLER-CELLS; TYROSINE PHOSPHORYLATION; INTEGRIN ACTIVATION; CROSS-LINKING; FC-RECEPTORS AB Natural killer (NK) cells provide innate control of infected and neoplastic cells. Multiple receptors have been implicated in natural cytotoxicity, but their individual contribution remains unclear. Here, we studied the activation of primary, resting human NK cells by Drosophila cells expressing ligands for receptors NKG2D, DNAM-1, 2B4, CD2, and LFA-1. Each receptor was capable of inducing inside-out signals for LFA-1, promoting adhesion, but none induced degranulation. Rather, release of cytolytic granules required synergistic activation through co-engagement of receptors, shown here for NKG2D and 2B4. Although engagement of NKG2D and 2B4 was not sufficient for strong target cell lysis, collective engagement of LFA-1, NKG2D, and 2B4 defined a minimal requirement for natural cytotoxicity. Remarkably, inside-out signaling induced by each one of these receptors, including LFA-1, was inhibited by receptor CD94/NKG2Abinding to HLA-E. Strong inside-out signals induced by the combination of NKG2D and 2B4 or by CD16 could overcome CD94/NKG2A inhibition. In contrast, degranulation induced by these receptors was still subject to inhibition by CD94/NKG2A. These results reveal multiple layers in the activation pathway for natural cytotoxicity and that steps as distinct as inside-out signaling to LFA-1 and signals for granule release are sensitive to inhibition by CD94/NKG2A. (Blood. 2009; 114: 2657-2666) C1 [Bryceson, Yenan T.; Ljunggren, Hans-Gustaf] Karolinska Univ, Karolinska Inst, Huddinge Hosp, Ctr Infect Med,Dept Med, S-14186 Huddinge, Sweden. [Bryceson, Yenan T.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bryceson, YT (reprint author), Karolinska Univ, Karolinska Inst, Huddinge Hosp, Ctr Infect Med,Dept Med, S-14186 Huddinge, Sweden. EM yenan.bryceson@ki.se; elong@nih.gov RI Long, Eric/G-5475-2011; OI Long, Eric/0000-0002-7793-3728; Bryceson, Yenan/0000-0002-7783-9934 FU NIH; Mary Beve Foundation; David and Astrid Hagelen Foundation; NIAID; Swedish Foundation for Strategic Research, Research Council and Cancer Society FX Y.T.B. was supported by the NIH-Karolinska Institutet Graduate Partnership Program, the Mary Beve Foundation, and the David and Astrid Hagelen Foundation. This research was supported by the Intramural Research Program of the NIH, NIAID (E.O.L.) and the Swedish Foundation for Strategic Research, Research Council and Cancer Society (H.-G.L.). NR 66 TC 102 Z9 106 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 24 PY 2009 VL 114 IS 13 BP 2657 EP 2666 DI 10.1182/blood-2009-01-201632 PG 10 WC Hematology SC Hematology GA 498KK UT WOS:000270138600018 PM 19628705 ER PT J AU Purdue, MP Lan, Q Martinez-Maza, O Oken, MM Hocking, W Huang, WY Baris, D Conde, B Rothman, N AF Purdue, Mark P. Lan, Qing Martinez-Maza, Otoniel Oken, Martin M. Hocking, William Huang, Wen-Yi Baris, Dalsu Conde, Betty Rothman, Nathaniel TI A prospective study of serum soluble CD30 concentration and risk of non-Hodgkin lymphoma SO BLOOD LA English DT Article ID CELL LYMPHOMA; TYPE-2; PATHOGENESIS; EXPRESSION; CYTOKINES; IMMUNITY AB Prediagnostic serum concentration of soluble CD30 (sCD30), a marker for chronic B-cell stimulation, has been associated with increased risk of developing AIDS-related non-Hodgkin lymphoma (NHL) in a recent study of HIV(+) patients. To investigate among healthy persons whether serum sCD30 is associated with NHL risk, we carried out a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. There was a strong dose-response relationship between prediagnostic sCD30 concentration and NHL risk among 234 cases and 234 individually matched controls (odds ratio [95% confidence interval] for second, third, and fourth quartiles vs first quartile: 1.4 [0.8-2.6], 2.2 [1.2-4.1], 4.1 [2.2-7.8]; P(trend) < .001), which persisted among cases diagnosed 6 to 10 years after providing a blood sample. Given that a similar relationship has been observed among HIV(+) patients, our findings suggest that chronic B-cell stimulation may be an important mechanism involved in B-cell lymphomagenesis among severely immunocompromised and healthy populations alike. (Blood. 2009; 114: 2730-2732) C1 [Purdue, Mark P.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol, Los Angeles, CA 90095 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Immunol, Los Angeles, CA 90095 USA. [Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol Genet, Los Angeles, CA 90095 USA. [Oken, Martin M.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Hocking, William] Marshfield Clin Fdn Med Res & Educ, Dept Hematol Oncol, Marshfield, WI USA. [Conde, Betty] SAIC Frederick Inc, Prot Express Lab, Adv Technol Program, NCI, Frederick, MD USA. RP Purdue, MP (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept Hlth & Human Serv, EPS 8009,6120 Execut Blvd, Bethesda, MD 20892 USA. EM purduem@mail.nih.gov RI Martinez-Maza, Otoniel/B-2667-2009; Purdue, Mark/C-9228-2016; OI Martinez-Maza, Otoniel/0000-0003-1364-0675; Purdue, Mark/0000-0003-1177-3108; Hocking, William/0000-0002-0690-3759 FU National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX This work was supported in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 14 TC 35 Z9 35 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 SEP 24 PY 2009 VL 114 IS 13 BP 2730 EP 2732 DI 10.1182/blood-2009-04-217521 PG 3 WC Hematology SC Hematology GA 498KK UT WOS:000270138600025 PM 19638620 ER PT J AU Fiskus, W Wang, YC Sreekumar, A Buckley, KM Shi, HD Jillella, A Ustun, C Rao, R Fernandez, P Chen, JG Balusu, R Koul, S Atadja, P Marquez, VE Bhalla, KN AF Fiskus, Warren Wang, Yongchao Sreekumar, Arun Buckley, Kathleen M. Shi, Huidong Jillella, Anand Ustun, Celalettin Rao, Rekha Fernandez, Pravina Chen, Jianguang Balusu, Ramesh Koul, Sanjay Atadja, Peter Marquez, Victor E. Bhalla, Kapil N. TI Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells SO BLOOD LA English DT Article ID GROUP PROTEIN EZH2; FOXO TRANSCRIPTION FACTORS; ACUTE MYELOID-LEUKEMIA; DNA METHYLATION; TUMOR SUPPRESSION; POLYCOMB; CANCER; REPRESSION; GENE; EXPRESSION AB The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2, SUZ12, and EED, in which the SET (suppressor of variegation-enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. In this study, we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) depletes EZH2 levels, and inhibits trimethylation of lysine 27 on histone H3 in the cultured human acute myeloid leukemia (AML) HL-60 and OCI-AML3 cells and in primary AML cells. DZNep treatment induced p16, p21, p27, and FBXO32 while depleting cyclin E and HOXA9 levels. Similar findings were observed after treatment with small interfering RNA to EZH2. In addition, DZNep treatment induced apoptosis in cultured and primary AML cells. Furthermore, compared with treatment with each agent alone, cotreatment with DZNep and the pan-histone deacetylase inhibitor panobinostat caused more depletion of EZH2, induced more apoptosis of AML, but not normal CD34(+) bone marrow progenitor cells, and significantly improved survival of nonobese diabetic/severe combined immunodeficiency mice with HL-60 leukemia. These findings indicate that the combination of DZNep and panobinostat is effective and relatively selective epigenetic therapy against AML cells. (Blood. 2009;114:2733-2743) C1 [Bhalla, Kapil N.] Med Coll Georgia, Ctr Canc, Augusta, GA 30912 USA. [Atadja, Peter] Novartis Inst Biomed Res, Cambridge, MA USA. [Marquez, Victor E.] NIH, Bethesda, MD 20892 USA. RP Bhalla, KN (reprint author), Med Coll Georgia, Ctr Canc, 1120 15th St,CN-2101, Augusta, GA 30912 USA. EM kbhalla@mcg.edu RI Fernandez, Pravina/H-6279-2011 FU National Institutes of Health/National Cancer Institute [R01 CA116629, R01 CA123207]; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was supported in part by National Institutes of Health/National Cancer Institute R01 CA116629 (K.N.B.) and R01 CA123207 (K.N.B.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 51 TC 188 Z9 193 U1 3 U2 16 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 24 PY 2009 VL 114 IS 13 BP 2733 EP 2743 DI 10.1182/blood-2009-03-213496 PG 11 WC Hematology SC Hematology GA 498KK UT WOS:000270138600026 PM 19638619 ER PT J AU Fandy, TE Herman, JG Kerns, P Jiemjit, A Sugar, EA Choi, SH Yang, AS Aucott, T Dauses, T Odchimar-Reissig, R Licht, J McConnell, MJ Nasrallah, C Kim, MKH Zhang, WJ Sun, YZ Murgo, A Espinoza-Delgado, I Oteiza, K Owoeye, I Silverman, LR Gore, SD Carraway, HE AF Fandy, Tamer E. Herman, James G. Kerns, Patrick Jiemjit, Anchalee Sugar, Elizabeth A. Choi, Si-Ho Yang, Allen S. Aucott, Timothy Dauses, Tianna Odchimar-Reissig, Rosalie Licht, Jonathan McConnell, Melanie J. Nasrallah, Chris Kim, Marianne K. H. Zhang, Weijia Sun, Yezou Murgo, Anthony Espinoza-Delgado, Igor Oteiza, Katharine Owoeye, Ibitayo Silverman, Lewis R. Gore, Steven D. Carraway, Hetty E. TI Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies SO BLOOD LA English DT Article ID HISTONE DEACETYLASE INHIBITION; 5-AZA-2'-DEOXYCYTIDINE DECITABINE TREATMENT; MYELODYSPLASTIC SYNDROME; VALPROIC ACID; METHYLTRANSFERASE INHIBITORS; HEMATOPOIETIC MALIGNANCIES; HEMATOLOGIC MALIGNANCIES; METHYLATION STATUS; HUMAN CANCER; LEUKEMIA AB Sequential administration of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors has demonstrated clinical efficacy in patients with hematologic malignancies. However, the mechanism behind their clinical efficacy remains controversial. In this study, the methylation dynamics of 4 TSGs (p15(INK4B), CDH-1, DAPK-1, and SOCS-1) were studied in sequential bone marrow samples from 30 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who completed a minimum of 4 cycles of therapy with 5-azacytidine and entinostat. Reversal of promoter methylation after therapy was observed in both clinical responders and nonresponders across all genes. There was no association between clinical response and either baseline methylation or methylation reversal in the bone marrow or purified CD34(+) population, nor was there an association with change in gene expression. Transient global hypomethylation was observed in samples after treatment but was not associated with clinical response. Induction of histone H3/H4 acetylation and the DNA damage-associated variant histone gamma-H2AX was observed in peripheral blood samples across all dose cohorts. In conclusion, methylation reversal of candidate TSGs during cycle 1 of therapy was not predictive of clinical response to combination "epigenetic" therapy. This trial is registered with http://www.clinicaltrials.gov under NCT00101179. (Blood. 2009;114:2764-2773) C1 [Fandy, Tamer E.; Herman, James G.; Kerns, Patrick; Jiemjit, Anchalee; Aucott, Timothy; Dauses, Tianna; Oteiza, Katharine; Owoeye, Ibitayo; Gore, Steven D.; Carraway, Hetty E.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Sugar, Elizabeth A.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Sugar, Elizabeth A.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Choi, Si-Ho; Yang, Allen S.] Univ So Calif, Norris Canc Ctr, Div Hematol, Los Angeles, CA USA. [Odchimar-Reissig, Rosalie; Silverman, Lewis R.] Mt Sinai Med Ctr, Div Med Oncol, New York, NY 10029 USA. [Licht, Jonathan; Kim, Marianne K. H.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Div Hematol Oncol, Chicago, IL 60611 USA. [McConnell, Melanie J.] Malaghan Inst Med Res, Wellington, New Zealand. [Nasrallah, Chris] Univ Calif Berkeley, Ctr Theoret Evolutionary Genet, Berkeley, CA 94720 USA. [Zhang, Weijia] Mt Sinai Sch Med, Div Hematol Oncol, New York, NY USA. [Sun, Yezou] Mt Sinai Sch Med, Personalized Med Res Program, New York, NY USA. [Murgo, Anthony; Espinoza-Delgado, Igor] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Gore, SD (reprint author), 1650 Orleans St,Canc Res Bldg 1,Rm 288, Baltimore, MD 21231 USA. EM gorest@jhmi.edu FU NCI NIH HHS [U01CA70095, U01 CA070095, R01 CA125635, R21 CA110507, K24 CA111717]; Wellcome Trust NR 44 TC 169 Z9 174 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 24 PY 2009 VL 114 IS 13 BP 2764 EP 2773 DI 10.1182/blood-2009-02-203547 PG 10 WC Hematology SC Hematology GA 498KK UT WOS:000270138600029 PM 19546476 ER PT J AU Fushan, AA Drayna, DT AF Fushan, Alexey A. Drayna, Dennis T. TI MALS: an efficient strategy for multiple site-directed mutagenesis employing a combination of DNA amplification, ligation and suppression PCR SO BMC BIOTECHNOLOGY LA English DT Article ID GENERATION; SINGLE; OLIGONUCLEOTIDES; POLYMERASES; MUTATIONS; DELETION AB Background: Multiple approaches for the site-directed mutagenesis (SDM) have been developed. However, only several of them are designed for simultaneous introduction of multiple nucleotide alterations, and these are time consuming. In addition, many of the existing multiple SDM methods have technical limitations associated with type and number of mutations that can be introduced, or are technically demanding and require special chemical reagents. Results: In this study we developed a quick and efficient strategy for introduction of multiple complex mutations in a target DNA without intermediate subcloning by using a combination of connecting SDM and suppression PCR. The procedure consists of sequential rounds, with each individual round including PCR amplification of target DNA with two non-overlapping pairs of oligonucleotides. The desired mutation is incorporated at the 5' end of one or both internal oligonucleotides. DNA fragments obtained during amplification are mixed and ligated. The resulting DNA mixture is amplified with external oligonucleotides that act as suppression adapters. Suppression PCR limits amplification to DNA molecules representing full length target DNA, while amplification of other types of molecules formed during ligation is suppressed. To create additional mutations, an aliquot of the ligation mixture is then used directly for the next round of mutagenesis employing internal oligonucleotides specific for another region of target DNA. Conclusion: A wide variety of complex multiple mutations can be generated in a short period of time. The procedure is rapid, highly efficient and does not require special chemical reagents. Thus, MALS represents a powerful alternative to the existing methods for multiple SDM. C1 [Fushan, Alexey A.; Drayna, Dennis T.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Fushan, AA (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. EM fushana@nidcd.nih.gov; drayna@nidcd.nih.gov FU NIDCD/NIH [Z01-000046-09] FX This research was supported by NIDCD/NIH funding Z01-000046-09. We thank Dr. Thomas Friedman and Dr. Robert Morell (Laboratory of Molecular Genetics, NIDCD/NIH) for their comments and suggestions on the manuscript. NR 19 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 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD SEP 24 PY 2009 VL 9 AR 83 DI 10.1186/1472-6750-9-83 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 510BR UT WOS:000271063500001 PM 19778447 ER PT J AU Bernstein, SL Guo, Y Peterson, K Wistow, G AF Bernstein, Steven L. Guo, Yan Peterson, Katherine Wistow, Graeme TI Expressed sequence tag analysis of adult human optic nerve for NEIBank: Identification of cell type and tissue markers SO BMC NEUROSCIENCE LA English DT Article ID 6000 NONREDUNDANT TRANSCRIPTS; RETINAL GANGLION-CELLS; SENSORY NEURONS; SPLICE VARIANTS; HUMAN GENOME; ISCHEMIA; PROJECT; TRANSPORT; RECEPTOR; GENES AB Background: The optic nerve is a pure white matter central nervous system (CNS) tract with an isolated blood supply, and is widely used in physiological studies of white matter response to various insults. We examined the gene expression profile of human optic nerve (ON) and, through the NEIBANK online resource, to provide a resource of sequenced verified cDNA clones. An unnormalized cDNA library was constructed from pooled human ON tissues and was used in expressed sequence tag (EST) analysis. Location of an abundant oligodendrocyte marker was examined by immunofluorescence. Quantitative real time polymerase chain reaction (qRT-PCR) and Western analysis were used to compare levels of expression for key calcium channel protein genes and protein product in primate and rodent ON. Results: Our analyses revealed a profile similar in many respects to other white matter related tissues, but significantly different from previously available ON cDNA libraries. The previous libraries were found to include specific markers for other eye tissues, suggesting contamination. Immune/inflammatory markers were abundant in the new ON library. The oligodendrocyte marker QKI was abundant at the EST level. Immunofluorescence revealed that this protein is a useful oligodendrocyte cell-type marker in rodent and primate ONs. L-type calcium channel EST abundance was found to be particularly low. A qRT-PCR-based comparative mammalian species analysis reveals that L-type calcium channel expression levels are significantly lower in primate than in rodent ON, which may help account for the class-specific difference in responsiveness to calcium channel blocking agents. Several known eye disease genes are abundantly expressed in ON. Many genes associated with normal axonal function, mRNAs associated with axonal transport, inflammation and neuroprotection are observed. Conclusion: We conclude that the new cDNA library is a faithful representation of human ON and EST data provide an initial overview of gene expression patterns in this tissue. The data provide clues for tissue-specific and species-specific properties of human ON that will help in design of therapeutic models. C1 [Bernstein, Steven L.; Guo, Yan] Univ Maryland, Sch Med, Dept Ophthalmol & Neurobiol, Baltimore, MD 21201 USA. [Bernstein, Steven L.; Guo, Yan] Univ Maryland, Sch Med, Dept Genet, Baltimore, MD 21201 USA. [Peterson, Katherine; Wistow, Graeme] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. RP Bernstein, SL (reprint author), Univ Maryland, Sch Med, Dept Ophthalmol & Neurobiol, Baltimore, MD 21201 USA. EM slbernst@umaryland.edu; yguo004@umaryland.edu; petersonk@nei.nih.gov; graeme@helix.nih.gov FU NIH [2RO1EY015304, 1R01EY19529]; Intramural program of the NEI FX This work was supported by NIH grant 2RO1EY015304 (SLB), NIH grant 1R01EY19529 (SLB) and by the Intramural program of the NEI (GW, KP). We thank James Gao, Patee Buchoff and Cynthia Jaworski (all NEI) for help with informatics. NR 29 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 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD SEP 24 PY 2009 VL 10 AR 121 DI 10.1186/1471-2202-10-121 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 513LF UT WOS:000271323100001 PM 19778450 ER PT J AU Burbelo, PD Ching, KH Issa, AT Loftus, CM Li, Y Satoh, M Reeves, WH Iadarola, MJ AF Burbelo, Peter D. Ching, Kathryn H. Issa, Alexandra T. Loftus, Caroline M. Li, Yi Satoh, Minoru Reeves, Westley H. Iadarola, Michael J. TI Rapid serological detection of autoantibodies associated with Sjogren's syndrome SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID LUCIFERASE IMMUNOPRECIPITATION SYSTEMS; 4-ANTIGEN MIXTURE; INFECTION; DIAGNOSIS; DISEASE; ASSAY; SENSITIVITY; ANTIBODIES; TESTS AB Background: Sjogren's syndrome (SjS) is a relatively common autoimmune disease characterized by oral and ocular dryness. There is an increasing need for simple, sensitive and rapid technologies for the diagnosis of SjS and other autoimmune diseases. Here we investigated whether a quick version of luciferase immunoprecipitation systems (QLIPS) could be used to produce a rapid, specific and quantitative test to detect autoantibodies associated with SjS. Methods: Using QLIPS, which requires only ten minutes of incubation, a cohort of control and SjS sera were tested for antibodies to three SjS autoantigens ( La, Ro60 and Ro52). Sensitivity and specificity of the QLIPS tests were compared with LIPS and existing ELISA data. The QLIPS test for Ro52 was then evaluated with a new validation cohort and its diagnostic performance determined. Results: Using QLIPS, autoantibodies to three SjS antigens, La, Ro60, and Ro52 were detected in 49%, 56% and 70%, respectively, of the SjS patients and none of the controls ( 100% specificity). With antibody titers in the Ro52-seropositive SjS samples approximately 1,000 times higher than the healthy controls, not only was Ro52 the most informative, but detection of anti-Ro52 antibodies under these non-equilibrium conditions was improved compared to the standard 2 hour LIPS format. Validation of the anti-Ro52 QLIPS test in a new, independent cohort of SjS and control serum samples showed 66% sensitivity and 100% specificity. Conclusion: Together these results suggest that the QLIPS format for Ro52 yields both a more rapid and more discriminating test for detecting Ro52 autoantibodies than existing immunoassays and has the potential to be adapted for point-of-care evaluation of patients with SjS and other rheumatologic diseases. C1 [Burbelo, Peter D.; Ching, Kathryn H.; Issa, Alexandra T.; Loftus, Caroline M.; Li, Yi; Satoh, Minoru; Reeves, Westley H.; Iadarola, Michael J.] Natl Inst Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Burbelo, Peter D.; Ching, Kathryn H.; Issa, Alexandra T.; Loftus, Caroline M.; Li, Yi; Satoh, Minoru; Reeves, Westley H.; Iadarola, Michael J.] Univ Florida, Div Rheumatol & Clin Immunol, Gainesville, FL USA. [Burbelo, Peter D.; Ching, Kathryn H.; Issa, Alexandra T.; Loftus, Caroline M.; Li, Yi; Satoh, Minoru; Reeves, Westley H.; Iadarola, Michael J.] Univ Florida, Ctr Autoimmune Dis, Gainesville, FL USA. RP Burbelo, PD (reprint author), Natl Inst Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. EM burbelop@nidcr.nih.gov; Chingk@mail.nih.gov; alexa.issa@gmail.com; c.marie.loftus@gmail.com; liyi@medicine.ufl.edu; minoru.satoh@medicine.ufl.edu; westley.reeves@gmail.com; miadarola@dir.nidcr.nih.gov RI Satoh, Minoru/E-2421-2011 FU Division of Intramural Research; National Institute of Dental and Craniofacial Research; NIH Clinical Research Center [AR44731] FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research and, in part, by a Bench to Bedside award from the NIH Clinical Research Center and by NIH grant (AR44731). We greatly thank Dr. Gabor Illei and Dr. Nikolay Nikolov for providing the initial cohort of SjS and control sera samples. NR 26 TC 13 Z9 13 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 24 PY 2009 VL 7 AR 83 DI 10.1186/1479-5876-7-83 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 508WN UT WOS:000270968900002 PM 19778440 ER PT J AU Guigon, CJ Cheng, SY AF Guigon, Celine J. Cheng, Sheue-yann TI Novel non-genomic signaling of thyroid hormone receptors in thyroid carcinogenesis SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Thyroid hormone receptor mutants; Thyroid cancer; Non-genomic action; Phosphatidylinositol 3 kinase; Pituitary tumor transforming gene; beta-catenin; Mouse model ID TUMOR-TRANSFORMING GENE; EPITHELIAL-MESENCHYMAL TRANSITION; SECRETING PITUITARY-TUMOR; BETA-CATENIN DEGRADATION; CLEAR-CELL CARCINOMA; PROTEIN-KINASE-B; MOUSE MODEL; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; HEPATOCELLULAR-CARCINOMA AB The thyroid hormone receptors (TRs) are transcription factors that mediate the pleiotropic activities of the thyroid hormone, T3. Four T3-binding isorforms, TR alpha 1, TR beta 1, TR beta 2, and TR beta 3, are encoded by two genes, THRA and THRB. Mutations and altered expression of TRs have been reported in human cancers. A targeted germ-line mutation of the Thr beta gene in the mouse leads to spontaneous development of follicular thyroid carcinoma (TR beta(PV/PV) mouse). The TR beta PV mutant has lost T3-binding activity and displays potent dominant negative activity. The striking phenotype of thyroid cancer exhibited by TR beta(PV/PV) mice has recently led to the discovery of novel non-genomic actions of TR beta PV that contribute to thyroid carcinogenesis. These actions involve direct physical interaction of TR beta PV with cellular proteins, namely the regulatory subunit of the phosphatidylinositol 3-kinase (p85 alpha), the pituitary tumor transforming gene (MG) and beta-catenin, that are critically involved in cell proliferation, motility, migration, and metastasis. Thus, a TR beta mutant (TR beta PV), via a novel mode of non-genomic action, acts as an oncogene in thyroid carcinogenesis. Published by Elsevier Ireland Ltd. C1 [Guigon, Celine J.; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural Research Program of Center for Cancer Research; National Cancer Institute; National Institutes of Health FX The present research was supported by the Intramural Research Program of Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 77 TC 20 Z9 23 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD SEP 24 PY 2009 VL 308 IS 1-2 BP 63 EP 69 DI 10.1016/j.mce.2009.01.007 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 472IS UT WOS:000268124400010 PM 19549593 ER PT J AU Fernandes, HB Catches, JS Petralia, RS Copits, BA Xu, J Russell, TA Swanson, GT Contractor, A AF Fernandes, Herman B. Catches, Justin S. Petralia, Ronald S. Copits, Bryan A. Xu, Jian Russell, Theron A. Swanson, Geoffrey T. Contractor, Anis TI High-Affinity Kainate Receptor Subunits Are Necessary for Ionotropic but Not Metabotropic Signaling SO NEURON LA English DT Article ID MOSSY-FIBER SYNAPSES; EXCITATORY SYNAPTIC-TRANSMISSION; SHORT-TERM PLASTICITY; RAT-BRAIN; HIPPOCAMPUS; MICE; CA3; ACTIVATION; EXPRESSION; NEURONS AB Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (I(SAHP)) which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels. C1 [Fernandes, Herman B.; Catches, Justin S.; Xu, Jian; Russell, Theron A.; Contractor, Anis] Northwestern Univ, Sch Med, Dept Physiol, Chicago, IL 60611 USA. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Copits, Bryan A.; Swanson, Geoffrey T.] Northwestern Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Chicago, IL 60611 USA. RP Contractor, A (reprint author), Northwestern Univ, Sch Med, Dept Physiol, 303 E Chicago Ave, Chicago, IL 60611 USA. EM a-contractor@northwestern.edu OI Contractor, Anis/0000-0002-5131-2536 FU National Institute of Health (NINDS) [R01NS044322, R01NS058894]; NIH intramural support (NIDCD) FX We gratefully thank Professor Stephen Heinemann in whose laboratory the floxed GluK4 mice were originally generated. Ashley Westwood provided technical help with mouse husbandry and genotyping and or Ya-Xian Wang contributed to the immunogold labeling. This work was supported by extramural grants from the National Institute of Health (NINDS) (R01NS044322 to G.T.S. and R01NS058894 to A.C.) and NIH intramural support (NIDCD) (to R.S.P.). Justin Catches is a John N. Nicholson Fellow. NR 44 TC 52 Z9 52 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 24 PY 2009 VL 63 IS 6 BP 818 EP 829 DI 10.1016/j.neuron.2009.08.010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 503VP UT WOS:000270569700014 PM 19778510 ER PT J AU Wan, X Kim, SY Guenther, LM Mendoza, A Briggs, J Yeung, C Currier, D Zhang, H Mackall, C Li, WJ Tuan, RS Deyrup, AT Khanna, C Helman, L AF Wan, X. Kim, S. Y. Guenther, L. M. Mendoza, A. Briggs, J. Yeung, C. Currier, D. Zhang, H. Mackall, C. Li, W-J Tuan, R. S. Deyrup, A. T. Khanna, C. Helman, L. TI Beta4 integrin promotes osteosarcoma metastasis and interacts with ezrin SO ONCOGENE LA English DT Article DE beta 4 integrin; osteosarcoma; metastases; ezrin; interaction ID ALPHA-6-BETA-4 INTEGRIN; CYTOPLASMIC DOMAINS; CELL-MIGRATION; BINDING; INVASION; KINASE; GROWTH; EXPRESSION; TUMORIGENESIS; TRANSDUCTION AB The development of pulmonary metastasis is the major cause of death in osteosarcoma, and its molecular basis is poorly understood. In this study, we show that beta 4 integrin is highly expressed in human osteosarcoma cell lines and tumor samples. Furthermore, highly metastatic MNNG-HOS cells have increased levels of beta 4 integrin. Suppression of beta 4 integrin expression by shRNA and disruption of beta 4 integrin function by transfection of dominant-negative beta 4 integrin was sufficient to revert this highly metastatic phenotype in the MNNG-HOS model without significantly affecting primary tumor growth. These findings suggest a role for beta 4 integrin expression in the metastatic phenotype in human osteosarcoma cells. In addition, we identified a previously uncharacterized interaction between beta 4 integrin and ezrin, a membrane-cytoskeletal linker protein that is implicated in the metastatic behavior of osteosarcoma. The beta 4 integrin-ezrin interaction appears to be critical for maintenance of beta 4 integrin expression. These data begin to integrate ezrin and beta 4 integrin expression into a model of action for the mechanism of osteosarcoma metastases. Oncogene (2009) 28, 3401-3411; doi: 10.1038/onc.2009.206; published online 13 July 2009 C1 [Wan, X.] NCI, Mol Oncol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Li, W-J; Tuan, R. S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. [Deyrup, A. T.] Emory Univ, Dept Pathol, Atlanta, GA USA. RP Wan, X (reprint author), NCI, Mol Oncol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bldg 10,Rm CRC-1W-3750, Bethesda, MD 20892 USA. EM xiaolinw@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX We thank Dr AM Mercurio for providing empty vector and beta 4 mutant (Y1494F), Dr L Trusolino for providing control-shRNA and beta 4-shRNA, Dr M Arpin for providing GST and GST-ezrin-CT, Dr R Nguyen for providing BSA and ezrinNT. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 39 TC 35 Z9 42 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 24 PY 2009 VL 28 IS 38 BP 3401 EP 3411 DI 10.1038/onc.2009.206 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 497ZD UT WOS:000270103300007 PM 19597468 ER PT J AU Lea, WA Xi, J Jadhav, A Lu, L Austin, CP Simeonov, A Eckenhoff, RG AF Lea, Wendy A. Xi, Jin Jadhav, Ajit Lu, Louis Austin, Christopher P. Simeonov, Anton Eckenhoff, Roderic G. TI A High-Throughput Approach for Identification of Novel General Anesthetics SO PLOS ONE LA English DT Article AB Anesthetic development has been a largely empirical process. Recently, we described a GABAergic mimetic model system for anesthetic binding, based on apoferritin and an environment-sensitive fluorescent probe. Here, a competition assay based on 1-aminoanthracene and apoferritin has been taken to a high throughput screening level, and validated using the LOPAC(1280) library of drug-like compounds. A raw hit rate of similar to 15% was reduced through the use of computational filters to yield an overall hit rate of similar to 1%. These hits were validated using isothermal titration calorimetry. The success of this initial screen and computational triage provides feasibility to undergo a large scale campaign to discover novel general anesthetics. RP Lea, WA (reprint author), NHGRI, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. EM asimeono@mail.nih.gov; roderic.eckenhoff@uphs.upenn.edu FU NIGMS NIH HHS [P01 GM055876, NIH P-01 GM55876]; NIMH NIH HHS [R03 MH084836, R-03 MH84836] NR 12 TC 10 Z9 12 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 SEP 24 PY 2009 VL 4 IS 9 AR e7150 DI 10.1371/journal.pone.0007150 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 498SW UT WOS:000270164600004 PM 19777064 ER PT J AU Plested, AJR Mayer, ML AF Plested, Andrew J. R. Mayer, Mark L. TI AMPA Receptor Ligand Binding Domain Mobility Revealed by Functional Cross Linking SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DISULFIDE BOND FORMATION; GLUTAMATE-RECEPTOR; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURES; SYNAPTIC DEPRESSION; CORE DIMER; DESENSITIZATION; COMPLEX; ANTAGONISTS; ACTIVATION AB Glutamate receptors mediate the majority of excitatory synaptic transmission in the CNS. The AMPA-subtype has rapid kinetics, with activation, deactivation and desensitization proceeding on the millisecond timescale or faster. Crystallographic, biochemical, and functional studies suggest that GluR2 Cys mutants which form intermolecular disulfide cross-links between the lower D2 lobes of the ligand binding cores can be trapped in a conformation that represents the desensitized state. We used multi-channel rapid perfusion techniques to examine the state dependence of cross-linking in these mutants. Under reducing conditions, both wild-type GluR2 and the G725C and S729C mutants have normal activation and desensitization kinetics, but the Cys mutants can be efficiently trapped in nonconducting states when oxidized. In contrast the I664C mutant is only partially inactivated under oxidizing conditions. For S729C, disulfide cross-links form rapidly when receptors are desensitized in the presence of glutamate, but receptors also become trapped at rest, in the absence of agonist. We assessed such spontaneous trapping in various conditions, including CNQX, a competitive antagonist; kainate, a weak partial agonist; or when desensitization was blocked by the L483Y mutation that stabilizes the D1 dimer interface. These experiments suggest that trapping in the absence of glutamate is due to two motions: Spontaneous breaking of the D1 dimer interface and hyperextension of the lower lobes of the ligand binding core. These data show that the glutamate binding domains are surprisingly mobile in the absence of ligand, which could influence receptor activity in the brain. C1 [Plested, Andrew J. R.; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bldg 35,Room 3B 1002,35 Lincoln Dr, Bethesda, MD 20892 USA. EM mlm@helix.nih.gov RI Mayer, Mark/H-5500-2013; OI Plested, Andrew/0000-0001-6062-0832 FU National Institute of Child Health and Human Development; National Institutes of Health; Department of Health and Human Services FX This work was supported by the intramural research program of the National Institute of Child Health and Human Development, National Institutes of Health, and Department of Health and Human Services. A.J.R. P performed experiments and analyzed data; A.J.R. P and M. L. M. designed experiments and wrote the paper. We thank Carla Glasser for preparing cDNAs; Drs. James Howe and Wei Zhang ( Yale University) for advice and the gift of piezo wafers; Dr. J. Diamond [National Institute of Neurological Disorders and Stroke (NINDS)] for the loan of the EX100 amplifier; and the NINDS DNA sequencing facility and Dr. P. Seeburg for the gift of wild-type cDNAs. NR 27 TC 34 Z9 34 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 23 PY 2009 VL 29 IS 38 BP 11912 EP 11923 DI 10.1523/JNEUROSCI.2971-09.2009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 497YS UT WOS:000270102000021 PM 19776277 ER PT J AU Zabow, G Dodd, SJ Moreland, J Koretsky, AP AF Zabow, G. Dodd, S. J. Moreland, J. Koretsky, A. P. TI The fabrication of uniform cylindrical nanoshells and their use as spectrally tunable MRI contrast agents SO NANOTECHNOLOGY LA English DT Article ID SUPERPARAMAGNETIC IRON-OXIDE; POROUS ALUMINA TEMPLATES; STEM-CELLS; NANOPARTICLES; ARRAYS; METAL; NANOCRYSTALS; REDEPOSITION; PARTICLES; NANOTUBES AB A new form of tunable magnetic resonance imaging agent based on precisely dimensioned cylindrical magnetic nanoshells is introduced. Using top-down prepatterned substrates, the nanoshells are fabricated by exploiting what is usually regarded as a detrimental processing side-effect, namely the redeposition of material back-sputtered during ion-milling. The well-resolved nuclear magnetic resonance peaks of the resulting nanostructures attest to the nanoscale fabrication control and the general feasibility of such sputter redeposition for fabrication of a variety of self-supporting, highly monodisperse nanoscale structures. C1 [Zabow, G.; Dodd, S. J.; Koretsky, A. P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Zabow, G.; Moreland, J.] Natl Inst Stand & Technol, Electromagnet Div, Boulder, CO USA. RP Zabow, G (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM zabow@boulder.nist.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NIH NINDS Intramural Research Program FX This work was supported in part by the NIH NINDS Intramural Research Program. NR 39 TC 21 Z9 21 U1 0 U2 11 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 EI 1361-6528 J9 NANOTECHNOLOGY JI Nanotechnology PD SEP 23 PY 2009 VL 20 IS 38 AR 385301 DI 10.1088/0957-4484/20/38/385301 PG 8 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 488NP UT WOS:000269356900004 PM 19713581 ER PT J AU Poulin, KW Smirnov, AV Hawkins, ME Balis, FM Knutson, JR AF Poulin, Kristi Wojtuszewski Smirnov, Aleksandr V. Hawkins, Mary E. Balis, Frank M. Knutson, Jay R. TI Conformational Heterogeneity and Quasi-Static Self-Quenching in DNA Containing a Fluorescent Guanine Analogue, 3MI or 6MI SO BIOCHEMISTRY LA English DT Article ID 2-AMINOPURINE FLUORESCENCE; NUCLEOTIDE INCORPORATION; GUANOSINE ANALOG; KLENOW FRAGMENT; BASE STACKING; POLYMERASE-I; OLIGONUCLEOTIDES; DEPENDENCE; DECAY AB Two different microenvironments in the DNA sequence 5'-act aGa gat ccc tca gac cct ttt agt cag tGt gga-3' (in both single-and double-stranded forms) are explored using two similar fluorescent nucleoside analogues, 3MI and 6MI. Each probe was evaluated in two environments, one strand with the probe flanked by thymines (PTRT) and the other by adenines (PTRA) with positions indicated by G's in the sequence. Both time-resolved anisotropies and lifetimes of the probes depend upon local interactions, and these are altered by duplex formation. Integrals of lifetime curves compared with quantum yields reveal that each probe displays a "dark" component (below detection limits, with a lifetime of < 70 ps). For 6MI in PTRA, this QSSQ "quasi-static self-quenching" or "dark" component represents approximately half the Molecules, whether in single- or double-stranded form. In PTRT, 6MI displays an unusual increase in the quantum yield upon formation of the double strand (from 0.107 to 0.189) apparently the result of escape from QSSQ which simultaneously declines from 66 to 33%. This is also accompanied by doubling of steady-state anisotropy. Only 6MI in the PTRT duplex displays a rotational correlation time of > 7 ns. In other words, the DS 6MI PTRA environment falls to constrain local motion and QSSQ remains the same as in the single strand; in contrast, the flanking T duplex environment restricts local motion and halves QSSQ. We collected both steady-state and time-resolved fluorescence quenching titrations of 3MI and 6MI in Solution with the mononucleotides AMP, CMP, GMP, and TMP. The dynamic quenching rank of the free probes (quenching constant, k(q): T > A > G > C) is totally different from that of incorporated probes. We hypothesize the production of weak 3MI.C or 6MI.C complexes that are somehow rendered less subject to dynamic quenching by collision with subsequent C molecules. C1 [Hawkins, Mary E.; Balis, Frank M.] NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Poulin, Kristi Wojtuszewski; Smirnov, Aleksandr V.; Knutson, Jay R.] NHLBI, Opt Spect, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Hawkins, ME (reprint author), NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM mh100x@nih.gov; jk1r@nih.gov NR 25 TC 14 Z9 14 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 22 PY 2009 VL 48 IS 37 BP 8861 EP 8868 DI 10.1021/bi9003414 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 492ZN UT WOS:000269702200013 ER PT J AU McDermott, MM Ferrucci, L Guralnik, J Tian, L Liu, K Hoff, F Liao, YH Criqui, MH AF McDermott, Mary McGrae Ferrucci, Luigi Guralnik, Jack Tian, Lu Liu, Kiang Hoff, Frederick Liao, Yihua Criqui, Michael H. TI Pathophysiological Changes in Calf Muscle Predict Mobility Loss at 2-Year Follow-Up in Men and Women With Peripheral Arterial Disease SO CIRCULATION LA English DT Article DE aging; claudication; muscles; peripheral vascular disease; prognosis ID ANKLE-BRACHIAL INDEX; LOWER-EXTREMITY ISCHEMIA; PHYSICAL-ACTIVITY; SKELETAL-MUSCLE; FUNCTIONAL DECLINE; DAILY-LIFE; CLASSIFICATION; OSTEOARTHRITIS; ASSOCIATIONS; CRITERIA AB Background-Associations of pathophysiological calf muscle characteristics with functional decline in people with lower extremity peripheral arterial disease are unknown. Methods and Results-Three hundred seventy participants with peripheral arterial disease underwent baseline measurement of calf muscle area, density, and percent fat with the use of computed tomography. Participants were followed up annually for 2 years. The outcome of mobility loss was defined as becoming unable to walk 1/4 mile or walk up and down 1 flight of stairs without assistance among those without baseline mobility limitations. Additional outcomes were >= 20% decline in 6-minute walk distance and becoming unable to walk for 6 minutes continuously among participants who walked continuously for 6 minutes at baseline. With adjustment for age, sex, race, body mass index, the ankle-brachial index, smoking, physical activity, relevant medications, and comorbidities, lower calf muscle density (P for trend <0.001) and lower calf muscle area (P for trend=0.039) were each associated with increased mobility loss rates. Compared with participants in the highest baseline tertiles, participants in the lowest tertile of calf muscle percent fat had a hazard ratio of 0.18 for incident mobility loss (95% confidence interval, 0.06 to 0.55; P = 0.003), and participants in the lowest tertile of muscle density had a 3.50 hazard ratio for incident mobility loss (95% confidence interval, 1.28 to 9.57; P = 0.015). No significant associations of calf muscle characteristics with 6-minute walk outcomes were observed. Conclusions-Our findings suggest that interventions to prevent mobility loss in peripheral arterial disease should focus on reversing pathophysiological findings in calf muscle. (Circulation. 2009; 120: 1048-1055.) C1 [McDermott, Mary McGrae; Liu, Kiang; Hoff, Frederick; Liao, Yihua] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Ferrucci, Luigi; Guralnik, Jack] NIA, Bethesda, MD 20892 USA. [Tian, Lu] Stanford Univ, Stanford, CA 94305 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung, and Blood Institute [R01-HL58099, R01-HL64739, R01-HL071223, R01-HL076298]; National Center for Research Resources [RR-00048]; National Institutes of Health; Intramural Research Program; National Institute on Aging FX This study was supported by grants R01-HL58099, R01-HL64739, R01-HL071223, and R01-HL076298 from the National Heart, Lung, and Blood Institute and by grant RR-00048 from the National Center for Research Resources, National Institutes of Health. This study was also supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 20 TC 26 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 22 PY 2009 VL 120 IS 12 BP 1048 EP 1055 DI 10.1161/CIRCULATIONAHA.108.842328 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 496YF UT WOS:000270015600006 PM 19738138 ER PT J AU Ma, J Sun, J Zhang, H Zhang, R Kang, WH Gao, CG Liu, HS Ma, XH Min, ZX Zhao, WX Ning, QL Wang, SH Zhang, YC Guo, TW Lu, SM AF Ma, Jie Sun, Jian Zhang, Huan Zhang, Rui Kang, Wan-Hu Gao, Cheng-Ge Liu, Hai-Sheng Ma, Xue-Hong Min, Zi-Xin Zhao, Wen-Xiang Ning, Qi-Lan Wang, Shu-Hong Zhang, Yin-Cang Guo, Ting-Wei Lu, She-Min TI Evidence for transmission disequilibrium at the DAOA gene locus in a schizophrenia family sample SO NEUROSCIENCE LETTERS LA English DT Article DE Schizophrenia; DAOA; SNP; TDT; Haplotype; Association ID AMINO-ACID OXIDASE; BIPOLAR-AFFECTIVE-DISORDER; G72/G30 LOCUS; CHINESE POPULATION; CANDIDATE GENES; NO ASSOCIATION; POLYMORPHISMS; SUSCEPTIBILITY; G72; LINKAGE AB Recently, the DAOA gene locus on chromosome 13q32-q34 has been implicated in the etiology of schizophrenia. We genotyped three single-nucleotide polymorphisms (SNPs: rs778294, rs779293 and rs3918342) in this region in 126 Chinese family trios. In this study, we have identified statistically Significant transmission disequilibrium in two markers rs778293 (P=0.01) and rs3918342 (P=0.02), and a highly significant under-transmission between haplotype CAT (P=0.0005) and schizophrenia. The results provide further evidence to support that DAOA gene locus is involved in conferring susceptibility to schizophrenia. (c) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Ma, Jie; Sun, Jian; Zhang, Rui; Min, Zi-Xin; Zhao, Wen-Xiang; Ning, Qi-Lan; Wang, Shu-Hong; Lu, She-Min] Xi An Jiao Tong Univ, Sch Med, Dept Genet & Mol Biol, Xian, Shaanxi, Peoples R China. [Kang, Wan-Hu; Gao, Cheng-Ge; Ma, Xue-Hong] Xi An Jiao Tong Univ, Sch Med, Affiliated Hosp 1, Xian, Shaanxi, Peoples R China. [Zhang, Huan] Xi An Jiao Tong Univ, Sch Med, Affiliated Hosp 2, Xian, Shaanxi, Peoples R China. [Liu, Hai-Sheng] Xian First Social Welf Hosp, Xian, Shaanxi, Peoples R China. [Zhang, Yin-Cang] Northwest Univ, Coll Int Cultural Exchanges, Xian, Shaanxi, Peoples R China. [Guo, Ting-Wei] NIDDK, NIH, Phoenix, AZ USA. RP Lu, SM (reprint author), Xi An Jiao Tong Univ, Sch Med, Dept Genet & Mol Biol, 76 W Yan Ta Rd, Xian, Shaanxi, Peoples R China. EM Lushemin@mail.xjtu.edu.cn OI Lu, Shemin/0000-0001-8250-850X FU National Natural Science Foundation of China [30800618]; Chinese Ministry of Education, PRC; Headmaster Foundation of Van Jiaotong University FX We are deeply grateful to all of the families who participated in this study, as well as to the psychiatrists and mental health workers who helped us with the identification of the families. This work was supported by grants from the National Natural Science Foundation of China (No. 30800618), the Chinese Ministry of Education, PRC, and the Headmaster Foundation of Van Jiaotong University. NR 38 TC 6 Z9 9 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 22 PY 2009 VL 462 IS 2 BP 105 EP 108 DI 10.1016/j.neulet.2009.06.070 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 484SR UT WOS:000269068300002 PM 19560517 ER PT J AU Li, QS Brass, AL Ng, A Hu, ZY Xavier, RJ Liang, TJ Elledge, SJ AF Li, Qisheng Brass, Abraham L. Ng, Aylwin Hu, Zongyi Xavier, Ramnik J. Liang, T. Jake Elledge, Stephen J. TI A genome-wide genetic screen for host factors required for hepatitis C virus propagation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HCV; RNA interference; viral host factors; functional genomics; viral lifecycle ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELLULAR COFACTORS; IN-VITRO; REPLICATION; INFECTION; IDENTIFICATION; CULTURE; PROTEINS AB Hepatitis C virus (HCV) infection is a major cause of end-stage liver disease and a leading indication for liver transplantation. Current therapy fails in many instances and is associated with significant side effects. HCV encodes only a few proteins and depends heavily on host factors for propagation. Each of these host dependencies is a potential therapeutic target. To find host factors required by HCV, we completed a genome-wide small interfering RNA (siRNA) screen using an infectious HCV cell culture system. We applied a two-part screening protocol to allow identification of host factors involved in the complete viral lifecycle. The candidate genes found included known or previously identified factors, and also implicate many additional host cell proteins in HCV infection. To create a more comprehensive view of HCV and host cell interactions, we performed a bioinformatic meta-analysis that integrates our data with those of previous functional and proteomic studies. The identification of host factors participating in the complete HCV lifecycle will both advance our understanding of HCV pathogenesis and illuminate therapeutic targets. C1 [Brass, Abraham L.; Elledge, Stephen J.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham & Womens Hosp,Dept Genet,Div Genet, Boston, MA 02115 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Li, Qisheng; Hu, Zongyi; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Brass, Abraham L.] Massachusetts Gen Hosp, Ragon Inst, MIT, Charlestown, MA 02129 USA. [Brass, Abraham L.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham & Womens Hosp,Dept Genet,Div Genet, Boston, MA 02115 USA. EM jakel@bdg10.niddk.nih.gov; selledge@genetics.med.harvard.edu RI Li, Qisheng/K-1909-2013 FU Center for the Study of Inflammatory Bowel Disease Genetics and Genomics Core and National Institutes of Health [DK043351]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health [U54 AI057159]; New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases; Howard Hughes Medical Institute FX We thank the ICCB-Longwood: C. Shamu, S. Chang, S. Rudnicki, S. Johnston, K. Rudnicki, D. Wrobel, and Z. Cooper. Funding support: A. L. B. (Harvard Center for AIDS Research), A. N. (Crohns and Colitis Foundation of America), R. J. X. (Center for the Study of Inflammatory Bowel Disease Genetics and Genomics Core and National Institutes of Health Grant DK043351). The ICCB-Longwood is in part supported by a grant to T. Mitchison (National Cancer Institute). This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (National Institutes of Health Grant U54 AI057159 to Dennis Kasper). S. J. E. is an Investigator with the Howard Hughes Medical Institute. NR 37 TC 220 Z9 225 U1 1 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 22 PY 2009 VL 106 IS 38 BP 16410 EP 16415 DI 10.1073/pnas.0907439106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 497PF UT WOS:000270071600074 PM 19717417 ER PT J AU Szentpetery, Z Balla, A Kim, YJ Lemmon, MA Balla, T AF Szentpetery, Zsofia Balla, Andras Kim, Yeun Ju Lemmon, Mark A. Balla, Tamas TI Live cell imaging with protein domains capable of recognizing phosphatidylinositol 4,5-bisphosphate; a comparative study SO BMC CELL BIOLOGY LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAINS; INOSITOL 1,4,5-TRISPHOSPHATE; PHOSPHOLIPASE-C; LIVING CELLS; RECEPTOR ACTIVATION; TUBBY PROTEINS; CA2+ RELEASE; PH DOMAINS; BINDING; PHOSPHOINOSITIDES AB Background: Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P-2] is a critically important regulatory phospholipid found in the plasma membrane of all eukaryotic cells. In addition to being a precursor of important second messengers, PtdIns(4,5)P-2 also regulates ion channels and transporters and serves the endocytic machinery by recruiting clathrin adaptor proteins. Visualization of the localization and dynamic changes in PtdIns(4,5)P-2 levels in living cells is critical to understanding the biology of PtdIns(4,5)P-2. This has been mostly achieved with the use of the pleckstrin homology (PH) domain of PLC delta 1 fused to GFP. Here we report on a comparative analysis of several recently-described yeast PH domains as well as the mammalian Tubby domain to evaluate their usefulness as PtdIns(4,5)P-2 imaging tools. Results: All of the yeast PH domains that have been previously shown to bind PtdIns(4,5)P-2 showed plasma membrane localization but only a subset responded to manipulations of plasma membrane PtdIns(4,5)P-2. None of these domains showed any advantage over the PLC delta 1PH-GFP reporter and were compromised either in their expression levels, nuclear localization or by causing peculiar membrane structures. In contrast, the Tubby domain showed high membrane localization consistent with PtdIns(4,5)P-2 binding and displayed no affinity for the soluble headgroup, Ins(1,4,5)P-3. Detailed comparison of the Tubby and PLC delta 1PH domains showed that the Tubby domain has a higher affinity for membrane PtdIns(4,5)P-2 and therefore displays a lower sensitivity to report on changes of this lipid during phospholipase C activation. Conclusion: These results showed that both the PLC delta 1PH-GFP and the GFP-Tubby domain are useful reporters of PtdIns(4,5)P-2 changes in the plasma membrane, with distinct advantages and disadvantages. While the PLC delta 1PH-GFP is a more sensitive reporter, its Ins(1,4,5)P-3 binding may compromise its accuracy to measure PtdIns(4,5)P-2 changes. The Tubby domain is more accurate to report on PtdIns(4,5)P-2 but its higher affinity and lower sensitivity may limit its utility when phospholipase C activation is only moderate. These studies also demonstrated that similar changes in PtdIns(4,5)P-2 levels in the plasma membrane can differentially regulate multiple effectors if they display different affinities to PtdIns(4,5)P-2. C1 [Szentpetery, Zsofia; Kim, Yeun Ju; Balla, Tamas] NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Balla, Andras] Semmelweis Univ, Sch Med, Dept Physiol, Budapest, Hungary. [Lemmon, Mark A.] Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. RP Balla, T (reprint author), NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM szentpeteryzsofia@yahoo.com; aballa@puskin.sote.hu; KimYJ@mail.nih.gov; mlemmon@mail.med.upenn.edu; ballat@mail.nih.gov OI Balla, Andras/0000-0002-6450-2793; Balla, Tamas/0000-0002-9077-3335; Lemmon, Mark/0000-0002-3379-5319 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX We are grateful to Dr. Roger Y. Tsien for the monomeric red fluorescent protein and to Dr Philip W. Majerus for the human type-IV 5-ptase clone. Confocal imaging was performed at the Microscopy & Imaging Core of the National Institute of Child Health and Human Development, NIH with the kind assistance of Drs. Vincent Schram and James T. Russell. This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 38 TC 44 Z9 45 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD SEP 21 PY 2009 VL 10 AR 67 DI 10.1186/1471-2121-10-67 PG 20 WC Cell Biology SC Cell Biology GA 511WX UT WOS:000271203500001 PM 19769794 ER PT J AU Sherman, KJ Cherkin, DC Ichikawa, L Avins, AL Barlow, WE Khalsa, PS Deyo, RA AF Sherman, Karen J. Cherkin, Daniel C. Ichikawa, Laura Avins, Andrew L. Barlow, William E. Khalsa, Partap S. Deyo, Richard A. TI Characteristics of patients with chronic back pain who benefit from acupuncture SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PRIMARY-CARE; CLINICAL-PREDICTION; DIAGNOSIS; EXPENDITURES; EXPECTATIONS; PATTERNS AB Background: Although many clinicians believe there are clinically important subgroups of persons with "non-specific" low back pain, such subgroups have not yet been clearly identified. As part of a large trial evaluating acupuncture for chronic low back pain, we sought to identify subgroups of participants that were particularly responsive to acupuncture. Methods: We performed a secondary analysis of data for the 638 participants in our clinical trial comparing different types of acupuncture to usual care to identify baseline characteristics that predicted responses to individualized, standardized, or simulated acupuncture treatments. After identifying factors that predicted improvements in back-related function or symptoms, we determined if these factors were more likely to predict improvement for those receiving the acupuncture treatments than for those receiving usual care. This was accomplished by testing for an interaction between the prognostic factors and treatment group in four models: functional outcomes (measured by the Roland-Morris Disability Scale) at 8 and 52 weeks post-randomization and symptom outcomes (measured with a numerical rating scale) at 8 and 52 weeks. Results: Overall, the strongest predictors of improvement in back function and symptoms were higher baseline levels of these measures, receipt of an acupuncture treatment, and non-use of narcotic analgesics. Benefit from acupuncture compared to usual care was greater with worse pretreatment levels of back dysfunction (interaction p < 0.004 for the functional outcome, Roland-Morris Disability Scale at 8 weeks). No other consistent interactions were observed. Conclusion: This secondary analysis found little evidence for the existence of subgroups of patients with chronic back pain that would be especially likely to benefit from acupuncture. However, persons with chronic low back pain who had more severe baseline dysfunction had the most short-term benefit from acupuncture. C1 [Sherman, Karen J.; Cherkin, Daniel C.; Ichikawa, Laura; Barlow, William E.] Grp Hlth Res Inst, Seattle, WA USA. [Avins, Andrew L.] No Calif Kaiser Permanente, Div Res, Oakland, CA USA. [Barlow, William E.] Canc Res & Biostat, Seattle, WA USA. [Khalsa, Partap S.] Natl Ctr Complementary & Alternat Med, Div Extramural Res & Training, NIH, Bethesda, MD USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. RP Sherman, KJ (reprint author), Grp Hlth Res Inst, Seattle, WA USA. EM sherman.k@ghc.org; cherkin.d@ghc.org; ichikawa.l@ghc.org; andrew.avins@ucsf.edu; williamb@crab.org; khalsap@mail.nih.gov; deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine (NCCAM) [U01 AT 001110] FX We also thank Lhasa OMS, Weymouth Massachusetts, for donating the Seirin acupuncture needles used in this study. We also thank the original members of the SPINE study team for their contributions to the conduct of the trial. NR 37 TC 18 Z9 20 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD SEP 21 PY 2009 VL 10 AR 114 DI 10.1186/1471-2474-10-114 PG 10 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 503RB UT WOS:000270555800002 PM 19772583 ER PT J AU Giaccone, G Zatloukal, P Roubec, J Floor, K Musil, J Kuta, M van Klaveren, RJ Chaudhary, S Gunther, A Shamsili, S AF Giaccone, Giuseppe Zatloukal, Petr Roubec, Jaromir Floor, Karijn Musil, Jaromir Kuta, Milan van Klaveren, Rob J. Chaudhary, Subhash Gunther, Adrie Shamsili, Setareh TI Multicenter Phase II Trial of YM155, a Small-Molecule Suppressor of Survivin, in Patients With Advanced, Refractory, Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT International Conference of the American-Association-for-Cancer-Research/National-Cancer-Institute/Europ ean-Organisation-for-Research-and-Treatment-of-Cancer CY OCT 22-26, 2007 CL San Francisco, CA SP Amer Assoc Canc Res, NCI, European Org Res & Treatment Canc ID ANTI-APOPTOSIS GENE; ANTIAPOPTOSIS GENE; PROGNOSTIC-FACTORS; EXPRESSION; CHEMOTHERAPY; DOCETAXEL; CARCINOMA; NEUROBLASTOMA; THERAPY; MARKER AB Purpose To evaluate the antitumor activity and safety of YM155, a novel, small-molecule suppressor of survivin, as single-agent therapy in patients with previously treated, advanced non-small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIb/IV NSCLC who had experienced treatment failure during one or two prior chemotherapy regimens (at least one of which was platinum based) received YM155 as a continuous intravenous infusion (4.8 mg/m(2)/d) over 168 hours followed by observation for 14 days in 21-day treatment cycles. The primary end point was objective tumor response rate (ORR). Secondary end points included duration of stable disease (SD), progression-free survival (PFS), overall survival (OS), safety and pharmacokinetic profiles, and pharmacodynamic evaluations. Results Thirty-seven patients received YM155. Two patients achieved a confirmed partial response, with an ORR of 5.4% (95% CI, 0.7% to 18.2%). An additional 14 patients (37.8%) achieved SD resulting in a disease control rate of 43.2% (95% CI, 27.1% to 60.5%). Median duration of PFS was 1.7 months (95% CI, 1.3 to 2.8 months). Median duration of OS was 6.6 months (95% CI, 4 to 12.2 months), with a 1-year survival rate of 35.1%. Treatment with YM155 was well tolerated with the majority of treatment discontinuations not treatment related. Conclusion YM155 exhibited modest single-agent activity in patients with refractory, advanced NSCLC. A favorable safety/tolerability profile was reported. Further evaluation of YM155 in combination with chemotherapy and other targeted agents may be warranted. J Clin Oncol 27:4481-4486. (C) 2009 by American Society of Clinical Oncology C1 Vrije Univ Med Ctr, Amsterdam, Netherlands. Erasmus MC, Rotterdam, Netherlands. Astellas Pharma Europe BV, Leiderdorp, Netherlands. Charles Univ Prague, Fac Med 3, Prague, Czech Republic. Teaching Hosp Bulovka, Prague, Czech Republic. Charles Univ Prague, Fac Med 2, Prague, Czech Republic. Teaching Hosp Motol, Prague, Czech Republic. Teaching Hosp Ostrava Poruba, Ostrava, Czech Republic. Nemocnice Chomutov, Chomutov, Czech Republic. Onkol Ctr JG Mendla, Novy Jicin, Czech Republic. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 35 TC 130 Z9 138 U1 0 U2 6 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 SEP 20 PY 2009 VL 27 IS 27 BP 4481 EP 4486 DI 10.1200/JCO.2008.21.1862 PG 6 WC Oncology SC Oncology GA 496ZO UT WOS:000270019900009 PM 19687333 ER PT J AU Veytsman, I Nieman, L Fojo, T AF Veytsman, Irina Nieman, Lynnette Fojo, Tito TI Management of Endocrine Manifestations and the Use of Mitotane As a Chemotherapeutic Agent for Adrenocortical Carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ADRENAL-CORTICAL CARCINOMA; PHASE-II TRIAL; POSITRON-EMISSION-TOMOGRAPHY; INDEPENDENT PROSTATE-CANCER; CLINICAL-PRACTICE GUIDELINE; SOUTHWEST-ONCOLOGY-GROUP; HIGH-DOSE KETOCONAZOLE; CUSHINGS-SYNDROME; ADJUVANT MITOTANE; PRIMARY ALDOSTERONISM AB Adrenal cortical carcinoma (ACC) is a rare malignancy in which patients have poor overall 5-year survival. Patients with ACC can present with symptoms of hormone excess, including Cushing's syndrome, virilization, feminization, or-less frequently-hypertension with hypokalemia. In many patients with ACC, advanced disease at presentation precludes surgery or is followed by local relapse or distant metastatic disease that cannot be managed surgically. In these instances, chemotherapy is often tried, but its limited efficacy all too often leaves the problem of persistent hormonal excess. Physicians who treat patients with ACC and severe hypercortisolism should recognize that uncontrolled hormone production is a malignant disease, which has severe consequences that require aggressive management. Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is administered. Diligent management with frequent adjustments is required, especially in patients with chemotherapy-refractory tumors that continue to grow. In the absence of randomized, controlled trials, adjuvant use of mitotane remains controversial, although the authors of a recent case-control study argue for its use. Despite difficulty administering effective doses, most clinicians agree that mitotane should be used if the tumor cannot be removed surgically or should be used as adjuvant therapy if there is a high likelihood of recurrence. The option of long-term monotherapy is restricted to patients who tolerate mitotane and either experience a clinical response or are at high risk for recurrence. Recommendations are provided to help manage patients with this difficult disease and to improve the quality of their lives. J Clin Oncol 27: 4619-4629. (C) 2009 by American Society of Clinical Oncology C1 [Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Program Reprod & Adult Endocrinol, Bethesda, MD USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov FU Intramural NIH HHS [ZIE HD008832-03] NR 121 TC 57 Z9 59 U1 0 U2 3 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 SEP 20 PY 2009 VL 27 IS 27 BP 4619 EP 4629 DI 10.1200/JCO.2008.17.2775 PG 11 WC Oncology SC Oncology GA 496ZO UT WOS:000270019900029 PM 19667279 ER PT J AU Bushel, PR AF Bushel, Pierre R. TI Delineation of Perturbed Biological Systems that Govern Hepatotoxic Potential SO MOLECULAR & CELLULAR TOXICOLOGY LA English DT Meeting Abstract C1 [Bushel, Pierre R.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KOREAN SOC TOXICOGENOMICS & TOXICOPROTEOMICS PI SEOUL PA KOREA INST SCIENCE & TECHNOLOGY, PO BOX 131 CHEONGRYANG, SEOUL, 130-650, SOUTH KOREA SN 1738-642X J9 MOL CELL TOXICOL JI Mol. Cell. Toxicol. PD SEP 20 PY 2009 VL 5 IS 3 BP 40 EP 40 PG 1 WC Biochemistry & Molecular Biology; Toxicology SC Biochemistry & Molecular Biology; Toxicology GA 497BG UT WOS:000270028200002 ER PT J AU Bushel, PR AF Bushel, Pierre R. TI Cross Tissue Inference: Genomic Indicators of Hepatotoxicity Conferred through Perturbed Systems in the Blood SO MOLECULAR & CELLULAR TOXICOLOGY LA English DT Meeting Abstract C1 [Bushel, Pierre R.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KOREAN SOC TOXICOGENOMICS & TOXICOPROTEOMICS PI SEOUL PA KOREA INST SCIENCE & TECHNOLOGY, PO BOX 131 CHEONGRYANG, SEOUL, 130-650, SOUTH KOREA SN 1738-642X J9 MOL CELL TOXICOL JI Mol. Cell. Toxicol. PD SEP 20 PY 2009 VL 5 IS 3 BP 42 EP 42 PG 1 WC Biochemistry & Molecular Biology; Toxicology SC Biochemistry & Molecular Biology; Toxicology GA 497BG UT WOS:000270028200009 ER PT J AU Paules, RS Bushel, PR Fannin, RD Cui, YX Heinloth, AN Auman, JT Lobenhofer, EK Chou, JW Li, JY Russo, M O'Connell, T Boorman, GA Jayadev, S Tennant, RW Watkins, PB AF Paules, Richard S. Bushel, Pierre R. Fannin, Rickie D. Cui, Yuxia Heinloth, Alexandra N. Auman, J. Todd Lobenhofer, Edward K. Chou, Jeff W. Li, Jianying Russo, Mark O'Connell, Thomas Boorman, Gary A. Jayadev, Supriya Tennant, Raymond W. Watkins, Paul B. TI An 'Omics' Approach for Identifying Biomarkers of Adverse Effects SO MOLECULAR & CELLULAR TOXICOLOGY LA English DT Meeting Abstract C1 [Paules, Richard S.; Bushel, Pierre R.; Fannin, Rickie D.; Cui, Yuxia; Heinloth, Alexandra N.; Auman, J. Todd; Chou, Jeff W.; Li, Jianying; Boorman, Gary A.; Tennant, Raymond W.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Lobenhofer, Edward K.] Cogenics, Morrisville, NC 27560 USA. [Russo, Mark; O'Connell, Thomas; Watkins, Paul B.] Univ N Carolina, Chapel Hill, NC 27599 USA. [O'Connell, Thomas; Watkins, Paul B.] Hamner Inst, Res Triangle Pk, NC 27709 USA. [Jayadev, Supriya] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KOREAN SOC TOXICOGENOMICS & TOXICOPROTEOMICS PI SEOUL PA KOREA INST SCIENCE & TECHNOLOGY, PO BOX 131 CHEONGRYANG, SEOUL, 130-650, SOUTH KOREA SN 1738-642X J9 MOL CELL TOXICOL JI Mol. Cell. Toxicol. PD SEP 20 PY 2009 VL 5 IS 3 BP 46 EP 46 PG 1 WC Biochemistry & Molecular Biology; Toxicology SC Biochemistry & Molecular Biology; Toxicology GA 497BG UT WOS:000270028200024 ER PT J AU Xiao, XD Feng, Y Vu, BK Ishima, R Dimitrov, DS AF Xiao, Xiaodong Feng, Yang Vu, Bang K. Ishima, Rieko Dimitrov, Dimiter S. TI A large library based on a novel (CH2) scaffold: Identification of HIV-1 inhibitors SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE CH2; Scaffold; Antibody library; HIV; Phage display; Human ID IMMUNODEFICIENCY-VIRUS TYPE-1; CORECEPTOR-BINDING-SITE; ANTIBODIES; DOMAINS; RECOGNITION; PROTEINS; RECEPTOR AB Isolated immunoglobulin CH2 domains were proposed as scaffolds for selection of binders with potential effector functions. We tested the feasibility of this approach by constructing a large (size 5 x 10(10)) library where all amino acids in two loops (BC and FG) were mutated to four residues (Y, A, D, or S). Three binders were selected from this library by panning against a gp120-CD4 complex. The strongest binder, m1a1, recognized specifically a highly conserved CD4i epitope and inhibited to various extents seven out of nine HIV-1 isolates from different clades. The loop BC and the conformational state of the scaffold are critical for its binding. These results provide a proof of concept for the potential of CH2 as a scaffold for construction of libraries containing potentially useful binders. The newly identified HIV-1 inhibitors could be further improved to candidate therapeutics and/or used as research reagents for exploration of conserved gp120 structures. Published by Elsevier Inc. C1 [Xiao, Xiaodong; Feng, Yang; Vu, Bang K.; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, CCRNP, NIH, Frederick, MD 21702 USA. [Ishima, Rieko] Univ Pittsburgh, Dept Biol Struct, Sch Med, Pittsburgh, PA 15260 USA. RP Dimitrov, DS (reprint author), NCI, Prot Interact Grp, CCRNP, NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM dimitrov@ncifcrf.gov FU Intramural AIDS Targeted Antiviral Program (IATAP); National Institutes of Health (NIH); Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX We thank Christopher Broder, Gerald Quinnan, Dennis Burton and Tim Fouts for providing reagents, and the members of our group Weizao Chen, Zhongyu Zhu, Rui Gong, John Owens and Meiyun Zhang for help. This work was supported by the Intramural AIDS Targeted Antiviral Program (IATAP), National Institutes of Health (NIH) and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 25 Z9 26 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 18 PY 2009 VL 387 IS 2 BP 387 EP 392 DI 10.1016/j.bbrc.2009.07.044 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 483OX UT WOS:000268978200031 PM 19615335 ER PT J AU Maragkakis, M Alexiou, P Papadopoulos, GL Reczko, M Dalamagas, T Giannopoulos, G Goumas, G Koukis, E Kourtis, K Simossis, VA Sethupathy, P Vergoulis, T Koziris, N Sellis, T Tsanakas, P Hatzigeorgiou, AG AF Maragkakis, Manolis Alexiou, Panagiotis Papadopoulos, Giorgio L. Reczko, Martin Dalamagas, Theodore Giannopoulos, George Goumas, George Koukis, Evangelos Kourtis, Kornilios Simossis, Victor A. Sethupathy, Praveen Vergoulis, Thanasis Koziris, Nectarios Sellis, Timos Tsanakas, Panagiotis Hatzigeorgiou, Artemis G. TI Accurate microRNA target prediction correlates with protein repression levels SO BMC BIOINFORMATICS LA English DT Article ID CAENORHABDITIS-ELEGANS; SMALL RNAS; IDENTIFICATION; GENOMICS; GENES AB Background: MicroRNAs are small endogenously expressed non-coding RNA molecules that regulate target gene expression through translation repression or messenger RNA degradation. MicroRNA regulation is performed through pairing of the microRNA to sites in the messenger RNA of protein coding genes. Since experimental identification of miRNA target genes poses difficulties, computational microRNA target prediction is one of the key means in deciphering the role of microRNAs in development and disease. Results: DIANA-microT 3.0 is an algorithm for microRNA target prediction which is based on several parameters calculated individually for each microRNA and combines conserved and non-conserved microRNA recognition elements into a final prediction score, which correlates with protein production fold change. Specifically, for each predicted interaction the program reports a signal to noise ratio and a precision score which can be used as an indication of the false positive rate of the prediction. Conclusion: Recently, several computational target prediction programs were benchmarked based on a set of microRNA target genes identified by the pSILAC method. In this assessment DIANA-microT 3.0 was found to achieve the highest precision among the most widely used microRNA target prediction programs reaching approximately 66%. The DIANA-microT 3.0 prediction results are available online in a user friendly web server at http://www.microrna.gr/microT C1 [Maragkakis, Manolis; Alexiou, Panagiotis; Papadopoulos, Giorgio L.; Reczko, Martin; Simossis, Victor A.; Hatzigeorgiou, Artemis G.] Biomed Sci Res Ctr Alexander Fleming, Inst Mol Oncol, Vari, Greece. [Maragkakis, Manolis] Univ Halle Wittenberg, Inst Comp Sci, D-06120 Halle, Germany. [Alexiou, Panagiotis] Aristotle Univ Thessaloniki, Sch Biol, Thessaloniki 54124, Greece. [Reczko, Martin] Synaptic Ltd, Iraklion, Greece. [Dalamagas, Theodore; Giannopoulos, George; Vergoulis, Thanasis; Sellis, Timos] Athena Res Ctr, Inst Management Informat Syst, Athens, Greece. [Giannopoulos, George; Vergoulis, Thanasis; Sellis, Timos] Natl Tech Univ Athens, Dept Comp Sci, Sch Elect & Comp Engn, Knowledge & Database Syst Lab, GR-10682 Athens, Greece. [Goumas, George; Koukis, Evangelos; Kourtis, Kornilios; Koziris, Nectarios; Tsanakas, Panagiotis] Natl Tech Univ Athens, Dept Comp Sci, Sch Elect & Comp Engn, Comp Syst Lab, GR-10682 Athens, Greece. [Sethupathy, Praveen] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20876 USA. [Hatzigeorgiou, Artemis G.] Univ Penn, Dept Comp & Informat Sci, Philadelphia, PA 19104 USA. RP Maragkakis, M (reprint author), Biomed Sci Res Ctr Alexander Fleming, Inst Mol Oncol, Vari, Greece. EM maragkakis@fleming.gr; pan.alexiou@fleming.gr; papadopoulos@fleming.gr; reczko@fleming.gr; dalamag@imis.athenainnovation.gr; giann@dblab.ece.ntua.gr; goumas@cslab.ece.ntua.gr; vkoukis@cslab.ece.ntua.gr; kkourt@cslab.ece.ntua.gr; simossis@fleming.gr; sethupathyp@mail.nih.gov; bergoulis@dblab.ece.ntua.gr; nkoziris@cslab.ece.ntua.gr; timos@imis.athena-innovation.gr; tsanakas@admin.grnet.gr; artemis@fleming.gr RI Maragkakis, Manolis/F-5427-2010; ALEXIOU, PANAGIOTIS/C-8906-2011; OI Maragkakis, Manolis/0000-0002-3158-1763; Alexiou, Panagiotis/0000-0003-3437-7482; Reczko, Martin/0000-0002-0005-8718 NR 26 TC 200 Z9 206 U1 1 U2 5 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 SEP 18 PY 2009 VL 10 AR 295 DI 10.1186/1471-2105-10-295 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 500DD UT WOS:000270276500001 PM 19765283 ER PT J AU Hsieh, SM Smith, RA Lintell, NA Hunter, KW Griffiths, LR AF Hsieh, Szu-Min Smith, Robert A. Lintell, Nicholas A. Hunter, Kent W. Griffiths, Lyn R. TI Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility SO BMC CANCER LA English DT Article ID METASTASIS; PROTEIN AB Background: The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 (Sipa1) underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing Sipa1 cell line developing 1.5 to 2 fold more surface pulmonary metastases. Sipa1 encodes a mitogen-inducible GTPase activating (GAP) protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline SIPA1 SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that SIPA1 may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of SIPA1 and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia. Methods: The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chisquare method and the Monte Carlo style CLUMP analysis program. Results: Results indicated significance with SIPA1 SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence. Conclusion: This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S) to Phe (F)) changes a hydrophilic residue (S) to a hydrophobic residue (F) and may significantly alter the protein functions of SIPA1 in breast tumourgenesis. SIPA1 SNPs rs931127 (5' near gene), and rs746429 (synonymous (Ala (A) to Ala (A)), did not show significant associations with breast cancer incidence, yet were associated with lymph node metastasis in the previous study. This suggests that SIPA1 may be involved in different stages of breast carcinogenesis and since this study replicates a previous study of the associated SNP, it implicates variants of the SIPA1 gene as playing a potential role in breast cancer. C1 [Hsieh, Szu-Min; Smith, Robert A.; Griffiths, Lyn R.] Griffith Univ, Griffith Inst Hlth & Med Res, Nathan, Qld 4111, Australia. [Hsieh, Szu-Min; Lintell, Nicholas A.; Hunter, Kent W.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Griffiths, LR (reprint author), Griffith Univ, Griffith Inst Hlth & Med Res, Gold Coast Campus, Nathan, Qld 4111, Australia. EM hsiehsz@mail.nih.gov; robert.a.smith@griffith.edu.au; lintelln@mail.nih.gov; hunterk@mail.nih.gov; l.griffiths@griffith.edu.au OI Griffiths, Lyn/0000-0002-6774-5475 NR 7 TC 8 Z9 9 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 18 PY 2009 VL 9 AR 331 DI 10.1186/1471-2407-9-331 PG 6 WC Oncology SC Oncology GA 500NW UT WOS:000270310600001 PM 19765277 ER PT J AU Iguchi, G Chrysovergis, K Lee, SH Baek, SJ Langenbach, R Eling, TE AF Iguchi, Genzo Chrysovergis, Kali Lee, Seong-Ho Baek, Seung Joon Langenbach, Robert Eling, Thomas E. TI A reciprocal relationship exists between non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) and cyclooxygenase-2 SO CANCER LETTERS LA English DT Article DE GDF-15; NAG-1; COX-2; Colorectal cancer ID CELECOXIB INDUCES APOPTOSIS; BETA SUPERFAMILY MEMBER; GROWTH-FACTOR RECEPTOR; INTESTINAL NEOPLASIA; CANCER PREVENTION; ADENOMA GROWTH; MIN MICE; EXPRESSION; INHIBITORS; PATHWAY AB Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) and COX-2 are involved in cellular processes such as inflammation, apoptosis, and tumorigenesis. To address the relationship between COX-2 and NAG-1 expression, we investigated the expression of NAG-1 and COX-2 in normal and tumor tissue from human patients, Apc(Min/+) mice, and COX-2(-/-) mice. While COX-2 expression is highly induced in tumor tissue, NAG-1 expression is reduced. Furthermore, PGE2 reduces NAGA while celebrex induces NAGA expression. The results suggest that a possible inverse relationship exists between the expression of NAGA and COX-2 in tumor formation of colon tissue. Published by Elsevier Ltd. C1 [Iguchi, Genzo; Chrysovergis, Kali; Langenbach, Robert; Eling, Thomas E.] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Iguchi, Genzo] Kobe Univ, Dept Biosignal Pathophysiol, Grad Sch Med, Nada Ku, Kobe, Hyogo 6578501, Japan. [Lee, Seong-Ho; Baek, Seung Joon] Univ Tennessee, Dept Pathobiol, Coll Vet Med, Knoxville, TN 37996 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov OI Baek, Seung/0000-0001-7866-7778 FU National Institute of Environmental Health Sciences; National Institutes of Health; Intramural program FX We wish to thank Chris Lee and Colleen Anna for their support. This work was supported, in part, by the National Institute of Environmental Health Sciences, National Institutes of Health, Intramural program. NR 33 TC 20 Z9 20 U1 0 U2 3 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 SEP 18 PY 2009 VL 282 IS 2 BP 152 EP 158 DI 10.1016/j.canlet.2009.03.006 PG 7 WC Oncology SC Oncology GA 483UQ UT WOS:000268994300004 PM 19375854 ER PT J AU Strober, W AF Strober, Warren TI The Multifaceted Influence of the Mucosal Microflora on Mucosal Dendritic Cell Responses SO IMMUNITY LA English DT Review ID INFLAMMATORY-BOWEL-DISEASE; INTESTINAL EPITHELIAL-CELLS; INVASIVE ESCHERICHIA-COLI; REGULATORY T-CELLS; ENTERIC BACTERIAL-ANTIGENS; NEONATAL FC-RECEPTOR; ILEAL CROHNS-DISEASE; TOLL-LIKE RECEPTORS; IMMUNE-RESPONSES; NEGATIVE REGULATOR AB Over the last decade, it has become apparent that the complex interactions between components of the mucosal microflora and the mucosal immune system can involve either direct contact with dendritic cells in the lamina propria or, alternatively, contact with epithelial cells lining the mucosa that then influence the function of dendritic cells. Although in some cases these interactions involve signaling specific to particular organisms and in others, to classes of organisms, a common theme is that signaling is invariably channeled through receptors that address many organisms or all organisms such as the pattern-recognition receptors TLR and NLR. Here, I review this information with the intention of identifying how the mucosal microflora influences specific functions of the mucosal immune system such the production of particular cytokines as well as broader functions such as the maintenance of mucosal immune homeostasis and host defense. C1 NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov NR 83 TC 55 Z9 58 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 18 PY 2009 VL 31 IS 3 BP 377 EP 388 DI 10.1016/j.immuni.2009.09.001 PG 12 WC Immunology SC Immunology GA 503IA UT WOS:000270525900004 PM 19766081 ER PT J AU Varma, R AF Varma, Rajat TI Diffusion and Signaling Revisited SO IMMUNITY LA English DT Editorial Material ID MAST-CELLS; RECEPTOR; IGE AB In this issue of Immunity, Andrews et al. (2009) used single-molecule fluorescence microscopy to demonstrate that the IgE receptor Fc epsilon RI in the plasma membrane can signal in a mobile state. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Varma, R (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM varmarajat@niaid.nih.gov RI Varma, Rajat/I-1209-2012 OI Varma, Rajat/0000-0001-5131-0402 NR 10 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 18 PY 2009 VL 31 IS 3 BP 452 EP 454 DI 10.1016/j.immuni.2009.08.018 PG 3 WC Immunology SC Immunology GA 503IA UT WOS:000270525900011 PM 19766088 ER PT J AU Sarafova, SD Van Laethem, F Adoro, S Guinter, T Sharrow, SO Feigenbaum, L Singer, A AF Sarafova, Sophia D. Van Laethem, Francois Adoro, Stanley Guinter, Terry Sharrow, Susan O. Feigenbaum, Lionel Singer, Alfred TI Upregulation of CD4 Expression during MHC Class II-Specific Positive Selection Is Essential for Error-free Lineage Choice SO IMMUNITY LA English DT Article ID T-CELL DEVELOPMENT; GENE-EXPRESSION; TRANSGENIC MICE; THYMOCYTE DIFFERENTIATION; LYMPHOCYTE DEVELOPMENT; CORECEPTOR EXPRESSION; TRANSCRIPTION FACTORS; STOCHASTIC MECHANISM; SILENCER ELEMENT; ANTIGEN RECEPTOR AB The lineage fate of developing thymocytes is determined by the persistence or cessation of T cell receptor (TCR) signaling during positive selection, with persistent TCR signaling required for CD4 lineage choice. We show here that transcriptional upregulation of CD4 expression is essential for error-free lineage choice during major histocompatibility complex class II (MHC II)-specific positive selection and is critical for error-free lineage choice in TCR-transgenic mice whose thymocytes compete for the identical selecting ligand. CD4 upregulation occurred for endogenously encoded CD4 coreceptors, but CD4 transgenes were downregulated during positive selection, disrupting MHC II-specific TCR signaling and causing lineage errors regardless of the absolute number or signaling strength of transgenic CD4 proteins. Thus, the kinetics of CD4 coreceptor expression during MIHC II-specific positive selection determines the integrity of CD4 lineage choice, revealing an elegant symmetry between coreceptor kinetics and lineage choice. C1 [Sarafova, Sophia D.; Van Laethem, Francois; Adoro, Stanley; Guinter, Terry; Sharrow, Susan O.; Singer, Alfred] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. [Sarafova, Sophia D.] Davidson Coll, Dept Biol, Davidson, NC 28036 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. EM singera@nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; enter for Cancer Research FX We thank N. Taylor, R. Bosselut, H. Park, and R. Hodes for helpful discussions and critical readings of the manuscript; R. Bosselut for the original construction of re-engineered CD4hCD2 transgenes; L. Granger and A. Adams for expert flow cytometry; D. Plugge for data analysis support; and K. Tsaneva-Atanasova for help with statistical analyses. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, and enter for Cancer Research. NR 42 TC 10 Z9 10 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 18 PY 2009 VL 31 IS 3 BP 480 EP 490 DI 10.1016/j.immuni.2009.07.006 PG 11 WC Immunology SC Immunology GA 503IA UT WOS:000270525900015 PM 19747858 ER PT J AU Uranishi, H Zolotukhin, AS Lindtner, S Warming, S Zhang, GM Bear, J Copeland, NG Jenkins, NA Pavlakis, GN Felber, BK AF Uranishi, Hiroaki Zolotukhin, Andrei S. Lindtner, Susan Warming, Soren Zhang, Gen-Mu Bear, Jenifer Copeland, Neal G. Jenkins, Nancy A. Pavlakis, George N. Felber, Barbara K. TI The RNA-binding Motif Protein 15B (RBM15B/OTT3) Acts as Cofactor of the Nuclear Export Receptor NXF1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DROSOPHILA EYE DEVELOPMENT; TRANSPORT ELEMENT RTE; HNRNP-LIKE PROTEINS; MESSENGER-RNA; SPLIT-ENDS; MENTAL-RETARDATION; SIGNALING PATHWAY; GENETIC SCREEN; FAMILY-MEMBERS; TARGET GENES AB The human SPEN family proteins SHARP, RBM15/OTT1, and RBM15B/OTT3 share the structural domain architecture but show distinct functional properties. Here, we examined the function of OTT3 and compared it with its paralogues RBM15 and SHARP. We found that OTT3, like RBM15, has post-transcriptional regulatory activity, whereas SHARP does not, supporting a divergent role of RBM15 and OTT3. OTT3 shares with RBM15 the association with the splicing factor compartment and the nuclear envelope as well as the binding to mRNA export factors NXF1 and Aly/REF. Mutational analysis revealed direct interaction of OTT3 and RBM15 with NXF1 via their C-terminal regions. Biochemical and subcellular localization studies showed that OTT3 and RBM15 also interact with each other in vivo, further supporting a shared function. Genetic knockdown of RBM15 in mouse is embryonically lethal, indicating that OTT3 cannot compensate for the RBM15 loss, which supports the notion that these proteins, in addition to sharing similar activities, likely have distinct biological roles. C1 [Uranishi, Hiroaki; Lindtner, Susan; Pavlakis, George N.] NCI, Human Retrovirus Sect, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Zolotukhin, Andrei S.; Zhang, Gen-Mu; Bear, Jenifer; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Warming, Soren; Copeland, Neal G.; Jenkins, Nancy A.] NCI, Mouse Canc Genet Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Felber, BK (reprint author), POB B,Bldg 535,Rm 209, Frederick, MD 21702 USA. EM felberb@mail.nih.gov FU National Institutes of Health Intramural Research Program FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program. NR 56 TC 24 Z9 24 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 18 PY 2009 VL 284 IS 38 BP 26106 EP 26116 DI 10.1074/jbc.M109.040113 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 493LK UT WOS:000269738000066 PM 19586903 ER PT J AU Luongo, C Yang, LJ Winter, CC Spann, KM Murphy, BR Collins, PL Buchholz, UJ AF Luongo, Cindy Yang, Lijuan Winter, Christine C. Spann, Kirsten M. Murphy, Brian R. Collins, Peter L. Buchholz, Ursula J. TI Codon stabilization analysis of the "248" temperature sensitive mutation for increased phenotypic stability of respiratory syncytial virus vaccine candidates SO VACCINE LA English DT Article DE Pneumovirus; Respiratory syncytial virus vaccine; Temperature sensitive ID F-GLYCOPROTEIN; RSV VACCINE; L GENE; LIVE; ATTENUATION; CHILDREN; MUTANT; ADULTS; CHIMPANZEES; IMMUNOGENICITY AB Human respiratory syncytial virus (RSV) is the most important viral agent of serious pediatric respiratory tract illness worldwide. Presently, the most promising vaccine candidate is a live, attenuated, cDNA-derived virus, RSV rA2cp248/404/1030 Delta SH, whose attenuation phenotype is based in large part on a series of point mutations including a glutamine to leucine (Q to L) substitution at amino acid residue 831 of the polymerase protein 1, a mutation originally called "248". This mutation specifies both a temperature sensitive (ts) and attenuation phenotype. Reversion of this mutation from leucine back to glutamine was detected in some samples in clinical phase 1 trials. To identify the most genetically stable "attenuating" codon at this position to be included in a more stable RSV vaccine, we sought to create and evaluate recombinant RSVs representing all 20 possible amino acid assignments at this position, as well as small insertions and deletions. The recoverable viruses constituted a panel representing 18 different amino acid assignments, and were evaluated for temperature sensitivity in vitro and attenuation in mice. The original leucine mutation was found to be the most attenuating, followed only by phenylalanine. The paucity of highly attenuating assignments limited the possibility of increasing genetic stability. Indeed, it was not possible to find a leucine or phenylalanine codon requiring more than a single nucleotide change to yield a "non-attenuating" codon, as is necessary for the stabilization strategy. Nonetheless, serial passage of the six possible leucine codons in vitro at increasing temperatures revealed differences, with slower reversion to non-attenuated phenotypes for a subset of codons. Thus, it should be possible to modestly increase the phenotypic stability of the rA2cp248/404/1030 Delta SH vaccine virus by codon modification at the locus of the 248 mutation. In addition to characterizing the phenotypes associated with a particular locus in the RSV L protein, this manuscript provides insight into the problem of the instability of point mutations and the limitations of strategies to stabilize them. Published by Elsevier Ltd. C1 [Luongo, Cindy; Yang, Lijuan; Winter, Christine C.; Murphy, Brian R.; Collins, Peter L.; Buchholz, Ursula J.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Spann, Kirsten M.] Univ Queensland, Clin Med Virol Ctr, Sir Albert Sakzewski Virus Res Ctr, Herston, Qld 4029, Australia. RP Buchholz, UJ (reprint author), Bldg 50,Room 6505,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov RI Spann, Kirsten/B-4524-2013 OI Spann, Kirsten/0000-0003-0567-8382 FU MedImmune, Inc., Gaithersburg; NIAID, NIH FX We thank the staff of the animal facility, Bldg. 50, for care of the mice used in this study. We thank Jeff Skinner, BCBB/NIAID, for support with the statistical analyses. This research was supported by a Cooperative Research and Development Agreement with MedImmune, Inc., Gaithersburg, and by the Intramural Research Program of NIAID, NIH. NR 29 TC 19 Z9 20 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 18 PY 2009 VL 27 IS 41 BP 5667 EP 5676 DI 10.1016/j.vaccine.2009.07.022 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 497OW UT WOS:000270070400018 PM 19646406 ER PT J AU Bergmann-Leitner, ES Leitner, WW Duncan, EH Savranskaya, T Angov, E AF Bergmann-Leitner, Elke S. Leitner, Wolfgang W. Duncan, Elizabeth H. Savranskaya, Tatyana Angov, Evelina TI Molecular adjuvants for malaria DNA vaccines based on the modulation of host-cell apoptosis SO VACCINE LA English DT Article DE Malaria; DNA vaccine; Molecular adjuvant; Circumsporozoite protein; Protection ID CIRCUMSPOROZOITE PROTEIN; PLASMODIUM-BERGHEI; PROTECTIVE IMMUNITY; T-CELLS; EFFICACY; INFECTION; RESPONSES; ANTIGEN; SPOROZOITES; ENHANCEMENT AB Malaria represents a major global health problem but despite extensive efforts, no effective vaccine is available. Various vaccine candidates have been developed that provide protection in animal models, such as a gene gun-delivered DNA vaccine encoding the circumsporozoite protein (CSP) of Plasmodium berghei. A common shortcoming of most malaria vaccines is the requirement for multiple immunizations leaving room for improvement even for established vaccine candidates such as the CSP-DNA vaccine. In this study, we explored whether regulating apoptosis in DNA vaccine transfected host cells could accelerate the onset of protective immunity and provide significant protection after a single immunization. A proapoptotic gene (Bax) was used as a molecular adjuvant in an attempt to mimic the immunostimulatory apoptosis triggered by viral or virus-derived vaccines, while anti-apoptotic genes such as Bcl-XL may increase the life span of transfected cells thus prolonging antigen production. Surprisingly, co-delivery of either Bax or Bcl-XL greatly reduced CSP-DNA vaccine efficacy after a single immunization. Co-delivery of Bax for three immunizations still had a detrimental effect on protective immunity, while repeated co-delivery of Bcl-XL had no negative impact. The fine characterization of humoral and cellular immune response modulated by these two molecular adjuvants revealed a previously unknown effect, i.e., a shift in the Th-profile. These results demonstrate that pro- or anti-apoptotic molecules should not be used as molecular adjuvants without careful evaluation of the resulting immune response. This finding represents yet another example that strategies to enhance vaccine efficacy developed for other model systems such as viral diseases cannot easily be applied to any vaccine. (c) 2009 Elsevier Ltd. All rights reserved. C1 [Bergmann-Leitner, Elke S.; Duncan, Elizabeth H.; Angov, Evelina] Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Dept Mol Parasitol, Silver Spring, MD 20910 USA. [Leitner, Wolfgang W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Savranskaya, Tatyana] Walter Reed Army Inst Res, Div Entomol, Silver Spring, MD 20910 USA. RP Bergmann-Leitner, ES (reprint author), Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Dept Mol Parasitol, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM Elke.Bergmannleitner@us.army.mil RI Bergmann-Leitner, Elke/B-3548-2011; Leitner, Wolfgang/F-5741-2011 OI Bergmann-Leitner, Elke/0000-0002-8571-8956; Leitner, Wolfgang/0000-0003-3125-5922 FU United States Agency for International Development [936-6001, AAG-P-00-98-00006, AAG-P-0098-00005]; United States Army Medical Research and Materiel Command FX The authors would like to thank Dr. Richard joule for the proand anti-apoptotic plasmids. The work was initiated under the guidance of Dr. Jeffrey Lyon and supported by the United States Agency for International Development, Project Number 936-6001, Award Number AAG-P-00-98-00006, Award Number AAG-P-0098-00005 and by the United States Army Medical Research and Materiel Command. NR 38 TC 13 Z9 14 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 18 PY 2009 VL 27 IS 41 BP 5700 EP 5708 DI 10.1016/j.vaccine.2009.06.059 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 497OW UT WOS:000270070400022 PM 19576940 ER PT J AU Stumpo, DJ Broxmeyer, HE Ward, T Cooper, S Hangoc, G Chung, YJ Shelley, WC Richfield, EK Ray, MK Yoder, MC Aplan, PD Blackshear, PJ AF Stumpo, Deborah J. Broxmeyer, Hal E. Ward, Toni Cooper, Scott Hangoc, Giao Chung, Yang Jo Shelley, William C. Richfield, Eric K. Ray, Manas K. Yoder, Mervin C. Aplan, Peter D. Blackshear, Perry J. TI Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis SO BLOOD LA English DT Article ID MESSENGER-RNA; STEM-CELLS; PROGENITOR CELLS; YOLK-SAC; TRISTETRAPROLIN FAMILY; CXC CHEMOKINES; MOUSE EMBRYO; EXPRESSION; REGULATOR; STABILITY AB Members of the tristetraprolin family of tandem CCCH finger proteins can bind to AU-rich elements in the 3'-untranslated region of mRNAs, leading to their deadenylation and subsequent degradation. Partial deficiency of 1 of the 4 mouse tristetraprolin family members, Zfp36l2, resulted in complete female infertility because of early embryo death. We have now generated mice completely deficient in the ZFP36L2 protein. Homozygous Zfp36l2 knockout (KO) mice died within approximately 2 weeks of birth, apparently from intestinal or other hemorrhage. Analysis of peripheral blood from KO mice showed a decrease in red and white cells, hemoglobin, hematocrit, and platelets. Yolk sacs from embryonic day 11.5 (E11.5) Zfp36l2 KO mice and fetal livers from E14.5 KO mice gave rise to markedly reduced numbers of definitive multilineage and lineage-committed hematopoietic progenitors. Competitive reconstitution experiments demonstrated that Zfp36l2 KO fetal liver hematopoietic stem cells were unable to adequately reconstitute the hematopoietic system of lethally irradiated recipients. These data establish Zfp36l2 as a critical modulator of definitive hematopoiesis and suggest a novel regulatory pathway involving control of mRNA stability in the life cycle of hematopoietic stem and progenitor cells. (Blood. 2009; 114: 2401-2410) C1 [Stumpo, Deborah J.; Ward, Toni; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Broxmeyer, Hal E.; Cooper, Scott; Hangoc, Giao] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Broxmeyer, Hal E.; Cooper, Scott; Hangoc, Giao] Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. [Chung, Yang Jo; Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Shelley, William C.; Yoder, Mervin C.] Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Shelley, William C.; Yoder, Mervin C.] Indiana Univ, Sch Med, Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. [Richfield, Eric K.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pathol & Lab Med, New Brunswick, NJ USA. [Richfield, Eric K.] Univ Med & Dent New Jersey, Mol Histol Ctr, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. [Ray, Manas K.] NIEHS, Knock Out Core, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov RI Aplan, Peter/K-9064-2016 FU National Institutes of Health [R01 HL56416, R01 HL67384, R01 HL63169]; National Institute of Environmental Health Sciences; National Cancer Institute FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, National Cancer Institute, and National Institutes of Health (grants R01 HL56416 and R01 HL67384, H.E.B.; grant R01 HL63169, M.C.Y.). NR 50 TC 60 Z9 61 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 17 PY 2009 VL 114 IS 12 BP 2401 EP 2410 DI 10.1182/blood-2009-04-214619 PG 10 WC Hematology SC Hematology GA 495WD UT WOS:000269925000008 PM 19633199 ER PT J AU Donahue, RE Jin, P Bonifacino, AC Metzger, ME Ren, JQ Wang, E Stroncek, DF AF Donahue, Robert E. Jin, Ping Bonifacino, Aylin C. Metzger, Mark E. Ren, Jiaqiang Wang, Ena Stroncek, David F. TI Plerixafor (AMD3100) and granulocyte colony-stimulating factor (G-CSF) mobilize different CD34(+) cell populations based on global gene and microRNA expression signatures SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELL; CXCR4 ANTAGONIST AMD3100; PROGENITOR CELLS; RAPID MOBILIZATION; NONHUMAN-PRIMATES; NOD/SCID MICE; BONE-MARROW; ENGRAFTMENT; VOLUNTEERS AB Plerixafor (AMD3100) and granulocyte colony-stimulating factor (G-CSF) mobilize peripheral blood stem cells by different mechanisms. A rhesus macaque model was used to compare plerixafor and G-CSF-mobilized CD34(+) cells. Three peripheral blood stem cell concentrates were collected from 3 macaques treated with G-CSF, plerixafor, or plerixafor plus G-CSF. CD34(+) cells were isolated by immunoselection and were analyzed by global gene and microRNA (miR) expression microarrays. Unsupervised hierarchical clustering of the gene expression data separated the CD34(+) cells into 3 groups based on mobilization regimen. Plerixafor-mobilized cells were enriched for B cells, T cells, and mast cell genes, and G-CSF mobilized cells were enriched for neutrophils and mononuclear phagocyte genes. Genes up-regulated in plerixafor plus G-CSF-mobilized CD34(+) cells included many that were not up-regulated by either agent alone. Two hematopoietic progenitor cell miR, miR-10 and miR-126, and a dendritic cell miR, miR-155, were up-regulated in G-CSF-mobilized CD34(+) cells. A pre-B-cell acute lymphocytic leukemia miR, miR-143-3p, and a T-cell miR, miR-143-5p, were up-regulated in plerixafor plus G-CSF-mobilized cells. The composition of CD34(+) cells is dependent on the mobilization protocol. Plerixafor-mobilized CD34(+) cells include more B-, T-, and mast cell precursors, whereas G-CSF-mobilized cells have more neutrophil and mononuclear phagocyte precursors. (Blood. 2009; 114: 2530-2541) C1 [Jin, Ping; Ren, Jiaqiang; Wang, Ena; Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Donahue, Robert E.; Bonifacino, Aylin C.; Metzger, Mark E.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm 1C711, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Hematology Branch, National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Transfusion Medicine; Clinical Center FX This study was funded by the Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, and the Department of Transfusion Medicine, Clinical Center, National Institutes of Health. NR 30 TC 56 Z9 57 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 17 PY 2009 VL 114 IS 12 BP 2530 EP 2541 DI 10.1182/blood-2009-04-214403 PG 12 WC Hematology SC Hematology GA 495WD UT WOS:000269925000022 PM 19602709 ER PT J AU Monaco, A Marincola, FM Sabatino, M Pos, Z Tornesello, ML Stroncek, DF Wang, E Lewis, GK Buonaguro, FM Buonaguro, L AF Monaco, Alessandro Marincola, Francesco M. Sabatino, Marianna Pos, Zoltan Tornesello, Maria Lina Stroncek, David F. Wang, Ena Lewis, George K. Buonaguro, Franco M. Buonaguro, Luigi TI Molecular immune signatures of HIV-1 vaccines in human PBMCs SO FEBS LETTERS LA English DT Article DE Immunogenomics; Vaccine; HIV-1; Peripheral blood mononuclear cell ID VIRUS-LIKE PARTICLES; BLOOD MONONUCLEAR-CELLS; GENE-EXPRESSION PROFILE; NEUTRALIZING ANTIBODIES; DENDRITIC CELLS; INNATE IMMUNITY; CLADE-A; STIMULATION; INDUCTION; PATTERNS AB The global transcriptional pro. le of peripheral blood mononuclear cells (PBMCs) stimulated with HIV candidate vaccine (virus-like particles, VLPs) has been evaluated in HIV-infected patients with low/high viral load compared to healthy volunteers. Baseline activation of chemokine production was observed in PBMC from HIV-infected patients and innate immune stimulation with HIV-VLPs was not blunted. The immune pro. le among HIV-infected patients was found to be qualitatively similar but quantitatively extremely variable. This diversity was independent of viral load and it might be dependent on individual immunogenetic traits or concurrent immunological status. This ex vivo screening strategy represents an efficient tool for guiding modi. cations/optimizations of vaccination strategies and understanding failures in individuals enrolled in clinical trials. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved. C1 [Monaco, Alessandro; Marincola, Francesco M.; Sabatino, Marianna; Pos, Zoltan; Stroncek, David F.; Wang, Ena] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Monaco, Alessandro] IRCCS Ist Nazl Tumori Giovanni Paolo II, Bari, Italy. [Tornesello, Maria Lina; Buonaguro, Franco M.; Buonaguro, Luigi] Ist Nazl Tumori Fdn G Pascale, Lab Mol Biol & Viral Oncogenesis, I-80131 Naples, Italy. [Tornesello, Maria Lina; Buonaguro, Franco M.; Buonaguro, Luigi] Ist Nazl Tumori Fdn G Pascale, AIDS Reference Ctr, I-80131 Naples, Italy. [Buonaguro, Luigi] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Buonaguro, Luigi] Sch Med, Baltimore, MD USA. RP Buonaguro, L (reprint author), Ist Nazl Tumori Fdn G Pascale, Lab Mol Biol & Viral Oncogenesis, Via Mariano Semmola 1, I-80131 Naples, Italy. EM irccsvir@unina.it RI Tornesello, Maria Lina/A-1564-2009; Pos, Zoltan/C-3623-2014; Monaco, Alessandro/O-5338-2015; OI Tornesello, Maria Lina/0000-0002-3523-3264; Pos, Zoltan/0000-0002-2574-7616; Monaco, Alessandro/0000-0002-9941-7003; Buonaguro, Luigi/0000-0002-6380-7114 FU Ministero Italiano Universita e Ricerca; Ministero Italiano della Sanita; Institute of Human Virology; NIH FX This study was supported by grants from the Ministero Italiano Universita e Ricerca (MIUR, 2004), the Ministero Italiano della Sanita (Ricerca Corrente and Progetto Finalizzato AIDS 2006), and the Institute of Human Virology and the NIH (NIH grants to G. K. L.). NR 24 TC 18 Z9 19 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 17 PY 2009 VL 583 IS 18 BP 3004 EP 3008 DI 10.1016/j.febslet.2009.07.060 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 512XB UT WOS:000271284200006 PM 19665024 ER PT J AU Mateja, A Szlachcic, A Downing, ME Dobosz, M Mariappan, M Hegde, RS Keenan, RJ AF Mateja, Agnieszka Szlachcic, Anna Downing, Maureen E. Dobosz, Malgorzata Mariappan, Malaiyalam Hegde, Ramanujan S. Keenan, Robert J. TI The structural basis of tail-anchored membrane protein recognition by Get3 SO NATURE LA English DT Article ID MITOCHONDRIAL OUTER-MEMBRANE; ARSA-ATPASE; CRYSTALLOGRAPHIC STRUCTURE; ENDOPLASMIC-RETICULUM; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; SIGNAL; PARTICLE; INSERTION; BINDING AB Targeting of newly synthesized membrane proteins to the endoplasmic reticulum is an essential cellular process. Most membrane proteins are recognized and targeted co-translationally by the signal recognition particle. However, nearly 5% of membrane proteins are 'tail-anchored' by a single carboxy-terminal transmembrane domain that cannot access the co-translational pathway. Instead, tail-anchored proteins are targeted post-translationally by a conserved ATPase termed Get3. The mechanistic basis for tail-anchored protein recognition or targeting by Get3 is not known. Here we present crystal structures of yeast Get3 in 'open' (nucleotide-free) and 'closed' (ADP center dot AlF(4)(-)-bound) dimer states. In the closed state, the dimer interface of Get3 contains an enormous hydrophobic groove implicated by mutational analyses in tail-anchored protein binding. In the open state, Get3 undergoes a striking rearrangement that disrupts the groove and shields its hydrophobic surfaces. These data provide a molecular mechanism for nucleotide-regulated binding and release of tail-anchored proteins during their membrane targeting by Get3. C1 [Mateja, Agnieszka; Szlachcic, Anna; Downing, Maureen E.; Dobosz, Malgorzata; Keenan, Robert J.] Univ Chicago, Dept Biochem & Mol Biol, Gordon Ctr Integrat Sci, Chicago, IL 60637 USA. [Mariappan, Malaiyalam; Hegde, Ramanujan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Szlachcic, Anna] Univ Wroclaw, Fac Biotechnol, Dept Prot Engn, PL-50137 Wroclaw, Poland. [Dobosz, Malgorzata] Jagiellonian Univ, Fac Chem, PL-30060 Krakow, Poland. RP Keenan, RJ (reprint author), Univ Chicago, Dept Biochem & Mol Biol, Gordon Ctr Integrat Sci, Room W238,920 E 57th St, Chicago, IL 60637 USA. EM bkeenan@uchicago.edu RI mariappan, malaiyalam/K-9024-2012; OI Hegde, Ramanujan/0000-0001-8338-852X FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Edward Mallinckrodt, Jr. Foundation; National Institutes of Health FX Data were collected at beamlines 21-IDG and 23-IDD at the Advanced Photon Source (APS), Argonne National Laboratory, and we thank the beamline staff for support. Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. We thank B. Glick and R. Strack for reagents and advice, X. Li for assay characterization, and A. Shiau and T. Steck for comments on the manuscript. This work was supported by a grant from the Edward Mallinckrodt, Jr. Foundation (to R. J. K.) and by the Intramural Research Program of the National Institutes of Health (to R. S. H.). NR 40 TC 80 Z9 82 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 17 PY 2009 VL 461 IS 7262 BP 361 EP U58 DI 10.1038/nature08319 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494QB UT WOS:000269828100032 PM 19675567 ER PT J AU Lauchle, JO Kim, D Le, DT Akagi, K Crone, M Krisman, K Warner, K Bonifas, JM Li, Q Coakley, KM Diaz-Flores, E Gorman, M Przybranowski, S Tran, M Kogan, SC Roose, JP Copeland, NG Jenkins, NA Parada, L Wolff, L Sebolt-Leopold, J Shannon, K AF Lauchle, Jennifer O. Kim, Doris Le, Doan T. Akagi, Keiko Crone, Michael Krisman, Kimberly Warner, Kegan Bonifas, Jeannette M. Li, Qing Coakley, Kristen M. Diaz-Flores, Ernesto Gorman, Matthew Przybranowski, Sally Tran, Mary Kogan, Scott C. Roose, Jeroen P. Copeland, Neal G. Jenkins, Nancy A. Parada, Luis Wolff, Linda Sebolt-Leopold, Judith Shannon, Kevin TI Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras SO NATURE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MALIGNANT MYELOID DISORDERS; BCR-ABL; HEMATOPOIETIC-CELLS; KINASE INHIBITORS; TYROSINE KINASE; BLAST CRISIS; BONE-MARROW; CHILDREN; PATHWAY AB The cascade comprising Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) is a therapeutic target in human cancers with deregulated Ras signalling, which includes tumours that have inactivated the Nf1 tumour suppressor(1,2). Nf1 encodes neurofibromin, a GTPase-activating protein that terminates Ras signalling by stimulating hydrolysis of Ras-GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed because of outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4 and Mapk14, which encodes p38 alpha. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance. C1 [Lauchle, Jennifer O.; Kim, Doris; Le, Doan T.; Crone, Michael; Krisman, Kimberly; Warner, Kegan; Bonifas, Jeannette M.; Diaz-Flores, Ernesto; Gorman, Matthew; Tran, Mary; Shannon, Kevin] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Li, Qing] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Coakley, Kristen M.; Roose, Jeroen P.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Kogan, Scott C.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Akagi, Keiko] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Przybranowski, Sally; Sebolt-Leopold, Judith] Pfizer Global Res & Dev, Ann Arbor, MI 48105 USA. [Copeland, Neal G.; Jenkins, Nancy A.] Inst Mol & Cell Biol, Singapore 138673, Singapore. [Parada, Luis] Univ Texas SW, Dallas, TX 75235 USA. [Wolff, Linda] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Shannon, K (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. EM shannonk@peds.ucsf.edu RI ASTAR, IMCB/E-2320-2012 FU National Institutes of Health [U01 CA84221, R37 CA72614, T32 CA09043, T32 HD044331, K08 CA119105]; Leukemia and Lymphoma Society [LLS 7019-04]; US Army Neurofibromatosis Research Program [DAMD 17-02-1-0638]; Ronald McDonald House Charities of Southern California/Couples Against Leukemia; Jeffrey and Karen Peterson Family Foundation; Frank A. Campini Foundation FX We are grateful to B. Braun, J. Downing, S. Lowe and C. Sawyers for discussion and advice throughout the project. We are thankful for C. Hartzell for studies on RasGRP protein expression. This work was supported by National Institutes of Health grants U01 CA84221, R37 CA72614, T32 CA09043, T32 HD044331 and K08 CA119105, by a Specialized Center of Research award from the Leukemia and Lymphoma Society (LLS 7019-04), by the US Army Neurofibromatosis Research Program (Project DAMD 17-02-1-0638), by the Ronald McDonald House Charities of Southern California/Couples Against Leukemia, by the Jeffrey and Karen Peterson Family Foundation and by the Frank A. Campini Foundation. S. C. K. is a Scholar of the Leukemia and Lymphoma Society of America. J. P. R. is a Kimmel Foundation Scholar. The Intramural Research Program of the National Cancer Institute's Center for Cancer Research supports research in the laboratory of L. W. at the National Institutes of Health. NR 25 TC 64 Z9 65 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 17 PY 2009 VL 461 IS 7262 BP 411 EP U110 DI 10.1038/nature08279 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494QB UT WOS:000269828100043 PM 19727076 ER PT J AU Zofall, M Fischer, T Zhang, K Zhou, M Cui, BW Veenstra, TD Grewal, SIS AF Zofall, Martin Fischer, Tamas Zhang, Ke Zhou, Ming Cui, Bowen Veenstra, Timothy D. Grewal, Shiv I. S. TI Histone H2A.Z cooperates with RNAi and heterochromatin factors to suppress antisense RNAs SO NATURE LA English DT Article ID FISSION YEAST; QUALITY CONTROL; NONCODING RNAS; VARIANT; TRANSCRIPTION; CHROMATIN; GENOME; DROSOPHILA; COMPLEX; EXOSOME AB Eukaryotic transcriptomes are characterized by widespread transcription of noncoding and antisense RNAs(1-3), which is linked to key chromosomal processes, such as chromatin remodelling, gene regulation and heterochromatin assembly(4-7). However, these transcripts can be deleterious, and their accumulation is suppressed by several mechanisms including degradation by the nuclear exosome(8,9). The mechanisms by which cells differentiate coding RNAs from transcripts targeted for degradation are not clear. Here we show that the variant histone H2A.Z, which is loaded preferentially at the 5' ends of genes by the Swr1 complex containing a JmjC domain protein, mediates suppression of antisense transcripts in the fission yeast Schizosaccharomyces pombe genome. H2A.Z is partially redundant in this regard with the Clr4 (known as SUV39H in mammals)-containing heterochromatin silencing complex that is also distributed at euchromatic loci, and with RNA interference component Argonaute (Ago1). Loss of Clr4 or Ago1 alone has little effect on antisense transcript levels, but cells lacking either of these factors and H2A.Z show markedly increased levels of antisense RNAs that are normally degraded by the exosome. These analyses suggest that as well as performing other functions, H2A.Z is a component of a genome indexing mechanism that cooperates with heterochromatin and RNAi factors to suppress read-through antisense transcripts. C1 [Zofall, Martin; Fischer, Tamas; Zhang, Ke; Cui, Bowen; Grewal, Shiv I. S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhou, Ming; Veenstra, Timothy D.] NCI Frederick, SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD 21702 USA. RP Grewal, SIS (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov RI Cui, Bowen/F-1038-2011; Fischer, Tamas/A-7729-2016 OI Fischer, Tamas/0000-0002-7996-4042 FU National Institutes of Health [N01-CO-12400]; National Cancer Institute FX Acknowledgements We thank K. Noma for strain constructions, D. McPheeters for the run-on protocol, M. Lichten, F. Reyes-Turcu, E. Bartlett and H. Cam for comments on the manuscript, P. Fitzgerald for designing microarrays, and D. Venzon for advice with data analyses. This research was supported by the Intramural Research Program, and under Contract N01-CO-12400 of the National Institutes of Health, National Cancer Institute. NR 30 TC 89 Z9 90 U1 5 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 17 PY 2009 VL 461 IS 7262 BP 419 EP U120 DI 10.1038/nature08321 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494QB UT WOS:000269828100045 PM 19693008 ER PT J AU Strebel, K Luban, J Jeang, KT AF Strebel, Klaus Luban, Jeremy Jeang, Kuan-Teh TI Human cellular restriction factors that target HIV-1 replication SO BMC MEDICINE LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 VPU PROTEIN; APOBEC3G CATALYTIC DOMAIN; RNA SILENCING SUPPRESSOR; VIRAL PARTICLE RELEASE; SMALL INTERFERING RNAS; AMINO-ACID-RESIDUES; PIG-TAILED MACAQUES; CD4(+) T-CELLS; CYCLOPHILIN-A AB Recent findings have highlighted roles played by innate cellular factors in restricting intracellular viral replication. In this review, we discuss in brief the activities of apolipoprotein B mRNA-editing enzyme 3G (APOBEC3G), bone marrow stromal cell antigen 2 (BST-2), cyclophilin A, tripartite motif protein 5 alpha (Trim5 alpha), and cellular microRNAs as examples of host restriction factors that target HIV-1. We point to countermeasures encoded by HIV-1 for moderating the potency of these cellular restriction functions. C1 [Strebel, Klaus; Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Luban, Jeremy] Univ Geneva, Dept Microbiol & Med, Geneva, Switzerland. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Kstrebel@NIH.gov; Jeremy.Luban@unige.ch; Kjeang@NIH.gov RI Jeang, Kuan-Teh/A-2424-2008 FU NIAID; NIH [RO1AI36199]; Swiss National Science Foundation office of the Director NIH [3100A0-113558] FX Work in the laboratories of KS and KTJ was supported by intramural funding from NIAID, NIH and the Intramural AIDS Targeted Antiviral Program (IATAP) of the office of the Director NIH. Work in the JL laboratory was supported by the National Institutes of Health grant RO1AI36199 and the Swiss National Science Foundation grant 3100A0-113558. We are grateful to D Schmidt for his assistance with Figure 5. NR 208 TC 99 Z9 100 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD SEP 16 PY 2009 VL 7 AR 48 DI 10.1186/1741-7015-7-48 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 512GS UT WOS:000271234900001 PM 19758442 ER PT J AU Bushel, PR Heard, NA Gutman, R Liu, LW Peddada, SD Pyne, S AF Bushel, Pierre R. Heard, Nicholas A. Gutman, Roee Liu, Liwen Peddada, Shyamal D. Pyne, Saumyadipta TI Dissecting the fission yeast regulatory network reveals phase-specific control elements of its cell cycle SO BMC SYSTEMS BIOLOGY LA English DT Article ID MESSENGER-RNA STABILITY; SCHIZOSACCHAROMYCES-POMBE; TRANSCRIPTION FACTOR; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; RIBOSOME BIOGENESIS; DIVISION CYCLE; GENOMIC SCALE; TIME-SERIES; PROTEIN AB Background: Fission yeast Schizosaccharomyces pombe and budding yeast Saccharomyces cerevisiae are among the original model organisms in the study of the cell-division cycle. Unlike budding yeast, no large-scale regulatory network has been constructed for fission yeast. It has only been partially characterized. As a result, important regulatory cascades in budding yeast have no known or complete counterpart in fission yeast. Results: By integrating genome-wide data from multiple time course cell cycle microarray experiments we reconstructed a gene regulatory network. Based on the network, we discovered in addition to previously known regulatory hubs in M phase, a new putative regulatory hub in the form of the HMG box transcription factor SPBC19G7.04. Further, we inferred periodic activities of several less known transcription factors over the course of the cell cycle, identified over 500 putative regulatory targets and detected many new phase-specific and conserved cis-regulatory motifs. In particular, we show that SPBC19G7.04 has highly significant periodic activity that peaks in early M phase, which is coordinated with the late G2 activity of the forkhead transcription factor fkh2. Finally, using an enhanced Bayesian algorithm to co-cluster the expression data, we obtained 31 clusters of co-regulated genes 1) which constitute regulatory modules from different phases of the cell cycle, 2) whose phase order is coherent across the 10 time course experiments, and 3) which lead to identification of phase-specific control elements at both the transcriptional and post-transcriptional levels in S. pombe. In particular, the ribosome biogenesis clusters expressed in G2 phase reveal new, highly conserved RNA motifs. Conclusion: Using a systems-level analysis of the phase-specific nature of the S. pombe cell cycle gene regulation, we have provided new testable evidence for post-transcriptional regulation in the G2 phase of the fission yeast cell cycle. Based on this comprehensive gene regulatory network, we demonstrated how one can generate and investigate plausible hypotheses on fission yeast cell cycle regulation which can potentially be explored experimentally. C1 [Bushel, Pierre R.; Liu, Liwen; Peddada, Shyamal D.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Heard, Nicholas A.] Univ London Imperial Coll Sci Technol & Med, Dept Math, London, England. [Gutman, Roee] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Pyne, Saumyadipta] Harvard Univ, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Pyne, Saumyadipta] MIT, Broad Inst, Cambridge, MA 02142 USA. [Bushel, Pierre R.] Harvard Univ, Sch Publ Hlth, Dept Stat, Boston, MA 02115 USA. [Bushel, Pierre R.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Pyne, Saumyadipta] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Bushel, PR (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. EM bushel@niehs.nih.gov; n.heard@imperial.ac.uk; rgutman@fas.harvard.edu; liuliw@niehs.nih.gov; peddada@niehs.nih.gov; Saumyadipta_Pyne@DFCI.HARVARD.EDU RI Peddada, Shyamal/D-1278-2012; Gutman, Roee/J-2355-2014 OI Gutman, Roee/0000-0001-7095-3016 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX Research of PRB, LL and SDP was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04]. We thank Jonathan H. Freedman and Reuben Thomas for their review of the manuscript. SP thanks Aviv Regev and Ana Paula Leite for programs on module network analysis. We also dearly thank James C. Liao for his personal communication regarding NCA. NR 65 TC 10 Z9 10 U1 0 U2 2 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 SEP 16 PY 2009 VL 3 AR 93 DI 10.1186/1752-0509-3-93 PG 21 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 506EE UT WOS:000270755700001 PM 19758441 ER PT J AU Albanes, D Weinstein, SJ Wright, ME Mannisto, S Limburg, PJ Snyder, K Virtamo, J AF Albanes, Demetrius Weinstein, Stephanie J. Wright, Margaret E. Mannisto, Satu Limburg, Paul J. Snyder, Kirk Virtamo, Jarmo TI Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Prostate Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GROWTH-FACTOR-I; DIABETES-MELLITUS; MALE SMOKERS; BINDING-PROTEINS; OBESITY; HYPERINSULINEMIA; METAANALYSIS; ASSOCIATION; SURVIVAL; MEN AB The mitogenic and growth-stimulatory effects of insulin-like growth factors appear to play a role in prostate carcinogenesis, yet any direct association of circulating insulin levels and risk of prostate cancer remains unclear. We investigated the relationship of the level of serum insulin, glucose, and surrogate indices of insulin resistance (ie, the molar ratio of insulin to glucose and the homeostasis model assessment of insulin resistance [HOMA-IR]) to the development of prostate cancer in a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish men. We studied 100 case subjects with incident prostate cancer and 400 noncase subjects without prostate cancer from the larger cohort. Fasting serum was collected 5-12 years before diagnosis. We determined insulin concentrations with a double-antibody immunochemiluminometric assay and glucose concentrations with a hexokinase assay. Multivariable logistic regression models estimated relative risks as odds ratios (ORs), and all statistical tests were two-sided. Insulin concentrations in fasting serum that was collected on average 9.2 years before diagnosis among case subjects were 8% higher than among noncase subjects, and the molar ratio of insulin to glucose and HOMA-IR were 10% and 6% higher, respectively, but these differences were not statistically significant. Among subjects in the second through fourth insulin quartiles, compared with those in the first quartile, increased insulin levels were associated with statistically significantly increased risks of prostate cancer (OR = 1.50, 95% confidence interval [CI] = 0.75 to 3.03; OR = 1.75, 95% CI = 0.86 to 3.56; and OR = 2.55, 95% CI = 1.18 to 5.51; for the second through fourth insulin quartiles, respectively; P-trend = .02). A similar pattern was observed with the HOMA-IR (OR = 2.10, 95% CI = 1.03 to 4.26; P-trend = .02) for the highest vs lowest quartiles. Risk varied inconsistently with glucose concentration (P-trend = .38). A stronger association between insulin level and prostate cancer risk was observed among leaner men and among men who were less physically active at work. Crude prostate cancer incidence was 154 prostate cancers per 100 000 person-years in the lowest quartile of fasting serum insulin vs 394 prostate cancers per 100 000 person-years in the highest quartile. Elevated fasting levels of serum insulin (but not glucose) within the normal range appear to be associated with a higher risk of prostate cancer. C1 [Albanes, Demetrius; Weinstein, Stephanie J.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wright, Margaret E.] Univ Illinois, Coll Med, Dept Pathol, Chicago, IL 60612 USA. [Mannisto, Satu; Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Limburg, Paul J.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Snyder, Kirk] Informat Management Serv Inc, Silver Spring, MD USA. RP Albanes, D (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Executive Blvd,Rm 3044, Bethesda, MD 20892 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mannisto, Satu/0000-0002-8668-3046 FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was supported in part by US Public Health Service contracts N01-CN-45165, N01-RC-45035, and N01-RC-37004 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 32 TC 54 Z9 55 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP 16 PY 2009 VL 101 IS 18 BP 1272 EP 1279 DI 10.1093/jnci/djp260 PG 8 WC Oncology SC Oncology GA 496YD UT WOS:000270015400009 PM 19700655 ER PT J AU Chen, KG Leapman, RD Zhang, GF Lai, B Valencia, JC Cardarelli, CO Vieira, WD Hearing, VJ Gottesman, MM AF Chen, Kevin G. Leapman, Richard D. Zhang, Guofeng Lai, Barry Valencia, Julio C. Cardarelli, Carol O. Vieira, Wilfred D. Hearing, Vincent J. Gottesman, Michael M. TI Influence of Melanosome Dynamics on Melanoma Drug Sensitivity SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BINDING CASSETTE TRANSPORTER; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; MALIGNANT-MELANOMA; CYTOTOXIC DRUGS; CELLS; TYROSINASE; CISPLATIN; CANCER; MELANOCYTES AB Malignant melanomas are intrinsically resistant to many conventional treatments, such as radiation and chemotherapy, for reasons that are poorly understood. Here we propose and test a model that explains drug resistance or sensitivity in terms of melanosome dynamics. The growth and sensitivity to cisplatin of MNT-1 cells, which are melanotic and enriched with mature stage III and IV melanosomes, and SK-MEL-28 cells, which have only immature stage I and II melanosomes, were compared using clonogenic assays. Differences in pigmentation, melanosome stages, melanosome number, and cellular structures in different cell lines in response to various treatments were examined by electron microscopy. The relative numbers of melanosomes of different stages were compared after treatment with 1-phenyl-2-thiourea. The relationship between drug transporter function and endogenous melanogenic toxicity was assessed by treating cells with the cyclosporin analog PSC-833 and by assessing vacuole formation and cell growth inhibition. All statistical tests were two-sided. Endogenous melanogenic cytotoxicity, produced by damaged melanosomes, resulted in pronounced cell growth inhibition in MNT-1 cells compared with amelanotic SK-MEL-28 cells. The sensitivity to CDDP of MNT-1 cells was 3.8-fold higher than that of SK-MEL-28 cells (mean IC(50) for SK-MEL-28 and MNT-1 = 2.13 mu M and 0.56 mu M, respectively; difference = 1.57 mu M, 95% confidence interval = 1.45 to 1.69; P = .0017). After treatment with 6.7 mu M CDDP for 72 hours, the number of stage II-III melanosomes in surviving MNT-1 cells was 6.8-fold that of untreated cells. Modulation of MNT-1 cells to earlier-stage (II, II-III, III) melanosomes by treatment with the tyrosinase inhibitor 1-phenyl-2-thiourea dramatically increased CDDP resistance. Furthermore, PSC-833 principally suppressed MNT-1 melanotic cell growth via an elevation of autophagosome-like vacuolar structures, possibly by inhibiting melanosome membrane transporters. Melanosome dynamics (including their biogenesis, density, status, and structural integrity) regulate the drug resistance of melanoma cells. Manipulation of melanosome functions may be an effective way to enhance the therapeutic activity of anticancer drugs against melanoma. C1 [Chen, Kevin G.; Valencia, Julio C.; Cardarelli, Carol O.; Vieira, Wilfred D.; Hearing, Vincent J.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Leapman, Richard D.; Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. [Lai, Barry] Argonne Natl Lab, Adv Photon Source, Argonne, IL 60439 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Rm 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI Chen, Kevin/D-6769-2011 OI Chen, Kevin/0000-0003-2983-6330 FU Intramural NIH HHS [Z99 NS999999] NR 40 TC 21 Z9 21 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 16 PY 2009 VL 101 IS 18 BP 1259 EP 1271 DI 10.1093/jnci/djp259 PG 13 WC Oncology SC Oncology GA 496YD UT WOS:000270015400008 PM 19704071 ER PT J AU Landgren, O Dunleavy, K Wilson, WH AF Landgren, Ola Dunleavy, Kieron Wilson, Wyndham H. TI Re: Rituximab Maintenance for the Treatment of Patients With Follicular Lymphoma: Systematic Review and Meta-analysis of Randomized trials SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID RESPONSE DURATION; FREE SURVIVAL; CYCLOPHOSPHAMIDE; PROGRESSION; THERAPY C1 [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10-Rm 13N240F, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 16 PY 2009 VL 101 IS 18 BP 1287 EP 1288 DI 10.1093/jnci/djp255 PG 3 WC Oncology SC Oncology GA 496YD UT WOS:000270015400014 PM 19687413 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI The importance of individualized article-specific metrics for evaluating research productivity SO RETROVIROLOGY LA English DT Editorial Material ID 2007 RETROVIROLOGY PRIZE; H-INDEX; SCIENCE; WINS; CALL; LIFE AB This editorial discusses the rationale for using article-specific rather than journal-specific metrics for evaluating highly published authors. C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 10 TC 2 Z9 2 U1 0 U2 3 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 SEP 16 PY 2009 VL 6 AR 82 DI 10.1186/1742-4690-6-82 PG 4 WC Virology SC Virology GA 509KN UT WOS:000271015500001 PM 19758447 ER PT J AU Platt, RW Schisterman, EF Cole, SR AF Platt, Robert W. Schisterman, Enrique F. Cole, Stephen R. TI Time-modified Confounding SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); confounding factors (epidemiology); structural model ID MARGINAL STRUCTURAL MODELS; PROPORTIONAL HAZARDS MODEL; CAUSAL INFERENCE; EPIDEMIOLOGY; DEFINITION; MORTALITY; KNOWLEDGE; RATIO; BIAS AB According to the authors, time-modified confounding occurs when the causal relation between a time-fixed or time-varying confounder and the treatment or outcome changes over time. A key difference between previously described time-varying confounding and the proposed time-modified confounding is that, in the former, the values of the confounding variable change over time while, in the latter, the effects of the confounder change over time. Using marginal structural models, the authors propose an approach to account for time-modified confounding when the relation between the confounder and treatment is modified over time. An illustrative example and simulation show that, when time-modified confounding is present, a marginal structural model with inverse probability-of-treatment weights specified to account for time-modified confounding remains approximately unbiased with appropriate confidence limit coverage, while models that do not account for time-modified confounding are biased. Correct specification of the treatment model, including accounting for potential variation over time in confounding, is an important assumption of marginal structural models. When the effect of confounders on either the treatment or outcome changes over time, time-modified confounding should be considered. C1 [Platt, Robert W.] McGill Univ, Dept Pediat & Epidemiol, Montreal, PQ, Canada. [Platt, Robert W.] McGill Univ, Dept Biostat, Montreal, PQ, Canada. [Platt, Robert W.] McGill Univ, Dept Occupat Hlth, Montreal, PQ, Canada. [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Rockville, MD USA. [Cole, Stephen R.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Platt, RW (reprint author), Montreal Childrens Hosp, Res Inst, 4060 Ste Catherine St W,205, Westmount, PQ H3Z 2Z3, Canada. EM robert.platt@mcgill.ca RI Platt, Robert/G-5847-2012; OI Platt, Robert/0000-0002-5981-8443; Schisterman, Enrique/0000-0003-3757-641X FU Fonds de Recherche en Santedu Quebec (FRSQ); Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institutes of Health [R03-AI-071763, R01-AA-017594, P30-AI-50410]; American Chemistry Council; Thrasher Research Fund; National Health Research and Development Program (Health Canada); United Nations Children's Fund; European Regional Office of the World Health Organization FX Robert Platt is supported by a salary award from the Fonds de Recherche en Santedu Quebec (FRSQ) and is a member of the Research Institute of the McGill University Health Centre, which is supported in part by the FRSQ. Enrique F. Schisterman is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. Stephen R. Cole was partially supported by National Institutes of Health grants R03-AI-071763, R01-AA-017594, and P30-AI-50410. The authors were partially funded by a grant from the American Chemistry Council to Enrique Schisterman. PROBIT was supported by grants from the Thrasher Research Fund, the National Health Research and Development Program (Health Canada), the United Nations Children's Fund, and the European Regional Office of the World Health Organization. NR 33 TC 19 Z9 19 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2009 VL 170 IS 6 BP 687 EP 694 DI 10.1093/aje/kwp175 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 491UX UT WOS:000269606900003 PM 19675141 ER PT J AU Wilson, RT Wang, JY Chinchilli, V Richie, JP Virtamo, J Moore, LE Albanes, D AF Wilson, Robin Taylor Wang, Jiangyue Chinchilli, Vernon Richie, John P. Virtamo, Jarmo Moore, Lee E. Albanes, Demetrius TI Fish, Vitamin D, and Flavonoids in Relation to Renal Cell Cancer Among Smokers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE carcinoma (renal cell); fish products; flavonoids; vitamin D ID PERSISTENT ORGANOCHLORINE COMPOUNDS; DIBENZO-P-DIOXINS; CARDIOVASCULAR-DISEASE; RISK-FACTORS; BALTIC SEA; MYOCARDIAL-INFARCTION; LIPID-PEROXIDATION; PANCREATIC-CANCER; SWEDISH FISHERMEN; MERCURY-COMPOUNDS AB Fish, vitamin D, flavonoids, and flavonoid-containing foods may have cardiovascular benefits and therefore may also reduce the risk of renal cell cancer. Risk was prospectively assessed in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (1985-2002) cohort (N = 27,111; 15.2 mean person-years of follow-up). At enrollment, demographic, health, and dietary history information was recorded. Individuals who smoked less than 5 cigarettes/day, with chronic renal insufficiency or prior cancer, were excluded. Hazard ratios and 95% confidence intervals from Cox regression were used to compare upper quartiles (quartiles 2-4) with the lowest quartile (quartile 1) of dietary intake. Among 228 cases, risk (quartile 4 vs. quartile 1) was associated with consumption of the flavonoid quercetin (hazard ratio = 0.6, 95% confidence interval: 0.4, 0.9; P(trend) = 0.015) and Baltic herring (hazard ratio = 2.0, 95% confidence interval: 1.4, 3.0; P(trend) < 0.001), with adjustment for age, body mass index, smoking, blood pressure, alcohol use, physical activity, urban residence, and education. In geographically stratified models, the risks associated with herring and total fish intake appeared to be highest in the urban coast region, although the interaction was not statistically significant. These results suggest that the flavonoid quercetin may prevent renal cell cancer among male smokers. The possible risk associated with fish intake warrants further investigation before conclusions may be drawn. C1 [Wilson, Robin Taylor; Wang, Jiangyue; Chinchilli, Vernon; Richie, John P.] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Div Epidemiol, Hershey, PA 17033 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Moore, Lee E.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Wilson, RT (reprint author), Penn State Univ, Coll Med, Dept Publ Hlth Sci, Div Epidemiol, 600 Ctr View Dr,Suite 2200,Mail Code A210, Hershey, PA 17033 USA. EM rwilson@psu.edu RI Albanes, Demetrius/B-9749-2015 FU Intramural Research Program of the National Institutes of Health; US Public Health Service [N01-CN-45165, N01-RC45035, N01-RC-37004]; National Cancer Institute, Department of Health and Human Services FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, by a postdoctoral research fellowship within the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, and by salary support from the Pennsylvania State University. Additionally, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC45035, and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services. NR 79 TC 19 Z9 20 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 SEP 15 PY 2009 VL 170 IS 6 BP 717 EP 729 DI 10.1093/aje/kwp178 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 491UX UT WOS:000269606900007 PM 19651663 ER PT J AU Schunemann, HJ Osborne, M Moss, J Manthous, C Wagner, G Sicilian, L Ohar, J McDermott, S Lucas, L Jaeschke, R AF Schuenemann, Holger J. Osborne, Molly Moss, Joel Manthous, Constantine Wagner, Gregory Sicilian, Leonard Ohar, Jill McDermott, Shane Lucas, Lance Jaeschke, Roman CA ATS Ethics Conflict Interest Comm Documents Dev Implementation Comm TI An Official American Thoracic Society Policy Statement: Managing Conflict of Interest in Professional Societies SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID PHYSICIAN-INDUSTRY RELATIONSHIPS AB Background. Competing interests occur frequently in health care. This results in the potential for conflict of interest (COI). COI can lead to biased generation or assessment of evidence and misinform healthcare decision makers. Declaration of COI is insufficient to neutralize potentially harmful effects. Medical professional societies are obliged to develop robust mechanisms to "manage" COI, particularly in the development of official guidance documents that affect health care. Purpose: This document describes the background, methods, and content of the new "American Thoracic Society (ATS) Policy on Management of COI in Official ATS Documents, Projects, and Conferences." Methods: We used existing reviews on COI policies that were prepared for the World Health Organization and for an ATS guideline methodology workshop as the evidence base for this work. We reviewed existing policies of selected organizations and other relevant literature. Members of the ATS Documents Development and Implementation Committee and the ATS Ethics and COI Committee collaborated to draft a COI policy. We used face-to-face meetings, electronic correspondence, and teleconferences to finalize the draft. The policy then underwent review and ultimate approval by the ATS Board of Directors. Results: The ATS developed a new policy and procedures for declaration and management of COL These procedures include: (1) self declaration of COI, (2) review of potential participants' COI, (3) disclosure of COI to project participants, (4) recusal or excusal from certain decisions or recommendations when appropriate, (5) disclosure of COI to users of documents or attendees of conferences, (6) handling disputes in COI resolution. This policy includes a tool that may be useful for supporting decision makers in management of COIs as they assess the value and relevance of conflicts. Conclusions: The ATS Policy on Management of COI in Official ATS Documents, Projects, and Conferences, in effect since March 2008, promises greater organizational transparency. Application and ongoing evaluation of the policy will give the ATS the opportunity to determine its usefulness in specific settings. C1 [Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Schuenemann, Holger J.] SUNY Buffalo, Dept Med, Buffalo, NY 14260 USA. [Schuenemann, Holger J.; Jaeschke, Roman] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Osborne, Molly] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Osborne, Molly] Portland VA Med Ctr, Portland, OR USA. [Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Manthous, Constantine] Yale Univ, Sch Med, Bridgeport Hosp, New Haven, CT USA. [Wagner, Gregory] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Sicilian, Leonard] Massachusetts Gen Hosp, Dept Med, Adult Cyst Fibrosis Program, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Ohar, Jill] Wake Forest Univ, Bowman Gray Sch Med, Sect Pulm Crit Care Allergy & Immunol Dis, Winston Salem, NC USA. [McDermott, Shane] Off Eth & Conflict Interest Policies, New York, NY USA. [Lucas, Lance] Amer Thorac Soc, Off Documents, New York, NY USA. [Lucas, Lance] Amer Thorac Soc, Ad Hoc Projects, New York, NY USA. RP Schunemann, HJ (reprint author), McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. NR 15 TC 34 Z9 35 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 15 PY 2009 VL 180 IS 6 BP 564 EP 580 DI 10.1164/rccm.200901-0126ST PG 17 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 496TV UT WOS:000270002600013 PM 19734351 ER PT J AU Whellan, DJ Ellis, SJ Kraus, WE Hawthorne, K Pina, IL Keteyian, SJ Kitzman, DW Cooper, L Lee, K O'Connor, CM AF Whellan, David J. Ellis, Stephen J. Kraus, William E. Hawthorne, Katie Pina, Ileana L. Keteyian, Steven J. Kitzman, Dalane W. Cooper, Lawton Lee, Kerry O'Connor, Christopher M. TI Method for Establishing Authorship in a Multicenter Clinical Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HEART-FAILURE; HF-ACTION; GUIDELINES; TIME AB With the emergence of large multicenter trials over the past 20 years, the numbers of investigators involved and publications resulting from each study have grown exponentially. An efficient, fair, and effective way to establish authorship on study-related manuscripts could diminish conflict among the investigators and help ensure robust and timely dissemination of study results. This article describes a process developed by the investigators in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (ClinicalTrials. gov registration number: NCT00047437) to establish authorship of the manuscripts describing the baseline characteristics, study design, and trial outcomes in an equitable and transparent manner based on objective, quantifiable contributions to the study as a whole. The HF-ACTION investigators developed a scoring system that assigned points to investigators by using the criteria established for enrollment, adherence to the exercise program, data completion, committee service, and other trial efforts. The scoring system has been successfully implemented for baseline manuscripts and has allowed many investigators to participate in the HF-ACTION publication process. C1 Duke Univ, Med Ctr, Durham, NC USA. Duke Clin Res Inst, Durham, NC USA. Wake Forest Univ, Sch Med, Winston Salem, NC USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Henry Ford Hosp, Detroit, MI 48202 USA. NHLBI, NIH, Bethesda, MD 20892 USA. [Whellan, David J.] Jefferson Med Coll, Dept Cardiol, Philadelphia, PA 19107 USA. RP Whellan, DJ (reprint author), Jefferson Med Coll, Dept Cardiol, 1015 Chestnut St,Suite 317, Philadelphia, PA 19107 USA. OI Kraus, William E/0000-0003-1930-9684 FU National Heart, Lung, and Blood Institute, National Institutes of Health [NIH/NHLBI U01HL063747] FX By the National Heart, Lung, and Blood Institute, National Institutes of Health, for the HF-ACTION trial (NIH/NHLBI U01HL063747). NR 9 TC 12 Z9 13 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 15 PY 2009 VL 151 IS 6 BP 414 EP W133 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 501OB UT WOS:000270390100006 PM 19755366 ER PT J AU van Bemmel, DM Brank, AS Eritja, R Marquez, VE Christman, JK AF van Bemmel, Dana M. Brank, Adam S. Eritja, Ramon Marquez, Victor E. Christman, Judith K. TI DNA (Cytosine-C5) methyltransferase inhibition by oligodeoxyribonucleotides containing 2-(1H)-pyrimidinone (zebularine aglycon) at the enzymatic target site SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Zebularine; DNA methylation; 2(1H)-Pyrimidinone riboside; DNA methyltransferase; 5-Aza-2 '-deoxycytidine ID CELL LUNG-CANCER; CYTIDINE DEAMINASE; ESCHERICHIA-COLI; PHASE-II; 5-AZA-2'-DEOXYCYTIDINE DECITABINE; HHAI METHYLTRANSFERASE; HYPOMETHYLATING AGENT; METHYLATION INHIBITOR; GENE-EXPRESSION; 5-AZACYTIDINE AB Aberrant cytosine methylation in promoter regions leads to gene silencing associated with cancer progression. A number of DNA methyltransferase inhibitors are known to reactivate silenced genes: including 5-azacytidine and 2-(1H)-pyrimidinone riboside (zebularine). Zebularine is a more stable, less cytotoxic inhibitor compared to 5-azacytidine. To determine the mechanistic basis for this difference, we carried out a detailed comparisons of the interaction between purified DNA methyltransferases and oligodeoxyribonucleotides (ODNs) containing either 5-azacytosine or 2-(1H)-pyrimidinone in place of the cytosine targeted for methylation. When incorporated into small ODNs, the rate of C5 DNA methyltransferase inhibition by both nucleosides is essentially identical. However, the stability and reversibility of the enzyme complex in the absence and presence of cofactor differs. 5-Azacytosine ODNs form complexes with C5 DNA methyltransferases that are irreversible when the 5-azacytosine ring is intact. ODNs containing 2-(1H)-pyrimidinone at the enzymatic target site are competitive inhibitors of both prokaryotic and mammalian DNA C5 methyltransferases. We determined that the ternary complexes between the enzymes, 2-(1H)-pyrimidinone inhibitor, and the cofactor S-adenosyl methionine are maintained through the formation of a reversible covalent interaction. The differing stability and reversibility of the covalent bonds may partially account for the observed differences in cytotoxicity between zebularine and 5-azacytidine inhibitors. Published by Elsevier Inc. C1 [van Bemmel, Dana M.; Brank, Adam S.; Christman, Judith K.] Dept Biochem & Mol Biol, Omaha, NE 68198 USA. [Christman, Judith K.] Univ Nebraska, Med Ctr, Eppley Canc Ctr, Omaha, NE 68198 USA. [Eritja, Ramon] CSIC, Ctr Invest & Desarrolo, E-08034 Barcelona, Spain. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP van Bemmel, DM (reprint author), NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. EM vanbemmeld@mail.nih.gov RI eritja, ramon/B-5613-2008 OI eritja, ramon/0000-0001-5383-9334 FU NIH/NCI [R21CA91315]; Graduate College at UNMC; Intramural Research Program of the NIH; Center for Cancer Research; NCI Frederick FX Partial support for this work was provided by a grant from the NIH/NCI (R21CA91315) to j.K.C. and a fellowship from the Graduate College at UNMC to D.V.B. We are grateful to S. Kumar of New England Biolabs for providing us with Escherichia coli strain ER1727 containing the pUHE25Hhal plasmid. This research was also supported in part with funds from the Intramural Research Program of the NIH, Center for Cancer Research, NCI Frederick. We also thank Dr. Michael Boland for critical reading of the manuscript and careful comments. NR 54 TC 16 Z9 17 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 15 PY 2009 VL 78 IS 6 BP 633 EP 641 DI 10.1016/j.bcp.2009.05.017 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 482IB UT WOS:000268877400010 PM 19467223 ER PT J AU Hobbs, CA Deterding, LJ Perera, L Bobay, BG Thompson, RJ Darden, TA Cavanagh, J Tomer, KB AF Hobbs, Carey A. Deterding, Leesa J. Perera, Lalith Bobay, Benjamin G. Thompson, Richele J. Darden, Thomas A. Cavanagh, John Tomer, Kenneth B. TI Structural Characterization of the Conformational Change in Calbindin-D-28k upon Calcium Binding Using Differential Surface Modification Analyzed by Mass Spectrometry SO BIOCHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; SELECTIVE CHEMICAL-MODIFICATION; MYOINOSITOL MONOPHOSPHATASE; DIETHYL PYROCARBONATE; CA2+ BINDING; PROTEINS; D-28K; PEPTIDE; DIVERSITY; TOPOLOGY AB Calbindin-D-28k is a calcium binding protein with six EF hand domains. Calbindin-D-28k is unique in that it functions as both a calcium buffer and a sensor protein. It is found in many tissues, including brain, pancreas, kidney, and intestine, playing important roles in each. Calbindin-D-28k is known to bind four calcium ions and upon calcium binding undergoes a conformational change. The structure of apo calbindin-D-28k is in an ordered state, transitioning into a disordered state as calcium is bound. Once fully loaded with four calcium ions, it again takes on ail ordered state. The solution structure of disulfide-reduced holo-calbindin-D-28k has been determined by NMR, while the structure of apo calbindin-D-28k has yet to be determined. Differential surface modification of lysine and histidine residues analyzed by mass spectrometry has been used in this study to identify, for the first time, the specific regions of calbindin-D-28k undergoing conformational changes between the holo and apo states. Using differential Surface modification in combination with mass spectrometry, EF hands 1 and 4 as well as the linkers before EF hand 1 and the linkers between EF hands 4 and 5 and EF hands 5 and 6 were identified as regions of conformational change between apo and holo calbindin-D-28k. Under the experimental conditions employed, EF hands 2 and 6, which are known not to bind calcium, were unaffected in either form. EF hand 2 is highly accessible; however, EF hand 6 was determined not to be surface accessible in either form. Previous research has identified a disulfide bond between cysteines 94 and 100 in the holo state. Until now, it was unknown whether this bond also exists in the apo form. Our data confirm the presence of the disulfide bond between cysteines 94 and 100 in the holo form and indicate that there is predominantly no disulfide bond between these residues in the apoprotein. C1 [Hobbs, Carey A.; Bobay, Benjamin G.; Thompson, Richele J.; Cavanagh, John] N Carolina State Univ, Dept Mol & Struct Biochem, Raleigh, NC 27695 USA. [Deterding, Leesa J.; Perera, Lalith; Darden, Thomas A.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cavanagh, J (reprint author), N Carolina State Univ, Dept Mol & Struct Biochem, Raleigh, NC 27695 USA. EM john_cavanagh@ncsu.edu; tomer@niehs.nih.gov RI perera, Lalith/B-6879-2012; Tomer, Kenneth/E-8018-2013; OI perera, Lalith/0000-0003-0823-1631; Bobay, Benjamin/0000-0003-4775-3686 FU Kenan Institute for Engineering, Technology and Science; National Institute of Environmental Health Sciences/National Institutes of Health [ES050127, ES04301023] FX This research was supported by a grant from the Kenan Institute for Engineering, Technology and Science and by the Intramural Research Program of the National Institute of Environmental Health Sciences/National Institutes of Health (Projects ES050127 and ES04301023). NR 51 TC 5 Z9 5 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 15 PY 2009 VL 48 IS 36 BP 8603 EP 8614 DI 10.1021/bi900350q PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 490FV UT WOS:000269485500013 PM 19658395 ER PT J AU Stojmirovic, A Yu, YK AF Stojmirovic, Aleksandar Yu, Yi-Kuo TI ITM Probe: analyzing information flow in protein networks SO BIOINFORMATICS LA English DT Article ID GENE ONTOLOGY; SOFTWARE; BIOLOGY AB Founded upon diffusion with damping, ITM Probe is an application for modeling information flow in protein interaction networks without prior restriction to the sub-network of interest. Given a context consisting of desired origins and destinations of information, ITM Probe returns the set of most relevant proteins with weights and a graphical representation of the corresponding sub-network. With a click, the user may send the resulting protein list for enrichment analysis to facilitate hypothesis formation or confirmation. C1 [Stojmirovic, Aleksandar; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov OI Stojmirovic, Aleksandar/0000-0003-0957-6893 FU National Library of Medicine at National Institutes of Health FX Intramural Research Program of the National Library of Medicine at National Institutes of Health. NR 11 TC 11 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD SEP 15 PY 2009 VL 25 IS 18 BP 2447 EP 2449 DI 10.1093/bioinformatics/btp398 PG 3 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 491VC UT WOS:000269607700029 PM 19561335 ER PT J AU Sambataro, F Reed, JD Murty, VP Das, S Tan, HY Callicott, JH Weinberger, DR Mattay, VS AF Sambataro, Fabio Reed, Jeff D. Murty, Vishnu P. Das, Saumitra Tan, Hao Yang Callicott, Joseph H. Weinberger, Daniel R. Mattay, Venkata S. TI Catechol-O-Methyltransferase Valine(158)Methionine Polymorphism Modulates Brain Networks Underlying Working Memory Across Adulthood SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Aging; COMT; functional magnetic resonance imaging; independent component analysis; working memory ID AGE-RELATED-CHANGES; PREFRONTAL CORTEX; FUNCTIONAL MRI; DOPAMINE MODULATION; COMT GENOTYPE; SCHIZOPHRENIA; PERFORMANCE; COGNITION; SYNCHRONIZATION; MANIPULATION AB Background: Cognitive abilities decline with age with large individual variability. Genetic variations have been suggested to be an important source for some of this heterogeneity. Among these variations, those related to the dopaminergic system, particularly the valine (158)methionine polymorphism in catechol-O-methyltransferase (COMTval(158)met), have been implicated in modulating age-related changes in executive function. Methods: We studied 75 subjects (age 21-90 years) using functional neuroimaging while they performed a low-level working memory (WM) task to explore the effects of aging, of the COMTval(158)met polymorphism, and their interactions on the physiological patterns of interconnected cortical activity engaged by WM. Results: Our results show that val homozygotes and older subjects showed increased activity in dorsolateral prefrontal cortex (DLPFC) and decreased activity in ventrolateral prefrontal cortex (VLPFC) relative to met homozygotes and younger subjects, respectively. Interestingly, there were also independent effects of the COMTval(158)met polymorphism and age on the strength of connectivity between brain regions within the left prefrontal-parietal network; val homozygotes and older subjects showed greater connectivity between the DLPFC and other brain regions within the network and met homozygotes showed greater connectivity between the VLPFC and other brain regions within the network. Furthermore, the greater functional connectivity strength of DLPFC in val homozygotes relative to met homozygotes was much more pronounced in older adults Conclusions: Our findings suggest that the COMTval(158)met polymorphism modulates both the activity and functional connectivity of brain regions within WM networks and most importantly that this effect is exaggerated with increasing age, contributing to the variability in age-related decline in executive cognition. C1 [Sambataro, Fabio; Reed, Jeff D.; Murty, Vishnu P.; Das, Saumitra; Tan, Hao Yang; Callicott, Joseph H.; Weinberger, Daniel R.; Mattay, Venkata S.] NIMH, Genes Cognit & Psychosis Program, NIH, Clin Brain Disorders Branch,Intramural Res Progra, Bethesda, MD 20892 USA. RP Mattay, VS (reprint author), NIMH, Genes Cognit & Psychosis Program, NIH, Clin Brain Disorders Branch,Intramural Res Progra, Bldg 10,Room 3C-108, Bethesda, MD 20892 USA. EM vsm@mail.nih.gov RI Sambataro, Fabio/E-3426-2010; Callicott, Joseph/C-9102-2009 OI Sambataro, Fabio/0000-0003-2102-416X; Callicott, Joseph/0000-0003-1298-3334 FU National Institute of Mental Health FX This work was supported by the National Institute of Mental Health Intramural Research Program. The study protocol was approved by the Intramural Review Board of the National Institute of Mental Health and appropriate procedures were used concerning the human subjects involved. NR 53 TC 33 Z9 34 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2009 VL 66 IS 6 BP 540 EP 548 DI 10.1016/j.biopsych.2009.04.014 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 490OO UT WOS:000269510600003 PM 19539269 ER PT J AU Pettit, RK Pettit, GR Hamel, E Hogan, F Moser, BR Wolf, S Pon, S Chapuis, JC Schmidt, JM AF Pettit, Robin K. Pettit, George R. Hamel, Ernest Hogan, Fiona Moser, Bryan R. Wolf, Sonja Pon, Sandy Chapuis, Jean-Charles Schmidt, Jean M. TI E-Combretastatin and E-resveratrol structural modifications: Antimicrobial and cancer cell growth inhibitory beta-E-nitrostyrenes SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Resveratrol; Combretastatin; beta-E-Nitrostyrene; Anticancer agent ID ANTINEOPLASTIC AGENTS; A-4 PRODRUG; PHOSPHATE; TUBULIN; ANALOGS; DERIVATIVES; NITROALKENES; POTENT; A4; PROLIFERATION AB As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three beta-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The beta-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy- 4,5-methylenedioxy derivatives. Two of the beta-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC(50) of < 10 mu M for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity. (C) 2009 Published by Elsevier Ltd. C1 [Pettit, Robin K.; Pettit, George R.; Hogan, Fiona; Wolf, Sonja; Pon, Sandy; Chapuis, Jean-Charles; Schmidt, Jean M.] Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. [Pettit, Robin K.; Pettit, George R.; Hogan, Fiona; Wolf, Sonja; Pon, Sandy; Chapuis, Jean-Charles; Schmidt, Jean M.] Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. [Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Moser, Bryan R.] ARS, USDA, Natl Ctr Agr Utilizat Res, Peoria, IL 61604 USA. RP Pettit, RK (reprint author), Arizona State Univ, Canc Res Inst, POB 871604, Tempe, AZ 85287 USA. EM robin.pettit@asu.edu; bpettit@asu.edu FU National Cancer Institute DHHS [CA44344-8-12, RO1 CA9044101-03, 5RO1 CA 090441-07]; Arizona Disease Control Research Commission; Robert B. Dalton Endowment Fund; Caitlin Robb Foundation FX The very necessary financial support was provided by Outstanding Investigator Grant CA44344-8-12, Grant RO1 CA9044101-03, and Grant 5RO1 CA 090441-07 awarded to GRP by the Division of Cancer Treatment and Diagnosis, National Cancer Institute DHHS; the Arizona Disease Control Research Commission; the Robert B. Dalton Endowment Fund; and the Caitlin Robb Foundation. For other helpful assistance, we thank Drs. Michael D. Williams and Mathew D. Minardi, as well as Lee Williams. NR 77 TC 20 Z9 22 U1 2 U2 14 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 SEP 15 PY 2009 VL 17 IS 18 BP 6606 EP 6612 DI 10.1016/j.bmc.2009.07.076 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 489DK UT WOS:000269399700014 PM 19709889 ER EF