FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Donohue, JM Boudreau, R Strotmeyer, ES Newman, AB Simonsick, EM Shorr, RI Hanlon, JT AF Donohue, J. M. Boudreau, R. Strotmeyer, E. S. Newman, A. B. Simonsick, E. M. Shorr, R. I. Hanlon, J. T. TI IMPACT OF MEDICARE PART D ON RACIAL DIFFERENCES IN DIABETES TREATMENT AND OUTCOMES IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Boudreau, R.; Strotmeyer, E. S.; Newman, A. B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Hanlon, J. T.] Pittsburgh VA, Pittsburgh, PA USA. [Simonsick, E. M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Shorr, R. I.] VA GRECC, Gainesville, FL USA. RI Strotmeyer, Elsa/F-3015-2014 NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 180 EP 181 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001130 ER PT J AU Alley, D Metter, E Conwit, R Ferrucci, L AF Alley, D. Metter, E. Conwit, R. Ferrucci, L. TI PREDICTORS OF DISCORDANCE BETWEEN MASS AND STRENGTH: THE BALTIMORE LONGITUDINAL STUDY OF AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Alley, D.] Univ Maryland, Baltimore, MD 21201 USA. [Conwit, R.] Natl Inst Neurol Disorders & Stroke, Baltimore, MD USA. [Metter, E.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 202 EP 202 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001233 ER PT J AU Alley, D Yerges-Armstrong, L Shardell, M Metter, E Simonsick, EM Snitker, S Mitchell, B Ferrucci, L AF Alley, D. Yerges-Armstrong, L. Shardell, M. Metter, E. Simonsick, E. M. Snitker, S. Mitchell, B. Ferrucci, L. TI AGE-RELATED CHANGES IN BODY COMPOSITION: COMPARING AMISH AND NON-AMISH POPULATIONS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Alley, D.; Yerges-Armstrong, L.; Shardell, M.; Snitker, S.; Mitchell, B.] Univ Maryland, Baltimore, MD 21201 USA. [Metter, E.; Simonsick, E. M.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 202 EP 202 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001232 ER PT J AU Lin, FR Ferrucci, L Metter, E An, Y Zonderman, AB Resnick, S AF Lin, F. R. Ferrucci, L. Metter, E. An, Y. Zonderman, A. B. Resnick, S. TI HEARING LOSS AND COGNITION IN THE BALTIMORE LONGITUDINAL STUDY OF AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Ferrucci, L.; Metter, E.; An, Y.; Zonderman, A. B.; Resnick, S.] NIA, Baltimore, MD 21224 USA. [Lin, F. R.] Johns Hopkins, Otolaryngol Head & Neck Surg, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 231 EP 232 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001385 ER PT J AU Ferrucci, L Lhotsky, A Milaneschi, Y Knuth, N Simonsick, EM AF Ferrucci, L. Lhotsky, A. Milaneschi, Y. Knuth, N. Simonsick, E. M. TI LOW LEVELS OF PRO-INFLAMMATORY MARKERS CHARACTERIZE OLDER PERSON WITH HIGH PHYSICAL FUNCTION SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Ferrucci, L.; Lhotsky, A.; Milaneschi, Y.; Knuth, N.; Simonsick, E. M.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 232 EP 232 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001390 ER PT J AU Knuth, N Simonsick, EM Ferrucci, L AF Knuth, N. Simonsick, E. M. Ferrucci, L. TI HEALTH STATUS MODIFIES THE ASSOCIATION BETWEEN AGE AND RESTING METABOLIC RATE IN MEN BUT NOT WOMEN SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Knuth, N.; Simonsick, E. M.; Ferrucci, L.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 232 EP 232 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001389 ER PT J AU Milaneschi, Y Simonsick, EM Tanaka, T Knuth, N Tolea, M Ferrucci, L AF Milaneschi, Y. Simonsick, E. M. Tanaka, T. Knuth, N. Tolea, M. Ferrucci, L. TI ASSOCIATION BETWEEN AGE AND URINARY CORTISOL BY FUNCTIONAL HEALTH STATUS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Milaneschi, Y.; Simonsick, E. M.; Tanaka, T.; Knuth, N.; Tolea, M.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 233 EP 233 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001391 ER PT J AU Tanaka, T Milaneschi, Y Simonsick, EM Ferrucci, L AF Tanaka, T. Milaneschi, Y. Simonsick, E. M. Ferrucci, L. TI NUTRITIONAL AND FUNCTIONAL HEALTH: ASSESSMENT OF CIRCULATING BIOMARKERS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Tanaka, T.; Milaneschi, Y.; Simonsick, E. M.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 233 EP 233 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001393 ER PT J AU Tolea, M Simonsick, EM Milaneschi, Y Ferrucci, L AF Tolea, M. Simonsick, E. M. Milaneschi, Y. Ferrucci, L. TI DO PERSONALITY CHARACTERISTICS DISTINGUISH PERSONS WITH EXCEPTIONAL FUNCTIONAL HEALTH ACROSS THE LIFESPAN? SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Tolea, M.; Simonsick, E. M.; Milaneschi, Y.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 233 EP 233 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001392 ER PT J AU De Cabo, R Mattison, J Minor, R Pearson, K Mercken, E AF De Cabo, R. Mattison, J. Minor, R. Pearson, K. Mercken, E. TI CALORIE RESTRICTION AND CALORIE RESTRICTION MIMETICS, WHERE ARE WE NOW? SO GERONTOLOGIST LA English DT Meeting Abstract C1 [De Cabo, R.; Mattison, J.; Minor, R.; Pearson, K.; Mercken, E.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 242 EP 242 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001443 ER PT J AU Danhauer, SC Legault, C Costantino, JP Avis, NE Rapp, S Coker, LH Terracciano, A Shumaker, SA AF Danhauer, S. C. Legault, C. Costantino, J. P. Avis, N. E. Rapp, S. Coker, L. H. Terracciano, A. Shumaker, S. A. TI AFFECT, DEPRESSION, AND COGNITION IN COGNITION IN THE STUDY OF TAMOXIFEN AND RALOXIFENE (CO-STAR) SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Danhauer, S. C.; Legault, C.; Avis, N. E.; Rapp, S.; Coker, L. H.; Shumaker, S. A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Costantino, J. P.] Univ Pittsburgh, Pittsburgh, PA USA. [Terracciano, A.] NIA, Baltimore, MD 21224 USA. RI terracciano, antonio/B-1884-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 292 EP 292 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602001686 ER PT J AU Nicklett, EJ Semba, R Simonsick, EM Szanton, SL Bandeen-Roche, K Ferrucci, L Guralnik, J Fried, LP AF Nicklett, E. J. Semba, R. Simonsick, E. M. Szanton, S. L. Bandeen-Roche, K. Ferrucci, L. Guralnik, J. Fried, L. P. TI TITLE: DIET QUALITY AND SOCIAL SUPPORT: FACTORS ASSOCIATED WITH SERUM CAROTENOID CONCENTRATIONS AMONG OLDER DISABLED WOMEN (THE WOMEN'S HEALTH AND AGING STUDY) SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Nicklett, E. J.] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Nicklett, E. J.; Semba, R.; Szanton, S. L.; Bandeen-Roche, K.; Ferrucci, L.] Johns Hopkins Univ, Baltimore, MD USA. [Simonsick, E. M.; Ferrucci, L.; Guralnik, J.] NIA, Baltimore, MD 21224 USA. [Fried, L. P.] Columbia Univ, New York, NY USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 318 EP 318 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002082 ER PT J AU Bellizzi, K Breslau, E AF Bellizzi, K. Breslau, E. TI STILL SCREENING AFTER ALL THESE YEARS: PREVALENCE OF CANCER SCREENING IN OLDER RACIALLY DIVERSE ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Bellizzi, K.] UConn, HDFS, Storrs, CT USA. [Breslau, E.] NCI, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 340 EP 340 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002184 ER PT J AU Rowland, J AF Rowland, J. TI CANCER PATIENT-CAREGIVER DYADS AND QUALITY OF LIFE: MENTAL HEALTH GOING DOWN IN SMOKE? SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Rowland, J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 341 EP 341 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002187 ER PT J AU Gudlaugsson, JF Gudnason, V Aspelund, T Jonsson, PV Arngrimsson, SA Olafsdottir, AS Harris, TB Johannsson, E AF Gudlaugsson, J. F. Gudnason, V. Aspelund, T. Jonsson, P. V. Arngrimsson, S. A. Olafsdottir, A. S. Harris, T. B. Johannsson, E. TI LONG-TERM EFFECTS OF A 6-MONTH MULTIMODAL TRAINING INTERVENTION ON THE RETENTION OF PHYSICAL FITNESS IN OLDER INDIVIDUALS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Gudlaugsson, J. F.; Arngrimsson, S. A.; Olafsdottir, A. S.; Johannsson, E.] Univ Iceland, Ctr Res Sport & Hlth Sci, Reykjavik, 20892, Iceland. [Gudnason, V.; Aspelund, T.] Iceland Heart Assoc, Reykjavik, Iceland. [Gudnason, V.; Aspelund, T.; Jonsson, P. V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Jonsson, P. V.] Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD USA. RI Aspelund, Thor/C-5983-2008; Olafsdottir, Anna/A-8804-2013; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Olafsdottir, Anna/0000-0002-7258-1727; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 369 EP 370 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002339 ER PT J AU Resnick, HE Fielding, R Guralnik, J Spector, W Limcangco, R Parker, L Griswold, M Foster, GL AF Resnick, H. E. Fielding, R. Guralnik, J. Spector, W. Limcangco, R. Parker, L. Griswold, M. Foster, G. L. TI RESULTS OF THE STAYING HEALTHY THROUGH EDUCATION AND PREVENTION (STEP) STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Resnick, H. E.; Foster, G. L.] Amer Assoc Homes & Serv Aging, Washington, DC USA. [Fielding, R.] Tufts Univ, Boston, MA 02111 USA. [Spector, W.; Limcangco, R.] Agcy Healthcare Res & Qual, Rockville, MD USA. [Parker, L.] Evangel Lutheran Good Samaritan Soc, Sioux Falls, SD USA. [Guralnik, J.] NIA, Bethesda, MD 20892 USA. [Resnick, H. E.] Georgetown Univ, Washington, DC USA. [Griswold, M.] Univ Mississippi, Oxford, MS USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 369 EP 369 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002338 ER PT J AU Leishear, K Rosano, C Boudreau, R Newman, AB Studenski, S Ferrucci, L Harris, TB Strotmeyer, ES AF Leishear, K. Rosano, C. Boudreau, R. Newman, A. B. Studenski, S. Ferrucci, L. Harris, T. B. Strotmeyer, E. S. TI THE LONGITUDINAL RELATIONSHIP OF VITAMIN B12 AND INFORMATION PROCESSING SPEED SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Leishear, K.; Rosano, C.; Boudreau, R.; Newman, A. B.; Studenski, S.; Strotmeyer, E. S.] Univ Pittsburgh, Pittsburgh, PA USA. [Ferrucci, L.] NIA, Baltimore, MD 21224 USA. [Harris, T. B.] NIA, Bethesda, MD 20892 USA. RI Strotmeyer, Elsa/F-3015-2014 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 372 EP 372 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002353 ER PT J AU Evans, J AF Evans, J. TI GERIATRIC TRANSLATIONAL NEUROSCIENCE AND PSYCHOPHARMACOLOGIC INTERVENTION RESEARCH: PRIORITIES AND SCIENTIFIC OPPORTUNITIES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Evans, J.] NIMH, Geriatr Res Branch, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 394 EP 394 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002468 ER PT J AU Evans, J AF Evans, J. TI NIMH FUNDING PROGRAMS AND APPLICATION PROCESSES: AN OVERVIEW SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Evans, J.] NIMH, Geriatr Res Branch, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 394 EP 394 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002466 ER PT J AU Niederehe, G AF Niederehe, G. TI TRANSLATIONAL BEHAVIORAL SCIENCE AND PSYCHOSOCIAL INTERVENTION OPPORTUNITIES IN GERIATRIC MENTAL HEALTH RESEARCH SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Niederehe, G.] NIMH, Geriatr Res Branch, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 394 EP 394 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002467 ER PT J AU Niederehe, G AF Niederehe, G. TI THE NIH RESEARCH CONTEXT: RECENT DEVELOPMENTS PERTINENT TO GERIATRIC MENTAL HEALTH RESEARCH SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Niederehe, G.] NIMH, Geriatr Res Branch, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 394 EP 394 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002465 ER PT J AU Leach, C AF Leach, C. TI EXPLORING NEW CAREER POSSIBILITIES IN GOVERNMENT AND THE NON-PROFIT WORLD SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Leach, C.] NCI, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 406 EP 406 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002530 ER PT J AU Leach, C Aziz, N Alfano, CM Rowland, J Weaver, K Forsythe, L AF Leach, C. Aziz, N. Alfano, C. M. Rowland, J. Weaver, K. Forsythe, L. TI MEDICAL CONDITIONS BEFORE AND AFTER CANCER AMONG LONG-TERM CANCER SURVIVORS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Leach, C.; Alfano, C. M.; Rowland, J.; Forsythe, L.] NCI, Bethesda, MD 20892 USA. [Aziz, N.] NINR, Bethesda, MD 20892 USA. [Weaver, K.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 421 EP 421 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002608 ER PT J AU Karasik, D Hsu, Y Matteini, A Tanaka, T Kiel, DP Lunetta, K Murabito, JM AF Karasik, D. Hsu, Y. Matteini, A. Tanaka, T. Kiel, D. P. Lunetta, K. Murabito, J. M. TI FACING THE CHALLENGE: IS THE MULTIVARIATE ANALYSIS A SOLUTION? SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Karasik, D.; Hsu, Y.; Kiel, D. P.] Hebrew SeniorLife, Boston, MA USA. [Tanaka, T.] NIA, Bethesda, DC USA. [Matteini, A.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Lunetta, K.; Murabito, J. M.] Boston Univ, Boston, MA 02215 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 426 EP 426 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002631 ER PT J AU Matteini, A Walston, JD Tanaka, T Smith, A Karasik, D Kiel, DP Newman, AB AF Matteini, A. Walston, J. D. Tanaka, T. Smith, A. Karasik, D. Kiel, D. P. Newman, A. B. TI BEYOND LONGEVITY: PHENOTYPE HARMONIZATION ACROSS COHORTS STUDIES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Matteini, A.; Walston, J. D.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Tanaka, T.] NIA, Bethesda, MD 20892 USA. [Smith, A.] Univ Iceland, Kopavogur, Iceland. [Karasik, D.; Kiel, D. P.] Harvard Univ, Sch Med, Boston, MA USA. [Newman, A. B.] Univ Pittsburgh, Pittsburgh, PA USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 426 EP 426 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602002632 ER PT J AU Akhtar, W Guralnik, J Patel, K AF Akhtar, W. Guralnik, J. Patel, K. TI ASSOCIATION OF ESTIMATED GLOMERULAR FILTRATION RATE WITH COGNITIVE PERFORMANCE AND GAIT SPEED IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Akhtar, W.; Guralnik, J.; Patel, K.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Akhtar, W.] Univ Florida, Dept Epidemiol, Gainesville, FL USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 486 EP 486 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003189 ER PT J AU Melzer, D Harries, L Pilling, L Bandinelli, S Guralnik, JM Singleton, A Hernandez, D Ferrucci, L AF Melzer, D. Harries, L. Pilling, L. Bandinelli, S. Guralnik, J. M. Singleton, A. Hernandez, D. Ferrucci, L. TI CONFIRMATION OF MOUSE MODEL OF SARCOPENIA BY GENOME WIDE EXPRESSION STUDY IN HUMANS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Melzer, D.; Harries, L.; Pilling, L.] Univ Exeter, Exeter, Devon, England. [Guralnik, J. M.; Singleton, A.; Hernandez, D.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. [Bandinelli, S.] Azienda Sanit Firenze, Florence, Italy. RI Harries, Lorna/D-2241-2014 NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 506 EP 507 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003278 ER PT J AU Koster, A Caserotti, P Patel, K Van Domelen, DR Harris, T AF Koster, A. Caserotti, P. Patel, K. Van Domelen, D. R. Harris, T. TI ASSOCIATION OF SEDENTARY BEHAVIOR WITH MORTALITY INDEPENDENT OF PHYSICAL ACTIVITY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Koster, A.; Caserotti, P.; Patel, K.; Van Domelen, D. R.; Harris, T.] NIA, Bethesda, MD 20892 USA. [Koster, A.] Maastricht Univ, Maastricht, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 517 EP 517 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003330 ER PT J AU Deshpande, N Zang, F Metter, E Guralnik, JM Ferrucci, L AF Deshpande, N. Zang, F. Metter, E. Guralnik, J. M. Ferrucci, L. TI DETERMINANTS OF SIT TO STAND PERFORMANCE IN OLDER PERSONS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Deshpande, N.; Zang, F.] Queens Univ, Sch Rehabil Therapy, Kingston, ON, Canada. [Metter, E.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. [Guralnik, J. M.] NIA, Bethesda, MD 20892 USA. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 525 EP 525 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003368 ER PT J AU Caserotti, P Koster, A Van Domelen, DR Chen, K Brychta, RJ Arnardottir, NY Harris, TB AF Caserotti, P. Koster, A. Van Domelen, D. R. Chen, K. Brychta, R. J. Arnardottir, N. Y. Harris, T. B. TI ABSOLUTE VERSUS INDIVIDUAL CUT-POINTS FOR MODERATE-TO-VIGOROUS PHYSICAL ACTIVITY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Caserotti, P.; Koster, A.; Van Domelen, D. R.; Harris, T. B.] NIA, Bethesda, MD 20892 USA. [Koster, A.] Maastricht Univ, Maastricht, Netherlands. [Chen, K.; Brychta, R. J.] NIDDK, Bethesda, MD USA. [Arnardottir, N. Y.] Univ Iceland, Res Ctr Movement Sci, Reykjavik, Iceland. NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 560 EP 560 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003548 ER PT J AU Visser, M Koster, A AF Visser, M. Koster, A. TI SEDENTARY ACTIVITY IN OLDER PERSONS - COMPARING QUESTIONNAIRE AND ACCELEROMETRY DATA SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Visser, M.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Visser, M.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Koster, A.] NIA, Bethesda, MD 20892 USA. [Koster, A.] Maastricht Univ, Med Ctr, Maastricht, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 560 EP 560 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003549 ER PT J AU Glynn, NW Santanasto, AJ Mackey, DC Simonsick, EM Manini, T Goodpaster, B Newman, AB AF Glynn, N. W. Santanasto, A. J. Mackey, D. C. Simonsick, E. M. Manini, T. Goodpaster, B. Newman, A. B. TI IMPACT OF FATIGABILITY AND FUNCTION ON ACTIVITY PATTERNS OF OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Glynn, N. W.; Santanasto, A. J.; Goodpaster, B.; Newman, A. B.] Univ Pittsburgh, Pittsburgh, PA USA. [Mackey, D. C.] Calif Pacific Med Ctr, San Francisco, CA USA. [Simonsick, E. M.] NIA, Baltimore, MD 21224 USA. [Manini, T.] Univ Florida, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 561 EP 561 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003552 ER PT J AU Mackey, DC Manini, T Schoeller, D Koster, A Glynn, NW Satterfield, S Harris, T Cummings, SR AF Mackey, D. C. Manini, T. Schoeller, D. Koster, A. Glynn, N. W. Satterfield, S. Harris, T. Cummings, S. R. TI VALIDATION OF AN ARMBAND TO MEASURE DAILY ENERGY EXPENDITURE IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Mackey, D. C.; Cummings, S. R.] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, San Francisco, CA USA. [Manini, T.] Univ Florida, Gainesville, FL USA. [Schoeller, D.] Univ Wisconsin, Madison, WI USA. [Koster, A.; Harris, T.] NIA, Bethesda, MD 20892 USA. [Glynn, N. W.] Univ Pittsburgh, Pittsburgh, PA USA. [Satterfield, S.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 561 EP 561 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602003551 ER PT J AU Chang, M Snaedal, J Saczynski, J Aspelund, T Gudnason, V Harris, TB Launer, LJ Jonsson, PV AF Chang, M. Snaedal, J. Saczynski, J. Aspelund, T. Gudnason, V. Harris, T. B. Launer, L. J. Jonsson, P. V. TI THE JOINT EFFECT OF PHYSICAL ACTIVITY AND BODY MASS INDEX AT MID-LIFE ON COGNITIVE FUNCTION IN LATE LIFE: AGE GENE/ENVIRONMENT SUSCEPTIBILITY - REYKJAVIK STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Chang, M.; Snaedal, J.; Jonsson, P. V.] Landspitali Univ Hosp, Reykjavik, Iceland. [Saczynski, J.] Univ Massachusetts, Worcester, MA 01605 USA. [Aspelund, T.; Gudnason, V.; Jonsson, P. V.] Univ Iceland, Reykjavik, Iceland. [Aspelund, T.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, T. B.; Launer, L. J.] NIA, Bethesda, MD 20892 USA. RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 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 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 583 EP 583 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602004062 ER PT J AU Brinkley, TE Sutton-Tyrrell, K Kanaya, A Harrris, TB Kim, LJ Lakatta, EG Simonsick, EM Kritchevsky, SB AF Brinkley, T. E. Sutton-Tyrrell, K. Kanaya, A. Harrris, T. B. Kim, L. J. Lakatta, E. G. Simonsick, E. M. Kritchevsky, S. B. TI ADIPOSITY AND ISOLATED SYSTOLIC HYPERTENSION IN OLDER ADULTS: DIFFERENTIAL ASSOCIATIONS BY SEX AND TREATMENT STATUS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Brinkley, T. E.; Kritchevsky, S. B.] Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. [Sutton-Tyrrell, K.] Univ Pittsburgh, Pittsburgh, PA USA. [Kanaya, A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harrris, T. B.; Kim, L. J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Lakatta, E. G.; Simonsick, E. M.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 584 EP 584 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602004065 ER PT J AU Unverzagt, F Guey, LT Jones, RN King, J Wadley, VG Crowe, M Rebok, G Tennstedt, SL AF Unverzagt, F. Guey, L. T. Jones, R. N. King, J. Wadley, V. G. Crowe, M. Rebok, G. Tennstedt, S. L. TI ACTIVE COGNITIVE TRAINING AND RATES OF INCIDENT DEMENTIA SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Unverzagt, F.] Indiana Univ, Indianapolis, IN 46204 USA. [Guey, L. T.; Tennstedt, S. L.] New England Res Inst, Watertown, MA 02172 USA. [Jones, R. N.] Harvard Univ, Sch Med, Boston, MA USA. [King, J.] NIA, Bethesda, MD 20892 USA. [Wadley, V. G.; Crowe, M.] Univ Alabama Birmingham, Birmingham, AL USA. [Rebok, G.] Johns Hopkins, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 604 EP 605 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602004163 ER PT J AU Volpato, S Bianchi, L Maraldi, C Lauretani, F Lauretani, F Zuliani, G Guralnik, JM Ferrucci, L AF Volpato, S. Bianchi, L. Maraldi, C. Lauretani, F. Lauretani, F. Zuliani, G. Guralnik, J. M. Ferrucci, L. TI THE ROLE OF MUSCLE MASS AND MUSCLE QUALITY IN THE ASSOCIATION BETWEEN DIABETES AND GAIT SPEED SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Volpato, S.; Bianchi, L.; Zuliani, G.] Univ Ferrara, I-44100 Ferrara, Italy. [Maraldi, C.] Hosp Ferrara, Dept Internal Med, Ferrara, Italy. [Lauretani, F.] Univ Hosp Parma, Dept Geriatr Rehabil, Parma, Italy. [Lauretani, F.] Tuscany Hlth Reg Agcy, Florence, Italy. [Guralnik, J. M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Ferrucci, L.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 607 EP 608 PG 2 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602004178 ER PT J AU Kurland, B Johnson, LL Egleston, BL Diehr, P AF Kurland, B. Johnson, L. L. Egleston, B. L. Diehr, P. TI LONGITUDINAL DATA WITH FOLLOW-UP TRUNCATED BY DEATH: MATCHING ANALYSIS METHODS TO RESEARCH AIMS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Kurland, B.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Egleston, B. L.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Washinton, Seattle, WA USA. [Johnson, L. L.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2011 VL 51 SU 2 BP 611 EP 611 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 936PH UT WOS:000303602004192 ER PT J AU Romanova, LY Mushinski, JF AF Romanova, Larisa Y. Mushinski, J. Frederic TI Central role of paxillin phosphorylation in regulation of LFA-1 integrins activity and lymphocyte migration SO CELL ADHESION & MIGRATION LA English DT Review DE lymphocytes; paxillin; actin; Rac1; RhoA; LFA-1; PKC-delta ID PROTEIN-KINASE-C; TYROSINE PHOSPHATASE-PEST; ACTIN CYTOSKELETON; CELL-ADHESION; IN-VIVO; EPITHELIAL MORPHOGENESIS; PLASMA-MEMBRANE; PTP-PEST; ACTIVATION; BINDING AB Coordinated changes of actin cytoskeleton and cell adhesion accompany maturation of lymphoid cells, their migration through lymphoid organs and to sites of inflammation, as well as metastasis of transformed cells. Here we discuss the central role of the actin-regulating adaptor protein, paxillin, during lymphocyte transition from a polarized, motile cell phenotype with partially active LFA-1 integrins to a round and immobile one with fully active LFA-1. In Baf3 murine pro-B lymphocytes, the former phenotype is induced by IL-3 that stimulates a FAK-mediated phosphorylation of paxillin at tyrosines (Y) 31 and 118 and a consequent Rac1 activation. Rearrangements of actin cytoskeleton that lead to the cell's acquisition of a spherical shape and LFA-1 activation are achieved upon activation of PKC-delta that binds and directly phosphorylates paxillin at threonine ( T) 538 with consequent RhoA activation. This is accompanied by dephosphorylation of paxillin Y31/118 and by Rac1 inactivation. We propose a model of signaling cascades that reflects the interplay between the IL-3-and PKC-delta-mediated pathways. C1 [Romanova, Larisa Y.; Mushinski, J. Frederic] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Romanova, LY (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM romanovl@mail.nih.gov FU NIH; National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. NR 55 TC 6 Z9 7 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6918 J9 CELL ADHES MIGR JI Celll Adhes. Migr. PD NOV-DEC PY 2011 VL 5 IS 6 BP 457 EP 462 DI 10.4161/cam.5.6.18219 PG 6 WC Cell Biology SC Cell Biology GA 898CW UT WOS:000300714000001 PM 22274710 ER PT J AU Wentzensen, N AF Wentzensen, N. TI Molecular diagnosis of HPV infections SO PATHOLOGE LA German DT Article DE Human papilloma virus; Cervical cancer; Screening; Cytology; Validation ID HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; BIOMARKERS; NEOPLASIA; WOMEN; RISK; TRIAGE AB Carcinogenic human papillomaviruses (HPV) cause the majority of cervical cancers and other anogenital cancers. Large randomized trials have shown that HPV testing can be efficiently used for primary cervical cancer screening. Other applications include the triage of abnormal cytology results and the follow-up of women after treatment. Many assays have been developed to measure DNA, RNA and proteins of HPV and the various tests can have very different applications. It is important to rigorously validate HPV assays before they are implemented in screening or clinical care. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut BoulevardRockville, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov FU Intramural NIH HHS [ZIA CP010124-18] NR 26 TC 1 Z9 1 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0172-8113 J9 PATHOLOGE JI Pathologe PD NOV PY 2011 VL 32 IS 6 BP 461 EP 466 DI 10.1007/s00292-011-1475-6 PG 6 WC Pathology SC Pathology GA 893PU UT WOS:000300368700003 PM 21845360 ER PT J AU Clark, GM McShane, LM AF Clark, Gary M. McShane, Lisa M. TI Biostatistical Considerations in Development of Biomarker-Based Tests to Guide Treatment Decisions SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Assay qualification; Clinical trial design; Marker; Predictive marker; Prognostic marker ID CLINICAL-TRIAL DESIGN; FACTOR RECEPTOR EXPRESSION; I ONCOLOGY TRIALS; CELL LUNG-CANCER; PROGNOSTIC-FACTORS; TUMOR-MARKER; PHASE-II; ERLOTINIB; RECOMMENDATIONS; THERAPY AB Biomarkers require several levels of assessment, including assay method validation and assay qualification, before they can be used to guide treatment decisions for patients. They must also be evaluated in clinical trials to link them with biological processes and clinical endpoints to show that they are "fit for purpose." This article briefly summarizes techniques that can be used for assay method validation and qualification. It also describes several clinical trial designs that have been described in the literature for evaluating biomarkers for guiding therapy. The concept of a prognostic factor is introduced as a consideration that must be taken into account when selecting appropriate clinical trial designs to distinguish biomarkers that predict for favorable response to a new therapy from biomarkers that predict for favorable response independently of therapy. The main focus is on Phase III trials, including both adaptive and nonadaptive designs. C1 [Clark, Gary M.] Array BioPharma, Biostat & Data Management, Boulder, CO 80301 USA. [McShane, Lisa M.] NCI, Biometr Res Branch, DCTD, Bethesda, MD 20892 USA. RP Clark, GM (reprint author), Array BioPharma, Biostat & Data Management, Boulder, CO 80301 USA. EM Gary.Clark@arraybiopharma.com; lm5h@nih.gov NR 31 TC 6 Z9 6 U1 2 U2 11 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD NOV PY 2011 VL 3 IS 4 BP 549 EP 560 DI 10.1198/sbr.2011.09038 PG 12 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 893GP UT WOS:000300344600006 ER PT J AU Ward, MM AF Ward, Michael M. TI Concordance of sibling's recall of measures of childhood socioeconomic position SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Education; Occupational groups; Childhood socioeconomic position ID LIFE-COURSE APPROACH; HISTORICAL RECORDS; HEALTH; PREDICTORS; ADULTHOOD; ACCURACY; DISEASE AB Background: Studies of socioeconomic determinants of health often rely on recalled information on childhood socioeconomic position, despite limited evidence of the validity of this information. This study examined concordance between siblings of recalled measures of childhood socioeconomic position. Methods: This cross-sectional study examined reports by 1280 adult sibling pairs in the National Survey of Midlife Development in the United States of seven measures of childhood socioeconomic position: father's occupation (in 9 categories), father having a professional occupation, father being a supervisor at work, father's education level, mother's education level, receipt of welfare payments, and subjective appraisal of being better or worse off financially than others. Results: Concordance was high for father's professional occupation (0.97; 95% confidence interval (CI) 0.96, 0.98), father's occupation in 9 categories (0.76; 95% CI 0.73, 0.80), and receipt of welfare payments (0.95; 95% CI 0.93, 0.97). Concordance was lower for father's and mother's education level, and lowest for subjective appraisal of socioeconomic position (0.60; 95% CI 0.57, 0.64). Concordance of parental education was lower for sibling pairs with high school educations or less. Conclusion: Concordance of recalled measures of childhood socioeconomic position by siblings is generally but not uniformly high. C1 NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 21 TC 5 Z9 5 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD NOV 1 PY 2011 VL 11 AR 147 DI 10.1186/1471-2288-11-147 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 890SE UT WOS:000300164400001 PM 22044489 ER PT J AU Eswaramoorthy, P Erb, ML Gregory, JA Silverman, J Pogliano, K Pogliano, J Ramamurthi, KS AF Eswaramoorthy, Prahathees Erb, Marcella L. Gregory, James A. Silverman, Jared Pogliano, Kit Pogliano, Joe Ramamurthi, Kumaran S. TI Cellular Architecture Mediates DivIVA Ultrastructure and Regulates Min Activity in Bacillus subtilis SO MBIO LA English DT Article ID DIVISION INHIBITOR MINC; TO-POLE OSCILLATION; ESCHERICHIA-COLI; STRUCTURED-ILLUMINATION; ASSEMBLY DYNAMICS; BACTERIAL-CELL; FISSION YEAST; CHROMOSOME SEGREGATION; PROTEIN DIVIVA; FTSZ-RINGS AB The assembly of the cell division machinery at midcell is a critical step of cytokinesis. Many rod-shaped bacteria position septa using nucleoid occlusion, which prevents division over the chromosome, and the Min system, which prevents division near the poles. Here we examined the in vivo assembly of the Bacillus subtilis MinCD targeting proteins DivIVA, a peripheral membrane protein that preferentially localizes to negatively curved membranes and resembles eukaryotic tropomyosins, and MinJ, which recruits MinCD to DivIVA. We used structured illumination microscopy to demonstrate that both DivIVA and MinJ localize as double rings that flank the septum and first appear early in septal biosynthesis. The subsequent recruitment of MinCD to these double rings would separate the Min proteins from their target, FtsZ, spatially regulating Min activity and allowing continued cell division. Curvature-based localization would also provide temporal regulation, since DivIVA and the Min proteins would localize to midcell after the onset of division. We use time-lapse microscopy and fluorescence recovery after photobleaching to demonstrate that DivIVA rings are highly stable and are constructed from newly synthesized DivIVA molecules. After cell division, DivIVA rings appear to collapse into patches at the rounded cell poles of separated cells, with little or no incorporation of newly synthesized subunits. Thus, changes in cell architecture mediate both the initial recruitment of DivIVA to sites of cell division and the subsequent collapse of these rings into patches (or rings of smaller diameter), while curvature-based localization of DivIVA spatially and temporally regulates Min activity. IMPORTANCE The Min systems of Escherichia coli and Bacillus subtilis both inhibit FtsZ assembly, but one key difference between these two species is that whereas the E. coli Min proteins localize to the poles, the B. subtilis proteins localize to nascent division sites by interaction with DivIVA and MinJ. It is unclear how MinC activity at midcell is regulated to prevent it from interfering with FtsZ engaged in medial cell division. We used superresolution microscopy to demonstrate that DivIVA and MinJ, which localize MinCD, assemble double rings that flank active division sites and septa. This curvature-based localization mechanism holds MinCD away from the FtsZ ring at midcell, and we propose that this spatial organization is the primary mechanism by which MinC activity is regulated to allow division at midcell. Curvature-based localization also conveys temporal regulation, since it ensures that MinC localizes after the onset of division. C1 [Erb, Marcella L.; Gregory, James A.; Pogliano, Kit; Pogliano, Joe] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Eswaramoorthy, Prahathees; Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Silverman, Jared] Cubist Pharmaceut, Lexington, MA USA. RP Pogliano, K (reprint author), Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. EM kpogliano@ucsd.edu; jpogliano@ucsd.edu; ramamurthiks@mail.nih.gov RI Ramamurthi, Kumaran/P-3516-2015 FU NIH [R01GM073898, R01GM084334, R01GM57045]; NIH National Cancer Institute Center for Cancer Research; UCSD [P30 NS047101] FX This work was funded by NIH grants R01GM073898 (to J.P.), R01GM084334 (to J.P.), and R01GM57045 (to K.P.) and by the Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research (to K.S.R.). Support for the OMX microscope was provided by UCSD Neuroscience Core grant P30 NS047101. NR 57 TC 23 Z9 25 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2011 VL 2 IS 6 AR e00257-11 DI 10.1128/mBio.00257-11 PG 9 WC Microbiology SC Microbiology GA 888GV UT WOS:000299992700018 ER PT J AU Koli, P Sudan, S Fitzgerald, D Adhya, S Kar, S AF Koli, Preeti Sudan, Sudhanshu Fitzgerald, David Adhya, Sankar Kar, Sudeshna TI Conversion of Commensal Escherichia coli K-12 to an Invasive Form via Expression of a Mutant Histone-Like Protein (vol 2, e00182, 2011) SO MBIO LA English DT Correction C1 [Koli, Preeti] Inst Mol Med, New Delhi, India. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Koli, P (reprint author), Inst Mol Med, New Delhi, India. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2011 VL 2 IS 6 AR e00263-11 DI 10.1128/mBio.00263-11 PG 1 WC Microbiology SC Microbiology GA 888GV UT WOS:000299992700020 ER PT J AU Sugui, JA Losada, L Wang, W Varga, J Ngamskulrungroj, P Abu-Asab, M Chang, YC O'Gorman, CM Wickes, BL Nierman, WC Dyer, PS Kwon-Chung, KJ AF Sugui, Janyce A. Losada, Liliana Wang, Wei Varga, John Ngamskulrungroj, Popchai Abu-Asab, Mones Chang, Yun C. O'Gorman, Celine M. Wickes, Brian L. Nierman, William C. Dyer, Paul S. Kwon-Chung, Kyung J. TI Identification and Characterization of an Aspergillus fumigatus "Supermater" Pair SO MBIO LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; CONIDIAL MORPHOLOGY; NEOSARTORYA; VIRULENCE; NEOFORMANS; GENE; GLIP; ALB1 AB The mating efficiency of 50 Aspergillus fumigatus isolates from both clinical and environmental sources was analyzed. Forty isolates completed the sexual cycle in 4 weeks with variable levels of fertility designated high, medium, or low. Two opposite-mating-type strains exhibiting the highest fertility, AFB62 (MAT1-1), isolated from a case of invasive aspergillosis, and AFIR928 (MAT1-2), isolated from the environment, were chosen as the supermater pair. Single cleistothecia obtained from a cross of the two strains harbored a minimum of 1 x 10(4) ascospores. The viability of ascospores increased with the age of the fruiting body, 17% at 4 weeks and reaching 95% at 20 weeks. AFB62 and AFIR928 were equally virulent in two different murine models, despite differences in their sources. High recombination frequencies were observed when the closely linked genes alb1 (AFUA_2G17600) and abr2 (AFUA_2G17530) were used as genetic markers. Comparative genome hybridization analyses revealed that only 86 genes (ca. 0.86% of the genome) are significantly diverged between AFB62 and AFIR928. The high fertility in a relatively short period, combined with a high degree of virulence and a high recombination frequency, demonstrates that the mating pair AFB62 and AFIR928 provides an excellent tool for genetic studies of A. fumigatus. IMPORTANCE Aspergillus fumigatus is a heterothallic fungal pathogen that causes life-threatening infections in immunocompromised hosts. Although heterothallism facilitates genetic study via recombinational analysis, previous work showed that a 6-month incubation period is required for the completion of sexual reproduction in this species. Such a long incubation period impedes progress in genetic research. To discover a highly fertile (supermater) pair that can complete the sexual cycle in a considerably shorter period, we screened 50 strains collected from various geographic regions for mating efficiency. We identified a highly virulent pair of supermaters that can be an invaluable tool for genetic study. C1 [Sugui, Janyce A.; Ngamskulrungroj, Popchai; Chang, Yun C.; Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Losada, Liliana; Wang, Wei; Varga, John; Nierman, William C.] J Craig Venter Inst, Rockville, MD USA. [O'Gorman, Celine M.; Dyer, Paul S.] Univ Nottingham, Sch Biol, Nottingham NG7 2RD, England. [Wickes, Brian L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM June_kwon-chung@nih.gov RI Varga, John/I-8130-2012; O'Gorman, Celine/E-7732-2010; OI Varga, John/0000-0002-4868-1971; O'Gorman, Celine/0000-0001-9618-8981; Abu-Asab, Mones/0000-0002-4047-1232 FU National Institute of Allergy and Infectious Diseases, United States National Institutes of Health (Bethesda, MD); Wellcome Trust (London, United Kingdom) FX This study was supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, United States National Institutes of Health (Bethesda, MD), and the Wellcome Trust (London, United Kingdom). NR 31 TC 18 Z9 19 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2011 VL 2 IS 6 AR e00234-11 DI 10.1128/mBio.00234-11 PG 9 WC Microbiology SC Microbiology GA 888GV UT WOS:000299992700011 ER PT J AU Becker, KG Holmes, KA Zhang, YQ AF Becker, Kevin G. Holmes, Karen A. Zhang, Yongqing TI Aging-kb: A knowledge base for the study of the aging process SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Aging database; Knowledge base; Wiki ID ANNOTATION AB As the science of the aging process moves forward, a recurring challenge is the integration of multiple types of data and information with classical aging theory while disseminating that information to the scientific community. Here we present AGING-kb, a public knowledge base with the goal of conceptualizing and presenting fundamental aspects of the study of the aging process. Aging-kb has two interconnected parts, the Aging-kb tree and the Aging Wiki, The Aging-kb tree is a simple intuitive dynamic tree hierarchy of terms describing the field of aging from the general to the specific. This enables the user to see relationships between areas of aging research in a logical comparative fashion. The second part is a specialized Aging Wiki which allows expert definition, description, supporting information, and documentation of each aging keyword term found in the Aging-kb tree. The Aging Wiki allows community participation in describing and defining concepts and terms in the Wiki format. This aging knowledge base provides a simple intuitive interface to the complexities of aging. Published by Elsevier Ireland Ltd. C1 [Becker, Kevin G.] NIA, Res Resources Branch, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Becker, KG (reprint author), NIA, Res Resources Branch, Biomed Res Ctr, NIH, Suite 100,Room 4B122,251 Bayview Blvd, Baltimore, MD 21224 USA. EM beckerk@grc.nia.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU NIH, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. The authors would like to thank Brad Lhotsky, Fred Pruitt, and James Sullivan for database consultation. NR 9 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD NOV-DEC PY 2011 VL 132 IS 11-12 BP 592 EP 594 DI 10.1016/j.mad.2011.10.008 PG 3 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 888CG UT WOS:000299980800009 PM 22100666 ER PT J AU Cizza, G Requena, M Galli, G de Jonge, L AF Cizza, G. Requena, M. Galli, G. de Jonge, L. TI Chronic sleep deprivation and seasonality: Implications for the obesity epidemic SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Review DE Obesity; seasonality; sleep ID BROWN ADIPOSE-TISSUE; AFFECTIVE-DISORDER; METABOLIC-RATE; MAMMALIAN HIBERNATION; ENERGY-EXPENDITURE; PLASMA LEPTIN; YOUNG-ADULTS; WEIGHT-GAIN; HUMANS; CHILDREN AB Sleep duration has progressively fallen over the last 100 years while obesity has increased in the past 30 years. Several studies have reported an association between chronic sleep deprivation and long-term weight gain. Increased energy intake due to sleep loss has been listed as the main mechanism. The consequences of chronic sleep deprivation on energy expenditure have not been fully explored. Sleep, body weight, mood and behavior are subjected to circannual changes. However, in our modern environment seasonal changes in light and ambient temperature are attenuated. Seasonality, defined as cyclic changes in mood and behavior, is a stable personality trait with a strong genetic component. We hypothesize that the attenuation in seasonal changes in the environment may produce negative consequences, especially in individuals more predisposed to seasonality, such as women. Seasonal affective disorder, a condition more common in women and characterized by depressed mood, hypersomnia, weight gain, and carbohydrate craving during the winter, represents an extreme example of seasonality. One of the postulated functions of sleep is energy preservation. Hibernation, a phenomenon characterized by decreased energy expenditure and changes in the state of arousal, may offer useful insight into the mechanisms behind energy preservation during sleep. The goals of this article are to: a) consider the contribution of changes in energy expenditure to the weight gain due to sleep loss; b) review the phenomena of seasonality, hibernation, and their neuroendocrine mechanisms as they relate to sleep, energy expenditure, and body weight regulation. (J. Endocrinol. Invest. 34: 793-800, 2011) (C)2011, Editrice Kurtis C1 [Cizza, G.; Requena, M.; de Jonge, L.] NIDDK, Sect Neuroendocrinol Obes, Bethesda, MD USA. [Galli, G.] Univ Hosp Pisa, Dept Endocrinol & Kidney, Pisa, Italy. RP Cizza, G (reprint author), CRC, Bldg 10,Rm 6-3940, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov FU NIH; NIDDK FX This research was supported by the Intramural Program of the NIH, and the NIDDK. NR 71 TC 24 Z9 24 U1 1 U2 16 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 EI 1720-8386 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD NOV PY 2011 VL 34 IS 10 BP 793 EP 800 DI 10.3275/7808 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 882SF UT WOS:000299583500011 PM 21720205 ER PT J AU Garcia, SPQ Greco, KE Loescher, LJ AF Garcia, Sylvia P. Quevedo Greco, Karen E. Loescher, Lois J. TI Teaching Strategies to Incorporate Genomics Education into Academic Nursing Curricula SO JOURNAL OF NURSING EDUCATION LA English DT Article ID HEALTH-PROFESSIONALS; CORE COMPETENCES; GENETICS; INTEGRATION AB The translation of genomic science into health care has expanded our ability to understand the effects of genomics on human health and disease. As genomic advances continue, nurses are expected to have the knowledge and skills to translate genomic information into improved patient care. This integrative review describes strategies used to teach genomics in academic nursing programs and their facilitators and barriers to inclusion in nursing curricula. The Learning Engagement Model and the Diffusion of Innovations Theory guided the interpretation of findings. CINAHL, Medline, and Web of Science were resources for articles published during the past decade that included strategies for teaching genomics in academic nursing programs. Of 135 articles, 13 met criteria for review. Examples of effective genomics teaching strategies included clinical application through case studies, storytelling, online genomics resources, student self-assessment, guest lecturers, and a genetics focus group. Most strategies were not evaluated for effectiveness. C1 [Garcia, Sylvia P. Quevedo] Univ Arizona, El Rio Community Hlth Ctr, Tucson, AZ 85710 USA. [Loescher, Lois J.] Univ Arizona, Coll Nursing, Tucson, AZ 85710 USA. [Loescher, Lois J.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ 85710 USA. [Greco, Karen E.] NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. RP Garcia, SPQ (reprint author), Univ Arizona, El Rio Community Hlth Ctr, 6456 E Calle Luna, Tucson, AZ 85710 USA. EM spquevedo@netzero.com NR 33 TC 5 Z9 5 U1 2 U2 20 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0148-4834 EI 1938-2421 J9 J NURS EDUC JI J. Nurs. Educ. PD NOV PY 2011 VL 50 IS 11 BP 612 EP U85 DI 10.3928/01484834-20110715-04 PG 14 WC Nursing SC Nursing GA 884VP UT WOS:000299737200003 ER PT J AU Lionakis, MS AF Lionakis, Michail S. TI Drosophila and Galleria insect model hosts New tools for the study of fungal virulence, pharmacology and immunology SO VIRULENCE LA English DT Review DE Drosophila; Galleria; insects; fungi; pathogenesis; host defense ID INNATE IMMUNE-RESPONSE; TOLL-DEFICIENT DROSOPHILA; ANTIFUNGAL DRUG EFFICACY; CANDIDA-ALBICANS; ASPERGILLUS-FUMIGATUS; CRYPTOCOCCUS-NEOFORMANS; MELLONELLA LARVAE; CAENORHABDITIS-ELEGANS; ANTIMICROBIAL PEPTIDES; HISTOPLASMA-CAPSULATUM AB Over recent years we have witnessed the emergence of several non-vertebrate mini-hosts as alternative pathosystems for the study of fungal disease. These heterologous organisms have unique advantages, as they are economical, ethically expedient and facile to use. Hence, they are amenable to high-throughput screening studies of fungal genomes for identification of novel virulence genes and of chemical libraries for discovery of new antifungal compounds. In addition, because they have evolutionarily conserved immunity they offer the opportunity to better understand innate immune responses against medically important fungi. In this review, we discuss how the insects Drosophila melanogaster and Galleria mellonella can be employed for the study of various facets of host-fungal interactions as complementary hosts to conventional vertebrate animal models. C1 NIAID, Clin Mycol Unit, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Clin Mycol Unit, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov NR 87 TC 41 Z9 41 U1 1 U2 20 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD NOV-DEC PY 2011 VL 2 IS 6 BP 521 EP 527 DI 10.4161/viru.2.6.18520 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 878MP UT WOS:000299261500006 PM 22186764 ER PT J AU Malachowa, N DeLeo, FR AF Malachowa, Natalia DeLeo, Frank R. TI Staphylococcus aureus survival in human blood SO VIRULENCE LA English DT Editorial Material DE Staphylococcus aureus; MRSA; blood transcriptome; gamma-hemolysin; leukotoxin; neutrophil C1 [Malachowa, Natalia; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 0 TC 12 Z9 12 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD NOV-DEC PY 2011 VL 2 IS 6 BP 567 EP 569 DI 10.4161/viru.2.6.17732 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 878MP UT WOS:000299261500014 PM 21971187 ER PT J AU Brownell, I Ramirez-Valle, F Sanchez, M Prystowsky, S AF Brownell, Isaac Ramirez-Valle, Francisco Sanchez, Miguel Prystowsky, Stephen TI Evidence for Mycobacteria in Sarcoidosis SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Review DE sarcoidosis; mycobacteria; granulomas; microorganisms; peptides; immune response ID POLYMERASE-CHAIN-REACTION; ACTIVE PULMONARY SARCOIDOSIS; CHRONIC BERYLLIUM DISEASE; BLOOD MONONUCLEAR-CELLS; TH-1 IMMUNE-RESPONSES; WALL-DEFICIENT FORMS; HEAT-SHOCK PROTEINS; ACID-FAST BACTERIA; ISLE-OF-MAN; SYSTEMIC SARCOIDOSIS AB Despite its recognition as a distinct granulomatous disease for over a century, the etiology of sarcoidosis remains to be defined. Since the early 1900s, infectious agents have been suspected in causing sarcoidosis. For much of this time, mycobacteria were considered a likely culprit, yet until recently, the supporting evidence has been tenuous at best. In this review, we evaluate the reported association between mycobacteria and sarcoidosis. Historically, mycobacterial infection has been investigated using histologic stains, cultures of lesional tissue or blood, and identification of bacterial nucleic acids or bacterial antigens. More recently, advances in biochemical, molecular, and immunological methods have produced a more rigorous analysis of the antigenic drivers of sarcoidosis. The result of these efforts indicates that mycobacterial products likely play a role in at least a subset of sarcoidosis cases. This information, coupled with a better understanding of genetic susceptibility to this complex disease, has therapeutic implications. C1 [Sanchez, Miguel; Prystowsky, Stephen] NYU, Sch Med, Dept Dermatol, New York, NY 10012 USA. [Brownell, Isaac] NCI, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Ramirez-Valle, Francisco] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. RP Prystowsky, S (reprint author), NYU, Sch Med, Dept Dermatol, New York, NY 10012 USA. EM Steveprystowmd@aol.com NR 105 TC 27 Z9 28 U1 0 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD NOV PY 2011 VL 45 IS 5 BP 899 EP 905 DI 10.1165/rcmb.2010-0433TR PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 884CF UT WOS:000299681800001 PM 21659662 ER PT J AU Martinez, JG Carroll, RJ Muller, S Sampson, JN Chatterjee, N AF Martinez, Josue G. Carroll, Raymond J. Mueller, Samuel Sampson, Joshua N. Chatterjee, Nilanjan TI Empirical Performance of Cross-Validation With Oracle Methods in a Genomics Context SO AMERICAN STATISTICIAN LA English DT Article DE Adaptive Lasso; Lasso; Model selection; Oracle estimation ID NONCONCAVE PENALIZED LIKELIHOOD; SELECTION; LASSO AB When employing model selection methods with oracle properties such as the smoothly clipped absolute deviation (SCA.D) and the Adaptive Lasso, it is typical to estimate the smoothing parameter by m-fold cross-validation, for example, m = 10. In problems where the true regression function is sparse and the signals large, such cross-validation typically works well. However, in regression modeling of genomic studies involving Single Nucleotide Polymorphisms (SNP), the true regression functions, while thought to be sparse, do not have large signals. We demonstrate empirically that in such problems, the number of selected variables using SCAD and the Adaptive Lasso, with 10-fold cross-validation, is a random variable that has considerable and surprising variation. Similar remarks apply to non-oracle methods such as the Lasso. Our study strongly questions the suitability of performing only a single run of m-fold crossvalidation with any oracle method, and not just the SCAD and Adaptive Lasso. C1 [Martinez, Josue G.] Texas A&M Hlth Sci Ctr, Dept Epidemiol & Biostat, Sch Rural Publ Hlth, College Stn, TX 77843 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Mueller, Samuel] Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. [Sampson, Joshua N.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM carroll@stat.tamu.edu; samuel.mueller@sydney.edu.au; Joshua.Sampson@nih.gov; chattern@mail.nih.gov RI Mueller, Samuel/D-4850-2009 OI Mueller, Samuel/0000-0002-3087-8127 FU National Cancer Institute [CA90301, R37-CA057030]; ARC [DP11010199]; National Heart Lung and Blood Institute (NHLBI) FX Josue G. Martinez was formerly at the Department of Epidemiology & Biostatistics, School of Rural. Public Health, Texas A&M Health Science Center, 1266 TAMU, College Station, TX 77843-1266. Raymond J. Carroll, Department of Statistics, Texas A&M University, 3143 TAMU, College Station, TX 77843-3143 (E-mail: carroll@stat.tamu.edu). Samuel Muller, School of Mathematics and Statistics, University of Sydney, NSW 2006 Australia (E-mail: samuel.mueller@sydney.edu.au). Joshua N. Sampson and Nilanjan Chatterjee, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS 8038 Rockville, MD 20852 (Email: Joshua.Sampson@nih.gov and chanern@mail.nih.gov). Martinez was supported by a Postdoctoral Training grant from the National Cancer Institute (CA90301). Carroll's research was supported by a grant from the National Cancer Institute (R37-CA057030). Muller's research was supported in part by ARC grant DP11010199. Chatterjee's research was supported by a Gene-Environment Initiative (GEI) grant from the National Heart Lung and Blood Institute (NHLBI) and by the Intramural research program of the National Cancer Institute. NR 9 TC 10 Z9 10 U1 0 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD NOV PY 2011 VL 65 IS 4 BP 223 EP 228 DI 10.1198/tas.2011.11052 PG 6 WC Statistics & Probability SC Mathematics GA 881OO UT WOS:000299496200003 PM 22347720 ER PT J AU Chan, JL Lutz, K Cochran, E Huang, WY Peters, Y Weyer, C Gorden, P AF Chan, Jean L. Lutz, Karen Cochran, Elaine Huang, Wenying Peters, Yvette Weyer, Christian Gorden, Phillip TI CLINICAL EFFECTS OF LONG-TERM METRELEPTIN TREATMENT IN PATIENTS WITH LIPODYSTROPHY SO ENDOCRINE PRACTICE LA English DT Article ID REVERSES INSULIN-RESISTANCE; LEPTIN-REPLACEMENT THERAPY; CONGENITAL LIPODYSTROPHY; EFFICACY AB Objective: To evaluate the long-term clinical effect of treatment with metreleptin (an analogue of human leptin) on glycemic and lipid abnormalities and markers of hepatic steatosis in patients with inherited or acquired lipodystrophy. Methods: Fifty-five patients (36 with generalized lipodystrophy and 19 with partial lipodystrophy) with at least 1 of 3 metabolic abnormalities (diabetes mellitus, fasting triglyceride level >= 200 mg/dL, and insulin resistance) and low leptin levels received subcutaneous injections of metreleptin once or twice daily in an ongoing clinical trial at the National Institutes of Health. Results: At baseline, hemoglobin A(1c) -8.5% +/- 2.1% (mean +/- standard deviation [SD])-and triglycerides-479 +/- 80 mg/dL (geometric mean +/- standard error [SE])-were substantially elevated. Robust and sustained reductions in both variables were evident for the observed patient population during a 3-year metreleptin treatment period (-2.1% +/- 0.5% [mean +/- SE] and -35.4% +/- 13.7% [mean +/- SE], respectively). Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at baseline (100 +/- 120 U/L and 71 +/- 77 U/L [mean +/- SD], respectively) and decreased by -45 +/- 19 U/L and -33 +/- 14 U/L (mean +/- SE), respectively, during the 3-year metreleptin treatment period. Improvements in hemoglobin A(1c), triglycerides, ALT, and AST were more pronounced in the subsets of patients having elevated levels at baseline. The most notable adverse events observed in this patient population were likely attributable to underlying metabolic abnormalities or comorbidities. Conclusion: Metreleptin treatment substantially reduced glycemic variables, triglycerides, and liver enzymes (ALT and AST) and demonstrated durability of response throughout a 3-year treatment period. These results support metreleptin as a potential treatment for certain metabolic disorders (for example, diabetes mellitus and hypertriglyceridemia) associated with lipodystrophy. (Endocr Pract. 2011;17:922-932) C1 [Chan, Jean L.; Lutz, Karen; Huang, Wenying; Peters, Yvette; Weyer, Christian] Amylin Pharmaceut Inc, San Diego, CA 92121 USA. [Cochran, Elaine; Gorden, Phillip] NIDDK, Diabet Endocrine & Obes Branch, Bethesda, MD USA. RP Chan, JL (reprint author), Amylin Pharmaceut Inc, 9360 Towne Ctr Dr, San Diego, CA 92121 USA. EM Jean.Chan@amylin.com FU Cooperative Research and Development Agreement FX All patient studies and data acquisition described in this report were conducted at the Clinical Center of the NIH (clinical trial registration number: NCT00025883). Thus, all the data presented were derived from the NIH study, and subsets of the data have been previously reported. The manuscript was conceptualized and written by representatives from Amylin Pharmaceuticals, Inc. (Drs. Jean L. Chan, Karen Lutz, Wenying Huang, Yvette Peters, and Christian Weyer) and the NIH (Elaine Cochran and Dr. Phillip Gorden), and the work was performed under the auspices of a Cooperative Research and Development Agreement. All the Amylin authors (Drs. Jean L. Chan, Karen Lutz, Wenying Huang, Yvette Peters, and Christian Weyer) are employees and stockholders of Amylin Pharmaceuticals, Inc. NR 19 TC 49 Z9 51 U1 0 U2 3 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X J9 ENDOCR PRACT JI Endocr. Pract. PD NOV-DEC PY 2011 VL 17 IS 6 BP 922 EP 932 DI 10.4158/EP11229.OR PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 876YQ UT WOS:000299144100011 PM 22068254 ER PT J AU Briassoulis, G Damjanovic, S Xekouki, P Lefebvre, H Stratakis, CA AF Briassoulis, George Damjanovic, Svetozar Xekouki, Paraskevi Lefebvre, Herve Stratakis, Constantine A. TI THE GLUCOCORTICOID RECEPTOR AND ITS EXPRESSION IN THE ANTERIOR PITUITARY AND THE ADRENAL CORTEX: A SOURCE OF VARIATION IN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTION; IMPLICATIONS FOR PITUITARY AND ADRENAL TUMORS SO ENDOCRINE PRACTICE LA English DT Review ID NODULAR ADRENOCORTICAL-DISEASE; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2; CORTICOTROPIN-RELEASING HORMONE; DEXAMETHASONE-SUPPRESSION TEST; SUBUNIT TYPE 1A; CUSHINGS-SYNDROME; CARNEY COMPLEX; REGULATORY SUBUNIT; IN-VITRO; MOLECULAR CHARACTERIZATION AB Objective: To review the expression of the glucocorticoid receptor (OR) in anterior pituitary and adrenocortical cells and tumors derived from these tissues as well as factors that may influence its expression. Methods: We present an overview of the relevant literature, with a focus on data generated from our studies. Results: The expression of the GR is an essential element of the negative feedback that closes the loop formed by corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol in the context of the hypothalamic-pituitary-adrenal (HPA) axis. Although the GR expression in anterior pituitary cells-and in particular the corticotrophs-was first demonstrated several years ago, it was not known until relatively recently where, by what cells, and in what form the OR is expressed in the adrenal cortex. The variability in the expression of the GR in pituitary and adrenocortical cells may underlie the substantial differences in HPA axis function across individuals, especially when testing for tumors associated with hypercortisolemia. This expression is influenced by a multitude of tissue-specific factors, which may explain why it is so difficult to interpret (or reproduce) studies that are based on OR functional polymorphisms on different cohorts of patients or even different sets of laboratory animals. Conclusion: This review highlights the variability in expression and function of the OR in pituitary and adrenocortical cells as one of the reasons for the appreciable differences in HPA axis function across individuals. Particular attention was paid to interactions that may affect the interpretation of diagnostic testing of the HPA axis in patients with pituitary adenomas (Cushing disease) or adrenocortical tumors (Cushing syndrome). (Endocr Pract. 2011;17:941-948) C1 [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. [Briassoulis, George; Xekouki, Paraskevi; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [Lefebvre, Herve] Univ Hosp, Inst Biomed Res & Innovat, INSERM U982, Dept Endocrinol Diabet & Metab Dis, Rouen, France. [Damjanovic, Svetozar] Univ Belgrade, Inst Endocrinol Diabet & Metab Dis, Sch Med, Belgrade, Serbia. [Briassoulis, George] Univ Hosp, Pediat Intens Care Unit, Iraklion, Crete, Greece. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; Department of Pediatrics, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA, and, in part, by the Department of Pediatrics, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece. NR 78 TC 14 Z9 14 U1 0 U2 5 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD NOV-DEC PY 2011 VL 17 IS 6 BP 941 EP 948 DI 10.4158/EP11061.RA PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 876YQ UT WOS:000299144100013 PM 21742609 ER PT J AU Nair, N Kourbatova, E Poole, K Huckabee, CM Murray, P Huskins, WC Blumberg, HM AF Nair, Nisha Kourbatova, Ekaterina Poole, Katharine Huckabee, Charmaine M. Murray, Patrick Huskins, W. Charles Blumberg, Henry M. TI Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus (MRSA) among Patients Admitted to Adult Intensive Care Units: The STAR*ICU Trial SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID BLOOD-STREAM INFECTIONS; EMERGING THREAT; USA-300 CLONE; EMERGENCE; SURVEILLANCE; BACTEREMIA; TRANSMISSION; MORTALITY; OUTCOMES; USA300 AB BACKGROUND. The multicenter, cluster-randomized Strategies to Reduce Transmission of Antimicrobial Resistant Bacteria in Intensive Care Units (STAR(star)ICU) trial was performed in 18 U. S. adult intensive care units (ICUs). It evaluated the effectiveness of infection control strategies to reduce the transmission of methicillin-resistant Staphylococcus aureus (MRSA) colonization and/or infection. Our study objective was to examine the molecular epidemiology of MRSA and assess the prevalence and risk factors for community acquired (CA)-MRSA genotype nasal carriage at the time of ICU admission. METHODS. Selected MRSA isolates were subjected to molecular typing using pulsed-field gel electrophoresis. RESULTS. Of 5,512 ICU patient admissions in the STAR(star)ICU trial during the intervention period, 626 (11%) had a nares sample culture result that was positive for MRSA. A total of 210 (34%) of 626 available isolates were selected for molecular typing by weighted random sampling. Of 210 patients, 123 (59%) were male; mean age was 63 years. Molecular typing revealed that 147 isolates (70%) were the USA100 clone, 26 (12%) were USA300, 12 (6%) were USA500, 8 (4%) were USA800, and 17 (8%) were other MRSA genotypes. In a multivariate analysis, patients who were colonized with a CA-MRSA genotype (USA300, USA400, or USA1000) were less likely to have been hospitalized during the previous 12 months (PR [prevalence ratio], 0.39 [95% confidence interval (CI), 0.21-0.73]) and were less likely to be older (PR, 0.97 [95% CI, 0.95-0.98] per year) compared with patients who were colonized with a healthcare-associated (HA)-MRSA genotype. CONCLUSION. CA-MRSA genotypes have emerged as a cause of MRSA nares colonization among patients admitted to adult ICUs in the United States. During the study period (2006), the predominant site of CA-MRSA genotype acquisition appeared to be in the community. Infect Control Hosp Epidemiol 2011; 32(11): 1057-1063 C1 [Nair, Nisha; Kourbatova, Ekaterina; Blumberg, Henry M.] Emory Univ, Sch Med, Div Infect Dis, Dept Med, Atlanta, GA 30303 USA. [Blumberg, Henry M.] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30303 USA. [Poole, Katharine; Huckabee, Charmaine M.] Rho Fed Syst Div, Chapel Hill, NC USA. [Murray, Patrick] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Huskins, W. Charles] Mayo Clin, Coll Med, Rochester, MN USA. [Blumberg, Henry M.] Grady Mem Hosp, Dept Epidemiol, Atlanta, GA USA. RP Blumberg, HM (reprint author), Emory Univ, Sch Med, Div Infect Dis, Dept Med, 49 Jesse Hill Jr Dr, Atlanta, GA 30303 USA. EM henry.m.blumberg@emory.edu OI Huskins, W. Charles/0000-0002-9989-175X FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID [N01 AI-15440, N01 AI-15441]; NIAID Bacterial and Mycoses Study Group; NIH/National Center for Research Resources [UL1 RR025008, M01-RR-00585, UL1 RR024150]; Merck; Elan Pharmaceuticals; Roche Diagnostics; Kimberly Clark FX Financial support. This study was supported in part by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID; contracts N01 AI-15440 and N01 AI-15441), including the NIAID Bacterial and Mycoses Study Group and the NIH/National Center for Research Resources (UL1 RR025008 [Atlanta Clinical and Translational Science Institute], M01-RR-00585, and UL1 RR024150 [Mayo Clinic Center for Translational Science Activities]), and by Merck, Elan Pharmaceuticals, Roche Diagnostics, and Kimberly Clark. NR 33 TC 16 Z9 16 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD NOV PY 2011 VL 32 IS 11 BP 1057 EP 1063 DI 10.1086/662178 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 876CB UT WOS:000299083500001 PM 22011531 ER PT J AU Kilpelainen, TO Qi, L Brage, S Sharp, SJ Sonestedt, E Demerath, E Ahmad, T Mora, S Kaakinen, M Sandholt, CH Holzapfel, C Autenrieth, CS Hypponen, E Cauchi, S He, MA Kutalik, Z Kumari, M Stancakova, A Meidtner, K Balkau, B Tan, JT Mangino, M Timpson, NJ Song, YQ Zillikens, MC Jablonski, KA Garcia, ME Johansson, S Bragg-Gresham, JL Wu, Y van Vliet-Ostaptchouk, JV Onland-Moret, NC Zimmermann, E Rivera, NV Tanaka, T Stringham, HM Silbernagel, G Kanoni, S Feitosa, MF Snitker, S Ruiz, JR Metter, J Larrad, MTM Atalay, M Hakanen, M Amin, N Cavalcanti-Proenca, C Grontved, A Hallmans, G Jansson, JO Kuusisto, J Kahonen, M Lutsey, PL Nolan, JJ Palla, L Pedersen, O Perusse, L Renstrom, F Scott, RA Shungin, D Sovio, U Tammelin, TH Ronnemaa, T Lakka, TA Uusitupa, M Rios, MS Ferrucci, L Bouchard, C Meirhaeghe, A Fu, M Walker, M Borecki, IB Dedoussis, GV Fritsche, A Ohlsson, C Boehnke, M Bandinelli, S van Duijn, CM Ebrahim, S Lawlor, DA Gudnason, V Harris, TB Sorensen, TIA Mohlke, KL Hofman, A Uitterlinden, AG Tuomilehto, J Lehtimaki, T Raitakari, O Isomaa, B Njolstad, PR Florez, JC Liu, SM Ness, A Spector, TD Tai, ES Froguel, P Boeing, H Laakso, M Marmot, M Bergmann, S Power, C Khaw, KT Chasman, D Ridker, P Hansen, T Monda, KL Illig, T Jarvelin, MR Wareham, NJ Hu, FB Groop, LC Orho-Melander, M Ekelund, U Franks, PW Loos, RJF AF Kilpelaeinen, Tuomas O. Qi, Lu Brage, Soren Sharp, Stephen J. Sonestedt, Emily Demerath, Ellen Ahmad, Tariq Mora, Samia Kaakinen, Marika Sandholt, Camilla Helene Holzapfel, Christina Autenrieth, Christine S. Hyppoenen, Elina Cauchi, Stephane He, Meian Kutalik, Zoltan Kumari, Meena Stancakova, Alena Meidtner, Karina Balkau, Beverley Tan, Jonathan T. Mangino, Massimo Timpson, Nicholas J. Song, Yiqing Zillikens, M. Carola Jablonski, Kathleen A. Garcia, Melissa E. Johansson, Stefan Bragg-Gresham, Jennifer L. Wu, Ying van Vliet-Ostaptchouk, Jana V. Onland-Moret, N. Charlotte Zimmermann, Esther Rivera, Natalia V. Tanaka, Toshiko Stringham, Heather M. Silbernagel, Guenther Kanoni, Stavroula Feitosa, Mary F. Snitker, Soren Ruiz, Jonatan R. Metter, Jeffery Martinez Larrad, Maria Teresa Atalay, Mustafa Hakanen, Maarit Amin, Najaf Cavalcanti-Proenca, Christine Grontved, Anders Hallmans, Goran Jansson, John-Olov Kuusisto, Johanna Kahonen, Mika Lutsey, Pamela L. Nolan, John J. Palla, Luigi Pedersen, Oluf Perusse, Louis Renstrom, Frida Scott, Robert A. Shungin, Dmitry Sovio, Ulla Tammelin, Tuija H. Ronnemaa, Tapani Lakka, Timo A. Uusitupa, Matti Serrano Rios, Manuel Ferrucci, Luigi Bouchard, Claude Meirhaeghe, Aline Fu, Mao Walker, Mark Borecki, Ingrid B. Dedoussis, George V. Fritsche, Andreas Ohlsson, Claes Boehnke, Michael Bandinelli, Stefania van Duijn, Cornelia M. Ebrahim, Shah Lawlor, Debbie A. Gudnason, Vilmundur Harris, Tamara B. Sorensen, Thorkild I. A. Mohlke, Karen L. Hofman, Albert Uitterlinden, Andre G. Tuomilehto, Jaakko Lehtimaki, Terho Raitakari, Olli Isomaa, Bo Njolstad, Pal R. Florez, Jose C. Liu, Simin Ness, Andy Spector, Timothy D. Tai, E. Shyong Froguel, Philippe Boeing, Heiner Laakso, Markku Marmot, Michael Bergmann, Sven Power, Chris Khaw, Kay-Tee Chasman, Daniel Ridker, Paul Hansen, Torben Monda, Keri L. Illig, Thomas Jarvelin, Marjo-Riitta Wareham, Nicholas J. Hu, Frank B. Groop, Leif C. Orho-Melander, Marju Ekelund, Ulf Franks, Paul W. Loos, Ruth J. F. TI Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children SO PLOS MEDICINE LA English DT Article ID BODY-MASS INDEX; UNITED-STATES; ENVIRONMENT INTERACTION; RS9939609 POLYMORPHISM; DIABETES PREVENTION; WAIST CIRCUMFERENCE; GENETIC-VARIANTS; IDENTICAL-TWINS; COMMON VARIANT; WEIGHT-LOSS AB Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. C1 [Kilpelaeinen, Tuomas O.; Brage, Soren; Sharp, Stephen J.; Palla, Luigi; Scott, Robert A.; Wareham, Nicholas J.; Ekelund, Ulf; Loos, Ruth J. F.] Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. [Qi, Lu; Renstrom, Frida; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Qi, Lu; Renstrom, Frida; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sonestedt, Emily; Renstrom, Frida; Shungin, Dmitry; Groop, Leif C.; Orho-Melander, Marju; Franks, Paul W.] Lund Univ, Skane Univ Hosp, Dept Clin Sci, Lund Univ Diabet Ctr, Malmo, Sweden. [Demerath, Ellen; Lutsey, Pamela L.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Ahmad, Tariq] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Sandholt, Camilla Helene; Pedersen, Oluf; Hansen, Torben] Hagedorn Res Inst, Gentofte, Denmark. [Holzapfel, Christina; Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Unit Mol Epidemiol, Neuherberg, Germany. [Holzapfel, Christina] Tech Univ Munich, Klinikum Rechts Isar, Univ Hosp, Else Kroener Fresenius Ctr Nutr Med, D-8000 Munich, Germany. [Autenrieth, Christine S.] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Hyppoenen, Elina; Power, Chris] UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Hyppoenen, Elina; Power, Chris] UCL, Inst Child Hlth, MRC, Ctr Epidemiol Child Hlth, London, England. [Cauchi, Stephane; Cavalcanti-Proenca, Christine; Froguel, Philippe] Inst Biol Lille, Dept Genom & Mol Physiol Metab Dis, CNRS UMR 8090, Lille, France. [Kutalik, Zoltan; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kumari, Meena] UCL, Dept Epidemiol, Genet Epidemiol Grp, London, England. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Meidtner, Karina; Boeing, Heiner] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Nuthetal, Germany. [Balkau, Beverley] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France. [Balkau, Beverley] Univ Paris 11, UMRS 1018, Villejuif, France. [Tan, Jonathan T.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol & Publ Hlth, Singapore 117595, Singapore. [Mangino, Massimo; Spector, Timothy D.] Kings Coll London, London WC2R 2LS, England. [Timpson, Nicholas J.; Lawlor, Debbie A.] Univ Bristol, Sch Social & Community Med, Ctr Causal Anal Translat Epidemiol, MRC, Bristol, Avon, England. [Song, Yiqing] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Zillikens, M. Carola; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Zillikens, M. Carola; van Duijn, Cornelia M.; Hofman, Albert; Uitterlinden, Andre G.] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Johansson, Stefan; Njolstad, Pal R.] Univ Bergen, Dept Clin Med, Bergen, Norway. [Bragg-Gresham, Jennifer L.; Stringham, Heather M.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Bragg-Gresham, Jennifer L.; Stringham, Heather M.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [van Vliet-Ostaptchouk, Jana V.] Univ Med Ctr Groningen, Dept Pathol & Med Biol, Mol Genet Sect, NL-9713 AV Groningen, Netherlands. [van Vliet-Ostaptchouk, Jana V.] Univ Groningen, Groningen, Netherlands. [Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Dept Med Genet, Complex Genet Sect, Utrecht, Netherlands. [Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Zimmermann, Esther; Sorensen, Thorkild I. A.] Copenhagen Univ Hosp, Inst Prevent Med, Copenhagen, Denmark. [Zimmermann, Esther; Pedersen, Oluf] Univ Copenhagen, Fac Hlth Sci, Inst Biomed Sci, Copenhagen, Denmark. [Rivera, Natalia V.; Amin, Najaf; van Duijn, Cornelia M.; Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD USA. [Tanaka, Toshiko; Metter, Jeffery; Ferrucci, Luigi] NIA, Longitudinal Study Sect, NIH, Baltimore, MD 21224 USA. [Silbernagel, Guenther; Fritsche, Andreas] Univ Tubingen, Dept Internal Med, Div Endocrinol Diabetol Nephrol Vasc Dis & Clin C, D-7400 Tubingen, Germany. [Kanoni, Stavroula; Dedoussis, George V.] Harokopio Univ Athens, Dept Nutr Dietet, Athens, Greece. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Snitker, Soren] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Ruiz, Jonatan R.] Karolinska Inst, Novum, Dept Biosci & Nutr, Unit Prevent Nutr, Huddinge, Sweden. [Ruiz, Jonatan R.] Univ Granada, Sch Phys Act & Sport Sci, Dept Phys Educ & Sport, Granada, Spain. [Martinez Larrad, Maria Teresa; Serrano Rios, Manuel] Hosp Clin San Carlos, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain. [Atalay, Mustafa; Lakka, Timo A.] Univ Eastern Finland, Dept Physiol, Inst Biomed, Kuopio, Finland. [Hakanen, Maarit; Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Grontved, Anders] Univ So Denmark, Inst Sport Sci & Clin Biomech, Odense, Denmark. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Sect Nutr Res, Umea, Sweden. [Jansson, John-Olov] Univ Gothenburg, Sahlgrenska Acad, Dept Physiol, Inst Neurosci & Physiol, Gothenburg, Sweden. [Nolan, John J.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kahonen, Mika; Lehtimaki, Terho] Tampere Univ Hosp, Tampere, Finland. [Pedersen, Oluf] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark. [Pedersen, Oluf; Hansen, Torben] Univ Copenhagen, Fac Hlth Sci, Marie Krogh Ctr Metab Res, Copenhagen, Denmark. [Perusse, Louis] Univ Laval, Dept Social & Prevent Med, Div Kinesiol, Ste Foy, PQ, Canada. [Renstrom, Frida; Shungin, Dmitry; Franks, Paul W.] Umea Univ Hosp, Med Sect, Dept Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. [Shungin, Dmitry] Umea Univ, Dept Odontol, Umea, Sweden. [Sovio, Ulla] London Sch Hyg & Trop Med, Dept Med Stat, London WC1, England. [Tammelin, Tuija H.] Finnish Inst Occupat Hlth, Oulu, Finland. [Tammelin, Tuija H.] LIKES Res Ctr Sport & Hlth Sci, Jyvaskyla, Finland. [Ronnemaa, Tapani] Univ Turku, Dept Med, Turku, Finland. [Uusitupa, Matti] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland. [Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA USA. [Meirhaeghe, Aline] Univ Lille 2, Univ Lille Nord France, Inst Pasteur Lille, INSERM,U744, Lille, France. [Fu, Mao] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Walker, Mark] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med, Gothenburg, Sweden. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [van Duijn, Cornelia M.] Netherlands Genom Initiat, Ctr Med Syst Biol, Leiden, Netherlands. [Ebrahim, Shah] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [Gudnason, Vilmundur] Iceland Heart Assoc, Heart Prevent Clin, Kopavogur, Iceland. [Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tuomilehto, Jaakko] Danube Univ Krems, Dept Clin & Prevent Med, Krems, Austria. [Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, FIN-33101 Tampere, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol, FIN-20520 Turku, Finland. [Isomaa, Bo] Folkhalsan Res Ctr, Helsinki, Finland. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari, Finland. [Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Liu, Simin] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Metab Dis Prevent, Los Angeles, CA 90024 USA. [Liu, Simin] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Ness, Andy] Univ Bristol, Sch Oral & Dent Sci, Bristol, Avon, England. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117595, Singapore. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Ctr Genom Med, London, England. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Genom Med, London, England. [Marmot, Michael] UCL, Dept Epidemiol & Publ Hlth, London, England. [Khaw, Kay-Tee] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Hansen, Torben] Univ So Denmark, Fac Hlth Sci, Odense, Denmark. [Monda, Keri L.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Life Course & Serv, Oulu, Finland. RP Kilpelainen, TO (reprint author), Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. EM luqi@hsph.harvard.edu; paul.franks@med.lu.se; ruth.loos@mrc-epid.cam.ac.uk RI Onland-Moret, N. Charlotte/G-9185-2011; Kilpelainen, Tuomas/F-8569-2012; Gudnason, Vilmundur/K-6885-2015; RUIZ, JONATAN/M-1338-2015; Perusse, Louis/A-3444-2012; Brage, Soren/C-6415-2013; Hypponen, Elina/B-2596-2014; Liu, Simin/I-3689-2014; Berryman, Katie/J-4236-2014; Meirhaeghe, Aline/E-4663-2015; Johansson, Stefan/C-4394-2011; Colaus, PsyColaus/K-6607-2013; Sonestedt, Emily/I-3814-2016; Bouchard, Claude/A-7637-2009; mangino, massimo/F-5134-2011; Fox, Laura /C-6249-2016; Palla, Luigi/Q-4950-2016; Rivera, Natalia V/S-4231-2016; Feitosa, Mary/K-8044-2012; OI Gudnason, Vilmundur/0000-0001-5696-0084; RUIZ, JONATAN/0000-0002-7548-7138; Brage, Soren/0000-0002-1265-7355; Hypponen, Elina/0000-0003-3670-9399; Liu, Simin/0000-0003-2098-3844; Johansson, Stefan/0000-0002-2298-7008; Sonestedt, Emily/0000-0002-0747-4562; mangino, massimo/0000-0002-2167-7470; Palla, Luigi/0000-0001-6944-1750; Rivera, Natalia V/0000-0002-1298-1243; Feitosa, Mary/0000-0002-0933-2410; Zimmermann, Esther/0000-0001-5854-0542; Kaakinen, Marika/0000-0002-9228-0462; Shungin, Dmitry/0000-0001-7900-5856; Meidtner, Karina/0000-0001-5810-4062; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Lakka, Timo/0000-0002-9199-2871; Grontved, Anders/0000-0003-1584-679X; Kumari, Meena/0000-0001-9716-1035; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Marmot, Michael/0000-0002-2431-6419; Lawlor, Debbie A/0000-0002-6793-2262; Tai, E Shyong/0000-0003-2929-8966 FU British Heart Foundation [RG/07/008/23674]; Cancer Research UK [14136]; Department of Health [PHCS/C4/4/016]; Medical Research Council [G0000934, G0100222, G0401527, G0601653, G0701863, G0902037, G1000143, G19/35, G8802774, G9815508, MC_U106179471, MC_U106179473, MC_U106188470]; NIDDK NIH HHS [P30 DK072488, P30 DK017047, P30 DK079637, R01 DK072041, R01 DK072193, R01 DK078150, R01 DK091718]; Wellcome Trust [092731] NR 39 TC 168 Z9 173 U1 1 U2 76 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD NOV PY 2011 VL 8 IS 11 AR e1001116 DI 10.1371/journal.pmed.1001116 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 862ZR UT WOS:000298133100003 PM 22069379 ER PT J AU Bourboulia, D Jensen-Taubman, S Rittler, MR Han, HY Chatterjee, T Wei, BY Stetler-Stevenson, WG AF Bourboulia, Dimitra Jensen-Taubman, Sandra Rittler, Matthew R. Han, Hui Ying Chatterjee, Tania Wei, Beiyang Stetler-Stevenson, William G. TI Endogenous Angiogenesis Inhibitor Blocks Tumor Growth via Direct and Indirect Effects on Tumor Microenvironment SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID BREAST EPITHELIAL-CELLS; TISSUE INHIBITOR; METALLOPROTEINASE-2 TIMP-2; MATRIX METALLOPROTEINASES; ENDOTHELIAL-CELLS; GENE-TRANSFER; IN-VIVO; INVASION; EXPRESSION; MECHANISM AB Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) belongs to a small family of endogenous proteins that inhibits a group of enzymes, the matrix metalloproteinases (MMPs). TIMP-2 inhibits endothelial cell proliferation and migration in vitro and angiogenesis in vivo, through MMP-dependent and -independent mechanisms. However, little is known regarding the contribution of these mechanisms to the antitumor effects of TIMP-2. Using a retroviral delivery system, we stably overexpressed TIMP-2 and its mutant Ala+TIMP-2 (devoid of MMP inhibitory activity) in human adenocarcinoma A549 cells. Using real time PCR, and enzyme-linked immunosorbent assay (ELISA), we confirmed enhanced TIMP-2 expression and its MMP inhibitory activity by reverse zymography. In vitro, growth assays suggested that TIMP-2 and Ala+TIMP-2 did not alter basal cell proliferation rates, however, tumor cell migration and invasion were inhibited. In vivo, both TIMP-2 and Ala+TIMP-2 A549 xenografts exhibited reduced growth rate, CD31 immunostaining indicated decreased intratumoral microvascular density, and TUNEL demonstrated enhanced tumor cell apoptosis. Immunoblotting and immunohistochemical analyses of A549 xenograft tissues with either phospho-FAK (Tyr397) or phospho-AKT (Ser473) showed decreased activation in both TIMP-2 and Ala+TIMP-2 tumor cells. We conclude that TIMP-2-mediated inhibition of tumor growth occurs, at least in part, independently of MMP inhibition, and is a consequence of both direct effects of TIMP-2 on tumor cells and modulation of the tumor microenvironment. (Am J Pathol 2011, 179:2589-2600; DOI: 10.1016/j.ajpath.2011.07.035) C1 [Bourboulia, Dimitra; Jensen-Taubman, Sandra; Rittler, Matthew R.; Han, Hui Ying; Chatterjee, Tania; Wei, Beiyang; Stetler-Stevenson, William G.] NCI, Extracellular Matrix Pathol Sect, Radiat Oncol Branch, Ctr Canc Res,NIH,Adv Technol Ctr, Bethesda, MD 20892 USA. [Chatterjee, Tania] Univ Maryland, Dept Biol Sci, Baltimore, MD 21201 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Extracellular Matrix Pathol Sect, Radiat Oncol Branch, Ctr Canc Res,NIH,Adv Technol Ctr, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM sstevenw@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 FU National Cancer Institute Center for Cancer Research [ZIA SC009179-21] FX Supported by National Cancer Institute Center for Cancer Research grant #ZIA SC009179-21. NR 52 TC 26 Z9 26 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2011 VL 179 IS 5 BP 2589 EP 2600 DI 10.1016/j.ajpath.2011.07.035 PG 12 WC Pathology SC Pathology GA 865JQ UT WOS:000298307600042 PM 21933655 ER PT J AU Pinar, H Koch, MA Hawkins, H Heim-Hall, J Shehata, B Thorsten, VR Carpenter, M Lowichik, A Reddy, UM AF Pinar, Halit Koch, Matthew A. Hawkins, Hal Heim-Hall, Josefine Shehata, Bahig Thorsten, Vanessa R. Carpenter, Marshall Lowichik, Amy Reddy, Uma M. TI The Stillbirth Collaborative Research Network (SCRN) Placental and Umbilical Cord Examination Protocol SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE Stillbirth; placenta; umbilical cord; cause of death ID PATHOLOGISTS CONFERENCE-XIX; OF-AMERICAN-PATHOLOGISTS; FETAL-DEATH; REACTION PATTERNS; REFERENCE VALUES; WORKING GROUP; COLLEGE; REPRODUCIBILITY; NOSOLOGY; WEIGHTS AB The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth. C1 [Pinar, Halit] Brown Univ, WIH, Div Perinatal Pathol, Providence, RI 02905 USA. [Koch, Matthew A.; Thorsten, Vanessa R.] RTI Int, N Carolina Dept Stat & Epidemiol, Res Triangle Pk, NC USA. [Hawkins, Hal] UTMB Galveston, Galveston, TX USA. [Heim-Hall, Josefine] UTHSC San Antonio Sch Med, San Antonio, TX USA. [Shehata, Bahig] Emory Univ, Sch Med, Egleston Hosp, Atlanta, GA USA. [Lowichik, Amy] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Carpenter, Marshall] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Pinar, H (reprint author), Brown Univ, WIH, Div Perinatal Pathol, 101 Dudley St, Providence, RI 02905 USA. EM halit.pinar@gmail.com FU Stillbirth Collaborative Research Network (Brown University, Rhode Island) [U10-HD045953]; Stillbirth Collaborative Research Network (Emory University, Georgia) [U10-HD045925]; Stillbirth Collaborative Research Network (University of Texas Medical Branch at Galveston, Texas) [U10-HD045952]; Stillbirth Collaborative Research Network (University of Texas Health Science Center at San Antonio, Texas) [U10-HD045955]; Stillbirth Collaborative Research Network (University of Utah Health Sciences Center, Utah) [U10-HD045944]; Stillbirth Collaborative Research Network (RTI International, North Carolina) [U01-HD45954]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported in part by grant funding from the Stillbirth Collaborative Research Network sites: U10-HD045953 (Brown University, Rhode Island); U10-HD045925 (Emory University, Georgia); U10-HD045952 (University of Texas Medical Branch at Galveston, Texas); U10-HD045955 (University of Texas Health Science Center at San Antonio, Texas); U10-HD045944 (University of Utah Health Sciences Center, Utah); and U01-HD45954 (RTI International, North Carolina); and by finding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 33 TC 18 Z9 18 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD NOV PY 2011 VL 28 IS 10 BP 781 EP 792 DI 10.1055/s-0031-1281509 PG 12 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 863XB UT WOS:000298200500007 PM 21717387 ER PT J AU Pinar, H Koch, MA Hawkins, H Heim-Hall, J Shehata, B Thorsten, VR Chin, S Willinger, M dela Monte, S AF Pinar, Halit Koch, Matthew A. Hawkins, Hal Heim-Hall, Josefine Shehata, Bahig Thorsten, Vanessa R. Chin, Steven Willinger, Marian dela Monte, Suzanne TI The Stillbirth Collaborative Research Network Neuropathologic Examination Protocol SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE SCRN; neuropathology; stillbirth; central nervous system ID CENTRAL-NERVOUS-SYSTEM; CEREBRAL WHITE-MATTER; HUMAN FETAL-BRAIN; STILLBORN FETUSES; HUMAN INFANCY; LAYER-I; MYELINATION; DEATH; AUTOPSY; CORTEX AB We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Network (SCRN), focusing on the examination of central nervous system (CNS) in stillbirth (SB). The SCRN was organized to perform a case-control study to determine the scope and causes of SB. Pathologists at all the participating centers agreed on and used the same standardized neuropathologic techniques. Standardized sections were taken and detailed data were collected. Fresh brain tissue was saved for investigative purposes. A total of 663 women with SB were enrolled into the case-control study: 620 delivered a single stillborn, 42 delivered twins, and 1 delivered triplets. Of the 560 (84.5%) who consented to postmortem examination, 465 (70.1%) also gave consent to the examination of the CNS. In the 440 stillborn infants in whom CNS examination was possible, 248 (56.4%) of the brains were intact, 72 were fragmented (16.4%), and 120 (27.3%) were liquefied. In summary, this is the largest prospective study dedicated to investigate the causes of SB and collect essential information and biological samples in the United States. A protocol for neuropathologic examination was instituted, and a brain tissue repository was created to provide samples and related data for future investigations. C1 [Pinar, Halit] Brown Univ, Div Perinatal Pathol, Women & Infants Hosp, Alpert Med Sch, Providence, RI 02905 USA. [Koch, Matthew A.] RTI Int, Dept Stat & Epidemiol, Res Triangle Pk, NC USA. [Hawkins, Hal] Univ Texas Med Branch Galveston, Dept Pediat Pathol, Galveston, TX USA. [Heim-Hall, Josefine] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, San Antonio, TX 78229 USA. [Shehata, Bahig] Egleston Hosp, Pathol Lab, Atlanta, GA USA. [Thorsten, Vanessa R.] RTI Int, Dept Stat & Data Anal, Kansas City, MO USA. [Chin, Steven] Huntsman Canc Inst, Salt Lake City, UT USA. [Willinger, Marian] NIH, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. [dela Monte, Suzanne] Rhode Isl Hosp, Providence, RI USA. RP Pinar, H (reprint author), Brown Univ, Div Perinatal Pathol, Women & Infants Hosp, Alpert Med Sch, 101 Dudley St, Providence, RI 02905 USA. EM halit.pinar@gmail.com FU Stillbirth Collaborative Research Network (Brown University, Rhode Island) [U10-HD045953]; Stillbirth Collaborative Research Network (Emory University, Georgia) [U10-HD045925]; Stillbirth Collaborative Research Network (University of Texas Medical Branch at Galveston, Texas) [U10-HD045952]; Stillbirth Collaborative Research Network (University of Texas Health Science Center at San Antonio, Texas) [U10-HD045955]; Stillbirth Collaborative Research Network (University of Utah Health Sciences Center, Utah) [U10-HD045944]; Stillbirth Collaborative Research Network (RTI International, North Carolina) [U01-HD45954]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported in part by grant funding from the Stillbirth Collaborative Research Network sites: U10-HD045953 (Brown University, Rhode Island); U10-HD045925 (Emory University, Georgia); U10-HD045952 (University of Texas Medical Branch at Galveston, Texas); U10-HD045955 (University of Texas Health Science Center at San Antonio, Texas); U10-HD045944 (University of Utah Health Sciences Center, Utah); and U01-HD45954 (RTI International, North Carolina); and by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 39 TC 5 Z9 5 U1 0 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD NOV PY 2011 VL 28 IS 10 BP 793 EP 802 DI 10.1055/s-0031-1284229 PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 863XB UT WOS:000298200500008 PM 21780010 ER PT J AU Dackor, RT Cheng, J Voltz, JW Card, JW Ferguson, CD Garrett, RC Bradbury, JA DeGraff, LM Lih, FB Tomer, KB Flake, GP Travlos, GS Ramsey, RW Edin, ML Morgan, DL Zeldin, DC AF Dackor, Ryan T. Cheng, Jennifer Voltz, James W. Card, Jeffrey W. Ferguson, Catherine D. Garrett, Ryan C. Bradbury, J. Alyce DeGraff, Laura M. Lih, Fred B. Tomer, Kenneth B. Flake, Gordon P. Travlos, Gregory S. Ramsey, Randle W., Jr. Edin, Matthew L. Morgan, Daniel L. Zeldin, Darryl C. TI Prostaglandin E-2 protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE mouse; cyclooxygenase; FlexiVent ID GROWTH-FACTOR-BETA; FIBROBLAST PROLIFERATION; CYCLOOXYGENASE-2-DEFICIENT MICE; COLLAGEN PRODUCTION; HUMAN MONOCYTES; MESSENGER-RNA; CYCLIC-AMP; EXPRESSION; MODULATION; GENE AB Dackor RT, Cheng J, Voltz JW, Card JW, Ferguson CD, Garrett RC, Bradbury JA, DeGraff LM, Lih FB, Tomer KB, Flake GP, Travlos GS, Ramsey RW Jr, Edin ML, Morgan DL, Zeldin DC. Prostaglandin E-2 protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction. Am J Physiol Lung Cell Mol Physiol 301: L645-L655, 2011. First published August 19, 2011; doi:10.1152/ajplung.00176.2011.-Prostaglandin E-2 (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 mu g/h), or the prostacyclin analog iloprost (0.33 mu g/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P < 0.05). When administered 7 days before bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it was administered before bleomycin challenge but had no therapeutic effect when administered after bleomycin challenge. C1 [Dackor, Ryan T.; Cheng, Jennifer; Voltz, James W.; Card, Jeffrey W.; Ferguson, Catherine D.; Garrett, Ryan C.; Bradbury, J. Alyce; DeGraff, Laura M.; Lih, Fred B.; Tomer, Kenneth B.; Flake, Gordon P.; Travlos, Gregory S.; Ramsey, Randle W., Jr.; Edin, Matthew L.; Morgan, Daniel L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr,Bldg 101,Rm A222, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013; OI Edin, Matthew/0000-0002-7042-500X FU NIH, National Institute of Environmental Health Sciences [Z01 ES025043, ES050167]; American Lung Association of North Carolina FX This work was supported with funds from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025043 and ES050167). J. Card was the recipient of a Senior Research Training Fellowship from the American Lung Association of North Carolina. NR 61 TC 26 Z9 26 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD NOV PY 2011 VL 301 IS 5 BP L645 EP L655 DI 10.1152/ajplung.00176.2011 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 863JH UT WOS:000298158100003 PM 21856819 ER PT J AU Scheffer, L Raghavendra, PR Ma, JJ Acharya, JK AF Scheffer, Luana Raghavendra, Pralhada Rao Ma, Jingjing Acharya, Jairaj K. TI Ceramide Transfer Protein and Cancer SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Ceramide; Ceramide transfer protein; cancer; shingolipids ID HAMSTER OVARY CELLS; KINASE-C-ZETA; ENDOPLASMIC-RETICULUM; GOLGI-APPARATUS; SPHINGOLIPID METABOLISM; BREAST-CANCER; SPHINGOMYELIN SYNTHESIS; ACID SPHINGOMYELINASE; DEPENDENT TRANSPORT; MOLECULAR MACHINERY AB Sphingolipids are important structural components of membranes, and play an equally important role in basic cellular processes as second messengers. Recently, sphingolipids are receiving increasing attention in cancer research. Ceramide is the central molecule that regulates sphingolipid metabolism forming the basic structural backbone of sphingolipids and the precursor of all complex sphingolipids. It is been proposed to be an important regulator of tumor cell death following exposure to stress stimuli. The increase or decrease of ceramide levels leading to change in sensitivity of cancer cells to stress stimuli provides support for a central role of ceramide signaling in cell death. In this review, we have focused on ceramide transfer protein (CERT) as a major regulator of ceramide flux in the cell. C1 [Scheffer, Luana; Raghavendra, Pralhada Rao; Ma, Jingjing; Acharya, Jairaj K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Acharya, JK (reprint author), NCI, Lab Cell & Dev Signaling, Rm 22-90 B,Bldg 560,1050 Boyle St, Frederick, MD 21702 USA. EM acharyaj@mail.nih.gov FU intramural division of the National Cancer Institute, National Institutes of Health, Department of Human Health and Services FX Funding from the intramural division of the National Cancer Institute, National Institutes of Health, Department of Human Health and Services supports the work in the authors' laboratory. NR 68 TC 8 Z9 8 U1 1 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD NOV PY 2011 VL 11 IS 9 BP 904 EP 910 PG 7 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 861YH UT WOS:000298056500013 PM 21707482 ER PT J AU Malozowski, S AF Malozowski, Saul TI Biosimilars SO ARQUIVOS BRASILEIROS DE ENDOCRINOLOGIA E METABOLOGIA LA English DT Editorial Material AB Although common themes permeate the environment across continents and particular divergences as to how to proceed exist between different regulatory agencies, it seems that policies are still in flux. Not all polices will suffice to fit all dissimilar biologics, and these in place or being developed may, in turn, change to accommodate new or unexpected developments. Consideration for accelerated approval for those compounds that do not present complex questions should be considered. The regulatory agencies should be more forthcoming, the industry sector exercise social responsibility, and the public should have realistic expectations. Arq Bras Endocrinol Metab. 2011;55(8):669-70 C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Malozowski, S (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM malozowskis@extra.niddk.nih.gov NR 3 TC 0 Z9 0 U1 1 U2 4 PU SBEM-SOC BRASIL ENDOCRINOLOGIA & METABOLOGIA PI RIO DE JANEIRO, RJ PA RUA HUMAITA, 85 CJ 501, RIO DE JANEIRO, RJ, 22261-000, BRAZIL SN 0004-2730 J9 ARQ BRAS ENDOCRINOL JI Arq. Bras. Endocrinol. Metabol. PD NOV PY 2011 VL 55 IS 8 BP 669 EP 670 PG 2 GA 873LX UT WOS:000298885900025 PM 22218453 ER PT J AU Kim, SR Paik, S AF Kim, Seong-Rim Paik, Soonmyung TI Genomics of Adjuvant Therapy for Breast Cancer SO CANCER JOURNAL LA English DT Review DE Breast cancer; systemic therapy ID GENE-EXPRESSION PROFILES; CHEMOTHERAPY; SUBTYPES; WOMEN; FLUOROURACIL; RECURRENCE; PREDICTOR; PROGNOSIS; SIGNATURE; TAMOXIFEN AB Therapeutic decision for adjuvant systemic therapy for breast cancer involves assessment of baseline risk and estimated benefit from systemic therapy. Molecular profiling studies have clearly demonstrated heterogeneity of chemotherapy response across different molecular subtypes of breast cancer. Meta-analyses of publicly available data from gene expression profiling studies have demonstrated that breast cancer can be divided into 4 basic categories based on expression levels of estrogen receptor (ER), HER2, and proliferation-associated genes; ER-, HER2+, ER+/HER2-/low proliferation, and ER+/HER2-/high proliferation. Notably ER- or HER2+ tumors are associated with high levels expression of proliferation genes, although there is a wide spectrum of expression levels of proliferation genes among ER+/HER2-tumors. Estrogen receptor-positive/HER2-/low-proliferation tumors are associated with a favorable prognosis. Synthetic lethal screening approach has demonstrated that most of the chemotherapeutic agents do not have specific molecular targets. Therefore, it could be hypothesized that chemosensitivity would be largely dictated by proliferation activity of tumor cells. Therefore, tumors with ER-, HER2+, or ER+/HER2-/high proliferation gene expression profile can be categorized as chemosensitive tumors, whereas ER+/HER-/low proliferation tumors categorized as chemoresistant. Therefore, clinical utility of gene expression profiling is mainly in aiding the chemotherapy decision for ER+ patients. Although evidence from prospective randomized clinical trials are lacking, because of the excellent baseline prognosis of patients with ER+/HER2-/low proliferation tumors when treated with endocrine therapy and because of scientific evidence of chemoresistance of these tumors, a comfort zone has been reached among oncologists to allow clinical use of gene expression tests to identify patients who do not require chemotherapy among node-negative ER+ patients. However, these tools are still probabilistic at best in their performances, and one cannot exactly predict which patient will have recurrence after assigned therapies until the time of recurrence. Therefore, strategies have to be established to identify patients who will fail standard chemoendocrine therapies among high-risk patients (ER+/HER2-/high proliferation, HER2+, or ER-) before recurrence events. Neoadjvant therapy can provide such venue because regardless of regimens used the prognosis of those achieving complete pathological response is excellent. Postneoadjuvant setting can be then used for patients with gross residual disease to test novel therapeutic agents. C1 [Kim, Seong-Rim; Paik, Soonmyung] Natl Surg Breast & Bowel Project Fdn, Div Pathol, Pittsburgh, PA USA. [Paik, Soonmyung] Samsung Canc Res Inst, Seoul, South Korea. RP Paik, S (reprint author), Four Allegheny Ctr, NSABP, Div Pathol, 5th Floor,E Commons Profess Bldg, Pittsburgh, PA 15212 USA. EM Soon.paik@nsabp.org NR 22 TC 8 Z9 8 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD NOV-DEC PY 2011 VL 17 IS 6 SI SI BP 500 EP 504 DI 10.1097/PPO.0b013e31823e5370 PG 5 WC Oncology SC Oncology GA 863HH UT WOS:000298152900012 PM 22157294 ER PT J AU Shakil, S Khan, R Tabrez, S Alam, Q Jabir, NR Sulaiman, MI Greig, NH Kamal, MA AF Shakil, Shazi Khan, Rosina Tabrez, Shams Alam, Qamre Jabir, Nasimudeen R. Sulaiman, Mansour I. Greig, Nigel H. Kamal, Mohammad A. TI Interaction of Human Brain Acetylcholinesterase with Cyclophosphamide: A Molecular Modeling and Docking Study SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Cyclophosphamide; docking; enzyme-inhibition; human brain acetylcholinesterase; hydrophobic interactions; modeling ID CHOLINESTERASE-INHIBITORS; ALZHEIMERS-DISEASE; PREDICTION; PROTEIN; SITE; RAT AB This study describes the interaction between human acetylcholinesterase (AChE), a key regulator of central and peripheral cholinergic function, and the widely used nitrogen mustard alkylating agent, cyclophosphamide (CP). Modeling of the AChE sequence (NCBI Accession No: AAI05061.1) was performed using 'Swiss Model Workspace'. The protein-model was submitted to the Protein Model Database and was assigned accession number PM0077393. A plot showing normalized QMEAN scores versus protein size was made to compare the model with a non-redundant set of Protein Data Bank structures, which gave a Z-score QMEAN as -0.58. The predicted local error for the modeled structure was found to be well within tolerable limits. Z-score values for C interaction, all atom interaction, solvation and torsion were found to be -1.10, -0.90, -0.06 and -0.40, respectively. Docking between CP and AChE was performed using 'Autodock4.2'. Apart from other interaction-types, six carbon atoms of CP (C1, C2, C3, C4, C6 and C7) were determined to be involved in hydrophobic interactions with amino acid residues Y121, W233, L323, F331, F335 and Y338 of the 'acyl pocket' within AChE. Five carbon atoms of CP (C2, C4, C5, C6 and C7) were involved in hydrophobic interactions with 3 amino acid residues within the enzyme's 'catalytic site'. In conclusion, hydrophobic interactions play a major role in the appropriate positioning of CP within the 'acyl pocket' as well as 'catalytic site' of AChE to permit suitable orientation and allow docking. This information may aid the design of more potent and versatile AChE-inhibitors as pharmacologic tools and drugs to characterize and treat neurological disorders, and additionally provides a model whose value can be quantitatively assessed by X-ray crystallographic analysis of the AChE-CP three-dimensional structure. C1 [Shakil, Shazi; Tabrez, Shams; Alam, Qamre; Jabir, Nasimudeen R.; Sulaiman, Mansour I.; Kamal, Mohammad A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Jeddah 21589, Saudi Arabia. [Khan, Rosina] Aligarh Muslim Univ, Interdisciplinary Biotechnol Unit, Aligarh 202002, Uttar Pradesh, India. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Kamal, MA (reprint author), King Abdulaziz Univ, King Fahd Med Res Ctr, POB 80216, Jeddah 21589, Saudi Arabia. EM ma.kamal@live.com RI Rehumathbeevi, Jabir/H-9483-2012; Tabrez, Shams/H-9476-2012; Alam, Qamre/H-9614-2012; Kamal, Mohammad/H-9643-2012; Kamal, Mohammad/J-4622-2013; Shakil, Shazi/K-4132-2015; OI Rehumathbeevi, Jabir/0000-0001-8548-7986; Tabrez, Shams/0000-0003-4550-415X; Kamal, Mohammad/0000-0003-1862-173X; Shakil, Shazi/0000-0003-4075-9153; Kamal, Mohammad Amjad/0000-0003-0088-0565 FU Intramural NIH HHS [Z01 AG000311-07] NR 28 TC 5 Z9 5 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2011 VL 10 IS 7 BP 845 EP 848 PG 4 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 864NY UT WOS:000298248100009 PM 21999734 ER PT J AU Ock, S Lee, SH Ahn, J Lee, TJ Cho, CH Abel, ED Kimura, S Kim, J AF Ock, Sangmi Lee, Seok Hong Ahn, Jihyun Lee, Tae Jin Cho, Chung-Hyun Abel, E. Dale Kimura, Shioko Kim, Jaetaek TI Conditional deletion of insulin receptor in thyrocytes does not affect thyroid structure and function SO ENDOCRINE JOURNAL LA English DT Article DE Insulin receptor; Mice; Thyroid ID GROWTH-FACTOR-I; SIGNALING PATHWAYS; TRANSGENIC MICE; IGF-I; THYROTROPIN; HORMONE; EXPRESSION; CELLS; DEFICIENT; GOITER AB Thyroid-stimulating hormone (TSH) is the primary regulator of thyroid growth and function acting via cyclic AMP signaling cascades. In cultured thyrocytes, insulin and/or insulin-like growth factor-1 (IGF-1) are required for mediating thyrocyte proliferation in concert with TSH. To determine the role of insulin signaling in thyroid, growth in vivo, mice with thyrocyte-selective ablation of the insulin receptor (IR) were generated by crossing mice homozygous for a foxed IR allele with transgenic mice in which thyrocyte-specific expression of Cre recombinase was driven by the human thyroid peroxidase (TPO) gene promoter. Immunohistochemistry and Western blot analysis confirmed near complete loss of IR expression in the thyroid of thyrocyte IR knockout mice. These mice are viable and have no obvious thyroid dysfunction and macro- and microscopic thyroid morphology was normal. Thus, insulin signaling in thyrocytes does not play an essential role in the architecture and function of the thyroid in vivo. C1 [Ock, Sangmi; Lee, Seok Hong; Ahn, Jihyun; Kim, Jaetaek] Chung Ang Univ, Div Endocrinol & Metab, Dept Internal Med, Coll Med, Seoul 156755, South Korea. [Lee, Tae Jin] Chung Ang Univ, Dept Pathol, Coll Med, Seoul 156755, South Korea. [Cho, Chung-Hyun] Seoul Natl Univ, Coll Med, Dept Pharmacol, Seoul, South Korea. [Abel, E. Dale] Univ Utah, Sch Med, Div Endocrinol Metab & Diabet, Program Mol Med, Salt Lake City, UT USA. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Kim, J (reprint author), Chung Ang Univ, Div Endocrinol & Metab, Dept Internal Med, Coll Med, Seoul 156755, South Korea. EM jtkim@cau.ac.kr RI Cho, Chung-Hyun/H-7286-2012 FU Ministry of Health & Welfare, Republic of Korea [A084811] FX We thank Dr. Samuel Refetoff (University of Chicago) for T4 and TSH measurements. This study was supported by a grant of the Korea Healthcare Technology R&D Project (A084811), Ministry of Health & Welfare, Republic of Korea to J.K. NR 26 TC 1 Z9 1 U1 0 U2 3 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD NOV PY 2011 VL 58 IS 11 BP 1013 EP 1019 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 871XH UT WOS:000298770500011 PM 21908931 ER PT J AU Lee, JE Heo, JI Park, SH Kim, JH Kho, YJ Kang, HJ Chung, HY Yoon, JL Lee, JY AF Lee, Jae-Eun Heo, Jee-In Park, Seong-Hoon Kim, Jeong-Hyeon Kho, Yoon-Jung Kang, Hong-Jun Chung, Hae Young Yoon, Jong-Lull Lee, Jae-Yong TI Calorie restriction (CR) reduces age-dependent decline of non-homologous end joining (NHEJ) activity in rat tissues SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Calorie restriction; NHEJ; Aging; XRCC4 ID STRAND BREAK REPAIR; BASE-EXCISION-REPAIR; DNA-REPAIR; V(D)J RECOMBINATION; TRANSCRIPTION FACTORS; SIRT1 DEACETYLASE; TUMOR-SUPPRESSOR; MICE; KU; TRANSLOCATIONS AB Even though CR has shown to enhance base excision repair (BER) and nucleotide excision repair (NER) capacities, it has not been reported whether CR can enhance non-homologous end joining (NHEJ) activity. To examine the effect of CR on NHEJ activity, ad libitum (AL)-and calorie restricted (CR)-dieted rats were used. Age-dependent decline of NHEJ activity was apparent in the lung, liver, and kidney and appeared to be slightly decreased in spleen. CR reduced age-dependent decline of NHEJ activity in all tissues, even though the extent of recovery was variable among tissues. Moreover, CR appeared to reduce age-dependent decline of XRCC4 protein level. These results suggest that CR could reduce age-dependent decline of NHEJ activity in various tissues of rats possibly through up-regulation of XRCC4. (C) 2011 Elsevier Inc. All rights reserved. C1 [Heo, Jee-In; Kim, Jeong-Hyeon; Lee, Jae-Yong] Hallym Univ, Coll Med, Dept Biochem, Chunchon 200702, Gangwon Do, South Korea. [Lee, Jae-Eun; Yoon, Jong-Lull] Hallym Univ, Hangang Secred Heart Hosp, Med Ctr, Dept Family Med, Seoul, South Korea. [Heo, Jee-In; Kho, Yoon-Jung; Lee, Jae-Yong] Hallym Univ, Coll Med, Inst Nat Med, Chunchon 200702, Gangwon Do, South Korea. [Park, Seong-Hoon] Vanderbilt Univ, Dept Pediat, Dept Radiat Oncol, Nashville, TN 37232 USA. [Kang, Hong-Jun] Pusan Natl Univ, Coll Pharm, Dept Biochem, Pusan 609735, South Korea. [Chung, Hae Young] NIDDK, Genet Dis Res Sect, GDDB, NIH, Bethesda, MD 20892 USA. RP Lee, JY (reprint author), Hallym Univ, Coll Med, Dept Biochem, 1 Okcheon Dong, Chunchon 200702, Gangwon Do, South Korea. EM jyolee@hallym.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2010-0029642]; Hallym University [2008 HRF-2008-034] FX This work was supported partly by Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0029642) and partly by Hallym University Research Fund (2008 HRF-2008-034). NR 39 TC 9 Z9 9 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD NOV PY 2011 VL 46 IS 11 BP 891 EP 896 DI 10.1016/j.exger.2011.07.009 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 853UD UT WOS:000297450300008 PM 21821112 ER PT J AU Willis, GB Miller, K AF Willis, Gordon B. Miller, Kristen TI Cross-Cultural Cognitive Interviewing: Seeking Comparability and Enhancing Understanding SO FIELD METHODS LA English DT Article DE cognitive interviewing; cross-cultural research; qualitative research; questionnaire design; survey pretesting ID DIVERSE POPULATIONS AB Cognitive interviewing (CI) has emerged as a key qualitative method for the pretesting and evaluation of self-report survey questionnaires. This article defines CI, describes its key features, and outlines the data analysis techniques that are commonly used. The authors then consider recent extensions of cognitive testing to the cross-cultural survey research realm, where the major practical objectives are: (1) to facilitate inclusion of a range of cultural and linguistic groups and (2) for purposes of comparative analysis, to produce survey questionnaire items that exhibit comparability of measurement, across groups. Challenges presented by this extension to the cross-cultural and multilingual areas are discussed. Finally, the authors introduce the articles contained within the current special issue of Field Methods (2011), which endeavor to apply cognitive testing in specific cross-cultural survey projects, and to both identify and suggest solutions to the unique problems that face questionnaire designers and researchers more generally, in the practice of survey pretesting and evaluation methods as these endeavor to cover the sociocultural spectrum. C1 [Willis, Gordon B.] NCI, NIH, Bethesda, MD 20892 USA. [Miller, Kristen] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Willis, GB (reprint author), NCI, NIH, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. EM willisg@mail.nih.gov NR 28 TC 11 Z9 13 U1 0 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1525-822X J9 FIELD METHOD JI Field Methods PD NOV PY 2011 VL 23 IS 4 SI SI BP 331 EP 341 DI 10.1177/1525822X11416092 PG 11 WC Anthropology; Social Sciences, Interdisciplinary SC Anthropology; Social Sciences - Other Topics GA 868YC UT WOS:000298561400001 ER PT J AU Reeve, BB Willis, G Shariff-Marco, SN Breen, N Williams, DR Gee, GC Alegria, M Takeuchi, DT Stapleton, M Levin, KY AF Reeve, Bryce B. Willis, Gordon Shariff-Marco, Salma N. Breen, Nancy Williams, David R. Gee, Gilbert C. Alegria, Margarita Takeuchi, David T. Stapleton, Martha Levin, Kerry Y. TI Comparing Cognitive Interviewing and Psychometric Methods to Evaluate a Racial/Ethnic Discrimination Scale SO FIELD METHODS LA English DT Article DE cognitive interviewing; differential item functioning; item response theory; discrimination; questionnaire evaluation ID PERCEIVED DISCRIMINATION; HEALTH AB Proponents of survey evaluation have long advocated the integration of qualitative and quantitative methodologies, but this recommendation has rarely been practiced. The authors used both methods to evaluate the "Everyday Discrimination" scale (EDS), which measures frequency of various types of discrimination, in a multiethnic population. Cognitive testing included 30 participants of various race/ethnic backgrounds and identified items that were redundant, unclear, or inconsistent (e.g., cognitive challenges in quantifying acts of discrimination). Psychometric analysis included secondary data from two national studies, including 570 Asian Americans, 366 Latinos, and 2,884 African Americans, and identified redundant items as well as those exhibiting differential item functioning (DIF) by race/ethnicity. Overall, qualitative and quantitative techniques complemented one another, as cognitive interviewing findings provided context and explanation for quantitative results. Researchers should consider further how to integrate these methods into instrument pretesting as a way to minimize response bias for ethnic and racial respondents in population-based surveys. C1 [Reeve, Bryce B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Reeve, Bryce B.] Univ N Carolina, Dept Hlth Policy & Management, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Breen, Nancy] NCI, Hlth Serv & Econ Branch, Appl Res Program, NIH, Bethesda, MD 20892 USA. [Shariff-Marco, Salma N.] Canc Prevent Inst Calif, Fremont, CA USA. [Williams, David R.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Gee, Gilbert C.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Alegria, Margarita] Cambridge Hlth Alliance, Ctr Multicultural Mental Hlth Res, Somerville, MA USA. [Alegria, Margarita] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Takeuchi, David T.] Univ Washington, Seattle, WA 98195 USA. [Stapleton, Martha; Levin, Kerry Y.] Westat Corp, Rockville, MD USA. RP Reeve, BB (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, 1101-D McGavran Greenberg Bldg,135 Dauer Dr,CB 74, Chapel Hill, NC 27599 USA. EM bbreeve@email.unc.edu NR 25 TC 13 Z9 13 U1 3 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1525-822X J9 FIELD METHOD JI Field Methods PD NOV PY 2011 VL 23 IS 4 SI SI BP 397 EP 419 DI 10.1177/1525822X11416564 PG 23 WC Anthropology; Social Sciences, Interdisciplinary SC Anthropology; Social Sciences - Other Topics GA 868YC UT WOS:000298561400005 ER PT J AU Meylan, F Richard, AC Siegel, RM AF Meylan, Francoise Richard, Arianne C. Siegel, Richard M. TI TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation SO IMMUNOLOGICAL REVIEWS LA English DT Review DE TL1A; DR3; tumor necrosis factor family cytokines; autoimmune disease; inflammatory bowel disease; allergic disease; asthma ID DOMAIN-CONTAINING RECEPTOR; T-CELL RESPONSES; ALLERGIC LUNG INFLAMMATION; IFN-GAMMA PRODUCTION; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; DEATH-DOMAIN; CROHNS-DISEASE; NKT CELLS; EXPRESSION AB DR3 (TNFRSF25) is a member of the tumor necrosis factor receptor (TNFR) superfamily expressed primarily on lymphocytes and is a receptor for the TNF family cytokine TL1A (TNFSF15). DR3 costimulates T-cell activation, but it is unique among these receptors in that it signals through an intracytoplasmic death domain and the adapter protein TRADD (TNFR-associated death domain). TL1A costimulates T cells to produce a wide variety of cytokines and can promote expansion of activated and regulatory T cells in vivo. Studies in mice deficient in DR3 or TL1A or in animals treated with antibodies that block the activity of TL1A have revealed a specific role for DR3 in enhancing effector T-cell proliferation at the site of tissue inflammation in autoimmune disease models. DR3 appears to be required in autoimmune disease models dependent on a variety of different T-cell subsets and also invariant natural killer T (iNKT) cells. Chronic expression of TL1A induces a distinct interleukin-13-dependent pathology in the small intestine marked by goblet cell hyperplasia and other features associated with allergic and anti-parasitic responses. These studies suggest that TL1A may be a viable target for therapies designed to inhibit the T-cell-dependent component of diverse autoimmune diseases. C1 [Meylan, Francoise; Richard, Arianne C.; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bldg 10,Room 13C103A, Bethesda, MD 20892 USA. EM rsiegel@nih.gov FU Intramural Research Program; NIAMS; NIH; Crohn's and Colitis Foundation of America FX This work was supported by funding from the Intramural Research Program, NIAMS, NIH, and a fellowship grant to F Meylan from the Crohn's and Colitis Foundation of America. The authors would like to thank Vera Siegel for editing the manuscript. The authors have no conflicts of interest to declare. NR 49 TC 44 Z9 46 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD NOV PY 2011 VL 244 SI SI BP 188 EP 196 DI 10.1111/j.1600-065X.2011.01068.x PG 9 WC Immunology SC Immunology GA 854PS UT WOS:000297507300013 PM 22017439 ER PT J AU Gaydos, CA Rizzo-Price, PA Balakrishnan, P Mateta, P Leon, SR Verevochkin, S Yin, YP Quinn, TC Strader, LC Pequegnat, W AF Gaydos, C. A. Rizzo-Price, P. A. Balakrishnan, P. Mateta, P. Leon, S. R. Verevochkin, S. Yin, Y. P. Quinn, T. C. Strader, L. C. Pequegnat, W. CA NIMH Collaborative HIV STD TI Impact of international laboratory partnerships on the performance of HIV/sexually transmitted infection testing in five resource-constrained countries SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE laboratory testing; training partnerships; resource-poor settings; capacity building; STI; STD; HIV; diagnosis; biological markers of sexual behaviour ID EDUCATING MEDICAL-STUDENTS; HEALTH-CARE; DISEASES; BIOTERRORISM AB To review a quality control and quality assurance (QC/QA) model established to ensure the validity and reliability of collection, storage and analysis of biological outcome data, and to promote good laboratory practices (GLPs) and sustained operational improvements in international clinical laboratories, we conducted a two-arm randomized community-level HIV behavioural intervention trial in five countries: China, India, Peru, Russia and Zimbabwe. The trial was based on diffusion theory utilizing a Community Popular Opinion Leaders (CPOLs) intervention model with behavioural and biological outcomes. The QC/QA model was established by the Biological Outcome Workgroup, which collaborated with the Data Coordinating Center and John Hopkins University Reference Laboratory. Five international laboratories conducted chlamydia/gonorrhoea polymerase chain reaction (PRC)-based assays, herpes simplex virus type 2 enzyme immunoassay (EIA), syphilis serology (rapid plasma regain and Treponema pallidum particle agglutination assay, HIV serology (EIA/Western blot) and Trichomonas vaginalis culture. Data were collected at baseline, 12 and 24 months. Laboratory performance and infrastructure improved throughout the trial. Recommendations for improvement were consistently followed. Quality laboratories in resource-poor settings can be established, operating standards can be improved and certification can be obtained with consistent training, monitoring and technical support. Building collaborative partnership relations can establish a sustainable network for clinical trials, and can lead to accreditation and international laboratory development. C1 [Gaydos, C. A.; Rizzo-Price, P. A.; Quinn, T. C.] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21205 USA. [Balakrishnan, P.] YRG CARE, Madras, Tamil Nadu, India. [Mateta, P.] ZiCHIRe, Harare, Zimbabwe. [Leon, S. R.] Cayetano Heredia Peruvian Univ, Lima, Peru. [Verevochkin, S.] Biomed Ctr, St Petersburg, Russia. [Yin, Y. P.] China CDC Natl Ctr AIDS STD Control & Prevent, Nanjing, Jiangsu, Peoples R China. [Quinn, T. C.] NIAID, NIH, Bethesda, MD 20892 USA. [Strader, L. C.] RTI Int, Res Triangle Pk, NC USA. [Pequegnat, W.] NIMH, NIH, Bethesda, MD 20892 USA. RP Gaydos, CA (reprint author), Johns Hopkins Univ, Div Infect Dis, 530 Rangos Bldg,855 N Wolfe St, Baltimore, MD 21205 USA. EM cgaydos@jhmi.edu RI Granskaya, Juliana/N-1835-2013; Borodkina, Olga/M-8251-2013; Verevochkin, Sergey/O-2029-2013; Kozlov, Andrei/H-2117-2016 OI Granskaya, Juliana/0000-0001-7657-0948; Borodkina, Olga/0000-0002-0936-5757; Kozlov, Andrei/0000-0003-4611-1534 FU The National Institute of Mental Health [U10 MH61513]; Division of Intramural Research, NIAID, NIH FX Paul Stamper MT(ASCP) MS laboratory technicians at each site and the Reference Laboratory technicians. This study was supported by The National Institute of Mental Health through the Cooperative Agreement mechanism: U10 MH61513, a 5-country Cooperative Agreement conducted in China, India, Peru, Russia and Zimbabwe. Each site selected a different venue and population in which to implement the prevention programme entitled 'The Community Popular Opinion Leader (C-POL) Intervention'. The protocol for collection, storage and analysis of biospecimens for this Trial was largely developed by the Biological Outcomes Workgroup (BOWG) under the initial leadership of Maria Wawer, Johns Hopkins University. Supported in part by the Division of Intramural Research, NIAID, NIH. NR 22 TC 1 Z9 1 U1 0 U2 11 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD NOV PY 2011 VL 22 IS 11 BP 645 EP 652 DI 10.1258/ijsa.2011.010527 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 867NN UT WOS:000298461200006 PM 22096049 ER PT J AU Emaminia, A Bandettini, WP Arai, AE Horvath, KA AF Emaminia, Abbas Bandettini, W. Patricia Arai, Andrew E. Horvath, Keith A. TI Off-Pump Surgery for Giant Right Coronary Artery Aneurysms SO JOURNAL OF CARDIAC SURGERY LA English DT Article ID SURGICAL-TREATMENT; FISTULA AB Coronary artery aneurysms larger than 5 cm are exceedingly rare, and a standard treatment for them is lacking. We report two cases of giant right coronary artery aneurysms successfully treated by off-pump resection of the aneurysm and bypass grafting. The controversy surrounding the proper management of such cases is discussed. (J Card Surg 2011;26:596-599) C1 [Emaminia, Abbas; Bandettini, W. Patricia; Arai, Andrew E.; Horvath, Keith A.] NHLBI, NIH, Ctr Heart, Bethesda, MD 20892 USA. RP Horvath, KA (reprint author), NHLBI, NIH, Ctr Heart, Bethesda, MD 20892 USA. EM horvathka@mail.nih.gov FU Intramural NIH HHS [ZID HL006140-02, ZID HL006140-01] NR 11 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0886-0440 J9 J CARDIAC SURG JI J. Card. Surg. PD NOV PY 2011 VL 26 IS 6 BP 596 EP 599 DI 10.1111/j.1540-8191.2011.01332.x PG 4 WC Cardiac & Cardiovascular Systems; Surgery SC Cardiovascular System & Cardiology; Surgery GA 861EU UT WOS:000298002800006 PM 22004527 ER PT J AU Jackson, WM Lozito, TP Djouad, F Kuhn, NZ Nesti, LJ Tuan, RS AF Jackson, Wesley M. Lozito, Thomas P. Djouad, Farida Kuhn, Nastaran Z. Nesti, Leon J. Tuan, Rocky S. TI Differentiation and regeneration potential of mesenchymal progenitor cells derived from traumatized muscle tissue SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE mesenchymal stem cells; progenitor cells; tissue engineering; regenerative medicine; immunoregulation; angiogenesis ID HUMAN BONE-MARROW; STEM-CELLS; SKELETAL-MUSCLE; CLINICAL-APPLICATIONS; STROMAL CELLS; EXPRESSION; TRANSPLANTATION; POPULATION; THERAPY; BIOLOGY AB Mesenchymal stem cell (MSC) therapy is a promising approach to promote tissue regeneration by either differentiating the MSCs into the desired cell type or by using their trophic functions to promote endogenous tissue repair. These strategies of regenerative medicine are limited by the availability of MSCs at the point of clinical care. Our laboratory has recently identified multipotent mesenchymal progenitor cells (MPCs) in traumatically injured muscle tissue, and the objective of this study was to compare these cells to a typical population of bone marrow derived MSCs. Our hypothesis was that the MPCs exhibit multilineage differentiation and expression of trophic properties that make functionally them equivalent to bone marrow derived MSCs for tissue regeneration therapies. Quantitative evaluation of their proliferation, metabolic activity, expression of characteristic cell-surface markers and baseline gene expression profile demonstrate substantial similarity between the two cell types. The MPCs were capable of differentiation into osteoblasts, adipocytes and chondrocytes, but they appeared to demonstrate limited lineage commitment compared to the bone marrow derived MSCs. The MPCs also exhibited trophic (i.e. immunoregulatory and pro-angiogenic) properties that were comparable to those of MSCs. These results suggest that the traumatized muscle derived MPCs may not be a direct substitute for bone marrow derived MSCs. However, because of their availability and abundance, particularly following orthopaedic injuries when traumatized muscle is available to harvest autologous cells, MPCs are a promising cell source for regenerative medicine therapies designed to take advantage of their trophic properties. C1 [Lozito, Thomas P.; Tuan, Rocky S.] Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Sch Med, Pittsburgh, PA 15219 USA. [Jackson, Wesley M.; Lozito, Thomas P.; Djouad, Farida; Kuhn, Nastaran Z.; Nesti, Leon J.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Jackson, Wesley M.; Nesti, Leon J.] NIAMSD, Clin & Expt Othopaed Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Nesti, Leon J.] Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Sch Med, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu OI Djouad, Farida/0000-0001-8248-6822 FU Walter Reed Army Medical Center [PO5-A011]; Comprehensive Neurosciences Program [CNP-2008-CR01]; NIH [Z01 AR41131]; University of Pennsylvania, Department of Health FX Support was provided by the Military Amputee Research Program at Walter Reed Army Medical Center (PO5-A011), the Comprehensive Neurosciences Program (CNP-2008-CR01), the NIH Intramural Research Program (Z01 AR41131) and the University of Pennsylvania, Department of Health. Immunophenotyping was performed in the NIAMS Flow Cytometry Group with the assistance of James Simone. Technical assistance was provided by Jun Onodera, Yingjie Song and Ibardo Zambrano. We thank Dr. Paul Manner, Department of Orthopaedic Surgery at the University of Washington, for providing human skeletal tissues. NR 56 TC 15 Z9 17 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1582-4934 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD NOV PY 2011 VL 15 IS 11 BP 2377 EP 2388 DI 10.1111/j.1582-4934.2010.01225.x PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 859DQ UT WOS:000297855400011 PM 21129154 ER PT J AU Vaidyanath, A Hashizume, T Nagaoka, T Takeyasu, N Satoh, H Chen, L Wang, J Kasai, T Kudoh, T Satoh, A Fu, L Seno, M AF Vaidyanath, Arun Hashizume, Toshihiro Nagaoka, Tadahiro Takeyasu, Nao Satoh, Hitomi Chen, Ling Wang, Jiyou Kasai, Tomonari Kudoh, Takayuki Satoh, Ayano Fu, Li Seno, Masaharu TI Enhanced internalization of ErbB2 in SK-BR-3 cells with multivalent forms of an artificial ligand SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE ErbB2; EC-1 peptide; internalization; multivalent display; bionanocapsule ID CLATHRIN-INDEPENDENT ENDOCYTOSIS; TUMOR NECROSIS FACTOR; BREAST-CANCER CELLS; DOWN-REGULATION; SIGNALING NETWORK; OVARIAN-CANCER; RECEPTOR; GELDANAMYCIN; TRASTUZUMAB; EXPRESSION AB Targeting and down-regulation of ErbB2, a member of EGF receptor family, is regarded as one of the key aspect for cancer treatment because it is often overexpressed in breast and ovarian cancer cells. Although natural ligands for ErbB2 have not been found, unlike other ErbB receptors, EC-1, a 20-amino acid circular peptide, has been shown to bind to ErbB2 as an artificial ligand. Previously we showed EC-1 peptide did not induce the internalization of ErbB2 in SK-BR-3 cells. In this report, we designed divalent and multivalent forms of EC-1 peptide with the Fc portion of the human IgG and bionanocapsule modified with ZZ-tag on its surface to improve the interaction with ErbB2. These forms showed higher affinity to ErbB2 than that of EC-1 monomer. Furthermore, prominent endosomal accumulation of ErbB2 occurred in SK-BR-3 cells when stimulated with EC-Fc ligand multivalently displayed on the surface of the bionanocapsule, whereas SK-BR-3 cells as themselves displayed stringent mechanism against ErbB2 internalization without stimulation. The multivalent form of EC-1 peptide appeared to internalize ErbB2 more efficiently than divalent form did. This internalization was unaffected by the inhibition of clathrin association, but inhibited when the cholesterol was depleted which explained either caveolar or GPI-AP-early endocytic compartment (GEEC) pathway. Because of the lack of caveolin-1 expression, caveolar machinery may be lost in SK-BR-3 cell line. Therefore, it is suggested that the multivalent form of EC-1 induces the internalization of ErbB2 through the GEEC pathway. C1 [Vaidyanath, Arun; Hashizume, Toshihiro; Nagaoka, Tadahiro; Takeyasu, Nao; Satoh, Hitomi; Chen, Ling; Wang, Jiyou; Kasai, Tomonari; Kudoh, Takayuki; Satoh, Ayano; Seno, Masaharu] Okayama Univ, Fac Engn, Dept Med Bioengn Sci,Lab Nanobiotechnol, Grad Sch Nat Sci & Biotechnol,Kita Ku, Okayama 700, Japan. [Nagaoka, Tadahiro] Natl Canc Inst, Ctr Canc Res, Mammary Biol & Tumorigenesis Lab, Tumour Growth Factor Sect, Bethesda, MD USA. [Satoh, Ayano] Okayama Univ, Res Core Interdisciplinary Sci, Kita Ku, Okayama 700, Japan. [Fu, Li] Tianjin Med Univ, Dept Breast Canc Pathol & Res Lab, State Key Lab Breast Canc Res, Canc Hosp, Tianjin, Peoples R China. RP Seno, M (reprint author), Okayama Univ, Fac Engn, Dept Med Bioengn Sci,Lab Nanobiotechnol, Grad Sch Nat Sci & Biotechnol,Kita Ku, Room 361,Bldg ENG 6,3-1-1, Okayama 700, Japan. EM mseno@cc.okayama-u.ac.jp RI SENO, Masaharu /B-2092-2011; SATOH, Ayano/B-2423-2011; OI SENO, Masaharu /0000-0001-8547-6259; SATOH, Ayano/0000-0003-3736-1283; Nagaoka, Tadahiro/0000-0002-9391-0243 FU Ministry of Education, Culture, Sports, Science and Technology in Japan [21300179, H21-nano-general-004]; National Natural Science Foundation of China [30930038] FX The authors thank Prof. N. Kanayama for his valuable help and suggestions in flow cytometric analysis. The authors also thank Prof. H. Matsui for helpful discussion throughout the work. This work was partly supported by Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology (No. 21300179) in Japan, Health and Labor Sciences Research Grants, Research on Nanotechnical Medical, H21-nano-general-004 and National Natural Science Foundation of China (Key Program, Grant No. 30930038). NR 47 TC 8 Z9 8 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD NOV PY 2011 VL 15 IS 11 BP 2525 EP 2538 DI 10.1111/j.1582-4934.2011.01277.x PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 859DQ UT WOS:000297855400024 PM 21323863 ER PT J AU Mete, M Wilson, C Lee, ET Silverman, A Russell, M Stylianou, M Umans, JG Wang, WY Howard, WJ Ratner, RE Howard, BV Fleg, JL AF Mete, Mihriye Wilson, Charlton Lee, Elisa T. Silverman, Angela Russell, Marie Stylianou, Mario Umans, Jason G. Wang, Wenyu Howard, Wm J. Ratner, Robert E. Howard, Barbara V. Fleg, Jerome L. TI Relationship of glycemia control to lipid and blood pressure lowering and atherosclerosis: the SANDS experience SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE LDL-C; A1c; Cardiovascular disease; Carotid arteries; Diabetes ID CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; AMERICAN-INDIANS; LOWER TARGETS; RISK-FACTORS; CHOLESTEROL; WOMEN; HYPERGLYCEMIA; ASSOCIATION; ADVANCE AB Objectives: Cardiovascular disease prevention for patients with type 2 diabetes is accomplished through hypertension and dyslipidemia management. Although studies have established strategies for lowering low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP), none have examined whether glycemia influences ability to achieve lipid and BP targets. This post hoc analysis from the Stop Atherosclerosis in Native Diabetics Study examines the role of baseline glycemia in achieving standard and aggressive targets and outcomes after 36 months. Methods: Diabetic individuals aged >40 years with no cardiovascular events (n=499) were randomized to aggressive versus standard targets for LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C) and systolic BP (SBP). Management algorithms were used for both groups. Carotid ultrasound and echocardiography were performed at baseline and after 36 months. Results: No differences were observed in baseline hemoglobin A1c between treatment groups nor any significant change in A1c after 36 months in either group. Baseline A1c, however, was significantly and negatively related to achieving LDL-C (P=.007), non-HDL-C (P=.03) and SBP targets (P=.007) and to changes in LDL-C (P=.007), non-HDL-C (P=.03) and SBP (P=.001) in both groups. Baseline A1c failed to predict progression of carotid intima medial thickness (CIMT) (P=.42) or left ventricular mass index (LVMI) (P=.10), nor was it related to the effects of lipid and BP lowering on CIMT and LVMI over 36 months. Conclusions: In diabetic adults with no cardiovascular disease events. A1c was negatively associated with ability to achieve LDL-C, non-HDL-C and SBP goals but was not independently related to treatment-associated changes in CIMT or LVMI over 36 months. (C) 2011 Elsevier Inc. All rights reserved. C1 [Mete, Mihriye; Silverman, Angela; Umans, Jason G.; Ratner, Robert E.; Howard, Barbara V.] Georgetown Univ, MedStar Hlth Res Inst, Hyattsville, MD 20782 USA. [Wilson, Charlton; Russell, Marie] Phoenix Indian Med Ctr, Phoenix, AZ USA. [Lee, Elisa T.; Wang, Wenyu] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Stylianou, Mario; Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Howard, Wm J.] Washington Hosp Ctr, Washington, DC 20010 USA. RP Howard, BV (reprint author), Georgetown Univ, MedStar Hlth Res Inst, 6525 Belcrest Rd,Ste 700, Hyattsville, MD 20782 USA. EM barbara.v.howard@medstar.net FU National Heart, Lung and Blood Institute [U01-HL067031] FX This study was supported by grant U01-HL067031 from the National Heart, Lung and Blood Institute. NR 26 TC 5 Z9 5 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD NOV-DEC PY 2011 VL 25 IS 6 BP 362 EP 367 DI 10.1016/j.jdiacomp.2011.04.001 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865UA UT WOS:000298335200002 PM 21775166 ER PT J AU Schug, TT Janesick, A Blumberg, B Heindel, JJ AF Schug, Thaddeus T. Janesick, Amanda Blumberg, Bruce Heindel, Jerrold J. TI Endocrine disrupting chemicals and disease susceptibility SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Endocrine disrupting chemicals; Hormone; Disease susceptibility; Bisphenol A; Nuclear receptor; Obesogen; Low dose effects; Developmental windows of susceptibility ID HUMAN SEMEN QUALITY; EPIGENETIC TRANSGENERATIONAL ACTIONS; POLYCYSTIC-OVARY-SYNDROME; BISPHENOL-A; PERINATAL EXPOSURE; ADIPOCYTE DIFFERENTIATION; DEVELOPMENTAL EXPOSURE; DIETHYLSTILBESTROL DES; PESTICIDE EXPOSURE; UTERINE LEIOMYOMAS AB Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products - including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption. Published by Elsevier Ltd. C1 [Schug, Thaddeus T.; Heindel, Jerrold J.] Natl Inst Environm Hlth Sci, Div Extramural Res & Training, Cellular Organ & Syst Pathobiol Branch, Res Triangle Pk, NC 27709 USA. [Janesick, Amanda; Blumberg, Bruce] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. RP Schug, TT (reprint author), Natl Inst Environm Hlth Sci, Div Extramural Res & Training, Cellular Organ & Syst Pathobiol Branch, Res Triangle Pk, NC 27709 USA. EM schugt@niehs.nih.gov OI Janesick, Amanda/0000-0001-7731-2756 FU Intramural NIH HHS [Z99 ES999999] NR 124 TC 228 Z9 238 U1 27 U2 189 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD NOV PY 2011 VL 127 IS 3-5 SI SI BP 204 EP 215 DI 10.1016/j.jsbmb.2011.08.007 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 868NZ UT WOS:000298531300008 PM 21899826 ER PT J AU Kuhn, NZ Nagahara, L AF Kuhn, Nastaran Zahir Nagahara, Larry TI Preface: A Physical Sciences Perspective of the Evolution of Drug Resistance in Cancer SO MOLECULAR PHARMACEUTICS LA English DT Editorial Material C1 [Kuhn, Nastaran Zahir; Nagahara, Larry] NCI, Off Phys Sci Oncol, Ctr Strateg Sci Initiat, Off Director,NIH, Bethesda, MD 20892 USA. RP Kuhn, NZ (reprint author), NCI, Off Phys Sci Oncol, Ctr Strateg Sci Initiat, Off Director,NIH, Bethesda, MD 20892 USA. EM nas.kuhn@nih.gov; larry.nagahara@nih.gov NR 9 TC 4 Z9 4 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV-DEC PY 2011 VL 8 IS 6 BP 1994 EP 1995 DI 10.1021/mp200529w PG 2 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 855BA UT WOS:000297537300002 PM 22136314 ER PT J AU Robey, RW Chakraborty, AR Basseville, A Luchenko, V Bahr, J Zhan, ZR Bates, SE AF Robey, Robert W. Chakraborty, Arup R. Basseville, Agnes Luchenko, Victoria Bahr, Julian Zhan, Zhirong Bates, Susan E. TI Histone Deacetylase Inhibitors: Emerging Mechanisms of Resistance SO MOLECULAR PHARMACEUTICS LA English DT Review DE histone deacetylase inhibitor; resistance; romidepsin; vorinostat; panobinostat ID T-CELL LYMPHOMA; SUBEROYLANILIDE HYDROXAMIC ACID; HUMAN LEUKEMIA-CELLS; LUNG-CANCER CELLS; NF-KAPPA-B; CHRONIC LYMPHOCYTIC-LEUKEMIA; ADVANCED SOLID TUMORS; XIAP DOWN-REGULATION; DNA-DAMAGE RESPONSE; PHASE-II TRIAL AB The histone deacetylase inhibitors (HDIs) have shown promise in the treatment of a number of hematologic malignancies, leading to the approval of vorinostat and romidepsin for the treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma by the U.S. Food and Drug Administration. Despite these promising results, clinical trials with the HDIs in solid tumors have not met with success. Examining mechanisms of resistance to HDIs may lead to strategies that increase their therapeutic potential in solid tumors. However, relatively few examples of drug-selected cell lines exist, and mechanisms of resistance have not been studied in depth. Very few clinical translational studies have evaluated resistance mechanisms. In the current review, we summarize many of the purported mechanisms of action of the HDIs in clinical trials and examine some of the emerging resistance mechanisms. C1 [Robey, Robert W.; Chakraborty, Arup R.; Basseville, Agnes; Luchenko, Victoria; Bahr, Julian; Zhan, Zhirong; Bates, Susan E.] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Chakraborty, Arup R.] Texas Tech Univ, Dept Biol Sci, Lubbock, TX 79409 USA. RP Robey, RW (reprint author), NCI, NIH, Med Oncol Branch, 9000 Rockville Pike,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov FU 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 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 organization imply endorsement by the U.S. Government. NR 126 TC 39 Z9 42 U1 2 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV-DEC PY 2011 VL 8 IS 6 BP 2021 EP 2031 DI 10.1021/mp200329f PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 855BA UT WOS:000297537300005 PM 21899343 ER PT J AU Gillett, JP Wang, JB Calcagno, AM Green, LJ Varma, S Elstrand, MB Trope, CG Ambudkar, SV Davidson, B Gottesman, MM AF Gillett, Jean-Pierre Wang, Junbai Calcagno, Anna Maria Green, Lisa J. Varma, Sudhir Elstrand, Mari Bunkholt Trope, Claes G. Ambudkar, Suresh V. Davidson, Ben Gottesman, Michael M. TI Clinical Relevance of Multidrug Resistance Gene Expression in Ovarian Serous Carcinoma Effusions SO MOLECULAR PHARMACEUTICS LA English DT Article DE ovarian serous carcinoma; effusion; multidrug resistance; gene signature ID DIHYDRODIOL DEHYDROGENASE; TISSUE INHIBITOR; TYROSINE KINASE; MICROARRAY DATA; SRC INHIBITION; BREAST-CANCER; CELL; MARKER; METALLOPROTEINASES-1; SURVIVAL AB The presence of tumor cells in effusions within serosal cavities is a clinical manifestation of advanced-stage cancer and is generally associated with poor survival. Identifying molecular targets may help to design efficient treatments to eradicate these aggressive cancer cells and improve patient survival. Using a state-of-the-art TaqMan-based qRT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of 32 unpaired ovarian serous carcinoma effusion samples obtained at diagnosis or at disease recurrence following chemotherapy. MDR genes were selected a priori based on an extensive curation of the literature published during the last three decades. We found three gene signatures with a statistically significant correlation with overall survival (OS), response to treatment [complete response (CR) vs other], and progression free survival (IFS). The median log-rank p-values for the signatures were 0.023, 0.034, and 0.008, respectively. No correlation was found with residual tumor status after cytoreductive surgery, treatment (with or without chemotherapy) and stage defined according to the International Federation of Gynecology and Obstetrics. Further analyses demonstrated that gene expression alone can effectively predict the survival outcome of women with ovarian serous carcinoma (OS, log-rank p = 0.0000; and PFS, log-rank p = 0.002). Interestingly, the signature for overall survival is the same in patients at first presentation and those who had chemotherapy and relapsed. This pilot study highlights two new gene signatures that may help in optimizing the treatment for ovarian carcinoma patients with effusions. C1 [Gillett, Jean-Pierre; Calcagno, Anna Maria; Green, Lisa J.; Ambudkar, Suresh V.; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Junbai; Davidson, Ben] Oslo Univ Hosp, Norwegian Radium Hosp, Div Pathol, N-0310 Oslo, Norway. [Varma, Sudhir] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, Off Sci Management & Operat,NIH, Bethesda, MD 20892 USA. [Elstrand, Mari Bunkholt; Trope, Claes G.] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Gynecol Oncol, N-0310 Oslo, Norway. [Trope, Claes G.; Davidson, Ben] Univ Oslo, Fac Med, N-0316 Oslo, Norway. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM gottesmanm@mail.nih.gov RI Wang, Junbai/B-2093-2008; gillet, jean-pierre/A-3714-2012; Calcagno, Anna Maria/A-5617-2012; Varma, Sudhir/N-8763-2014; OI Varma, Sudhir/0000-0002-4096-4782; Calcagno, Anna Maria/0000-0002-0804-2753 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Inger and John Fredriksen Foundation for Ovarian Cancer Research FX We thank George Leiman for editorial assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by the Inger and John Fredriksen Foundation for Ovarian Cancer Research. NR 50 TC 18 Z9 18 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV-DEC PY 2011 VL 8 IS 6 BP 2080 EP 2088 DI 10.1021/mp200240a PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 855BA UT WOS:000297537300012 PM 21761824 ER PT J AU Zhu, L Zhang, F Ma, Y Liu, G Kim, K Fang, XX Lee, S Chen, XY AF Zhu, Lei Zhang, Fan Ma, Ying Liu, Gang Kim, Kwangmeyung Fang, Xuexun Lee, Seulki Chen, Xiaoyuan TI In Vivo Optical Imaging of Membrane-Type Matrix Metalloproteinase (MT-MMP) Activity SO MOLECULAR PHARMACEUTICS LA English DT Article DE activatable probe; fluorogenic probe; membrane-type matrix metalloproteinase; optical imaging; protease ID CELL PENETRATING PEPTIDES; TUMOR MICROENVIRONMENT; THERAPEUTIC TARGET; FLUOROGENIC PROBE; CANCER-THERAPY; INHIBITORS; PROTEASES; INVASION; MT1-MMP; BEACON AB Herein we demonstrate for the first time that a fluorogenic probe can be used as an in vivo imaging agent for visualizing activities of membrane-tethered, membrane-type matrix metalloproteinases (MT-MMPs). An MT-MMP fluorogenic probe that consisted of an MT1-MMP (MMP-14) substrate and near-infrared (NIR) dye-quencher pair exhibited rapid, efficient boosts in fluorescence upon cleavage by MT1-MMP in tumor-bearing mice. In particular, unlike similar fluorogenic probes designed to target extracellular, soluble-type MMPs (EC-MM.Ps) which can be cleared from the bloodstream after activation-the fluorescence signals activated by MT1-MIMP enable clear visualization of MT1-MMP-positive tumors in animal models for up to 24 h. The results indicate that a simple form of a fluorogenic probe that is less effective in EC-MMP imaging is an effective probe for imaging MT-MMP activities in vivo. These findings can be widely applied to designing probes and to applications targeting various membrane-anchored proteases in vivo. C1 [Zhu, Lei; Zhang, Fan; Ma, Ying; Liu, Gang; Lee, Seulki; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Zhu, Lei; Fang, Xuexun] Jilin Univ, Minist Educ, Key Lab Mol Enzymol & Enzyme Engn, Changchun 130023, Peoples R China. [Kim, Kwangmeyung] Korea Inst Sci & Technol, Biomed Res Ctr, Seoul 136791, South Korea. RP Chen, XY (reprint author), 31 Ctr Dr,1C22, Bethesda, MD 20892 USA. EM seulki.lee@nih.gov; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009]; Chinese Scholarship Council (CSC); NIH [K99/R00] FX This work was supported in part by the Intramural Research Program (IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), and the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). L.Z. is partially supported by the Chinese Scholarship Council (CSC). S.L. is partially supported by the NIH pathway to independence (K99/R00) award. We thank Ms. Maggie Swierczewska and Dr. Henry S. Eden for proof-reading the manuscript. NR 33 TC 24 Z9 26 U1 3 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV-DEC PY 2011 VL 8 IS 6 BP 2331 EP 2338 DI 10.1021/mp2002297 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 855BA UT WOS:000297537300035 PM 22014151 ER PT J AU Voon, V Brezing, C Gallea, C Hallett, M AF Voon, Valerie Brezing, Christina Gallea, Cecile Hallett, Mark TI Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder SO MOVEMENT DISORDERS LA English DT Article DE conversion disorder; action selection; motor initiation; supplementary motor area; psychogenic movement disorder ID PREFRONTAL CORTEX; WILLED ACTION; CORTICOSPINAL PROJECTIONS; CINGULATE AREAS; ARM MOVEMENTS; HUMAN BRAIN; PARALYSIS; MONKEY; INHIBITION; SELECTION AB Conversion disorder (CD) is characterized by unexplained neurological symptoms presumed related to psychological issues. The main hypotheses to explain conversion paralysis, characterized by a lack of movement, include impairments in either motor intention or disruption of motor execution, and further, that hyperactive self-monitoring, limbic processing or top-down regulation from higher order frontal regions may interfere with motor execution. We have recently shown that CD with positive abnormal or excessive motor symptoms was associated with greater amygdala activity to arousing stimuli along with greater functional connectivity between the amygdala and supplementary motor area. Here we studied patients with such symptoms focusing on motor initiation. Subjects performed either an internally or externally generated 2-button action selection task in a functional MRI study. Eleven CD patients without major depression and 11 age- and gender-matched normal volunteers were assessed. During both internally and externally generated movement, conversion disorder patients relative to normal volunteers had lower left supplementary motor area (SMA) (implicated in motor initiation) and higher right amygdala, left anterior insula, and bilateral posterior cingulate activity (implicated in assigning emotional salience). These findings were confirmed in a subgroup analysis of patients with tremor symptoms. During internally versus externally generated action in CD patients, the left SMA had lower functional connectivity with bilateral dorsolateral prefrontal cortices. We propose a theory in which previously mapped conversion motor representations may in an arousing context hijack the voluntary action selection system, which is both hypoactive and functionally disconnected from prefrontal top-down regulation. (c) 2011 Movement Disorder Society C1 [Voon, Valerie] Univ Cambridge, Dept Expt Psychol, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Brezing, Christina; Gallea, Cecile; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. RP Voon, V (reprint author), Univ Cambridge, Dept Expt Psychol, Behav & Clin Neurosci Inst, Downing Site, Cambridge CB2 3EB, England. EM voonval@gmail.com FU Intramural National Institutes of Health; Neurotoxin Institute; NIH (from Brainsway); NIH; US Army via the Henry Jackson Foundation; Ariston Pharmaceutical Company; Kinetics Foundation; intramural National Institute of Neurological Disorders; Stroke, National Institutes of Health FX Funding agencies: Intramural National Institutes of Health.; Dr. Voon has not had any activities to disclose for the last 2 years. Dr. Brezing has not had any activities to disclose for the last 2 years. Dr. Gallea has not had any activities to disclose for the last 2 years. Dr. Hallett serves as Chair of the Medical Advisory Board for and receives honoraria and funding for travel from the Neurotoxin Institute. He may accrue revenue on US Patent #6,780,413 B2 (Issued: August 24, 2004): Immunotoxin (MAB-Ricin) for the treatment of focal movement disorders, and US Patent #7,407,478 (Issued: August 5, 2008): Coil for Magnetic Stimulation and methods for using the same (H-coil); in relation to the latter, he has received license fee payments from the NIH (from Brainsway) for licensing of this patent. Dr. Hallett's research at the NIH is largely supported by the NIH Intramural Program. Supplemental research funds came from the US Army via the Henry Jackson Foundation, Ariston Pharmaceutical Company via a Cooperative Research and Development Agreement (CRADA) with NIH, and the Kinetics Foundation via a Clinical Trials Agreement (CTA) with NIH. Dr. Hallett serves as Chair of the Medical Advisory Board of the Benign Essential Blepharospasm Foundation and Chair of the Medical Advisory Board of the International Essential Tremor Foundation. He serves on editorial advisory boards for Clinical Neurophysiology, Brain, Acta Neurologica Scandinavica, Journal of Clinical Neurophysiology, Italian Journal of Neurological Sciences, Medical Problems of Performing Artists, Annals of Neurology, Neurology and Clinical Neurophysiology, The Cerebellum, NeuroRx, Current Trends in Neurology, Faculty of 1000 Medicine, Brain Stimulation, Journal of Movement Disorders (Korea), and is Editor-in-Chief of World Neurology. He receives publishing royalties from Blackwell Publisher, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, Massachusetts Medical Society, Wolters Kluwer, and Elsevier. He has received honoraria for lecturing from Columbia University, the Parkinson and Aging Research Foundation, University of Maryland, University of Wisconsin, State of New York, and University of Navara.; This study was funded by and conducted at the intramural National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 39 TC 56 Z9 56 U1 0 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD NOV PY 2011 VL 26 IS 13 BP 2396 EP 2403 DI 10.1002/mds.23890 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 858ZP UT WOS:000297843300015 PM 21935985 ER PT J AU Stranahan, AM Mattson, MP AF Stranahan, Alexis M. Mattson, Mark P. TI Bidirectional metabolic regulation of neurocognitive function SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Review DE Diabetes; Exercise; Caloric restriction; Cognition; Hippocampus ID TRANSGENIC MOUSE MODEL; INSULIN-DEGRADING ENZYME; GLUCAGON-LIKE PEPTIDE-1; PITUITARY-ADRENOCORTICAL AXIS; MILD COGNITIVE IMPAIRMENT; TYPE-2 DIABETES-MELLITUS; TERM VOLUNTARY EXERCISE; HIGH-FAT DIET; CALORIC RESTRICTION; ALZHEIMERS-DISEASE AB The efficiency of somatic energy metabolism is correlated with cognitive change over the lifespan. This relationship is bidirectional, with improved overall fitness associated with enhanced synaptic function and neuroprotection, and synaptic endangerment occurring in the context of impaired energy metabolism. In this review, we discuss recent advancements in the fields of exercise, dietary energy intake and diabetes, as they relate to neuronal function in the hippocampus. Because hippocampal neurons have energy requirements that are relatively higher than those of other brain regions, they are uniquely poised to benefit from exercise, and to be harmed by diabetes. We view exercise and dietary energy restriction as being associated with enhanced hippocampal plasticity at one end of a continuum, with obesity and diabetes accompanied by cognitive impairment at the other end of the continuum. Understanding the mechanisms for this continuum may yield novel therapeutic targets for the prevention and treatment of cognitive decline following aging, disease, or injury. (C) 2011 Elsevier Inc. All rights reserved. C1 [Stranahan, Alexis M.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. [Mattson, Mark P.] NIA, Cellular & Mol Neurosci Sect, Neurosci Lab, Baltimore, MD 21224 USA. RP Stranahan, AM (reprint author), Johns Hopkins Univ, Dept Psychol & Brain Sci, 3400N Charles St, Baltimore, MD 21218 USA. EM astranahan@mail.mcg.edu RI Mattson, Mark/F-6038-2012 FU NIH NRSA [AG034818-01]; National Institute on Aging FX This work was supported by NIH NRSA AG034818-01 to A.M.S., and by the Intramural Research Program of the National Institute on Aging (M.P.M.). NR 156 TC 20 Z9 21 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD NOV PY 2011 VL 96 IS 4 SI SI BP 507 EP 516 DI 10.1016/j.nlm.2011.01.004 PG 10 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 859UD UT WOS:000297900400002 PM 21236352 ER PT J AU Procino, G Barbieri, C Carmosino, M Tamma, G Milano, S De Benedictis, L Mola, MG Lazo-Fernandez, Y Valenti, G Svelto, M AF Procino, Giuseppe Barbieri, Claudia Carmosino, Monica Tamma, Grazia Milano, Serena De Benedictis, Leonarda Mola, Maria Grazia Lazo-Fernandez, Yoskaly Valenti, Giovanna Svelto, Maria TI Fluvastatin modulates renal water reabsorption in vivo through increased AQP2 availability at the apical plasma membrane of collecting duct cells SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Nephrogenic diabetes insipidus; Aquaporins; Vasopressin; Statins; Kidney; Diuresis; Epithelial transport; Diabetes insipidus ID NEPHROGENIC DIABETES-INSIPIDUS; COA REDUCTASE INHIBITORS; CORONARY-HEART-DISEASE; AQUAPORIN-2 TRAFFICKING; PROTEIN PRENYLATION; CLINICALLY RELEVANT; COTRANSPORTER NKCC2; CHOLESTEROL LEVELS; PRINCIPAL CELLS; NITRIC-OXIDE AB X-linked nephrogenic diabetes insipidus (XNDI), a severe pathological condition characterized by greatly impaired urine-concentrating ability of the kidney, is caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene. The lack of functional V2Rs prevents vasopressin-induced shuttling of aquaporin-2 (AQP2) water channels to the apical plasma membrane of kidney collecting duct principal cells, thus promoting water reabsorption from urine to the interstitium. At present, no specific pharmacological therapy exists for the treatment of XNDI. We have previously reported that the cholesterol-lowering drug lovastatin increases AQP2 membrane expression in renal cells in vitro. Here we report the novel finding that fluvastatin, another member of the statins family, greatly increases kidney water reabsorption in vivo in mice in a vasopressin-independent fashion. Consistent with this observation, fluvastatin is able to increase AQP2 membrane expression in the collecting duct of treated mice. Additional in vivo and in vitro experiments indicate that these effects of fluvastatin are most likely caused by fluvastatin-dependent changes in the prenylation status of key proteins regulating AQP2 trafficking in collecting duct cells. We identified members of the Rho and Rab families of proteins as possible candidates whose reduced prenylation might result in the accumulation of AQP2 at the plasma membrane. In conclusion, these results strongly suggest that fluvastatin, or other drugs of the statin family, may prove useful in the therapy of XNDI. C1 [Procino, Giuseppe; Barbieri, Claudia; Carmosino, Monica; Tamma, Grazia; Milano, Serena; Mola, Maria Grazia; Valenti, Giovanna; Svelto, Maria] Univ Bari, Dept Gen & Environm Physiol, Bari, Italy. [Valenti, Giovanna; Svelto, Maria] Ctr Eccellenza Genom Campo Biomed Agr CEGBA, Bari, Italy. [De Benedictis, Leonarda] Univ Bari, Sch Med, Dept Biomed Sci & Human Oncol, Bari, Italy. [Lazo-Fernandez, Yoskaly] NIDDK, NIH, Bethesda, MD USA. RP Procino, G (reprint author), Univ Bari, Dept Gen & Environm Physiol, Bari, Italy. EM g.procino@biologia.uniba.it RI Carmosino, Monica/O-2594-2014; Tamma, Grazia/F-8823-2016; OI Carmosino, Monica/0000-0001-7600-8816; VALENTI, GIOVANNA/0000-0003-0233-0778; Svelto, Maria/0000-0002-5584-9541; Procino, Giuseppe/0000-0002-0043-7523; Tamma, Grazia/0000-0002-8890-0278 FU Fondazione Cassa di Risparmio di Puglia (FCRP) [25/2009]; PRIN (Research Program of National Interest) [20078ZZMZW]; Fondo per gli Investimenti della Ricerca di Base-Rete Nazionale di Proteomica [RBRN07BMCT_009] FX This work has been funded by grants from Fondazione Cassa di Risparmio di Puglia (FCRP) No. 25/2009 to G. Procino, from PRIN (Research Program of National Interest) projects to M. Svelto (20078ZZMZW), and from Fondo per gli Investimenti della Ricerca di Base-Rete Nazionale di Proteomica (RBRN07BMCT_009). We are grateful to G. Devito for the excellent technical assistance with the animal experiments. We would like to thank Prof. F. Palmisano (Department of Chemistry, University of Bari) for the helpful discussions and supervision of the HPLC measurements. NR 70 TC 21 Z9 26 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD NOV PY 2011 VL 462 IS 5 BP 753 EP 766 DI 10.1007/s00424-011-1007-5 PG 14 WC Physiology SC Physiology GA 877CB UT WOS:000299153000011 PM 21858457 ER PT J AU Maxwell, CA Benitez, J Gomez-Baldo, L Osorio, A Bonifaci, N Fernandez-Ramires, R Costes, SV Guino, E Chen, H Evans, GJR Mohan, P Catala, I Petit, A Aguilar, H Villanueva, A Aytes, A Serra-Musach, J Rennert, G Lejbkowicz, F Peterlongo, P Manoukian, S Peissel, B Ripamonti, CB Bonanni, B Viel, A Allavena, A Bernard, L Radice, P Friedman, E Kaufman, B Laitman, Y Dubrovsky, M Milgrom, R Jakubowska, A Cybulski, C Gorski, B Jaworska, K Durda, K Sukiennicki, G Lubinski, J Shugart, YY Domchek, SM Letrero, R Weber, BL Hogervorst, FBL Rookus, MA Collee, JM Devilee, P Ligtenberg, MJ van der Luijt, RB Aalfs, CM Waisfisz, Q Wijnen, J van Roozendaal, CEP Easton, DF Peock, S Cook, M Oliver, C Frost, D Harrington, P Evans, DG Lalloo, F Eeles, R Izatt, L Chu, C Eccles, D Douglas, F Brewer, C Nevanlinna, H Heikkinen, T Couch, FJ Lindor, NM Wang, XS Godwin, AK Caligo, MA Lombardi, G Loman, N Karlsson, P Ehrencrona, H von Wachenfeldt, A Barkardottir, RB Hamann, U Rashid, MU Lasa, A Caldes, T Andres, R Schmitt, M Assmann, V Stevens, K Offit, K Curado, J Tilgner, H Guigo, R Aiza, G Brunet, J Castellsague, J Martrat, G Urruticoechea, A Blanco, I Tihomirova, L Goldgar, DE Buys, S John, EM Miron, A Southey, M Daly, MB Schmutzler, RK Wappenschmidt, B Meindl, A Arnold, N Deissler, H Varon-Mateeva, R Sutter, C Niederacher, D Imyamitov, E Sinilnikova, OM Stoppa-Lyonne, D Mazoyer, S Verny-Pierre, C Castera, L de Pauw, A Bignon, YJ Uhrhammer, N Peyrat, JP Vennin, P Ferrer, SF Collonge-Rame, MA Mortemousque, I Spurdle, AB Beesley, J Chen, XQ Healey, S Barcellos-Hoff, MH Vidal, M Gruber, SB Lazaro, C Capella, G McGuffog, L Nathanson, KL Antoniou, AC Chenevix-Trench, G Fleisch, MC Moreno, V Pujana, MA AF Maxwell, Christopher A. Benitez, Javier Gomez-Baldo, Laia Osorio, Ana Bonifaci, Nuria Fernandez-Ramires, Ricardo Costes, Sylvain V. Guino, Elisabet Chen, Helen Evans, Gareth J. R. Mohan, Pooja Catala, Isabel Petit, Anna Aguilar, Helena Villanueva, Alberto Aytes, Alvaro Serra-Musach, Jordi Rennert, Gad Lejbkowicz, Flavio Peterlongo, Paolo Manoukian, Siranoush Peissel, Bernard Ripamonti, Carla B. Bonanni, Bernardo Viel, Alessandra Allavena, Anna Bernard, Loris Radice, Paolo Friedman, Eitan Kaufman, Bella Laitman, Yael Dubrovsky, Maya Milgrom, Roni Jakubowska, Anna Cybulski, Cezary Gorski, Bohdan Jaworska, Katarzyna Durda, Katarzyna Sukiennicki, Grzegorz Lubinski, Jan Shugart, Yin Yao Domchek, Susan M. Letrero, Richard Weber, Barbara L. Hogervorst, Frans B. L. Rookus, Matti A. Collee, J. Margriet Devilee, Peter Ligtenberg, Marjolijn J. van der Luijt, Rob B. Aalfs, Cora M. Waisfisz, Quinten Wijnen, Juul van Roozendaal, Cornelis E. P. Easton, Douglas F. Peock, Susan Cook, Margaret Oliver, Clare Frost, Debra Harrington, Patricia Evans, D. Gareth Lalloo, Fiona Eeles, Rosalind Izatt, Louise Chu, Carol Eccles, Diana Douglas, Fiona Brewer, Carole Nevanlinna, Heli Heikkinen, Tuomas Couch, Fergus J. Lindor, Noralane M. Wang, Xianshu Godwin, Andrew K. Caligo, Maria A. Lombardi, Grazia Loman, Niklas Karlsson, Per Ehrencrona, Hans von Wachenfeldt, Anna Barkardottir, Rosa Bjork Hamann, Ute Rashid, Muhammad U. Lasa, Adriana Caldes, Trinidad Andres, Raquel Schmitt, Michael Assmann, Volker Stevens, Kristen Offit, Kenneth Curado, Joao Tilgner, Hagen Guigo, Roderic Aiza, Gemma Brunet, Joan Castellsague, Joan Martrat, Griselda Urruticoechea, Ander Blanco, Ignacio Tihomirova, Laima Goldgar, David E. Buys, Saundra John, Esther M. Miron, Alexander Southey, Melissa Daly, Mary B. Schmutzler, Rita K. Wappenschmidt, Barbara Meindl, Alfons Arnold, Norbert Deissler, Helmut Varon-Mateeva, Raymonda Sutter, Christian Niederacher, Dieter Imyamitov, Evgeny Sinilnikova, Olga M. Stoppa-Lyonne, Dominique Mazoyer, Sylvie Verny-Pierre, Carole Castera, Laurent de Pauw, Antoine Bignon, Yves-Jean Uhrhammer, Nancy Peyrat, Jean-Philippe Vennin, Philippe Ferrer, Sandra Fert Collonge-Rame, Marie-Agnes Mortemousque, Isabelle Spurdle, Amanda B. Beesley, Jonathan Chen, Xiaoqing Healey, Sue Barcellos-Hoff, Mary Helen Vidal, Marc Gruber, Stephen B. Lazaro, Conxi Capella, Gabriel McGuffog, Lesley Nathanson, Katherine L. Antoniou, Antonis C. Chenevix-Trench, Georgia Fleisch, Markus C. Moreno, Victor Angel Pujana, Miguel CA HEBON EMBRACE SWE-BRCA BCFR GEMO Study Collaborators kConFab TI Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer SO PLOS BIOLOGY LA English DT Article ID CENTROSOMAL MICROTUBULE NUCLEATION; PROGENITOR-CELL FATE; MUTATION CARRIERS; MAMMARY-GLAND; MITOTIC SPINDLE; STEM-CELLS; MULTIPLE-MYELOMA; BRCA1-DEPENDENT UBIQUITINATION; ADHERENS JUNCTIONS; MISSENSE MUTATIONS AB Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM. C1 [Maxwell, Christopher A.; Gomez-Baldo, Laia; Bonifaci, Nuria; Aguilar, Helena; Villanueva, Alberto; Aytes, Alvaro; Serra-Musach, Jordi; Aiza, Gemma; Martrat, Griselda; Urruticoechea, Ander; Angel Pujana, Miguel] Bellvitge Biomed Res Inst IDIBELL, Catalan Inst Oncol, Translat Res Lab, Lhospitalet De Llobregat, Catalonia, Spain. [Benitez, Javier; Osorio, Ana; Fernandez-Ramires, Ricardo] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Madrid, Spain. [Bonifaci, Nuria; Guino, Elisabet; Serra-Musach, Jordi; Moreno, Victor; Angel Pujana, Miguel] IDIBELL, Catalan Inst Oncol, Biomarkers & Susceptibil Unit, Lhospitalet De Llobregat, Catalonia, Spain. [Costes, Sylvain V.; Barcellos-Hoff, Mary Helen] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Catala, Isabel; Petit, Anna] Univ Hosp Bellvitge, IDIBELL, Dept Pathol, Lhospitalet De Llobregat, Catalonia, Spain. [Rennert, Gad; Lejbkowicz, Flavio] Technion Israel Inst Technol, Carmel Med Ctr, Dept Community Med & Epidemiol, CHS Natl Canc Control Ctr, Haifa, Israel. [Rennert, Gad; Lejbkowicz, Flavio] Technion Israel Inst Technol, B Rappaport Fac Med, Haifa, Israel. [Peterlongo, Paolo; Ripamonti, Carla B.; Radice, Paolo] Fdn IRCCS, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Ist Nazl Tumori, Milan, Italy. [Peterlongo, Paolo; Ripamonti, Carla B.; Radice, Paolo] IFOM Fdn, Ist FIRC Oncol Mol, Milan, Italy. [Manoukian, Siranoush; Peissel, Bernard; Ripamonti, Carla B.] Fdn IRCCS, Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Viel, Alessandra] IRCCS, Ctr Riferimento Oncol, Div Expt Oncol 1, Aviano, Italy. [Allavena, Anna] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Bernard, Loris] Ist Europeo Oncol, Dept Expt Oncol, Milan, Italy. [Bernard, Loris] Consortium Genom Technol Cogentech, Milan, Italy. [Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Dubrovsky, Maya; Milgrom, Roni] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, Ramat Gan, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Fac Med, Ramat Aviv, Israel. [Jakubowska, Anna; Cybulski, Cezary; Gorski, Bohdan; Jaworska, Katarzyna; Durda, Katarzyna; Sukiennicki, Grzegorz; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Shugart, Yin Yao] NIMH, Unit Stat Genet, Div Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Domchek, Susan M.; Letrero, Richard; Weber, Barbara L.; Nathanson, Katherine L.] Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Hogervorst, Frans B. L.] Netherlands Canc Inst, Dept Pathol, Family Canc Clin, NL-1066 CX Amsterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Dept Clin Genet, Med Ctr, Rotterdam Family Canc Clin, NL-3000 DR Rotterdam, Netherlands. [Devilee, Peter] Leiden Univ, Dept Genet Epidemiol, Med Ctr, Leiden, Netherlands. [Ligtenberg, Marjolijn J.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [van der Luijt, Rob B.] Univ Utrecht, Med Ctr, Dept Clin Mol Genet, Utrecht, Netherlands. [Aalfs, Cora M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Waisfisz, Quinten] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Wijnen, Juul] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands. [van Roozendaal, Cornelis E. P.] Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Easton, Douglas F.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; McGuffog, Lesley; Antoniou, Antonis C.; EMBRACE] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Harrington, Patricia] Univ Cambridge, Dept Oncol, Cambridge, England. [Evans, D. Gareth; Lalloo, Fiona] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, Sutton, Surrey, England. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, London, England. [Chu, Carol] St James Hosp, Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Eccles, Diana] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Douglas, Fiona] Newcastle Upon Tyne Hosp NHS Trust, Ctr Life, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England. [Nevanlinna, Heli; Heikkinen, Tuomas] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Lindor, Noralane M.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Caligo, Maria A.; Lombardi, Grazia] Univ Pisa, Sect Genet Oncol, Dept Oncol, Pisa, Italy. [Caligo, Maria A.; Lombardi, Grazia] Univ Hosp Pisa, Dept Lab Med, Pisa, Italy. [Loman, Niklas] Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. [Karlsson, Per] Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden. [Ehrencrona, Hans] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, Uppsala, Sweden. [von Wachenfeldt, Anna] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Barkardottir, Rosa Bjork] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Hamann, Ute; Rashid, Muhammad U.] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. [Rashid, Muhammad U.] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan. [Lasa, Adriana] Hosp Santa Creu & Sant Pau, Genet Serv, Barcelona, Catalonia, Spain. [Caldes, Trinidad] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Andres, Raquel] Hosp Clin Zaragoza, Div Med Oncol, Zaragoza, Spain. [Schmitt, Michael] Univ Rostock, Dept Internal Med 3, Rostock, Germany. [Assmann, Volker] Univ Hosp Hamburg Eppendorf, Inst Tumor Biol, Ctr Med Expt, Hamburg, Germany. [Stevens, Kristen] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Curado, Joao; Tilgner, Hagen; Guigo, Roderic] Biomed Res Pk Barcelona PRBB, Ctr Genom Regulat CRG, Bioinformat & Genom Grp, Barcelona, Catalonia, Spain. [Brunet, Joan; Castellsague, Joan; Blanco, Ignacio; Lazaro, Conxi; Capella, Gabriel] Girona Biomed Res Inst IdIBGi, Catalonia, Spain. [Brunet, Joan; Castellsague, Joan; Blanco, Ignacio; Lazaro, Conxi; Capella, Gabriel] IDIBELL, Catalan Inst Oncol, Genet Counseling & Hereditary Canc Programme, Catalonia, Spain. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [Buys, Saundra] Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Miron, Alexander] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Miron, Alexander] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Southey, Melissa] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt MEGA Epidemiol, Melbourne, Vic 3010, Australia. [Daly, Mary B.] Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Cologne, Ctr Familial Breast & Ovarian Canc, D-50931 Cologne, Germany. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Cologne, Ctr Integrated Oncol, D-50931 Cologne, Germany. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, D-8000 Munich, Germany. [Arnold, Norbert] Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Div Oncol, Kiel, Germany. [Deissler, Helmut] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Varon-Mateeva, Raymonda] Charite, Inst Humangenet, D-13353 Berlin, Germany. [Sutter, Christian] Univ Heidelberg, Inst Human Genet, Heidelberg, Germany. [Niederacher, Dieter] Univ Dusseldorf, Ctr Clin, Dept Obstet & Gynaecol, Div Mol Genet, D-40225 Dusseldorf, Germany. [Imyamitov, Evgeny] NN Petrov Inst Oncol, St Petersburg, Russia. [Sinilnikova, Olga M.] CHU Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Sinilnikova, Olga M.; Mazoyer, Sylvie; Verny-Pierre, Carole] Univ Lyon, Ctr Leon Berard, CNRS UMR5201, Equipe Labellisee LIGUE 2008, Lyon, France. [Stoppa-Lyonne, Dominique; Castera, Laurent; de Pauw, Antoine] Univ Paris 05, Serv Genet Oncol, INSERM, Inst Curie,U509, Paris, France. [Bignon, Yves-Jean; Uhrhammer, Nancy] Univ Clermont Ferrand, Ctr Jean Perrin, Dept Oncogenet, Clermont Ferrand, France. [Peyrat, Jean-Philippe] Ctr Oscar Lambret, Lab Oncol Mol Humaine, F-59020 Lille, France. [Ferrer, Sandra Fert] Hotel Dieu Ctr Hosp, Lab Genet Chromosom, Chambery, France. [Collonge-Rame, Marie-Agnes] CHU Besancon, Serv Genet Histol Biol Dev & Reprod, F-25030 Besancon, France. [Mortemousque, Isabelle] CHU Bretonneau, Serv Genet, F-37044 Tours, France. [Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Healey, Sue; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. Peter MacCallum Canc Inst, Kathleen Cuningham Fdn, Consortium Res Familial Breast Canc, Melbourne, Australia. [Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Vidal, Marc] Harvard Univ, Sch Med, Ctr Canc Syst Biol CCSB, Boston, MA USA. [Gruber, Stephen B.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Fleisch, Markus C.] Univ Dusseldorf, Dept Obstet & Gynaecol, D-40225 Dusseldorf, Germany. RP Maxwell, CA (reprint author), Child & Family Res Inst, Dept Pediat, Vancouver, BC, Canada. EM cmaxwell@cfri.ubc.ca; mapujana@ico.scs.es RI Spurdle, Amanda/A-4978-2011; Jakubowska, Anna/O-8050-2014; Guigo, Roderic/D-1303-2010; Ligtenberg, Marjolijn/N-9666-2013; Fernandez-Ramires, Ricardo/H-3707-2014; Ripamonti, Carla Barbara/D-2247-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Ehrencrona, Hans/M-5619-2014; pujana, Miguel Angel/N-3127-2014; Arnold, Norbert/E-3012-2010; Maxwell, Christopher/B-3044-2011; Costes, Sylvain/D-2522-2013; Radice, Paolo/O-3119-2013; Aytes, Alvaro/B-5803-2014; Blanco, Ignacio/D-2565-2013; Fleisch, Markus/E-4134-2014; Osorio, Ana/I-4324-2014; Bernard, Loris/K-5953-2014; Aytes, Alvaro/M-1360-2014 OI Evans, Gareth/0000-0002-8482-5784; Spurdle, Amanda/0000-0003-1337-7897; Brunet, Joan/0000-0003-1945-3512; Nevanlinna, Heli/0000-0002-0916-2976; Moreno, Victor/0000-0002-2818-5487; Guigo, Roderic/0000-0002-5738-4477; Ligtenberg, Marjolijn/0000-0003-1290-1474; Ripamonti, Carla Barbara/0000-0002-2892-8164; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Ehrencrona, Hans/0000-0002-5589-3622; pujana, Miguel Angel/0000-0003-3222-4044; Arnold, Norbert/0000-0003-4523-8808; Maxwell, Christopher/0000-0002-0860-4031; Costes, Sylvain/0000-0002-8542-2389; Aytes, Alvaro/0000-0003-0725-5340; Blanco, Ignacio/0000-0002-7414-7481; Fleisch, Markus/0000-0002-8966-4721; Osorio, Ana/0000-0001-8124-3984; Aytes, Alvaro/0000-0003-0725-5340 FU Spanish Ministries of Health, and Science ane Innovation [CB07/02/2005]; FIS [08/1120, 08/1359, 08/1635, 09/02483]; RTICCC [RD06/0020/1060, RD06/0020/0028]; Transversal Action Against Cancer; Spanish Biomedical Research Centre Networks for Epidemiology and Public Health, and Rare Diseases; "Ramon y Cajal" Young Investigator Program; Spanish National Society of Medical Oncology; Spanish Association Against Cancer [AECC 2010]; AGAUR Catalan Government Agency [2009SGR1489, 2009SGR293]; Beatriu Pinos Postdoctoral Program; Ramon Areces Foundation; "Roses Contra el Cancer" Foundation; Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK [C490/A10119, C1287/A8874, C1287/A10118, C5047/A8385, C8197/A10123]; National Institute for Health Research (UK); Association for International Cancer Research [AICR-07-0454]; Ligue National Contre le Cancer (France); Association "Le cancer du sein, parlons-en!"; Dutch Cancer Society [NKI 1998-1854, 2004-3088, 2007-3756]; Fondazione Italiana per la Ricerca sul Cancro ("Hereditary Tumors"); Associazione Italiana per la Ricerca sul Cancro [4017]; Italian Ministero della Salute [RFPS-2006-3-340203]; Italian Ministero dell'Universita e Ricerca [RBLAO3-BETH]; Fondazione IRCCS Istituto Nazionale Tumori [INT "5x1000"]; Fondazione Cassa di Risparmio di Pisa (Istituto Toscano Tumori); National Breast Cancer Foundation (Australia); Australian National Health and Medical Research Council [145684, 288704, 454508]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; Cancer Foundation of Western Australia; German Cancer Aid [107054]; Center for Molecular Medicine Cologne [TV93]; National Cancer Institute (USA) [CA128978, CA122340]; National Institutes of Health [RFA-CA-06-503, BCFR U01 CA69398, CA69417, CA69446, CA69467, CA69631, CA69638]; Research Triangle Institute Informatics Support Center [RFP N02PC45022-46]; Specialized Program of Research Excellence (SPORE) [P50 CA83638, CA113916]; Department of Defense [05/0612]; Eileen Stein Jacoby Fund; Breast Cancer Research Foundation; Marianne and Robert MacDonald Foundation; Komen Foundation; Helsinki University Central Hospital; Academy of Finland [110663]; Finnish Cancer Society; Sigrid Juselius Foundation; EU [223175, HEALTH-F2-2009-223175] FX This work was funded by the Spanish Ministries of Health, and Science ane Innovation (CB07/02/2005; FIS 08/1120, 08/1359, 08/1635, and 09/02483; RTICCC RD06/0020/1060 and RD06/0020/0028; Transversal Action Against Cancer; the Spanish Biomedical Research Centre Networks for Epidemiology and Public Health, and Rare Diseases; and the "Ramon y Cajal" Young Investigator Program), the Spanish National Society of Medical Oncology (2010), the Spanish Association Against Cancer (AECC 2010), the AGAUR Catalan Government Agency (2009SGR1489 and 2009SGR293; and the Beatriu Pinos Postdoctoral Program), the Ramon Areces Foundation (XV), the "Roses Contra el Cancer" Foundation, the Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK (C490/A10119, C1287/A8874, C1287/A10118, C5047/A8385, and C8197/A10123), the National Institute for Health Research (UK), the Association for International Cancer Research (AICR-07-0454), the Ligue National Contre le Cancer (France), the Association "Le cancer du sein, parlons-en!", the Dutch Cancer Society (NKI 1998-1854, 2004-3088, and 2007-3756), the Fondazione Italiana per la Ricerca sul Cancro ("Hereditary Tumors"), the Associazione Italiana per la Ricerca sul Cancro (4017), the Italian Ministero della Salute (RFPS-2006-3-340203 and "Progetto Tumori Femminili"), the Italian Ministero dell'Universita e Ricerca (RBLAO3-BETH), the Fondazione IRCCS Istituto Nazionale Tumori (INT "5x1000"), the Fondazione Cassa di Risparmio di Pisa (Istituto Toscano Tumori), the National Breast Cancer Foundation (Australia), the Australian National Health and Medical Research Council (145684, 288704, and 454508), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, the Cancer Foundation of Western Australia, the German Cancer Aid (107054), the Center for Molecular Medicine Cologne (TV93), the National Cancer Institute (USA; CA128978 and CA122340), National Institutes of Health (RFA-CA-06-503, BCFR U01 CA69398, CA69417, CA69446, CA69467, CA69631, and CA69638), the Research Triangle Institute Informatics Support Center (RFP N02PC45022-46), the Specialized Program of Research Excellence (SPORE P50 CA83638 and CA113916), the Department of Defense Breast Cancer Research Program (05/0612), the Eileen Stein Jacoby Fund, the Breast Cancer Research Foundation, the Marianne and Robert MacDonald Foundation, the Komen Foundation, the Helsinki University Central Hospital Research Fund, the Academy of Finland (110663), the Finnish Cancer Society, the Sigrid Juselius Foundation, and the EU FP7 (223175, HEALTH-F2-2009-223175). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 28 Z9 28 U1 1 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2011 VL 9 IS 11 AR e1001199 DI 10.1371/journal.pbio.1001199 PG 18 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 863HE UT WOS:000298152600012 PM 22110403 ER PT J AU Pelak, K Need, AC Fellay, J Shianna, KV Feng, S Urban, TJ Ge, DL De Luca, A Martinez-Picado, J Wolinsky, SM Martinson, JJ Jamieson, BD Bream, JH Martin, MP Borrow, P Letvin, NL McMichael, AJ Haynes, BF Telenti, A Carrington, M Goldstein, DB Alter, G AF Pelak, Kimberly Need, Anna C. Fellay, Jacques Shianna, Kevin V. Feng, Sheng Urban, Thomas J. Ge, Dongliang De Luca, Andrea Martinez-Picado, Javier Wolinsky, Steven M. Martinson, Jeremy J. Jamieson, Beth D. Bream, Jay H. Martin, Maureen P. Borrow, Persephone Letvin, Norman L. McMichael, Andrew J. Haynes, Barton F. Telenti, Amalio Carrington, Mary Goldstein, David B. Alter, Galit CA NIAID Ctr HIV AIDS Vaccine TI Copy Number Variation of KIR Genes Influences HIV-1 Control SO PLOS BIOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; MHC CLASS-I; LY49 RECEPTOR REPERTOIRE; VIRUS TYPE-1 INFECTION; HLA CLASS-I; NK CELLS; INHIBITORY RECEPTORS; DISEASE PROGRESSION; CUTTING EDGE; KIR3DS1 AB A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection. C1 [Pelak, Kimberly; Need, Anna C.; Fellay, Jacques; Shianna, Kevin V.; Urban, Thomas J.; Ge, Dongliang; Goldstein, David B.] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27710 USA. [Fellay, Jacques] Ecole Polytech Fed Lausanne, Sch Life Sci, Global Hlth Inst, Lausanne, Switzerland. [Feng, Sheng] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [De Luca, Andrea] Univ Cattolica Sacro Cuore, Inst Clin Infect Dis, I-00168 Rome, Italy. [De Luca, Andrea] Siena Univ Hosp, Div Infect Dis, Siena, Italy. [Martinez-Picado, Javier] IrsiCaixa Fdn, Badalona, Spain. [Martinez-Picado, Javier] Hosp Badalona Germans Trias & Pujol, Badalona, Spain. [Martinez-Picado, Javier] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. [Wolinsky, Steven M.] Northwestern Univ, Div Infect Dis, Feinberg Sch Med, Chicago, IL 60611 USA. [Martinson, Jeremy J.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Jamieson, Beth D.; Carrington, Mary] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Bream, Jay H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Martin, Maureen P.] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Borrow, Persephone] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [McMichael, Andrew J.] John Radcliffe Hosp, Weatherall Inst Mol Med, Med Res Council, Human Immunol Unit, Oxford OX3 9DU, England. [Letvin, Norman L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis, Boston, MA 02215 USA. [Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Telenti, Amalio] Univ Hosp Ctr, Inst Microbiol, Lausanne, Switzerland. [Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Carrington, Mary; Alter, Galit] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. RP Pelak, K (reprint author), Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27710 USA. EM galter@partners.org RI De Luca, Andrea/G-8810-2011; Wolinsky, Steven/B-2893-2012; Martinez-Picado, Javier/G-5507-2012; SHCS, int. coll. A/G-4083-2011; SHCS, all/G-4072-2011; Fellay, Jacques/A-6681-2009; OI Martinez-Picado, Javier/0000-0002-4916-2129; Fellay, Jacques/0000-0002-8240-939X; Need, Anna/0000-0003-3955-8207; Martinson, Jeremy/0000-0003-4673-7238; Wolinsky, Steven/0000-0002-9625-6697 FU Center for HIV/AIDS Vaccine Immunology ("CHAVI"); National Institute of Allergy and Infectious Diseases (NIAID); US National Institutes of Health (US NIH) [UO1AIO67854, HHSN261200800001E]; National Cancer Institute (NCI); NIH, NCI, Center for Cancer Research; National Heart, Lung, and Blood Institute [UO1-AI-35042, 5-M01-RR-00052, UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041]; NIH [5 T32 GM007754-29]; Swiss National Science Foundation FX This research has been funded in whole or part with federal funds by the Center for HIV/AIDS Vaccine Immunology ("CHAVI") under a grant from the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (US NIH), grant number UO1AIO67854. This project has been funded in whole or in part with federal funds from the National Cancer Institute (NCI), US NIH, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The MACS is funded by NIAID, with additional supplemental funding from NCI; and the National Heart, Lung, and Blood Institute: UO1-AI-35042, 5-M01-RR-00052 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041. KP was funded by NIH Genetics Training Grant 5 T32 GM007754-29. AT is supported by the Swiss National Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 74 Z9 76 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2011 VL 9 IS 11 AR e1001208 DI 10.1371/journal.pbio.1001208 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 863HE UT WOS:000298152600019 PM 22140359 ER PT J AU Bahia, AC Kubota, MS Tempone, AJ Araujo, HRC Guedes, BAM Orfano, AS Tadei, WP RioOs-Velasquez, CM Han, YS Secundino, NFC Barillas-Mury, C Pimenta, PFP Traub-Csekoe, YM AF Bahia, Ana C. Kubota, Marina S. Tempone, Antonio J. Araujo, Helena R. C. Guedes, Bruno A. M. Orfano, Alessandra S. Tadei, Wanderli P. RioOs-Velasquez, Claudia M. Han, Yeon S. Secundino, Nagila F. C. Barillas-Mury, Carolina Pimenta, Paulo F. P. Traub-Csekoe, Yara M. TI The JAK-STAT Pathway Controls Plasmodium vivax Load in Early Stages of Anopheles aquasalis Infection SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID BACTERIAL-INFECTION; SIGNAL-TRANSDUCTION; IMMUNE-RESPONSES; HOST-DEFENSE; NITRIC-OXIDE; TIME BOMB; DROSOPHILA; MIDGUT; MALARIA; GENE AB Malaria affects 300 million people worldwide every year and 450,000 in Brazil. In coastal areas of Brazil, the main malaria vector is Anopheles aquasalis, and Plasmodium vivax is responsible for the majority of malaria cases in the Americas. Insects possess a powerful immune system to combat infections. Three pathways control the insect immune response: Toll, IMD, and JAK-STAT. Here we analyze the immune role of the A. aquasalis JAK-STAT pathway after P. vivax infection. Three genes, the transcription factor Signal Transducers and Activators of Transcription (STAT), the regulatory Protein Inhibitors of Activated STAT (PIAS) and the Nitric Oxide Synthase enzyme (NOS) were characterized. Expression of STAT and PIAS was higher in males than females and in eggs and first instar larvae when compared to larvae and pupae. RNA levels for STAT and PIAS increased 24 and 36 hours (h) after P. vivax challenge. NOS transcription increased 36 h post infection (hpi) while this protein was already detected in some midgut epithelial cells 24 hpi. Imunocytochemistry experiments using specific antibodies showed that in non-infected insects STAT and PIAS were found mostly in the fat body, while in infected mosquitoes the proteins were found in other body tissues. The knockdown of STAT by RNAi increased the number of oocysts in the midgut of A. aquasalis. This is the first clear evidence for the involvement of a specific immune pathway in the interaction of the Brazilian malaria vector A. aquasalis with P. vivax, delineating a potential target for the future development of disease controlling strategies. C1 [Bahia, Ana C.; Kubota, Marina S.; Tempone, Antonio J.; Traub-Csekoe, Yara M.] Inst Oswaldo Cruz, Lab Biol Mol Parasitas & Vetores, BR-20001 Rio De Janeiro, Brazil. [Araujo, Helena R. C.; Guedes, Bruno A. M.; Orfano, Alessandra S.; Secundino, Nagila F. C.; Pimenta, Paulo F. P.] Inst Rene Rachou, Lab Entomol Med, Belo Horizonte, MG, Brazil. [Tadei, Wanderli P.] Inst Nacl de Pesquisas da Amazonia, Lab Malaria & Dengue, Manaus, Amazonas, Brazil. [Han, Yeon S.] Chonnam Natl Univ, Dept Agr Biol, Kwangju, South Korea. [Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Bahia, AC (reprint author), Inst Oswaldo Cruz, Lab Biol Mol Parasitas & Vetores, BR-20001 Rio De Janeiro, Brazil. EM pimenta@cpqrr.fiocruz.br; ytraub@ioc.fiocruz.br RI Bahia Nascimento, Ana/G-2372-2015; Araujo, Helena/J-9209-2015; Rios Velasquez, Claudia Maria/K-2901-2015 OI Bahia Nascimento, Ana/0000-0002-4584-1888; FU CNPq; CAPES; FAPERJ; FAPEMIG; PRONEX FX This work was funded by CNPq, CAPES, FAPERJ, FAPEMIG, and PRONEX. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 33 Z9 34 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2011 VL 5 IS 11 AR e1317 DI 10.1371/journal.pntd.0001317 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 863AA UT WOS:000298134000004 PM 22069502 ER PT J AU Tamura, D Merideth, M DiGiovanna, JJ Zhou, XL Tucker, MA Goldstein, AM Brooks, BP Khan, SG Oh, KS Ueda, T Boyle, J Moslehi, R Kraemer, KH AF Tamura, Deborah Merideth, Melissa DiGiovanna, John J. Zhou, Xiaolong Tucker, Margaret A. Goldstein, Alisa M. Brooks, Brian P. Khan, Sikandar G. Oh, Kyu-Seon Ueda, Takahiro Boyle, Jennifer Moslehi, Roxana Kraemer, Kenneth H. TI High-risk pregnancy and neonatal complications in the DNA repair and transcription disorder trichothiodystrophy: report of 27 affected pregnancies SO PRENATAL DIAGNOSIS LA English DT Article DE trichothiodystrophy; pregnancy; maternal serum screening; hCG; preeclampsia; HELLP syndrome ID HUMAN CHORIONIC-GONADOTROPIN; SERUM ALPHA-FETOPROTEIN; XERODERMA-PIGMENTOSUM; COCKAYNE-SYNDROME; PRENATAL-DIAGNOSIS; BRITTLE HAIR; 2ND-TRIMESTER; ABNORMALITIES; PREECLAMPSIA; PREDICTION AB Objective To identify the frequency of pregnancy and neonatal complications in pregnancies carrying fetuses affected with trichothiodystrophy (TTD). Methods We identified pregnancy and neonatal complications and serum screening results from mothers of TTD patients in a DNA repair diseases study from 2001 to 2011. Results Pregnancy reports of 27 TTD patients and their 23 mothers were evaluated and 81% of the pregnancies had complications: 56% had preterm delivery, 30% had preeclampsia, 19% had placental abnormalities, 11% had HELLP syndrome, and 4% had an emergency c-section for fetal distress, while 44% had two or more complications. Only 19% of the pregnancies delivered at term without complications. Eight of the ten pregnancies tested had abnormal multiple marker results including elevated levels of human chorionic gonadotrophin. Eighty-five percent of the neonates had complications: 70% were low birth weight (<2500 g), 35% had birth weight <10 centile for gestational age, 70% had NICU admission, 67% had a collodion membrane, and 31% of the 16 males had cryptorchidism. Cataracts were present in 54% of the TTD patients examined. Conclusion TTD is a multisystem disease that predisposes mothers of affected patients to substantial risks for pregnancy complications and TTD neonates have a high incidence of multiple abnormalities. Published 2011. This article is a U. S. Government work and is in the public domain in the USA C1 [Tamura, Deborah; DiGiovanna, John J.; Zhou, Xiaolong; Khan, Sikandar G.; Oh, Kyu-Seon; Ueda, Takahiro; Boyle, Jennifer; Kraemer, Kenneth H.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Merideth, Melissa] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Merideth, Melissa] Off Director, Intramural Off Rare Dis, Bethesda, MD USA. [Zhou, Xiaolong] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Tucker, Margaret A.; Goldstein, Alisa M.] NCI, Genet Epidemiol Branch, DCEG, Rockville, MD USA. [Brooks, Brian P.] NEI, Unit Pediat Dev & Genet Ophthalmol, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Moslehi, Roxana] SUNY Albany, Dept Epidemiol & Biostat, Sch Publ Hlth, Albany, NY 12222 USA. [Moslehi, Roxana] SUNY Albany, Canc Res Ctr, Albany, NY 12222 USA. [Moslehi, Roxana] NCI, Biostat Branch, DCEG, NIH, Rockville, MD USA. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 37,Room 4002, Bethesda, MD 20892 USA. EM kraemerk@nih.gov RI Tucker, Margaret/B-4297-2015; OI Zhou, Alan/0000-0002-6177-2472 FU Center for Cancer Research and the Division of Cancer Epidemiology and Genetics, National Cancer Institute; National Human Genome Research Institute; National Eye Institute, and National Institutes of Health (NIH), Bethesda, MD; NIH; Pfizer Inc. FX This research was supported by the Intramural Research Program of the Center for Cancer Research and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, the National Human Genome Research Institute and the National Eye Institute, and National Institutes of Health (NIH), Bethesda, MD. Support for author Zhou was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). We thank Dr Amy Thompson for assistance in compiling data on eye abnormalities in the patients. NR 35 TC 13 Z9 13 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD NOV PY 2011 VL 31 IS 11 BP 1046 EP 1053 DI 10.1002/pd.2829 PG 8 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 864SU UT WOS:000298261200005 PM 21800331 ER PT J AU Parekh, S Weniger, MA Wiestner, A AF Parekh, Samir Weniger, Marc A. Wiestner, Adrian TI New molecular targets in mantle cell lymphoma SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE Lymphoma; Targeted therapy; Treatment ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; PROTEASOME INHIBITOR BORTEZOMIB; HISTONE DEACETYLASE INHIBITORS; DEPENDENT KINASE INHIBITOR; SINGLE-AGENT TEMSIROLIMUS; PHASE-1 DOSE-ESCALATION; MULTIPLE-MYELOMA CELLS; CANCER-CELLS; PHOSPHOINOSITIDE 3-KINASE AB Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by aberrant expression of cyclin D1 due to the translocation t(11;14). Epigenomic and genomic lesions in pathways regulating B-cell activation, cell cycle progression, protein homeostasis, DNA damage response, cell proliferation and apoptosis contribute to its pathogenesis. While patients typically respond to first-line chemotherapy, relapse is the rule resulting in a median survival of 5-7 years. The PI3K/AKT/mTOR appears as a key pathway in the pathogenesis and can be targeted with small molecules. Most experience is with mTOR inhibitors of the rapamycin class. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 are novel options to more effectively target this pathway. Bruton's tyrosine kinase inhibition by PCI-32765 has promising activity and indicates immunoreceptor signaling as a novel therapeutic target. Up to 50% of relapsed patients respond to the proteasome inhibitor bortezomib suggesting that MCL may be particularly sensitive to disruption of protein homeostasis and/or induction of oxidative stress. Recent work has focused on elucidating the mechanism of bortezomib-induced cytotoxicity and the development of second-generation proteasome inhibitors. DNA hypomethylating agents and histone deacetylase inhibitors effect epigenetic de-repression of aberrantly silenced genes. These epigenetic pharmaceuticals and HSP90 inhibitors can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients a chance to benefit from these advances and is essential to maintain the momentum of progress. Innovative trial designs may be needed to expedite the clinical development of these targeted agents. Published by Elsevier Ltd. C1 [Weniger, Marc A.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Parekh, Samir] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM samir.parekh@einstein.yu.edu; wiestnera@mail.nih.gov FU National Heart, Lung, and Blood Institute; Chemotherapy Foundation; Leukemia and Lymphoma Society Translational Research Project; Paul Calabresi Career Development Award [K12-CA132783-01] FX Marc A. Weniger and Adrian Wiestner are supported by the intramural research program of the National Heart, Lung, and Blood Institute. Samir Parekh is funded by the Chemotherapy Foundation, Leukemia and Lymphoma Society Translational Research Project Grant and Paul Calabresi Career Development Award K12-CA132783-01. NR 124 TC 25 Z9 25 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD NOV PY 2011 VL 21 IS 5 BP 335 EP 346 DI 10.1016/j.semcancer.2011.09.008 PG 12 WC Oncology SC Oncology GA 863YI UT WOS:000298203800007 PM 21945517 ER PT J AU Farci, P AF Farci, Patrizia TI New Insights into the HCV Quasispecies and Compartmentalization SO SEMINARS IN LIVER DISEASE LA English DT Review DE Hepatitis C virus; quasispecies; compartmentalism; immune escape; viral persistence ID HEPATITIS-C-VIRUS; HYPERVARIABLE REGION 1; BLOOD MONONUCLEAR-CELLS; SENSITIVITY-DETERMINING REGION; INTERFERON-ALPHA THERAPY; CENTRAL-NERVOUS-SYSTEM; NONSTRUCTURAL 5A GENE; 2ND ENVELOPE PROTEIN; NEGATIVE-STRAND RNA; NON-B-HEPATITIS AB Hepatitis C virus (HCV) is a hepatotropic RNA virus with an extraordinary propensity to persist in the vast majority of infected individuals. During replication, because of the inherent infidelity of the viral RNA polymerase, each progeny RNA genome contains mutations that lead to a continuous diversification of the viral population. Consequently, HCV circulates in vivo as a quasispecies, which is a dynamic distribution of divergent but closely related genomes subjected to a continuous process of genetic variation, competition, and selection. This genomic heterogeneity confers a remarkable advantage to the viral population allowing for a rapid adaptation to a changing environment when the virus is subject to selective constraints exerted by the host, such as antiviral immunity, or external to the host, such as antiviral therapy. The large reservoir of variants provided by the quasispecies represents a great challenge for the control of HCV infection and has important biologic implications for viral persistence, host cell tropism, antiviral drug resistance, and development of an HCV vaccine. This review discusses the molecular mechanisms of HCV genetic variation and the biologic and clinical relevance of the quasispecies nature of HCV. C1 NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Farci, P (reprint author), NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, 50 South Dr,MSC 8009,Bldg 50,Room 6529, Bethesda, MD 20892 USA. EM pfarci@niaid.nih.gov FU 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 229 TC 52 Z9 55 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD NOV PY 2011 VL 31 IS 4 BP 356 EP 374 DI 10.1055/s-0031-1297925 PG 19 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 866QS UT WOS:000298396900005 PM 22189976 ER PT J AU Sullivan, SD Castrillon, DH AF Sullivan, Shannon D. Castrillon, Diego H. TI Insights into Primary Ovarian Insufficiency through Genetically Engineered Mouse Models (vol 29, pg 286, 2011) SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Correction C1 [Castrillon, Diego H.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Sullivan, Shannon D.] NICHD, NIH, Bethesda, MD USA. RP Castrillon, DH (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pathol, Room NB6-452,6000 Harry Hines Blvd, Dallas, TX 75390 USA. EM diego.castrillon@utsouthwestern.edu NR 1 TC 0 Z9 0 U1 0 U2 5 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD NOV PY 2011 VL 29 IS 6 BP 569 EP 569 DI 10.1055/s-0031-1298711 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 864ZY UT WOS:000298281100013 ER PT J AU Chulada, PC Vainorius, E Garantziotis, S Burch, LH Blackshear, PJ Zeldin, DC AF Chulada, Patricia C. Vainorius, Enrikas Garantziotis, Stavros Burch, Lauranell H. Blackshear, Perry J. Zeldin, Darryl C. TI The Environmental Polymorphism Registry: A Unique Resource that Facilitates Translational Research of Environmental Disease SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE DNA biorepository; environmental response gene; environmental risk assessment; genotypes; phenotype-by-genotype; polymorphisms; toxicity studies; translational research ID GENE-EXPRESSION; PATHWAY; PROTEIN; GENOME AB BACKGROUND: Dissecting complex disease has become more feasible because of the availability of large-scale DNA resources and advances in high-throughput genomic technology. Although these tools help scientists identify potential susceptibility loci, subjects with relevant genotypes are needed for clinical phenotyping and toxicity studies. OBJECTIVE: We have developed a resource of subjects and their DNA to use for translational research of environmental disease. METHODS: More than 15,000 individuals of diverse sex, age, race, and ethnicity were recruited from North Carolina. DNA was isolated from their blood and coded with personal identification numbers linked to their identities. This linked resource of subjects and their DNA-the Environmental Polymorphism Registry (EPR)-allows scientists to screen for individuals with genotypes of interest and invite them to participate in follow-up studies. DISCUSSION: The EPR is a phenotype-by-genotype resource designed to facilitate translational studies of environmental disease. Based on their genotypes, subjects are invited to participate at all levels of research, from basic laboratory ex vivo cell phenotyping experiments that require viable tissue to in vivo observational studies and clinical trials. Here we report on progress of the EPR since 2008. We also describe a major effort at the National Institute of Environmental Health Sciences (NIEHS) to investigate susceptibility loci in 87 environmental response genes and gene x environment interactions using EPR resources. CONCLUSION: The EPR is a unique and novel resource and is ideal for genotype-driven translational research of environmental disease. We expect that it will serve as a model for future resources. Such tools help scientists attain their ultimate goals: to identify at-risk populations and develop strategies for preventing and treating human disease. C1 [Chulada, Patricia C.; Garantziotis, Stavros; Zeldin, Darryl C.] NIEHS, Clin Res Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Vainorius, Enrikas] Integrated Lab Syst Inc, Clin Program, Res Triangle Pk, NC USA. [Burch, Lauranell H.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Chulada, PC (reprint author), NIEHS, Clin Res Program, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM chulada@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU National Institute of Environmental Health Sciences, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 22 TC 1 Z9 1 U1 0 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2011 VL 119 IS 11 BP 1523 EP 1527 DI 10.1289/ehp.1003348 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 844XL UT WOS:000296785900016 PM 21659040 ER PT J AU Jefferson, WN Padilla-Banks, E Phelps, JY Gerrish, KE Williams, CJ AF Jefferson, Wendy N. Padilla-Banks, Elizabeth Phelps, Jazma Y. Gerrish, Kevin E. Williams, Carmen J. TI Permanent Oviduct Posteriorization after Neonatal Exposure to the Phytoestrogen Genistein SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE developmental patterning; female reproductive tract; genistein; homeobox gene ID DIETHYLSTILBESTROL DES; REPRODUCTIVE-TRACT; GENE-EXPRESSION; MULLERIAN DUCT; IN-UTERO; MICE; MOUSE; ESTROGEN; HOMEOBOX; HINDLIMB AB BACKGROUND: Preimplantation embryo loss during oviduct transit has been observed in adult mice after a 5-day neonatal exposure to the phytoestrogen genistein (Gen; 50 mg/kg/day). OBJECTIVE: We investigated the mechanisms underlying the contribution of the oviduct to infertility. METHODS: Female mice were treated on postnatal days 1-5 with corn oil or Gen (50 mg/kg/day). We compared morphology, gene expression, and protein expression in different regions of the reproductive tracts of Gen-treated mice with those of control littermates at several time points. RESULTS: Neonatal Gen treatment resulted in substantial changes in expression of genes that modulate neonatal oviduct morphogenesis, including Hoxa (homeobox A cluster), Wnt (wingless-related MMTV integration site), and hedgehog signaling genes. An estrogen receptor antagonist blocked these effects, indicating that they were induced by the estrogenic activity of Gen. Oviducts of adults treated neonatally with Gen had abnormal morphology and were stably "posteriorized," as indicated by altered Hoxa gene patterning during the time of treatment and dramatic, permanent up-regulation of homeobox genes (e. g., Pitx1, Six1) normally expressed only in the cervix and vagina. CONCLUSIONS: Neonatal exposure to estrogenic environmental chemicals permanently disrupts oviduct morphogenesis and adult gene expression patterns, and these changes likely contribute to the infertility phenotype. C1 [Jefferson, Wendy N.; Padilla-Banks, Elizabeth; Phelps, Jazma Y.; Williams, Carmen J.] NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin E.] NIEHS, Microarray Grp, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Williams, CJ (reprint author), NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH,Dept Hlth & Human Serv, POB 12233,MD E4-05, Res Triangle Pk, NC 27709 USA. EM williamsc5@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES102405] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES102405). NR 45 TC 11 Z9 11 U1 0 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2011 VL 119 IS 11 BP 1575 EP 1582 DI 10.1289/ehp.1104018 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 844XL UT WOS:000296785900024 PM 21810550 ER PT J AU Beard, JD Umbach, DM Hoppin, JA Richards, M Alavanja, MCR Blair, A Sandler, DP Kamel, F AF Beard, John D. Umbach, David M. Hoppin, Jane A. Richards, Marie Alavanja, Michael C. R. Blair, Aaron Sandler, Dale P. Kamel, Freya TI Suicide and Pesticide Use among Pesticide Applicators and Their Spouses in the Agricultural Health Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE farmers; pesticide applicators; pesticides; spouses; suicide ID MORTALITY; FARMERS; EXPOSURE; COHORT; STATES; DEATH; DEPRESSION; WORKERS; CANCER AB BACKGROUND: An association may exist between pesticide exposure and suicide. OBJECTIVE: We sought to evaluate the existence of an association between pesticide use and suicide using data from the Agricultural Health Study (AHS), a prospective cohort study of licensed pesticide applicators and their spouses in Iowa and North Carolina. METHODS: Via linkage to state mortality files and the National Death Index, we identified 110 suicides occurring between enrollment in the AHS (from 1993 to 1997) and 31 May 2009, among 81,998 cohort members contributing 1,092,943 person-years of follow-up. The average length of follow-up was 13.3 years. AHS participants provided data on pesticide use and potential confounders via self-administered questionnaires at enrollment. We evaluated several measures of pesticide use: use of any pesticide, ever use of 50 specific pesticides, cumulative lifetime days of use and intensity-adjusted cumulative lifetime days of use of 22 specific pesticides, and ever use of 10 functional and chemical classes of pesticides. We used Cox proportional hazards regression models to estimate adjusted hazard ratios and 95% confidence intervals. RESULTS: After adjusting for age at enrollment, sex, number of children in family, frequency of alcohol consumption during the past 12 months, and smoking status, we found no association between prior pesticide use and suicide in applicators and their spouses. Results were the same for applicators and spouses together or for applicators alone and were consistent across several measures of pesticide use. CONCLUSIONS: Our findings do not support an association between moderate pesticide use and suicide. C1 [Hoppin, Jane A.; Sandler, Dale P.; Kamel, Freya] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Beard, John D.] Brigham Young Univ, Coll Life Sci, Dept Hlth Sci, Provo, UT USA. [Richards, Marie] Westat Corp, Durham, NC USA. [Alavanja, Michael C. R.; Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr,A3-05, Res Triangle Pk, NC 27709 USA. EM kamel@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) [Z01 ES049030]; National Cancer Institute [Z01 CP044008]; NIEHS [T32ES007018] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) (Z01 ES049030), the National Cancer Institute (Z01 CP044008), and NIEHS Award T32ES007018. NR 33 TC 8 Z9 9 U1 1 U2 14 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2011 VL 119 IS 11 BP 1610 EP 1615 DI 10.1289/ehp.1103413 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 844XL UT WOS:000296785900029 PM 21749962 ER PT J AU Vlaanderen, J Lan, Q Rothman, N Kromhout, H Vermeulen, R AF Vlaanderen, Jelle Lan, Qing Rothman, Nat Kromhout, Hans Vermeulen, Roel TI Occupational Benzene Exposure and Lymphoma Risks: Vlaanderen et al. Response SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID COHORT C1 [Vlaanderen, Jelle] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Lan, Qing; Rothman, Nat] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kromhout, Hans; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. RP Vlaanderen, J (reprint author), Int Agcy Res Canc, Sect Environm & Radiat, 150 Cours Albert Thomas, F-69372 Lyon, France. EM R.C.H.Vermeulen@uu.nl RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 2 TC 2 Z9 2 U1 0 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2011 VL 119 IS 11 BP A468 EP A469 DI 10.1289/ehp.1104167R PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 844XL UT WOS:000296785900004 ER PT J AU Pickering, RP Goldstein, RB Hasin, DS Blanco, C Smith, SM Huang, BJ Pulay, AJ Ruan, WJ Saha, TD Stinson, FS Dawson, DA Chou, SP Grant, BF AF Pickering, Roger P. Goldstein, Rise B. Hasin, Deborah S. Blanco, Carlos Smith, Sharon M. Huang, Boji Pulay, Attila J. Ruan, W. June Saha, Tulshi D. Stinson, Frederick S. Dawson, Deborah A. Chou, S. Patricia Grant, Bridget F. TI Temporal Relationships Between Overweight and Obesity and DSM-IV Substance Use, Mood, and Anxiety Disorders: Results From a Prospective Study, the National Epidemiologic Survey on Alcohol and Related Conditions SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID BODY-MASS INDEX; INTERVIEW SCHEDULE AUDADIS; MAJOR DEPRESSIVE DISORDER; GENERAL-POPULATION SAMPLE; PSYCHIATRIC DIAGNOSTIC MODULES; MENTAL-HEALTH; UNITED-STATES; DRUG MODULES; ADULT OBESITY; YOUNG-ADULTS AB Objective: To present nationally representative findings on the prospective relationships between overweight and obesity and DSM-IV substance use, mood, and anxiety disorders. Method: A nationally representative sample of 34,653 US adults was interviewed in Wave 1(2001-2002) and Wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. The target population was the civilian population residing in households and group quarters, with gathered data adjusted to be representative of the civilian population of the United States on the basis of the 2000 Decennial Census. The main outcome measures were the incidence of DSM-IV substance use, mood, and anxiety disorders and changes in body mass index status during the 3-year follow-up period. Results: Regression analyses that controlled for a wide array of covariates showed that overweight and obese women were at increased risk (P < .05) for incident major depressive disorder during the follow-up period (adjusted OR [AOR] = 1.3 [95% CI, 1.02-1.56] and AOR = 1.2 [95% CI, 1.02-1.51], respectively). Overweight men and obese men were at decreased risk (P < .05) of incident drug abuse and alcohol dependence (AOR = 0.7 [95% CI, 0.44-0.96] and AOR = 0.7 [95% CI, 0.52-0.97]), respectively. Obese women had a decreased risk (P < .05) of incident alcohol abuse and drug dependence (AOR = 0.6 [95% CI, 0.45-0.88] and AOR = 0.4 [95% CI, 0.21-0.91], respectively). Men with drug dependence and women with specific phobia had a decreased risk (P < .05) of becoming overweight or obese during the follow-up period (AOR = 0.4 [95% CI, 0.19-0.99] and AOR = 0.8 [95% CI, 0.66-0.95], respectively). Conclusions: Increased risk of major depressive disorder among overweight and obese women could be attributed to stigma and greater body dissatisfaction among women in Western cultures. Overweight and obesity may serve as protective factors against developing incident substance use disorders, possibly due to shared neural functions in the brain underlying addictions to numerous substances. Results are discussed in terms of their clinical implications, including the need to update treatment guidelines for the management of overweight, obesity, and major depressive disorder. C1 [Pickering, Roger P.; Goldstein, Rise B.; Smith, Sharon M.; Huang, Boji; Pulay, Attila J.; Ruan, W. June; Saha, Tulshi D.; Stinson, Frederick S.; Dawson, Deborah A.; Chou, S. Patricia; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Hasin, Deborah S.; Blanco, Carlos] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Hasin, Deborah S.; Blanco, Carlos] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Room 3077,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov RI Blanco, Carlos/I-4906-2013; OI Blanco, Carlos/0000-0001-6187-3057; Goldstein, Rise/0000-0002-9603-9473 FU NIH, NIAAA; NIH [AA08159, AA018111, AA00161, DA019606, DA020783, DA023200, DA023973, MH076051, MH082773]; New York State Psychiatric Institute; American Foundation for Suicide Prevention; NIAAA; National Institute on Drug Abuse (NIDA) FX The National Epidemiologic Survey on Alcohol and Related Conditions was funded by NIAAA, with supplemental support from the National Institute on Drug Abuse (NIDA). This research was supported in part by the Intramural Program of NIH, NIAAA. The study was also supported by NIH grants AA08159, AA018111, and AA00161 (Dr Hasin) and DA019606, DA020783, DA023200, DA023973, MH076051, and MH082773 (Dr Blanco); the New York State Psychiatric Institute (Drs Hasin and Blanco); and the American Foundation for Suicide Prevention (Dr Blanco). NR 76 TC 25 Z9 27 U1 2 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD NOV PY 2011 VL 72 IS 11 BP 1494 EP 1502 DI 10.4088/JCP.10m06077gry PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 855ME UT WOS:000297567700008 PM 21457678 ER PT J AU Kopp, JB Nelson, GW Sampath, K Johnson, RC Genovese, G An, P Friedman, D Briggs, W Dart, R Korbet, S Mokrzycki, MH Kimmel, PL Limou, S Ahuja, TS Berns, JS Fryc, J Simon, EE Smith, MC Trachtman, H Michel, DM Schelling, JR Vlahov, D Pollak, M Winkler, CA AF Kopp, Jeffrey B. Nelson, George W. Sampath, Karmini Johnson, Randall C. Genovese, Giulio An, Ping Friedman, David Briggs, William Dart, Richard Korbet, Stephen Mokrzycki, Michele H. Kimmel, Paul L. Limou, Sophie Ahuja, Tejinder S. Berns, Jeffrey S. Fryc, Justyna Simon, Eric E. Smith, Michael C. Trachtman, Howard Michel, Donna M. Schelling, Jeffrey R. Vlahov, David Pollak, Martin Winkler, Cheryl A. TI APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; AFRICAN-AMERICANS; RENAL-DISEASE; MYH9; PREVALENCE; RELEVANCE; TRENDS; REGION; AIDS; MAP AB Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeen-fold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-ninefold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice. C1 [Kopp, Jeffrey B.; Sampath, Karmini] NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Kimmel, Paul L.] NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Nelson, George W.; Johnson, Randall C.] NCI, Basic Sci Program Genet Core, Frederick, MD 21701 USA. [An, Ping; Limou, Sophie; Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, SAIC Frederick Inc, Frederick, MD 21701 USA. [Johnson, Randall C.] Conservatoire Natl Arts & Metiers, Chaire Bioinformat, F-75003 Paris, France. [Genovese, Giulio; Friedman, David; Pollak, Martin] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Briggs, William] Oakwood Univ, William Beaumont Sch Med, Royal Oak, MI USA. [Dart, Richard] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Korbet, Stephen] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Mokrzycki, Michele H.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Ahuja, Tejinder S.] Univ Texas Med Branch, Galveston, TX USA. [Berns, Jeffrey S.] Univ Penn, Philadelphia, PA 19104 USA. [Fryc, Justyna] Bialystok Med Univ, Bialystok, Poland. [Simon, Eric E.] Tulane Univ, New Orleans, LA 70118 USA. [Smith, Michael C.] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Trachtman, Howard] Albert Einstein Coll Med, Cohen Childrens Med Ctr New York, Bronx, NY USA. [Michel, Donna M.] Renal Phys Associates Winchester, Winchester, VA USA. [Schelling, Jeffrey R.] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Vlahov, David] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jeffreyk@intra.niddk.nih.gov RI Johnson, Randall/B-1517-2014; OI Johnson, Randall/0000-0001-7754-0847; Trachtman, Howard/0000-0001-7447-9489; Kopp, Jeffrey/0000-0001-9052-186X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIDDK, NIH FX We thank E. Binns-Roemer and Y. Zhou for excellent technical support and Bailey Kessing for database support. This project has been funded, in whole or in part, with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E and the intramural Program of NIDDK, NIH. 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 29 TC 217 Z9 220 U1 3 U2 7 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2011 VL 22 IS 11 BP 2129 EP 2137 DI 10.1681/ASN.2011040388 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 862ES UT WOS:000298073200021 PM 21997394 ER PT J AU Chopra, A Shan, L Eckelman, WC Leung, K Menkens, AE AF Chopra, Arvind Shan, Liang Eckelman, William C. Leung, Kam Menkens, Anne E. TI Important parameters to consider for the characterization of PET and SPECT imaging probes SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Editorial Material C1 [Chopra, Arvind; Shan, Liang; Eckelman, William C.; Leung, Kam] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Menkens, Anne E.] NCI, NIH, Bethesda, MD 20894 USA. RP Chopra, A (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM chopraa@mail.nih.gov NR 9 TC 9 Z9 9 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD NOV PY 2011 VL 38 IS 8 BP 1079 EP 1084 DI 10.1016/j.nucmedbio.2011.05.011 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 862DQ UT WOS:000298070400001 PM 21855359 ER PT J AU Shin, IS Lee, SM Kim, HS Yao, ZS Regino, C Sato, N Cheng, KT Hassan, R Campo, MF Albone, EF Choyke, PL Pastan, I Paik, CH AF Shin, In Soo Lee, Sang-Myung Kim, Hyung Sub Yao, Zhengsheng Regino, Celeste Sato, Noriko Cheng, Kenneth T. Hassan, Raffit Campo, Melissa F. Albone, Earl F. Choyke, Peter L. Pastan, Ira Paik, Chang H. TI Effect of chelator conjugation level and injection dose on tumor and organ uptake of In-111-labeled MORAb-009, an anti-mesothelin antibody SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE In-111-anti-mesothelin antibody (In-111-MORAb-009); Chelator conjugation; Biodistribution; Dose effect ID REFRACTORY LOW-GRADE; MONOCLONAL-ANTIBODY; PHASE-I; OVARIAN CANCERS; MICE BEARING; DTPA LIGAND; BIODISTRIBUTION; RADIOIMMUNOTHERAPY; IN-111; QUANTITATION AB Introduction: Radiolabeling of a monoclonal antibody (mAb) with a metallic radionuclide requires the conjugation of a bifunctional chelator to the mAb. The conjugation, however, can alter the physical and immunological properties of the mAb, consequently affecting its tumor-targeting pharmacokinetics. In this study, we investigated the effect of the amount of 2-(p-isothiocyanatobenzyl)-cyclohexyl-diethylenetriamine-pentaacetic acid (CHX-A '') conjugated to MORAb-009, a mAb directed against mesothelin, and the effect of MORAb dose on the biodistribution of In-111-labeled MORAb-009. Methods: We used nude mice bearing the A431/K5 tumor as a mesothelin-positive tumor model and the A431 tumor as a mesothelin-negative control. To find the optimal level of CHX-A '' conjugation, CHX-A ''-MORAb-009 conjugates with 2.4, 3.5 and 5.5 CHX-A '' molecules were investigated. To investigate the effect of injected MORAb-009 dose on neutralizing the shed mesothelin in the circulation, biodistribution studies were performed after the intravenous co-injection of In-111-labeled MORAb-009 (2.4 CHX-A ''/MORAb-009) with three different doses: 0.2, 2 and 30 mu g of MORAb-009. Results: The tumor uptake in A431/K5 tumor was four times higher than that in A431 tumor, indicating that the tumor uptake in A431/K5 was mesothelin mediated. The conjugate with 5.5 CHX-A '' showed a lower isoelectric point (pI) and lower immunoreactivity (IR) than the 2.4 CHX-A '' conjugate. These differences were reflected in the biodistribution of the In-111 label. The In-111-labeled MORAb-009 conjugated with 2.4 CHX-A '' produced higher tumor uptake and lower liver and spleen uptakes than the 5.5 CHX-A '' conjugate. The biodistribution studies also revealed that the tumor uptake was significantly affected by the injected MORAb-009 dose and tumor size. The 30-mu g dose produced higher tumor uptake than the 0.2- and 2-mu g doses, whereas the 30-mu g dose produced lower liver and spleen uptakes than the 0.2-mu g dose. Conclusion: This study demonstrates that the number of chelate conjugation and the injected dose are two important parameters to achieve high tumor and low non-target organ uptake of In-111-labeled MORAb-009. This study also suggests that the injected dose of mAb could be individualized based on the tumor size or the blood level of shed antigen in a patient to achieve the ideal tumor-to-organ radioactivity ratios. Published by Elsevier Inc. C1 [Shin, In Soo; Lee, Sang-Myung; Kim, Hyung Sub; Yao, Zhengsheng; Cheng, Kenneth T.; Paik, Chang H.] NIH, Radiopharmaceut Lab, Div Nucl Med, Dept Radiol & Imaging Sci,Clin Ctr, Bethesda, MD 20892 USA. [Regino, Celeste; Sato, Noriko; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Hassan, Raffit; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Campo, Melissa F.; Albone, Earl F.] Morphotek Inc, Exton, PA 19342 USA. RP Paik, CH (reprint author), NIH, Radiopharmaceut Lab, Div Nucl Med, Dept Radiol & Imaging Sci,Clin Ctr, Bethesda, MD 20892 USA. EM cpaik@mail.nih.gov FU NIH Clinical Center FX This research was supported by the Intramural Research Program of NIH Clinical Center. NR 30 TC 13 Z9 14 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD NOV PY 2011 VL 38 IS 8 BP 1119 EP 1127 DI 10.1016/j.nucmedbio.2011.05.003 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 862DQ UT WOS:000298070400006 PM 21741258 ER PT J AU Cherkasova, E Malinzak, E Rao, S Takahashi, Y Senchenko, VN Kudryavtseva, AV Nickerson, ML Merino, M Hong, JA Schrump, DS Srinivasan, R Linehan, WM Tian, X Lerman, MI Childs, RW AF Cherkasova, E. Malinzak, E. Rao, S. Takahashi, Y. Senchenko, V. N. Kudryavtseva, A. V. Nickerson, M. L. Merino, M. Hong, J. A. Schrump, D. S. Srinivasan, R. Linehan, W. M. Tian, X. Lerman, M. I. Childs, R. W. TI Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer SO ONCOGENE LA English DT Article DE renal cell carcinoma; endogenous retrovirus; VHL; HIF; DNA methylation ID RENAL-CELL CARCINOMA; HYPOXIA-INDUCIBLE FACTORS; HERV-K18 SUPERANTIGEN; BREAST-CANCER; MESSENGER-RNA; B-CELLS; GENE; METHYLATION; TRANSPLANTATION; PROTEIN AB A human endogenous retrovirus type E (HERV-E) was recently found to be selectively expressed in most renal cell carcinomas (RCCs). Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T cells that kill RCC cells in vitro and in vivo. Here, we show HERV-E expression is restricted to the clear cell subtype of RCC (ccRCC) characterized by an inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene with subsequent stabilization of hypoxia-inducible transcription factors (HIFs)-1 alpha and -2 alpha. HERV-E expression in ccRCC linearly correlated with HIF-2 alpha levels and could be silenced in tumor cells by either transfection of normal VHL or small interfering RNA inhibition of HIF-2 alpha. Using chromatin immunoprecipitation, we demonstrated that HIF-2 alpha can serve as transcriptional factor for HERV-E by binding with HIF response element (HRE) localized in the proviral 5' long terminal repeat (LTR). Remarkably, the LTR was found to be hypomethylated only in HERV-E-expressing ccRCC while other tumors and normal tissues possessed a hypermethylated LTR preventing proviral expression. Taken altogether, these findings provide the first evidence that inactivation of a tumor suppressor gene can result in aberrant proviral expression in a human tumor and give insights needed for translational research aimed at boosting human immunity against antigenic components of this HERV-E. Oncogene (2011) 30, 4697-4706; doi:10.1038/onc.2011.179; published online 23 May 2011 C1 [Cherkasova, E.; Malinzak, E.; Rao, S.; Takahashi, Y.; Lerman, M. I.; Childs, R. W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Senchenko, V. N.; Kudryavtseva, A. V.] Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow, Russia. [Nickerson, M. L.] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. [Merino, M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Hong, J. A.; Schrump, D. S.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Srinivasan, R.; Linehan, W. M.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Tian, X.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM childsr@mail.nih.gov RI Takahashi, Yoshiyuki/I-1929-2012; Senchenko, Vera/C-8992-2014; Kudryavtseva, Anna/C-9032-2014 OI Senchenko, Vera/0000-0002-3119-515X; Kudryavtseva, Anna/0000-0002-3722-8207 FU NIH, National Heart, Lung, and Blood Institute, Hematology Branch; ACKC (Action to Cure Kidney Cancer); Dean R O'Neill Memorial Fellowship FX This work was supported by the intramural research program of NIH, National Heart, Lung, and Blood Institute, Hematology Branch. We wish to acknowledge ACKC (Action to Cure Kidney Cancer) for their support of the ACKC fellow who conducted this research and the Dean R O'Neill Memorial Fellowship for generous contributions supporting this research. We also thank Bill and Giuliana Rancic for their contributions supporting kidney cancer research. We thank Robert Worrell for his assistance in providing tissue samples. NR 30 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD NOV PY 2011 VL 30 IS 47 BP 4697 EP 4706 DI 10.1038/onc.2011.179 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 861QG UT WOS:000298033700002 PM 21602888 ER PT J AU Berkhout, B Jeang, KT AF Berkhout, B. Jeang, K. -T. TI MicroRNAs in viral gene regulation Preface SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Editorial Material C1 [Berkhout, B.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Cambridge, MA 02138 USA. [Berkhout, B.] Univ Amsterdam, NL-1012 WX Amsterdam, Netherlands. [Jeang, K. -T.] NIAID, NIH, Bethesda, MD 20892 USA. [Jeang, K. -T.] MIT, Boston, MA USA. RP Berkhout, B (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Cambridge, MA 02138 USA. RI Jeang, Kuan-Teh/A-2424-2008 NR 0 TC 5 Z9 5 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD NOV-DEC PY 2011 VL 1809 IS 11-12 SI SI BP 587 EP 587 DI 10.1016/j.bbagrm.2011.10.009 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 858WP UT WOS:000297834200001 PM 22055652 ER PT J AU Ziegelbauer, JM AF Ziegelbauer, Joseph M. TI Functions of Kaposi's sarcoma-associated herpesvirus microRNAs SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE KSHV; miRNA; microRNA; Virus host interaction; Post-transcriptional regulation ID VIRUS-ENCODED MICRORNAS; GENE-EXPRESSION; VIRAL MICRORNA; TARGET; CELL; IDENTIFICATION; REPLICATION; LATENCY; PROTEIN; TRANSCRIPTION AB MicroRNAs can modulate gene expression post-transcriptionally by altering mRNA stability and protein translation. Multiple DNA viruses express viral microRNAs and have been shown to modulate expression of host and viral genes. Through various methods of microRNA target identification, we are beginning to understand the various roles of viral miRNAs including viral replication, immune evasion and apoptosis. This review is focused on the roles of microRNAs expressed by Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8. This article is part of a Special Issue entitled: "MicroRNAs in viral gene regulation". Published by Elsevier B.V. C1 NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ziegelbauer, JM (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM ziegelbauerjm@mail.nih.gov FU NCI, NIH FX Thank you to J. Abend and P. Kieffer-Kwon for comments on the manuscript. Research is supported by intramural funds from NCI, NIH. NR 59 TC 14 Z9 14 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD NOV-DEC PY 2011 VL 1809 IS 11-12 SI SI BP 623 EP 630 DI 10.1016/j.bbagrm.2011.05.003 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 858WP UT WOS:000297834200005 PM 21616184 ER PT J AU Houzet, L Jeang, KT AF Houzet, Laurent Jeang, Kuan-Teh TI MicroRNAs and human retroviruses SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE MicroRNA; Virus replication; Innate immunity; RNA silencing suppressor; Viral gene expression; Virus-host interaction ID T-CELL LEUKEMIA; HUMAN-IMMUNODEFICIENCY-VIRUS; RNA SILENCING SUPPRESSOR; HEPATITIS-C VIRUS; SHORT INTERFERING RNA; SMALL NONCODING RNAS; HIV-1 TAR ELEMENT; INFLUENZA-A VIRUS; VIRAL TRANSFORMATION; ONCOMIR ADDICTION AB MicroRNAs (miRNAs) are small non-coding RNAs that control a multitude of critical processes in mammalian cells. Increasing evidence has emerged that host miRNAs serve in animal cells to restrict viral infections. In turn, many viruses encode RNA silencing suppressors (RSS) which are employed to moderate the potency of the cell's miRNA selection against viral replication. Some viruses also encode viral miRNAs. In this review, we summarize findings from human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) that illustrate examples of host cell miRNAs that target the viruses, of RSS encoded by viruses, and of host cell miRNA profile changes that are seen in infected cells. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. Published by Elsevier B.V. C1 [Houzet, Laurent; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lhouzet@mail.nih.gov; kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU NIAID; Office of the Director, NIH FX Work in our laboratory is supported in part by NIAID intramural fund and by the IATAP program from the Office of the Director, NIH. We thank members of our laboratory for critical readings of this manuscript. NR 111 TC 51 Z9 54 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD NOV-DEC PY 2011 VL 1809 IS 11-12 SI SI BP 686 EP 693 DI 10.1016/j.bbagrm.2011.05.009 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 858WP UT WOS:000297834200012 PM 21640212 ER PT J AU Marcus-Sekura, C Richardson, JC Harston, RK Sane, N Sheets, RL AF Marcus-Sekura, Carol Richardson, James C. Harston, Rebecca K. Sane, Nandini Sheets, Rebecca L. TI Evaluation of the human host range of bovine and porcine viruses that may contaminate bovine serum and porcine trypsin used in the manufacture of biological products SO BIOLOGICALS LA English DT Review DE Adventitious agent testing; Animal cell culture; Viral contamination; Bovine virus; Porcine virus; Human host range ID BORNA-DISEASE-VIRUS; HEPATITIS-E VIRUS; EASTERN EQUINE ENCEPHALOMYELITIS; EPIZOOTIC HEMORRHAGIC-DISEASE; DES PETITS RUMINANTS; HUMAN CELL-LINES; PERSISTENT INFECTION; DOMESTIC-ANIMALS; NIPAH VIRUS; ONCOLYTIC PICORNAVIRUS AB Current U.S. requirements for testing cell substrates used in production of human biological products for contamination with bovine and porcine viruses are U.S. Department of Agriculture (USDA) 9CFR tests for bovine serum or porcine trypsin. 9CFR requires testing of bovine serum for seven specific viruses in six families (immunofluorescence) and at least 2 additional families non-specifically (cytopathicity and hemadsorption). 9CFR testing of porcine trypsin is for porcine parvovirus. Recent contaminations suggest these tests may not be sufficient. Assay sensitivity was not the issue for these contaminations that were caused by viruses/virus families not represented in the 9CFR screen. A detailed literature search was undertaken to determine which viruses that infect cattle or swine or bovine or porcine cells in culture also have human host range [ability to infect humans or human cells in culture] and to predict their detection by the currently used 9CFR procedures. There are more viruses of potential risk to biological products manufactured using bovine or porcine raw materials than are likely to be detected by 9CFR testing procedures; even within families, not all members would necessarily be detected. Testing gaps and alternative methodologies should be evaluated to continue to ensure safe, high quality human biologicals. (C) 2011 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved. C1 [Marcus-Sekura, Carol] Biotechnol Assessment Serv Inc BASI, Rockville, MD 20855 USA. [Richardson, James C.; Harston, Rebecca K.; Sane, Nandini] Adv BioSci Labs Inc, Rockville, MD 20850 USA. [Sheets, Rebecca L.] NIAID, CAPT USPHS, Bethesda, MD 20892 USA. RP Marcus-Sekura, C (reprint author), Biotechnol Assessment Serv Inc BASI, 7413 Ottenbrook Terrace, Rockville, MD 20855 USA. EM crsek@aol.com; james.richardson@ablinc.com; rebecca.harston@ablinc.com; nandini.sane@ablinc.com; RSheets@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN266200400045C]; Biotechnology Assessment Services, Inc. FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN266200400045C. Support was also provided by Biotechnology Assessment Services, Inc. NR 151 TC 11 Z9 13 U1 1 U2 14 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 J9 BIOLOGICALS JI Biologicals PD NOV PY 2011 VL 39 IS 6 BP 359 EP 369 DI 10.1016/j.biologicals.2011.08.003 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 853AT UT WOS:000297399300001 PM 22000165 ER PT J AU Spector, AA Campbell, WB Zeldin, DC AF Spector, Arthur A. Campbell, William B. Zeldin, Darryl C. TI Special Issue Eicosanoids and disease Introduction SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Editorial Material C1 [Spector, Arthur A.] NIAAA, NIH, Bethesda, MD 20892 USA. [Campbell, William B.] Med Coll Wisconsin, Milwaukee, WI USA. [Zeldin, Darryl C.] NIEHS, NIH, Bethesda, MD USA. RP Spector, AA (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. EM spectora@mail.nih.gov NR 0 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 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD NOV PY 2011 VL 96 IS 1-4 SI SI BP 1 EP 2 DI 10.1016/j.prostaglandins.2011.10.001 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860RC UT WOS:000297964400001 PM 22004919 ER PT J AU Chen, GZ Wang, PH Zhao, G Xu, G Gruzdev, A Zeldin, DC Wang, DW AF Chen, Guangzhi Wang, Peihua Zhao, Gang Xu, Gang Gruzdev, Artiom Zeldin, Darryl C. Wang, Dao Wen TI Cytochrome P450 epoxygenase CYP2J2 attenuates nephropathy in streptozotocin-induced diabetic mice SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE Arachidonic acids; Cytochrome P450 epoxygenase; Streptozotocin; Diabetic nephropathy; Tubular epithelial-inesenchymal; transdifferentiation ID GROWTH-FACTOR-BETA; SOLUBLE EPOXIDE HYDROLASE; EPITHELIAL-MYOFIBROBLAST TRANSDIFFERENTIATION; ACTIVATED PROTEIN-KINASE; PROXIMAL TUBULAR CELLS; EPOXYEICOSATRIENOIC ACIDS; TGF-BETA; MESENCHYMAL TRANSITION; SIGNALING PATHWAYS; TUBULOINTERSTITIAL FIBROSIS AB Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs). which play important and diverse roles in the cardiovascular system. The anti-inflammatory, antiapoptotic, pro-angiogenic, and anti-hypertensive properties of EETs in the cardiovascular system suggest a beneficial role for EETs in diabetic nephropathy. This study investigated the effects of endothelial specific overexpression of CYP2J2 epoxygenase on diabetic nephropathy in streptozotocin-induced diabetic mice. Endothelial CYP2J2 overexpression attenuated renal damage as measured by urinary microalbumin and glomerulosclerosis. These effects were associated with inhibition of TGF-beta/Smad signaling in the kidney. Indeed, overexpression of CYP2J2 prevented TGF-beta 1-induced renal tubular epithelial-mesenchymal transition in vitro. These findings highlight the beneficial roles of the CYP epoxygenase-EET system in the pathogenesis of diabetic nephropathy. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chen, Guangzhi; Wang, Peihua; Zhao, Gang; Xu, Gang; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. [Chen, Guangzhi; Wang, Peihua; Zhao, Gang; Xu, Gang; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Gene Therapy Ctr, Wuhan 430030, Peoples R China. [Gruzdev, Artiom; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn FU National Education Ministration project; Nature Science Foundation Committee [30930039, 30700377]; Wuhan City grant FX This work was supported by funds from the National Education Ministration project, Nature Science Foundation Committee projects (Nos. 30930039, 30700377) and Wuhan City grant. NR 55 TC 18 Z9 19 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD NOV PY 2011 VL 96 IS 1-4 SI SI BP 63 EP 71 DI 10.1016/j.prostaglandins.2011.06.009 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860RC UT WOS:000297964400011 PM 21742052 ER PT J AU Rapoport, SI Ramadan, E Basselin, M AF Rapoport, Stanley I. Ramadan, Epolia Basselin, Mireille TI Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Review DE Docosahexaenoic acid; PL-A(2); Biomarker; Imaging; Calcium; PET ID POLYUNSATURATED FATTY-ACIDS; ALPHA-LINOLENIC ACID; PHOSPHOLIPASE A(2); RAT-BRAIN; UNANESTHETIZED RATS; NUTRITIONAL DEPRIVATION; ARACHIDONIC-ACID; RECEPTOR; LIVER; TURNOVER AB Docosahexaenoic acid (DHA) is critical for maintaining normal brain structure and function, and is considered neuroprotective. Its brain concentration depends on dietary DHA content and hepatic conversion from its dietary derived n-3 precursor, alpha-linolenic acid (alpha-LNA). We have developed an in vivo method in rats using quantitative autoradiography and intravenously injected radiolabeled DHA to image net incorporation into the brain of unesterified plasma DHA, and showed with this method that the incorporation rate of DHA equals the rate of brain metabolic DHA consumption. The method has been extended for use in humans with positron emission tomography (PET). Furthermore, imaging in unanesthetized rats using DHA incorporation as a biomarker in response to acute N-methyl-D-aspartate administration confirms that regional DHA signaling is independent of extracellular calcium, and likely mediated by a calcium-independent phospholipase A(2) (iPLA(2)). Studies in mice in which iPLA(2)-VIA (beta) was knocked out confirmed that this enzyme is critical for baseline and muscarinic cholinergic signaling involving DHA. Thus, quantitative imaging of DHA incorporation from plasma into brain can be used as an in vivo biomarker of brain DHA metabolism and neurotransmission. Published by Elsevier Inc. C1 [Rapoport, Stanley I.; Ramadan, Epolia; Basselin, Mireille] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Ramadan, E (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM ramadanir@mail.nih.gov FU National Institute on Aging FX This study was supported entirely by the Intramural Program of the National Institute on Aging. No author has a conflict of interest with regard to the research. Part of this paper will be published as a lecture given by S. Rapoport at journees Chevreul, 2011, Lipids and the Brain, Paris, March 28, 2011. NR 48 TC 28 Z9 28 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD NOV PY 2011 VL 96 IS 1-4 SI SI BP 109 EP 113 DI 10.1016/j.prostaglandins.2011.06.003 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860RC UT WOS:000297964400018 PM 21704722 ER PT J AU Kim, HY Spector, AA Xiong, ZM AF Kim, Hee-Yong Spector, Arthur A. Xiong, Zheng-Mei TI A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Review DE N-Docosahexaenoylethanolamide; Synaptamide; DHA; Hippocampus; Neuron; Anandamide; N-Docosahexaenoyl-amino acylamide ID ENDOGENOUS CANNABINOID PRECURSOR; DOCOSAHEXAENOIC ACID; NEUROPROTECTIN D1; AMINO-ACIDS; MOUSE-BRAIN; RAT-BRAIN; RECEPTOR; ANANDAMIDE; NEURONS; ARACHIDONYLGLYCINE AB Docosahexaenoic acid (DHA). the n-3 essential fatty acid that is highly enriched in the brain, increases neurite growth and synaptogenesis in cultured mouse fetal hippocampal neurons. These cellular effects may underlie the DHA-induced enhancement of hippocampus-dependent learning and memory functions. We found that N-docsahexaenoylethanolamide (DEA), an ethanolamide derivative of DHA, is a potent mediator for these actions. This is supported by the observation that DHA is converted to DEA by fetal mouse hippocampal neuron cultures and a hippocampal homogenate, and DEA is present endogenously in the mouse hippocampus. Furthermore, DEA stimulates neurite growth and synaptogenesis at substantially lower concentrations than DHA, and it enhances glutamatergic synaptic activities with concomitant increases in synapsin and glutamate receptor subunit expression in the hippocampal neurons. These findings suggest that DEA, an ethanolamide derivative of DHA, is a synaptogenic factor, and therefore we suggest utilizing the term 'synaptamide'. This brief review summarizes the neuronal production and actions of synaptamide and describes other N-docosahexaenoyl amides that are present in the brain. Published by Elsevier Inc. C1 [Kim, Hee-Yong; Spector, Arthur A.; Xiong, Zheng-Mei] NIAAA, Lab Mol Signaling, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Lab Mol Signaling, NIH, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov RI Xiong, Zhengmei/I-2439-2016 FU Intramural NIH HHS [ZIA AA000284-20] NR 56 TC 31 Z9 31 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD NOV PY 2011 VL 96 IS 1-4 SI SI BP 114 EP 120 DI 10.1016/j.prostaglandins.2011.07.002 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860RC UT WOS:000297964400019 PM 21810478 ER PT J AU Launer, LJ Hughes, TM White, LR AF Launer, Lenore J. Hughes, Timothy M. White, Lon R. TI Microinfarcts, brain atrophy, and cognitive function: The Honolulu Asia Aging Study Autopsy Study SO ANNALS OF NEUROLOGY LA English DT Article ID JAPANESE-AMERICAN MEN; ALZHEIMERS-DISEASE; DEMENTIA; HYPOTHESIS AB Objective: This study was untaken to investigate the association of micro brain infarcts (MBIs) with antemortem global cognitive function (CF), and whether brain weight (BW) and Alzheimer lesions (neurofibrillary tangles [NFTs] or neuritic plaques [NPs]) mediate the association. C1 [Launer, Lenore J.] NIA, LEDB, NIH, Bethesda, MD 20892 USA. [Hughes, Timothy M.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [White, Lon R.] Univ Hawaii, Dept Geriatr Med, John A Burns Sch Med, Honolulu, HI 96822 USA. [White, Lon R.] Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu, HI USA. RP Launer, LJ (reprint author), NIA, LEDB, NIH, 7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov FU NIH National Institute on Aging (NIA) [1 U01 AG19349, 5 R01 AG017155]; NIA FX This work was supported by the NIH National Institute on Aging (NIA) grant numbers 1 U01 AG19349 and 5 R01 AG017155 to LRW, and the NIA Intramural Research Program. NR 20 TC 69 Z9 70 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD NOV PY 2011 VL 70 IS 5 BP 774 EP 780 DI 10.1002/ana.22520 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 857TB UT WOS:000297741600013 PM 22162060 ER PT J AU Lee, M Cronin, KA Gail, MH Dignam, JJ Feuer, EJ AF Lee, Minjung Cronin, Kathleen A. Gail, Mitchell H. Dignam, James J. Feuer, Eric J. TI Multiple imputation methods for inference on cumulative incidence with missing cause of failure SO BIOMETRICAL JOURNAL LA English DT Article DE Cause-specific hazard function; Competing risks; Counting process; Missing at random; Proportional hazards model ID PROPORTIONAL HAZARDS MODEL; SURGICAL ADJUVANT BREAST; COMPETING RISKS MODEL; SURVIVAL-DATA; REGRESSION-COEFFICIENTS; LARGE-SAMPLE; CANCER; CYCLOPHOSPHAMIDE; DEATH; TIMES AB Analysis of cumulative incidence (sometimes called absolute risk or crude risk) can be difficult if the cause of failure is missing for some subjects. Assuming missingness is random conditional on the observed data, we develop asymptotic theory for multiple imputation methods to estimate cumulative incidence. Covariates affect cause-specific hazards in our model, and we assume that separate proportional hazards models hold for each cause-specific hazard. Simulation studies show that procedures based on asymptotic theory have near nominal operating characteristics in cohorts of 200 and 400 subjects, both for cumulative incidence and for prediction error. The methods are illustrated with data on survival after breast cancer, obtained from the National Surgical Adjuvant Breast and Bowel Project (NSABP). C1 [Lee, Minjung; Cronin, Kathleen A.] NCI, Data Anal & Interpretat Branch, Div Canc Control & Populat Studies, Bethesda, MD 20852 USA. [Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Dignam, James J.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Feuer, Eric J.] NCI, Stat Methodol & Applicat Branch, Div Canc Control & Populat Studies, Bethesda, MD 20852 USA. RP Lee, M (reprint author), NCI, Data Anal & Interpretat Branch, Div Canc Control & Populat Studies, Bethesda, MD 20852 USA. EM leem5@mail.nih.gov FU National Institute of Health [U10-CA12027, U10-CA37377, U10-CA69651, U10-CA69974]; [U10-CA21661] FX The NSABP clinical trials used in the example were supported by National Institute of Health grants U10-CA12027, U10-CA37377, U10-CA69651 and U10-CA69974. J. Dignam received support from U10-CA21661. The authors thank the editor, associate editor, and two reviewers for their helpful comments and Dr. Kaifeng Lu for sharing the codes from his previous work. NR 26 TC 7 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD NOV PY 2011 VL 53 IS 6 SI SI BP 974 EP 993 DI 10.1002/bimj.201000175 PG 20 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 856LT UT WOS:000297643400008 PM 22028204 ER PT J AU Foster, MC Yang, Q Hwang, SJ Hoffmann, U Fox, CS AF Foster, Meredith C. Yang, Qiong Hwang, Shih-Jen Hoffmann, Udo Fox, Caroline S. TI Heritability and genome-wide association analysis of renal sinus fat accumulation in the Framingham Heart Study SO BMC MEDICAL GENETICS LA English DT Article ID BODY-MASS INDEX; CHRONIC KIDNEY-DISEASE; METABOLIC SYNDROME; RISK; CKD; CIRCUMFERENCE; LIPODYSTROPHY; LINKAGE; OBESITY; VARIANT AB Background: Ectopic fat accumulation in the renal sinus is associated with chronic kidney disease and hypertension. The genetic contributions to renal sinus fat accumulation in humans have not been well characterized. Methods: The present analysis consists of participants from the Framingham Offspring and Third Generation who underwent computed tomography; renal sinus fat and visceral adipose tissue (VAT) were quantified. Renal sinus fat was natural log transformed and sex- and cohort-specific residuals were created, adjusted for (1) age, (2) age and body mass index (BMI), and (3) age and VAT. Residuals were pooled and used to calculate heritability using variance-components analysis in SOLAR. A genome-wide association study (GWAS) for renal sinus fat was performed using an additive model with approximately 2.5 million imputed single nucleotide polymorphisms (SNPs). Finally, we identified the associations of renal sinus fat in our GWAS results with validated SNPs for renal function (n = 16), BMI (n = 32), and waist-to-hip ratio (WHR, n = 14), and applied a multi-SNP genetic risk score method to determine if the SNPs for each renal and obesity trait were in aggregate associated with renal sinus fat. Results: The heritability of renal sinus fat was 39% (p < 0.0001); results were not materially different after adjustment for BMI (39%) or VAT (40%). No SNPs reached genome-wide significance in our GWAS. In our candidate gene analysis, we observed nominal, direction consistent associations with renal sinus fat for one SNP associated with renal function (p = 0.01), two associated with BMI (p < 0.03), and two associated with WHR (p < 0.03); however, none remained significant after accounting for multiple testing. Finally, we observed that in aggregate, the 32 SNPs associated with BMI were nominally associated with renal sinus fat (multi-SNP genetic risk score p = 0.03). Conclusions: Renal sinus fat is a heritable trait, even after accounting for generalized and abdominal adiposity. This provides support for further research into the genetic determinants of renal sinus fat. While our study was underpowered to detect genome-wide significant loci, our candidate gene BMI risk score results suggest that variability in renal sinus fat may be associated with SNPs previously known to be associated with generalized adiposity. C1 [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA 01702 USA. [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Foster, Meredith C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. RP Fox, CS (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov RI Yang, Qiong/G-5438-2014 FU National Heart, Lung and Blood Institute [N01-HC-25195] FX We would like to acknowledge and thank Toby Johnson for sharing his method for creating the multi-SNP genetic risk score test statistic. The Framingham Heart Study is supported by the National Heart, Lung and Blood Institute (N01-HC-25195). The funding body did not play a role in the study design, collection, analysis, and interpretation of data, in the writing of the manuscript, or the decision to submit the manuscript for publication. NR 33 TC 3 Z9 3 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD NOV 1 PY 2011 VL 12 AR 148 DI 10.1186/1471-2350-12-148 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 856UT UT WOS:000297669900001 PM 22044751 ER PT J AU Zhou, YD Sheets, KG Knott, EJ Regan, CE Tuo, JS Chan, CC Gordon, WC Bazan, NG AF Zhou, Yongdong Sheets, Kristopher G. Knott, Eric J. Regan, Cornelius E., Jr. Tuo, Jingsheng Chan, Chi-Chao Gordon, William C. Bazan, Nicolas G. TI Cellular and 3D optical coherence tomography assessment during the initiation and progression of retinal degeneration in the Ccl2/Cx3cr1-deficient mouse SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE Ccl2; Cx3cr1; rodent model; confocal scanning laser ophthalmoscopy; optical coherence tomography; 3D OCT; photoreceptor degeneration; reactive gliosis; Muller cell ID MACULAR DEGENERATION; PHOTORECEPTOR DEGENERATION; RETINITIS-PIGMENTOSA; PROTEIN EXPRESSION; DEFICIENT MICE; LIGHT-DAMAGE; ANIMAL-MODEL; ALBINO-RATS; CX3CR1; ACCUMULATION AB Retinal pathologies common to human eye diseases, including abnormal retinal pigment epithelial (RPE) cells, drusen-like accumulation, photoreceptor atrophy, and choroidal neovascularization, have been reported in the Ccl2/Cx3cr1-deficient mouse. The Ccl2 gene encodes the pro-inflammatory chemokine CCL2 (MCP-1), which is responsible for chemotactic recruitment of monocyte-derived macrophages to sites of inflammation. The Cx3cr1 gene encodes the fractalkine receptor, CX3CR1, and is required for accumulation of monocytes and microglia recruited via CCL2. Chemokine-mediated inflammation is implicated in retinal degenerative diseases such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, and uveoretinitis, and proper chemokine signaling from the RPE, Muller glia, and astrocytes is necessary to regulate leukocyte trafficking. Therefore, this mouse, possessing aberrant chemokine signaling coupled with retinal degenerative pathologies, presents an ideal opportunity to investigate the effect of altered signaling on retinal homeostasis and photoreceptor degeneration. Since this mouse is a recent development, more data covering the onset, location, and progression rate of pathologies is needed. In the present study we establish these parameters and show two photoreceptor cell death processes. Our observations of decreased glutamine synthetase and increased glial fibrillary acidic protein suggest that Muller cells respond very early within regions where lesions are forming. Finally, we suggest that retinal angiomatous proliferation contributes to pathological angiogenesis in this Ccl2/Cx3cr1-deficient mouse. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Bazan, Nicolas G.] Louisiana State Univ, Sch Med, Dept Ophthalmol, Hlth Sci Ctr,Neurosci Ctr Excellence, New Orleans, LA 70112 USA. [Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Bazan, NG (reprint author), Louisiana State Univ, Sch Med, Dept Ophthalmol, Hlth Sci Ctr,Neurosci Ctr Excellence, 2020 Gravier St,Suite D, New Orleans, LA 70112 USA. EM nbazan@lsuhsc.edu OI Tuo, Jingsheng/0000-0002-1372-7810 FU National Institutes of Health, NCRR [P20 RR016816]; NEI [R01 EY005121]; American Health Assistance Foundation [M2010091]; Foundation Fighting Blindness [TA-NP-0808-0463-LSUNO] FX This research was supported by grants from the National Institutes of Health, NCRR (P20 RR016816) and NEI (R01 EY005121), the American Health Assistance Foundation (M2010091), and the Foundation Fighting Blindness (TA-NP-0808-0463-LSUNO). NR 39 TC 17 Z9 17 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD NOV PY 2011 VL 93 IS 5 BP 636 EP 648 DI 10.1016/j.exer.2011.07.017 PG 13 WC Ophthalmology SC Ophthalmology GA 855AK UT WOS:000297535700010 PM 21854772 ER PT J AU Griffith, AJ Wangemann, P AF Griffith, Andrew J. Wangemann, Philine TI Hearing loss associated with enlargement of the vestibular aqueduct: Mechanistic insights from clinical phenotypes, genotypes, and mouse models SO HEARING RESEARCH LA English DT Article ID PENDRED-SYNDROME GENE; CONGENITAL CYTOMEGALOVIRUS-INFECTION; COCHLEAR ENDOLYMPH; INNER-EAR; CARBONIC-ANHYDRASE; SLC26A4 MUTATION; PDS MUTATIONS; K+ SECRETION; GUINEA-PIG; DEAFNESS AB Enlargement of the vestibular aqueduct (EVA) is one of the most common inner ear malformations associated with sensorineural hearing loss in children. The delayed onset and progressive nature of this phenotype offer a window of opportunity to prevent or retard progression of hearing loss. EVA is not the direct cause of hearing loss in these patients, but rather is a radiologic marker for some underlying pathogenetic defect. Mutations of the SLC26A4 gene are a common cause of EVA. Studies of an Slc26a4 knockout mouse demonstrate that acidification and enlargement of the scala media are early events in the pathogenesis of deafness. The enlargement is driven by fluid secretion in the vestibular labyrinth and a failure of fluid absorption in the embryonic endolymphatic sac. Elucidating the mechanism of hearing loss may offer clues to potential therapeutic strategies. Published by Elsevier B.V. C1 [Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, Rockville, MD 20850 USA. [Wangemann, Philine] Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, 5 Res Court, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov RI Wangemann, Philine/N-2826-2013 FU NIH [Z01-DC-000060]; Kansas State University FX The authors are supported by NIH intramural research fund Z01-DC-000060 (A.J.G.) and Kansas State University (P.W.). We thank our colleagues for critical review of this manuscript. Figs. 1 and 2 were provided by the National Institute on Deafness and Other Communication Disorders. NR 77 TC 18 Z9 19 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 EI 1878-5891 J9 HEARING RES JI Hear. Res. PD NOV PY 2011 VL 281 IS 1-2 SI SI BP 11 EP 17 DI 10.1016/j.heares.2011.05.009 PG 7 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 853ML UT WOS:000297430300003 PM 21669267 ER PT J AU Munoz, B Stare, D Mkocha, H Gaydos, C Quinn, T West, SK AF Munoz, Beatriz Stare, Dianne Mkocha, Harran Gaydos, Charlotte Quinn, Thomas West, Sheila K. TI Can Clinical Signs of Trachoma Be Used after Multiple Rounds of Mass Antibiotic Treatment to Indicate Infection? SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CHLAMYDIA-TRACHOMATIS; AZITHROMYCIN; COMMUNITY; TANZANIA; COVERAGE AB PURPOSE. To evaluate combinations of clinical signs, using a modified World Health Organization (WHO) grading scheme, to predict a very low prevalence of infection at the community level after at least three rounds of mass drug administration (MDA). METHODS. Seventy-one villages had three to seven rounds of MDA. A random sample of 7828 children ages 5 years and younger was evaluated for trachoma, and determination of Chlamydia trachomatis infection was made. Proportions of children positive for infection were evaluated against all possible combinations of follicular trachoma (TF) and inflammatory trachoma (TI). High-risk signs (HRS) for infection were defined as those indicating the infection prevalence was >20%. The sensitivity and specificity of prevalence of HRS in identifying communities with infection was examined. RESULTS. The median community infection prevalence was 3.8% interquartile range (IQR) (1.8%, 7.7%); the median trachoma prevalence was 9.4%, IQR (6.6%, 15%). Severe TI, combination of TF and TI (WHO criteria), or severe TF with signs of inflammation were predictive of infection in the community, but the absence of these HRS was not an indicator of low infection rates. CONCLUSIONS. The use of HRS to determine the infection status of a community was not useful in predicting whether MDA could be stopped. (Invest Ophthalmol Vis Sci. 2011;52:8806-8810) DOI:10.1167/iovs.11-8074 C1 [Munoz, Beatriz; Stare, Dianne; West, Sheila K.] Johns Hopkins Univ, Dana Ctr Prevent Ophthalmol, Baltimore, MD USA. [Gaydos, Charlotte; Quinn, Thomas] Johns Hopkins Univ, Dept Med, Div Infect Dis, Baltimore, MD USA. [Mkocha, Harran] Kongwa Trachoma Project, Kongwa, Tanzania. [Quinn, Thomas] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Munoz, B (reprint author), Johns Hopkins Univ Hosp, Wilmer Eye Inst, Wilmer Room 129,600 N Wolfe St, Baltimore, MD 21287 USA. EM bmunoz@jhmi.edu; shwest@jhmi.edu FU National Eye Institute [EY16429]; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; Research to Prevent Blindness FX Supported by the National Eye Institute Grant EY16429 and in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (TQ). SKW is the recipient of a Senior Scientist award from Research to Prevent Blindness. NR 19 TC 12 Z9 12 U1 0 U2 4 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 NOV PY 2011 VL 52 IS 12 BP 8806 EP 8810 DI 10.1167/iovs.11-8074 PG 5 WC Ophthalmology SC Ophthalmology GA 856IB UT WOS:000297631400009 PM 22025578 ER PT J AU Stanton, CM Yates, JRW den Hollander, AI Seddon, JM Swaroop, A Stambolian, D Fauser, S Hoyng, C Yu, Y Atsuhiro, K Branham, K Othman, M Chen, W Kortvely, E Chalmers, K Hayward, C Moore, AT Dhillon, B Ueffing, M Wright, AF AF Stanton, Chloe M. Yates, John R. W. den Hollander, Anneke I. Seddon, Johanna M. Swaroop, Anand Stambolian, Dwight Fauser, Sascha Hoyng, Carel Yu, Yi Atsuhiro, Kanda Branham, Kari Othman, Mohammad Chen, Wei Kortvely, Elod Chalmers, Kevin Hayward, Caroline Moore, Anthony T. Dhillon, Baljean Ueffing, Marius Wright, Alan F. TI Complement Factor D in Age-Related Macular Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALTERNATIVE PATHWAY; SERINE-PROTEASE; ADIPOSE-TISSUE; BIOSYNTHESIS; ACTIVATION; COMPONENTS; PROTEINS; SUSCEPTIBILITY; ASSOCIATION; ADIPOCYTES AB PURPOSE. To examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by analysis of genetic association, copy number variation, and plasma CFD concentrations. METHODS. Single nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy number was analyzed by gene copy number assay. Plasma CFD was measured by an enzyme-linked immunosorbent assay. RESULTS. Genetic association was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-analysis of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the association almost confined to females. Copy number variation in the CFD gene was identified in 13 out of 640 samples examined but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concentration was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest versus lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females. CONCLUSIONS. CFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic association between a CFD gene SNP and AMD and a significant increase in plasma CFD concentration in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis. (Invest Ophthalmol Vis Sci. 2011;52:8828-8834) DOI:10.1167/iovs.11-7933 C1 [Stanton, Chloe M.; Chalmers, Kevin; Hayward, Caroline; Wright, Alan F.] Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Yates, John R. W.; Moore, Anthony T.] UCL, Inst Ophthalmol, London, England. [den Hollander, Anneke I.; Hoyng, Carel] Radboud Univ Nijmegen, Dept Ophthalmol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Seddon, Johanna M.; Yu, Yi] Tufts Med Ctr, Dept Ophthalmol, New England Eye Ctr, Boston, MA USA. [Swaroop, Anand; Atsuhiro, Kanda] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA. [Fauser, Sascha] Univ Eye Clin Cologne, Cologne, Germany. [Branham, Kari; Othman, Mohammad] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Chen, Wei] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Kortvely, Elod; Ueffing, Marius] Inst Ophthalm Res, Ctr Ophthalmol, Tubingen, Germany. [Dhillon, Baljean] Univ Edinburgh, Edinburgh, Midlothian, Scotland. RP Wright, AF (reprint author), Inst Genet & Mol Med, MRC Human Genet Unit, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland. EM alan.wright@hgu.mrc.ac.uk RI Hollander, Anneke/N-4911-2014; Hoyng, C.B./H-8050-2014; Hayward, Caroline/M-8818-2016; OI Hayward, Caroline/0000-0002-9405-9550; Swaroop, Anand/0000-0002-1975-1141 FU Medical Research Council (UK); Macula Vision Research Foundation, Fight for Sight; National Eye Institute (NEI) [RO1-EY11309]; Netherlands Organisation for Scientific Research [016.096.309, AIdH]; Massachusetts Lions Eye Research Fund, Inc.; Ophthalmic Epidemiology and Genetics Service, Tufts University School of Medicine, Boston, MA, USA FX Supported by the Medical Research Council (UK); Macula Vision Research Foundation, Fight for Sight (AFW),; the National Eye Institute (NEI) intramural program (AS); the Netherlands Organisation for Scientific Research (Grant 016.096.309; AIdH); NEI Grant RO1-EY11309 (JMS); Massachusetts Lions Eye Research Fund, Inc.; Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, Tufts University School of Medicine, Boston, MA, USA. NR 32 TC 27 Z9 27 U1 0 U2 6 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 NOV PY 2011 VL 52 IS 12 BP 8828 EP 8834 DI 10.1167/iovs.11-7933 PG 7 WC Ophthalmology SC Ophthalmology GA 856IB UT WOS:000297631400012 PM 22003108 ER PT J AU Ramirez, M Wu, ZJ Moreno-Carranza, B Jeziorski, MC Arnold, E Diaz-Lezama, N de la Escalera, GM Colosi, P Clapp, C AF Ramirez, Mayda Wu, Zhijian Moreno-Carranza, Bibiana Jeziorski, Michael C. Arnold, Edith Diaz-Lezama, Nundehui Martinez de la Escalera, Gonzalo Colosi, Peter Clapp, Carmen TI Vasoinhibin Gene Transfer by Adenoassociated Virus Type 2 Protects against VEGF- and Diabetes-Induced Retinal Vasopermeability SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; FACTOR 16K HPRL; NITRIC-OXIDE SYNTHASE; N-TERMINAL FRAGMENT; MACULAR EDEMA; VASCULAR-PERMEABILITY; VITREOUS LEVELS; HUMAN PROLACTIN; VIRAL VECTORS; TUMOR-GROWTH AB PURPOSE. Specific proteolytic cleavages of the hormone prolactin (PRL) generate vasoinhibins, a family of peptides (including 16-kDa PRL) that are able to inhibit the pathologic increase in retinal vasopermeability (RVP) associated with diabetes. Here the authors tested the ability of an adenoassociated virus type 2 (AAV2) vasoinhibin vector to inhibit vascular endothelial growth factor (VEGF)- and diabetes-induced RVP. METHODS. AAV2 vectors encoding vasoinhibin, PRL, or soluble VEGF receptor 1 (soluble FMS-like tyrosine kinase-1 [sFlt-1]) were injected intravitreally into the eyes of rats. Four weeks later, either VEGF was injected intravitreally or diabetes was induced with streptozotocin. Tracer accumulation was evaluated as an index of RVP using fluorescein angiography or the Evans blue dye method. RT-PCR verified transgene expression in the retina, and the intravitreal injection of an AAV2 vector encoding green fluorescent protein revealed transduced cells in the retinal ganglion cell layer. In addition, Western blot analysis of AAV2-transduced HEK293 cells confirmed the expression and secretion of the vectorencoded proteins. RESULTS. The AAV2-vasoinhibin vector prevented the increase in tracer accumulation that occurs 24 hours after the intravitreal injection of VEGF. Diabetes induced a significant increase in tracer accumulation compared with nondiabetic controls. This increase was blocked by the AAV2-vasoinhibin vector and reduced by the AAV2-sFlt-1 vector. The AAV2-PRL vector had no effect. CONCLUSIONS. These results show that an AAV2-vasoinhibin vector prevents pathologic RVP and suggest it could have therapeutic value in patients with diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2011;52:8944-8950) DOI: 10.1167/iovs.11-8190 C1 [Ramirez, Mayda; Moreno-Carranza, Bibiana; Jeziorski, Michael C.; Arnold, Edith; Diaz-Lezama, Nundehui; Martinez de la Escalera, Gonzalo; Clapp, Carmen] Univ Nacl Autonoma Mexico, Inst Neurobiol, Queretaro 76230, Mexico. [Wu, Zhijian; Colosi, Peter] NEI, Ocular Gene Therapy Lab, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Clapp, C (reprint author), Univ Nacl Autonoma Mexico, Inst Neurobiol, Campus UNAM Juriquilla, Queretaro 76230, Mexico. EM clapp@unam.mx FU National Council of Science and Technology of Mexico (CONACYT) [SALUD-2008-C01-87015, SALUD-2011-1-161594] FX Supported in part by National Council of Science and Technology of Mexico (CONACYT) Grants SALUD-2008-C01-87015 and SALUD-2011-1-161594 (CC). NR 56 TC 13 Z9 14 U1 4 U2 19 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 NOV PY 2011 VL 52 IS 12 BP 8944 EP 8950 DI 10.1167/iovs.11-8190 PG 7 WC Ophthalmology SC Ophthalmology GA 856IB UT WOS:000297631400026 PM 22003113 ER PT J AU Song, J Smaoui, N Ayyagari, R Stiles, D Benhamed, S MacDonald, IM Daiger, SP Tumminia, SJ Hejtmancik, F Wang, XJ AF Song, Jin Smaoui, Nizar Ayyagari, Radha Stiles, David Benhamed, Sonia MacDonald, Ian M. Daiger, Stephen P. Tumminia, Santa J. Hejtmancik, Fielding Wang, Xinjing TI High-Throughput Retina-Array for Screening 93 Genes Involved in Inherited Retinal Dystrophy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RESEQUENCING MICROARRAY; USHER-SYNDROME; MUTATIONS; VALIDATION; PIGMENTOSA; DISEASE; IDENTIFICATION; GENETICS; PLATFORM AB PURPOSE. Retinal dystrophy (RD) is a broad group of hereditary disorders with heterogeneous genotypes and phenotypes. Current available genetic testing for these diseases is complicated, time consuming, and expensive. This study was conducted to develop and apply a microarray-based, high-throughput resequencing system to detect sequence alterations in genes related to inherited RD. METHODS. A customized 300-kb resequencing chip, Retina-Array, was developed to detect sequence alterations of 267,550 bases of both sense and antisense sequence in 1470 exons spanning 93 genes involved in inherited RD. Retina-Array was evaluated in 19 patient samples with inherited RD provided by the eyeGENE repository and four Centre d'Etudes du Polymorphisme Humaine reference samples through a high-throughput experimental approach that included an automated PCR assay setup and quantification, efficient post-quantification data processing, optimized pooling and fragmentation, and standardized chip processing. RESULTS. The performance of the chips demonstrated that the average base pair call rate and accuracy were 93.56% and 99.86%, respectively. In total, 304 candidate variations were identified using a series of customized screening filters. Among 174 selected variations, 123 (70.7%) were further confirmed by dideoxy sequencing. Analysis of patient samples using Retina-Array resulted in the identification of 10 known mutations and 12 novel variations with high probability of deleterious effects. CONCLUSIONS. This study suggests that Retina-Array might be a valuable tool for the detection of disease-causing mutations and disease severity modifiers in a single experiment. Retinal-Array may provide a powerful and feasible approach through which to study genetic heterogeneity in retinal diseases. (Invest Ophthalmol Vis Sci. 2011;52:9053-9060) DOI: 10.1167/iovs.11-7978 C1 [Wang, Xinjing] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Smaoui, Nizar; Benhamed, Sonia] GeneDx, Gaithersburg, MD USA. [Ayyagari, Radha] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA. [MacDonald, Ian M.] Univ Alberta, Dept Ophthalmol, Edmonton, AB, Canada. [Daiger, Stephen P.] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. RP Wang, XJ (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 10D43,10 Ctr Dr, Bethesda, MD 20892 USA. EM wangx6@nei.nih.gov OI MacDonald, Ian/0000-0001-7472-8385 FU Department of Health and Human Services/National Institutes of Health/National Eye Institute FX Supported by the Department of Health and Human Services/National Institutes of Health/National Eye Institute extramural, clinical, and intramural programs. NR 27 TC 19 Z9 19 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 NOV PY 2011 VL 52 IS 12 BP 9053 EP 9060 DI 10.1167/iovs.11-7978 PG 8 WC Ophthalmology SC Ophthalmology GA 856IB UT WOS:000297631400039 PM 22025579 ER PT J AU Bowles, K Cukras, C Turriff, A Sergeev, Y Vitale, S Bush, RA Sieving, PA AF Bowles, Kristen Cukras, Catherine Turriff, Amy Sergeev, Yuri Vitale, Susan Bush, Ronald A. Sieving, Paul A. TI X-Linked Retinoschisis: RS1 Mutation Severity and Age Affect the ERG Phenotype in a Cohort of 68 Affected Male Subjects SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RETINAL VEIN OCCLUSION; JUVENILE RETINOSCHISIS; BIPOLAR CELLS; XLRS1 GENE; PHOTORECEPTOR; EXPRESSION; ELECTRORETINOGRAPHY; FAMILIES; KNOCKOUT AB PURPOSE. To assess the effect of age and RS1 mutation on the phenotype of X-linked retinoschisis (XLRS) subjects using the clinical electroretinogram (ERG) in a cross-sectional analysis. METHODS. Sixty-eight XLRS males 4.5 to 55 years of age underwent genotyping, and the retinoschisis (RS1) mutations were classified as less severe (27 subjects) or more severe (41 subjects) based on the putative impact on the protein. ERG parameters of retinal function were analyzed by putative mutation severity with age as a continuous variable. RESULTS. The a-wave amplitude remained greater than the lower limit of normal (mean, -2 SD) for 72% of XLRS males and correlated with neither age nor mutation class. However, b-wave and b/a-ratio amplitudes were significantly lower in the more severe than in the less severe mutation groups and in older than in younger subjects. Subjects up to 10 years of age with more severe RS1 mutations had significantly greater b-wave amplitudes and faster a-wave trough implicit times than older subjects in this group. CONCLUSIONS. RS1 mutation putative severity and age both had significant effects on retinal function in XLRS only in the severe mutation group, as judged by ERG analysis of the b-wave amplitude and the b/a-ratio, whereas the a-wave amplitude remained normal in most. A new observation was that increasing age (limited to those aged 55 and younger) caused a significant delay in XLRS b-wave onset (i.e., a-wave implicit time), even for those who retained considerable b-wave amplitudes. The delayed b-wave onset suggested that dysfunction of the photoreceptor synapse or of bipolar cells increases with age of XLRS subjects. (Invest Ophthalmol Vis Sci. 2011;52:9250-9256) DOI: 10.1167/iovs.11-8115 C1 [Bowles, Kristen; Turriff, Amy; Sergeev, Yuri; Sieving, Paul A.] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Cukras, Catherine; Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Bush, Ronald A.; Sieving, Paul A.] Natl Inst Deafness & Other Commun Disorders, Sect Translat Res Retinal & Macular Degenerat, NIH, Bethesda, MD USA. RP Sieving, PA (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, 31 Ctr Dr,31-6A03, Bethesda, MD 20892 USA. EM paulsieving@nei.nih.gov FU National Eye Institute, National Institutes of Health [DC000065-08 DIR] FX Supported by National Eye Institute, National Institutes of Health Grant DC000065-08 DIR. NR 30 TC 11 Z9 11 U1 0 U2 4 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 NOV PY 2011 VL 52 IS 12 BP 9250 EP 9256 DI 10.1167/iovs.11-8115 PG 7 WC Ophthalmology SC Ophthalmology GA 856IB UT WOS:000297631400061 PM 22039241 ER PT J AU Chin, LMK Kowalchuk, JM Barstow, TJ Kondo, N Amano, T Shiojiri, T Koga, S AF Chin, Lisa M. K. Kowalchuk, John M. Barstow, Thomas J. Kondo, Narihiko Amano, Tatsuro Shiojiri, Tomoyuki Koga, Shunsaku TI The relationship between muscle deoxygenation and activation in different muscles of the quadriceps during cycle ramp exercise SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE incremental exercise; near-infrared spectroscopy; surface electromyography ID NEAR-INFRARED SPECTROSCOPY; PULMONARY O-2 UPTAKE; OXYGEN-UPTAKE; FIBER TYPES; INTENSITY EXERCISE; MUSCULAR-ACTIVITY; GAS-EXCHANGE; RAT MUSCLES; BLOOD-FLOW; KINETICS AB Chin LM, Kowalchuk JM, Barstow TJ, Kondo N, Amano T, Shiojiri T, Koga S. The relationship between muscle deoxygenation and activation in different muscles of the quadriceps during cycle ramp exercise. J Appl Physiol 111: 1259-1265, 2011. First published July 28, 2011; doi:10.1152/japplphysiol.01216.2010.-The relationship between muscle deoxygenation and activation was examined in three different muscles of the quadriceps during cycling ramp exercise. Seven young male adults (24 +/- 3 yr; mean +/- SD) pedaled at 60 rpm to exhaustion, with a work rate (WR) increase of 20 W/min. Pulmonary oxygen uptake was measured breath-by-breath, while muscle deoxygenation (HHb) and activity were measured by time-resolved near-infrared spectroscopy (NIRS) and surface electromyography (EMG), respectively, at the vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM). Muscle deoxygenation was corrected for adipose tissue thickness and normalized to the amplitude of the HHb response, while EMG signals were integrated (iEMG) and normalized to the maximum iEMG determined from maximal voluntary contractions. Muscle deoxygenation and activation were then plotted as a percentage of maximal work rate (%WR(max)). The HHb response for all three muscle groups was fitted by a sigmoid function, which was determined as the best fitting model. The c/d parameter for the sigmoid fit (representing the %WR(max) at 50% of the total amplitude of the HHb response) was similar between VL (47 +/- 12% WR(max)) and VM (43 +/- 11% WR(max)), yet greater (P < 0.05) for RF (65 +/- 13% WR(max)), demonstrating a "right shift" of the HHb response compared with VL and VM. The iEMG also showed that muscle activation of the RF muscle was lower (P < 0.05) compared with VL and VM throughout the majority of the ramp exercise, which may explain the different HHb response in RF. Therefore, these data suggest that the sigmoid function can be used to model the HHb response in different muscles of the quadriceps; however, simultaneous measures of muscle activation are also needed for the HHb response to be properly interpreted during cycle ramp exercise. C1 [Chin, Lisa M. K.; Koga, Shunsaku] Kobe Design Univ, Appl Physiol Lab, Kobe, Hyogo 6512196, Japan. [Chin, Lisa M. K.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Kowalchuk, John M.] Univ Western Ontario, Sch Kinesiol, London, ON, Canada. [Kowalchuk, John M.] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON, Canada. [Barstow, Thomas J.] Kansas State Univ, Dept Kinesiol, Manhattan, KS 66506 USA. [Kondo, Narihiko; Amano, Tatsuro] Kobe Univ, Fac Human Dev, Kobe, Hyogo 657, Japan. [Shiojiri, Tomoyuki] Yokohama City Univ, Lab Exercise & Sports Sci, Yokohama, Kanagawa 232, Japan. RP Koga, S (reprint author), Kobe Design Univ, Appl Physiol Lab, 8-1-1 Gakuennishi Machi, Kobe, Hyogo 6512196, Japan. EM s-koga@kobe-du.ac.jp RI Chin, Lisa/O-4706-2014 OI Chin, Lisa/0000-0002-0178-739X FU Ministry of Education, Science, and Culture of Japan [20650103]; National Institutes of Health FX This investigation was supported by a grant for scientific research from the Ministry of Education, Science, and Culture of Japan (Grant-in-Aid for Scientific Research 20650103) to S. Koga. Additional support was provided to L. M. K. Chin by intramural funds from the National Institutes of Health. NR 51 TC 37 Z9 37 U1 0 U2 17 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD NOV PY 2011 VL 111 IS 5 BP 1259 EP 1265 DI 10.1152/japplphysiol.01216.2010 PG 7 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 856ZX UT WOS:000297684500007 PM 21799133 ER PT J AU Khan, S Zou, YX Amjad, A Gardezi, A Smith, CL Winters, C Reese, TS AF Khan, Shahid Zou, Yixiao Amjad, Asma Gardezi, Ailia Smith, Carolyn L. Winters, Christine Reese, Thomas S. TI Sequestration of CaMKII in dendritic spines in silico SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE Smoldyn; Hippocampal cultures; FRAP; Protein self-aggregation ID PROTEIN-KINASE-II; LONG-TERM POTENTIATION; POSTSYNAPTIC DENSITY; HIPPOCAMPAL-NEURONS; STOCHASTIC SIMULATION; DIFFUSION; BINDING; SITES; TRANSLOCATION; STIMULATION AB Calcium calmodulin dependent kinase II (CaMKII) is sequestered in dendritic spines within seconds upon synaptic stimulation. The program Smoldyn was used to develop scenarios of single molecule CaMKII diffusion and binding in virtual dendritic spines. We first validated simulation of diffusion as a function of spine morphology. Additional cellular structures were then incorporated to simulate binding of CaMKII to the post-synaptic density (PSD); binding to cytoskeleton; or their self-aggregation. The distributions of GFP tagged native and mutant constructs in dissociated hippocampal neurons were measured to guide quantitative analysis. Intra-spine viscosity was estimated from fluorescence recovery after photo-bleach (FRAP) of red fluorescent protein. Intra-spine mobility of the GFP-CaMKII alpha constructs was measured, with hundred-millisecond or better time resolution, from FRAP of distal spine tips in conjunction with fluorescence loss (FLIP) from proximal regions. Different FRAP \ FLIP profiles were predicted from our Scenarios and provided a means to differentiate binding to the PSDs from self-aggregation. The predictions were validated by experiments. Simulated fits of the Scenarios provided estimates of binding and rate constants. We utilized these values to assess the role of self-aggregation during the initial response of native CaMKII holoenzymes to stimulation. The computations revealed that self-aggregation could provide a concentration-dependent switch to amplify CaMKII sequestration and regulate its activity depending on its occupancy of the actin cytoskeleton. C1 [Khan, Shahid; Amjad, Asma; Gardezi, Ailia] LUMS Sch Sci & Engn, Lahore 54792, Pakistan. [Khan, Shahid; Zou, Yixiao; Smith, Carolyn L.; Winters, Christine; Reese, Thomas S.] NINDS, Neurobiol Lab, Bethesda, MD 20892 USA. [Khan, Shahid] Mol Biol Consortium, Chicago, IL 60612 USA. RP Khan, S (reprint author), LUMS Sch Sci & Engn, Lahore 54792, Pakistan. EM shahidkh@lums.edu.pk FU National Institutes of Health [R01-GM49319]; School of Science & Engineering, LUMS FX We thank Steven Andrews for advice on Smoldyn and Ayse Dosemeci for comments on the manuscript. This work was supported by grant R01-GM49319 from the National Institutes of Health (to SK). YZ was an NIH summer student intern. AA was supported by start-up funds (to SK) from the School of Science & Engineering, LUMS. NR 55 TC 10 Z9 10 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD NOV PY 2011 VL 31 IS 3 BP 581 EP 594 DI 10.1007/s10827-011-0323-2 PG 14 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 858RR UT WOS:000297820900007 PM 21491127 ER PT J AU Seely, J Chow, CC AF Seely, Jeffrey Chow, Carson C. TI Role of mutual inhibition in binocular rivalry SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE cortical circuit; perception; ambiguity; visual competition; computational neuroscience ID PRIMARY VISUAL-CORTEX; NEURONAL COMPETITION MODELS; LATERAL GENICULATE-NUCLEUS; SYNAPTIC DEPRESSION; PERCEPTUAL BISTABILITY; NEURAL MODEL; STOCHASTIC PROPERTIES; CORTICAL RESPONSES; ADAPTATION; NETWORK AB Seely J, Chow CC. Role of mutual inhibition in binocular rivalry. J Neurophysiol 106: 2136-2150, 2011. First published July 20, 2011; doi:10.1152/jn.00228.2011.-Binocular rivalry is a phenomenon that occurs when a different image is presented to each eye. The observer generally perceives just one image at a time, with perceptual switches occurring every few seconds. A natural assumption is that this perceptual mutual exclusivity is achieved via mutual inhibition between populations of neurons that encode for either percept. Theoretical models that incorporate mutual inhibition have been largely successful at capturing experimental features of rivalry, including Levelt's propositions, which characterize perceptual dominance durations as a function of image contrasts. However, basic mutual inhibition models do not fully comply with Levelt's fourth proposition, which states that percepts alternate faster as the stimulus contrasts to both eyes are increased simultaneously. This theory-experiment discrepancy has been taken as evidence against the role of mutual inhibition for binocular rivalry. Here, we show how various biophysically plausible modifications to mutual inhibition models can resolve this problem. C1 [Seely, Jeffrey; Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Chow, CC (reprint author), NIDDK, Lab Biol Modeling, NIH, Bldg 12A,Rm 4007,MSC 5621, Bethesda, MD 20892 USA. EM carsonc@niddk.nih.gov RI Chow, Carson/A-7970-2009 FU National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, NIH Intramural Research Program. NR 73 TC 29 Z9 29 U1 0 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD NOV PY 2011 VL 106 IS 5 BP 2136 EP 2150 DI 10.1152/jn.00228.2011 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 857CA UT WOS:000297690500005 PM 21775721 ER PT J AU Zhang, H Lin, SC Nicolelis, MAL AF Zhang, Hao Lin, Shih-Chieh Nicolelis, Miguel A. L. TI A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE medial septum; small-amplitude irregular activity, auditory response; theta oscillations; cholinergic ID GLUTAMIC-ACID DECARBOXYLASE; IRREGULAR ACTIVITY STATE; LONG-TERM POTENTIATION; DIAGONAL BAND; CHOLINE-ACETYLTRANSFERASE; SEPTOHIPPOCAMPAL NEURONS; ACETYLCHOLINE-RELEASE; SELECTIVE LESION; UNIT ACTIVITY; RAT-BRAIN AB Zhang H, Lin SC, Nicolelis MA. A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations. J Neurophysiol 106: 2749-2763, 2011. First published August 24, 2011; doi: 10.1152/jn.00267.2011.-The medial septum-vertical limb of the diagonal band of Broca (MSvDB) is important for normal hippocampal functions and theta oscillations. Although many previous studies have focused on understanding how MSVDB neurons fire rhythmic bursts to pace hippocampal theta oscillations, a significant portion of MSVDB neurons are slow-firing and thus do not pace theta oscillations. The function of these MSVDB neurons, especially their role in modulating hippocampal activity, remains unknown. We recorded MSVDB neuronal ensembles in behaving rats, and identified a distinct physiologically homogeneous subpopulation of slow-firing neurons (overall firing <4 Hz) that shared three features: 1) much higher firing rate during rapid eye movement sleep than during slow-wave (SW) sleep; 2) temporary activation associated with transient arousals during SW sleep; 3) brief responses (latency 15 similar to 30 ms) to auditory stimuli. Analysis of the fine temporal relationship of their spiking and theta oscillations showed that unlike the theta-pacing neurons, the firing of these "pro-arousal" neurons follows theta oscillations. However, their activity precedes short-term increases in hippocampal oscillation power in the theta and gamma range lasting for a few seconds. Together, these results suggest that these pro-arousal slow-firing MSvDB neurons may function collectively to promote hippocampal activation. C1 [Zhang, Hao] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27705 USA. [Lin, Shih-Chieh; Nicolelis, Miguel A. L.] Duke Univ, Ctr Neuroengn, Durham, NC 27705 USA. [Lin, Shih-Chieh] NIA, NIH, Baltimore, MD 21224 USA. [Nicolelis, Miguel A. L.] Duke Univ, Dept Biomed Engn, Durham, NC 27705 USA. [Nicolelis, Miguel A. L.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27705 USA. [Nicolelis, Miguel A. L.] Edmond & Lily Safra Int Inst Neurosci Natal, Natal, RN, Brazil. RP Zhang, H (reprint author), Duke Univ, Med Ctr, Dept Neurobiol, 101 Bryan Res Bldg,311 Res Dr, Durham, NC 27705 USA. EM zhanghao@neuro.duke.edu RI Zhang, Hao/D-7270-2013; OI Zhang, Hao/0000-0003-1833-7069; Lin, Shih-Chieh/0000-0003-3693-5476 FU National Institutes of Health [5R01 DE011451-11, R33 NS049534]; National Alliance for Research on Schizophrenia and Depression 2008 Young Investi-gator Award; Intramural Research Program of the National Institute on Aging FX This research was supported by National Institutes of Health Grants 5R01 DE011451-11 and R33 NS049534 to M. A. L. Nicolelis and a National Alliance for Research on Schizophrenia and Depression 2008 Young Investi-gator Award and the Intramural Research Program of the National Institute on Aging to S.-C. Lin. NR 61 TC 18 Z9 18 U1 0 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD NOV PY 2011 VL 106 IS 5 BP 2749 EP 2763 DI 10.1152/jn.00267.2011 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 857CA UT WOS:000297690500053 PM 21865435 ER PT J AU Mathai, SC Sibley, CT Forfia, PR Mudd, JO Fisher, MR Tedford, RJ Lechtzin, N Boyce, D Hummers, LK Housten, T Zaiman, AL Girgis, RE Hassoun, PM AF Mathai, Stephen C. Sibley, Christopher T. Forfia, Paul R. Mudd, James O. Fisher, Micah R. Tedford, Ryan J. Lechtzin, Noah Boyce, Danielle Hummers, Laura K. Housten, Traci Zaiman, Ari L. Girgis, Reda E. Hassoun, Paul M. TI Tricuspid Annular Plane Systolic Excursion Is a Robust Outcome Measure in Systemic Sclerosis-associated Pulmonary Arterial Hypertension SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE SYSTEMIC SCLEROSIS; PULMONARY HYPERTENSION; ECHOCARDIOGRAPHY; SURVIVAL ID RIGHT-HEART CATHETERIZATION; DOPPLER-ECHOCARDIOGRAPHY; MYOCARDIAL-INFARCTION; RIGHT VENTRICLE; LUNG-DISEASE; SCLERODERMA; SURVIVAL; PREDICTORS; ELEVATION; ACCURACY AB Objective. The tricuspid annular plane systolic excursion (TAPSE) strongly reflects right ventricular (RV) function and predicts survival in idiopathic pulmonary arterial hypertension (PAH). But its role in systemic sclerosis (SSc)-associated PAH has not been established. Our objective was to validate the TAPSE in the assessment of RV function and prediction of survival in SSc-PAH. Methods. Fifty consecutive patients with SSc-PAH who underwent echocardiography with TAPSE measurement within 1 h of clinically indicated right heart catheterization were followed prospectively. The relationship between TAPSE and measures of RV function and measures of survival was assessed. Results. The majority of the cohort were women in New York Heart Association class III/IV with severe PAH (mean cardiac index 2.4 +/- 0.8 l/min/m(2)). RV function was significantly impaired (mean cardiac index 2.1 +/- 0.7 vs 2.9 +/- 0.8 l/min/m(2); p < 0.01) and RV afterload was significantly greater (mean pulmonary vascular resistance 11.1 +/- 5.1 vs 5.8 +/- 2.5 Wood units; p < 0.01) in subjects with a TAPSE <= 1.7 cm. The proportion surviving in the low TAPSE group was significantly lower [0.56 (95% CI 0.37-0.71) and 0.46 (95% CI 0.28-0.62) vs 0.87 (95% CI 0.55-0.96) and 0.79 (95% CI 0.49-0.93), 1- and 2-year survival, respectively]. TAPSE <= 1.7 cm conferred a nearly 4-fold increased risk of death (HR 3.81, 95% CI 1.31-11.1, p < 0.01). Conclusion. TAPSE is a robust measure of RV function and strongly predicts survival in patients with PAH-SSc. Future studies are needed to identify the responsiveness of TAPSE to PAH-specific therapy and to assess its diagnostic utility in PAH-SSc. (First Release Oct 1 2011; J Rheumatol 2011;38:2410-18; doi:10.3899/jrheum.110512) C1 [Mathai, Stephen C.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Div Cardiol, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Div Rheumatol, Dept Med, Baltimore, MD 21205 USA. Univ Penn, Dept Med, Sch Med, Div Cardiol, Philadelphia, PA 19104 USA. Emory Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, Atlanta, GA USA. [Mudd, James O.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Sibley, Christopher T.] NIH, Bethesda, MD 20892 USA. RP Mathai, SC (reprint author), Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Dept Med, 1830 E Monument St,Room 516, Baltimore, MD 21205 USA. EM smathai4@jhmi.edu RI Sibley, Christopher/C-9900-2013; OI Tedford, Ryan/0000-0001-9045-7722; Hummers, Laura/0000-0002-4864-4011 FU US National Heart, Lung and Blood Institute (NHLBI) [K23 HL093387]; NHLBI [1P50HL08946] FX Supported by US National Heart, Lung and Blood Institute (NHLBI) K23 HL093387 (SCM) and NHLBI 1P50HL08946 (PMH). NR 39 TC 48 Z9 49 U1 0 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD NOV PY 2011 VL 38 IS 11 BP 2410 EP 2418 DI 10.3899/jrheum.110512 PG 9 WC Rheumatology SC Rheumatology GA 855KU UT WOS:000297564100021 PM 21965638 ER PT J AU Wassel, CL Jacobs, DR Duprez, DA Bluemke, DA Sibley, CT Criqui, MH Peralta, CA AF Wassel, Christina L. Jacobs, David R., Jr. Duprez, Daniel A. Bluemke, David A. Sibley, Christopher T. Criqui, Michael H. Peralta, Carmen A. TI Association of self-reported race/ethnicity and genetic ancestry with arterial elasticity: the Multi-Ethnic Study of Atherosclerosis (MESA) SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Article DE Large artery elasticity; small artery elasticity; admixture; pulse pressure ID PULSE-WAVE VELOCITY; COUNTRY-OF-ORIGIN; CARDIOVASCULAR EVENTS; BLOOD-PRESSURE; OLDER-ADULTS; ESSENTIAL-HYPERTENSION; INDEPENDENT PREDICTOR; AORTIC STIFFNESS; YOUNG-ADULTS; ALL-CAUSE AB African Americans have a disproportionate burden of hypertension compared with white, whereas data on Hispanics is less well-defined. Mechanisms underlying these differences are unclear, but could be in part because of ancestral background and vascular function. We studied 660 African Americans and 635 Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) with complete data on genetic ancestry, pulse pressure (PP), and large and small arterial elasticity (LAE, SAE). LAE and SAE were obtained using the HDI Pulse Wave CR-2000 Research CardioVascular Profiling Instrument. Among African Americans, higher European ancestry was marginally associated with higher LAE (P = .05) and lower PP (P = .05); results for LAE were attenuated after adjustment for potential mediators (P = .30). Among Hispanics, higher Native American ancestry was associated with higher SAE (P = .0006); higher African ancestry was marginally associated with lower SAE (P = .07). Ancestry was not significantly associated with LAE or PP in Hispanics. Among African Americans, higher European ancestry may be associated with less large artery damage, as measured by LAE and PP, although these associations warrant further study. Among Hispanics, ancestry is strongly associated with SAE. Future studies should consider genetic ancestry when studying hypertension in race/ethnic minorities, particularly among Hispanics. J Am Soc Hypertens 2011;5(6):463-472. (C) 2011 American Society of Hypertension. All rights reserved. C1 [Peralta, Carmen A.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Wassel, Christina L.; Criqui, Michael H.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Jacobs, David R., Jr.; Duprez, Daniel A.] Univ Minnesota, Minneapolis, MN USA. [Bluemke, David A.; Sibley, Christopher T.] NIH, Bethesda, MD 20892 USA. RP Peralta, CA (reprint author), Univ Calif San Francisco, Div Nephrol, 512 Parnassus Ave,C443, San Francisco, CA 94143 USA. EM CarmenAlicia.Peralta@ucsf.edu RI Sibley, Christopher/C-9900-2013; OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [T32 HL097972, T32HL07779]; Robert Wood Johnson Harold Amos award; National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, R01HL071051, R01HL071205, R01HL071250, RO1HL071251, R01HL071252, R01HL071258, R01HL071259]; [1K23DK082793-01] FX C.L.W. was supported by the National Institutes of Health training grant in cardiovascular genetic epidemiology (T32 HL097972) and cardiovascular epidemiology and prevention (T32HL07779) during a portion of this research. C.A.P. is currently supported by 1K23DK082793-01 and the Robert Wood Johnson Harold Amos award. This research was supported by contracts N01-HC-95159 through N01-HC-95169 and grants R01HL071051, R01HL071205, R01HL071250, RO1HL071251, R01HL071252, R01HL071258, and R01HL071259 from the National Heart, Lung, and Blood Institute. NR 50 TC 9 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-1711 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD NOV-DEC PY 2011 VL 5 IS 6 BP 463 EP 472 DI 10.1016/j.jash.2011.07.005 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 856QO UT WOS:000297658700005 PM 21890448 ER PT J AU Teng, RF Gavrilova, O Suzuki, N Chanturiya, T Schimel, D Hugendubler, L Mammen, S Yver, DR Cushman, SW Mueller, E Yamamoto, M Hsu, LL Noguchi, CT AF Teng, Ruifeng Gavrilova, Oksana Suzuki, Norio Chanturiya, Tatyana Schimel, Daniel Hugendubler, Lynne Mammen, Selin Yver, Dena R. Cushman, Samuel W. Mueller, Elisabetta Yamamoto, Masayuki Hsu, Lewis L. Noguchi, Constance Tom TI Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production SO NATURE COMMUNICATIONS LA English DT Article ID REVERSES INSULIN-RESISTANCE; ACTIVATED PROTEIN-KINASE; PPAR-GAMMA; FOOD-INTAKE; MAP KINASE; ENERGY HOMEOSTASIS; MICE LACKING; MUTANT MICE; RECEPTOR; EXPRESSION AB Although erythropoietin (Epo) is the cytokine known to regulate erythropoiesis, erythropoietin receptor (EpoR) expression and associated activity beyond haematopoietic tissue remain uncertain. Here we show that mice with EpoR expression restricted to haematopoietic tissues (Tg) develop obesity and insulin resistance. Tg-mice exhibit a decrease in energy expenditure and an increase in white fat mass and adipocyte number. Conversely, Epo treatment of wild-type (WT)-mice increases energy expenditure and reduces food intake and fat mass accumulation but shows no effect in body weight of Tg-mice. EpoR is expressed at a high level in white adipose tissue and in the proopiomelanocortin (POMC) neurons of the hypothalamus. Although Epo treatment in WT-mice induces the expression of the polypeptide hormone precursor, POMC, mice lacking EpoR show reduced levels of POMC in the hypothalamus. This study provides the first evidence that mice lacking EpoR in non-haematopoietic tissue become obese and insulin resistant with loss of Epo regulation of energy homeostasis. C1 [Teng, Ruifeng; Mammen, Selin; Noguchi, Constance Tom] NIDDK, Mol Cell Biol Branch, Bethesda, MD 20892 USA. [Gavrilova, Oksana; Chanturiya, Tatyana] NIDDK, Mouse Metab Core Lab, Bethesda, MD 20892 USA. [Suzuki, Norio; Yamamoto, Masayuki] Tohoku Univ, Dept Med Biochem, Grad Sch Med, Sendai, Miyagi 9808575, Japan. [Schimel, Daniel] Natl Inst Neurol Disorders & Stroke, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Hugendubler, Lynne; Mueller, Elisabetta] NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. [Yver, Dena R.; Cushman, Samuel W.] NIDDK, Diabet Branch, Bethesda, MD 20892 USA. [Hsu, Lewis L.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. RP Noguchi, CT (reprint author), NIDDK, Mol Cell Biol Branch, Bethesda, MD 20892 USA. EM cnoguchi@helix.nih.gov RI Suzuki, Norio/F-3456-2010 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX We thank William Jou and Kimya Davani for technical assistance. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health. NR 50 TC 35 Z9 39 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV PY 2011 VL 2 AR 520 DI 10.1038/ncomms1526 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 857AQ UT WOS:000297686500007 PM 22044999 ER PT J AU Koenigs, M Acheson, DJ Barbey, AK Solomon, J Postle, BR Grafman, J AF Koenigs, Michael Acheson, Daniel J. Barbey, Aron K. Solomon, Jeffrey Postle, Bradley R. Grafman, Jordan TI Areas of left perisylvian cortex mediate auditory-verbal short-term memory SO NEUROPSYCHOLOGIA LA English DT Article DE Short-term memory; Language; Lesion; Neuropsychology ID WORKING-MEMORY; SELECTIVE IMPAIRMENT; BRAIN; DISSOCIATION; INFORMATION; SOFTWARE; LANGUAGE; SPEECH; STORE AB A contentious issue in memory research is whether verbal short-term memory (STM) depends on a neural system specifically dedicated to the temporary maintenance of information, or instead relies on the same brain areas subserving the comprehension and production of language. In this study, we examined a large sample of adults with acquired brain lesions to identify the critical neural substrates underlying verbal STM and the relationship between verbal STM and language processing abilities. We found that patients with damage to selective regions of left perisylvian cortex - specifically the inferior frontal and posterior temporal sectors - were impaired on auditory-verbal STM performance (digit span), as well as on tests requiring the production and/or comprehension of language. These results support the conclusion that verbal STM and language processing are mediated by the same areas of left perisylvian cortex. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Koenigs, Michael; Postle, Bradley R.] Univ Wisconsin, Dept Psychiat, Madison, WI 53719 USA. [Acheson, Daniel J.; Postle, Bradley R.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. [Barbey, Aron K.] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Solomon, Jeffrey] Med Numer Inc, Germantown, MD 20876 USA. [Grafman, Jordan] Kessler Fdn Res Ctr, Traumat Brain Injury Res Lab, W Orange, NJ 07052 USA. RP Koenigs, M (reprint author), Univ Wisconsin, Dept Psychiat, 6001 Res Pk Blvd, Madison, WI 53719 USA. EM mrkoenigs@wisc.edu; jgrafman@kesslerfoundation.org RI Acheson, Daniel/E-8851-2012; Barbey, Aron/L-7312-2015; OI Barbey, Aron/0000-0002-6092-0912; Grafman, Jordan H./0000-0001-8645-4457; Koenigs, Michael/0000-0002-5799-4881 FU U.S. National Institute of Neurological Disorders and Stroke; United States Army Medical Research and Material Command [DAMD17-01-1-0675]; [MH064498] FX This work was supported by funding from the U.S. National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the United States Army Medical Research and Material Command administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study, grant number DAMD17-01-1-0675). B.R.P. received support from MH064498. NR 38 TC 13 Z9 13 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD NOV PY 2011 VL 49 IS 13 BP 3612 EP 3619 DI 10.1016/j.neuropsychologia.2011.09.013 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 853WH UT WOS:000297455900012 PM 21945329 ER PT J AU Chan, CC Rubenstein, JL Coupland, SE Davis, JL Harbour, JW Johnston, PB Cassoux, N Touitou, V Smith, JR Batchelor, TT Pulido, JS AF Chan, Chi-Chao Rubenstein, James L. Coupland, Sarah E. Davis, Janet L. Harbour, J. William Johnston, Patrick B. Cassoux, Nathalie Touitou, Valerie Smith, Justine R. Batchelor, Tracy T. Pulido, Jose S. TI Primary Vitreoretinal Lymphoma: A Report from an International Primary Central Nervous System Lymphoma Collaborative Group Symposium SO ONCOLOGIST LA English DT Article ID PRIMARY INTRAOCULAR LYMPHOMA; PRIMARY CNS LYMPHOMA; B-CELL LYMPHOMA; ATTRACTING CHEMOKINE-1 CXCL13; POLYMERASE-CHAIN-REACTION; NON-HODGKINS-LYMPHOMA; INTRAVITREAL METHOTREXATE; MALIGNANT-LYMPHOMA; GENE-EXPRESSION; RITUXIMAB INJECTIONS AB Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%-90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellu-lar infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of Ig H or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies. The Oncologist 2011;16:1589-1599 C1 [Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Rubenstein, James L.] Univ Calif San Francisco, Sch Med, Div Hematol & Oncol, San Francisco, CA USA. [Coupland, Sarah E.] Royal Liverpool Hosp, Dept Cell & Mol Pathol, Liverpool L7 8XP, Merseyside, England. [Davis, Janet L.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Dept Ophthalmol, Miami, FL 33136 USA. [Johnston, Patrick B.] Mayo Clin, Dept Hematol & Internal Med, Rochester, MN USA. [Pulido, Jose S.] Mayo Clin, Dept Ophthalmol, Rochester, MN USA. [Harbour, J. William] Washington Univ, Sch Med, Barnes Retina Inst, Ocular Oncol Serv, St Louis, MO USA. [Cassoux, Nathalie; Touitou, Valerie] Hop La Pitie Salpetriere, Dept Ophthalmol, Paris, France. [Cassoux, Nathalie] Inst Curie, Dept Ophthalmol, Paris, France. [Smith, Justine R.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Batchelor, Tracy T.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Batchelor, Tracy T.] Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov RI Inov Farmaceutica, Inct/K-2313-2013 FU Novartis; Genentech; NIH; Pfizer; Millennium; AstraZeneca; Wyeth; National Cancer Institute [1R13CA124293-01]; National Eye Institute FX Disclosures: Chi-Chao Chan: None; James L. Rubenstein: None; Sarah E. Coupland: None; Janet L. Davis: Centocor (C/A), Novartis (C/A, RF); J. William Harbour: None; Patrick B. Johnston: Daiichi Sankyo, Spectrum Pharmaceutical (C/A); Nathalie Cassoux: None; Valerie Touitou: None; Justine R. Smith: Genentech (RF); Tracy T. Batchelor: Merck, Roche/Genentech, Imedex, Educational Concepts (H); NIH, Pfizer, Millennium, AstraZeneca, Wyeth (RF); Jose S. Pulido: None.; This work was partially supported by a grant from the National Cancer Institute (1R13CA124293-01) and the National Eye Institute intramural research program. NR 94 TC 80 Z9 87 U1 2 U2 8 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD NOV PY 2011 VL 16 IS 11 BP 1589 EP 1599 DI 10.1634/theoncologist.2011-0210 PG 11 WC Oncology SC Oncology GA 859EZ UT WOS:000297860900015 PM 22045784 ER PT J AU Chen, Y Moradin, A Schlessinger, D Nagaraja, R AF Chen, Y. Moradin, A. Schlessinger, D. Nagaraja, R. TI RXR alpha and LXR activate two promoters in placenta- and tumor-specific expression of PLAC1 SO PLACENTA LA English DT Article DE Promoter; RXR alpha; LXR; Nuclear receptor ID HUMAN TROPHOBLAST INVASION; NUCLEAR RECEPTORS; X-RECEPTORS; ES CELLS; MOUSE; GENE; LOCUS AB PLAC1 expression, first characterized as restricted to developing placenta among normal tissues, is also found in a wide range of tumors and transformed cell lines. To understand the basis for its unusual expression profile, we have analyzed the gene structure and its mode of transcription. We find that the gene has a hitherto unique feature, with two promoters, P1 and P2, separated by 105 kb. P2 has been described before. Here we define P1 and show that it and P2 are activated by RXR alpha in conjunction with LXR alpha or LXR beta. In placenta, P2 is the preferred promoter, whereas various tumor cell lines tend to express predominantly either one or the other promoter. Furthermore, when each promoter is fused to a luciferase reporter gene and transfected into cancer cell lines, the promoter corresponding to the more active endogenous promoter is preferentially transcribed. Joint expression of activating nuclear receptors can partially account for the restricted expression of PLAC1 in placenta, and may be co-opted for preferential P1 or P2 PLAC1 expression in various tumor cells. Published by Elsevier Ltd. C1 [Chen, Y.; Moradin, A.; Schlessinger, D.; Nagaraja, R.] NIA, Genet Lab, Bayview Res Ctr, Baltimore, MD 21224 USA. RP Nagaraja, R (reprint author), NIA, Genet Lab, Bayview Res Ctr, 251 Bayview Blvd,RM 10B117, Baltimore, MD 21224 USA. EM nagarajar@mail.nih.gov FU National Institute on Aging, National Institutes of Health [ZO1 AG000646-12 LG] FX This work was fully supported by Intramural funding by the National Institute on Aging, National Institutes of Health, [ZO1 AG000646-12 LG]. NR 28 TC 7 Z9 7 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD NOV PY 2011 VL 32 IS 11 BP 877 EP 884 DI 10.1016/j.placenta.2011.08.011 PG 8 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 859WN UT WOS:000297906600013 PM 21937108 ER PT J AU Snoeck, J Fellay, J Bartha, I Douek, DC Telenti, A AF Snoeck, Joke Fellay, Jacques Bartha, Istvan Douek, Daniel C. Telenti, Amalio TI Mapping of positive selection sites in the HIV-1 genome in the context of RNA and protein structural constraints SO RETROVIROLOGY LA English DT Article DE HIV; evolution; positive selection; RNA structure ID OVERLAPPING GENES; EVOLUTION; INFECTION; TRANSMISSION; ADAPTATION; MUTATION AB Background: The HIV-1 genome is subject to pressures that target the virus resulting in escape and adaptation. On the other hand, there is a requirement for sequence conservation because of functional and structural constraints. Mapping the sites of selective pressure and conservation on the viral genome generates a reference for understanding the limits to viral escape, and can serve as a template for the discovery of sites of genetic conflict with known or unknown host proteins. Results: To build a thorough evolutionary, functional and structural map of the HIV-1 genome, complete subtype B sequences were obtained from the Los Alamos database. We mapped sites under positive selective pressure, amino acid conservation, protein and RNA structure, overlapping coding frames, CD8 T cell, CD4 T cell and antibody epitopes, and sites enriched in AG and AA dinucleotide motives. Globally, 33% of amino acid positions were found to be variable and 12% of the genome was under positive selection. Because interrelated constraining and diversifying forces shape the viral genome, we included the variables from both classes of pressure in a multivariate model to predict conservation or positive selection: structured RNA and a-helix domains independently predicted conservation while CD4 T cell and antibody epitopes were associated with positive selection. Conclusions: The global map of the viral genome contains positive selected sites that are not in canonical CD8 T cell, CD4 T cell or antibody epitopes; thus, it identifies a class of residues that may be targeted by other host selective pressures. Overall, RNA structure represents the strongest determinant of HIV-1 conservation. These data can inform the combined analysis of host and viral genetic information. C1 [Snoeck, Joke; Fellay, Jacques; Bartha, Istvan; Telenti, Amalio] Univ Hosp Ctr, Inst Microbiol, Lausanne, Switzerland. [Snoeck, Joke; Fellay, Jacques; Bartha, Istvan; Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Snoeck, Joke] Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium. [Fellay, Jacques; Bartha, Istvan] Ecole Polytech Fed Lausanne, Sch Life Sci, Global Hlth Inst, CH-1015 Lausanne, Switzerland. [Bartha, Istvan] Eotvos Lorand Univ, Inst Biol, Budapest, Hungary. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Telenti, A (reprint author), Univ Hosp Ctr, Inst Microbiol, Lausanne, Switzerland. EM Amalio.telenti@chuv.ch RI Fellay, Jacques/A-6681-2009 OI Fellay, Jacques/0000-0002-8240-939X FU Swiss National Science Foundation; Research Foundation Flanders (FWO) [1.2.627.07.N.01] FX This work is supported by the Swiss National Science Foundation. Joke Snoeck was supported by a postdoctoral grant from the Research Foundation Flanders (FWO, grant 1.2.627.07.N.01) NR 28 TC 23 Z9 23 U1 0 U2 9 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 NOV 1 PY 2011 VL 8 AR 87 DI 10.1186/1742-4690-8-87 PG 8 WC Virology SC Virology GA 857WL UT WOS:000297754800001 PM 22044801 ER PT J AU Konkel, JE Chen, WJ AF Konkel, Joanne E. Chen, WanJun TI Balancing acts: the role of TGF-beta in the mucosal immune system SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID REGULATORY T-CELLS; INTESTINAL INTRAEPITHELIAL LYMPHOCYTES; GROWTH-FACTOR-BETA; DENDRITIC CELLS; RETINOIC-ACID; IN-VIVO; ORAL TOLERANCE; AUTOIMMUNE ENCEPHALOMYELITIS; T(H)17 CELLS; HOST-DEFENSE AB The gastrointestinal mucosal immune system faces unique challenges in dealing not only with fed antigens but also both commensal and pathogenic bacteria. It is tasked with digesting, transporting and using nutritional antigens while protecting the host from pathogenic organisms. As such, mechanisms that mediate effective immunity and immune tolerance are active within the gut environment. To accomplish this, the mucosal immune system has evolved sophisticated mechanisms that safeguard the integrity of the mucosa! barrier. Transforming growth factor-beta (TGF-beta) emerges as a key mediator, balancing the tolerogenic and immunogenic forces at play in the gut. In this review, we discuss the role of TGF-beta in the generation and functioning of gut lymphocyte populations. We highlight recent findings, summarize controversies, outline remaining questions and provide our personal perspectives. C1 [Konkel, Joanne E.; Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, OIIB, NIH, Bethesda, MD 20982 USA. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, OIIB, NIH, Bethesda, MD 20982 USA. EM wchen@dir.nidcr.nih.gov FU National Institute of Dental and Craniofacial Research at the National Institutes of Health FX The authors would like to apologize for omitting the citation of many important primary articles due to length limitations. We would also like to thank Dr J.R. Grainger for critical reading of the manuscript. This research is supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research at the National Institutes of Health. NR 70 TC 38 Z9 39 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD NOV PY 2011 VL 17 IS 11 BP 668 EP 676 DI 10.1016/j.molmed.2011.07.002 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 854VX UT WOS:000297524000009 PM 21890412 ER PT J AU Bratslavsky, G AF Bratslavsky, Gennady TI Argument in favor of performing partial nephrectomy for tumors greater than 7 cm: The metastatic prescription has already been written SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article; Proceedings Paper CT 11th Annual Meeting of the Society-of-Urologic-Oncology on Extraordinary Opportunities for Discovery CY DEC 08-10, 2010 CL Natl Inst Hlth, Bethesda, MD SP Soc Urol Oncol HO Natl Inst Hlth DE Partial nephrectomy; Nephron sparing surgery; Large renal masses; Oncologic efficacy; Micrometastasis ID RENAL-CELL CARCINOMA; NEPHRON-SPARING SURGERY; CHRONIC KIDNEY-DISEASE; RADICAL NEPHRECTOMY; BREAST-CANCER; OUTCOMES; EXPERIENCE; ASSOCIATION; MORTALITY; SURVIVAL AB The acceptance of partial nephrectomy over the past few decades has been gradual with initial utilization of nephron sparing approach for tumors up to 4 cm and more recently up to 7 cm. The arbitrary cutoff values used in the historic recommendations are based on the oncologic outcomes documenting the increase in metastatic potential of renal lesions that is strongly associated with increase in tumor size. Despite these observations, radical nephrectomy has not been found to be protective from development of metastatic disease, and oncologic outcomes of partial nephrectomy for tumors matched for size or stage have not been inferior to radical nephrectomy. The present manuscript argues for avoidance of specific size cutoffs as patients with larger masses may benefit from maximal preservation of nephrons. These are the very patients at higher risk for metastatic disease, who may benefit from preserved renal function to allow for future additional therapies or adjuvant trials. Published by Elsevier Inc. C1 [Bratslavsky, Gennady] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. [Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Bratslavsky, G (reprint author), SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. EM bratslag@upstate.edu NR 45 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD NOV-DEC PY 2011 VL 29 IS 6 BP 829 EP 832 DI 10.1016/j.urolonc.2011.05.010 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 853RL UT WOS:000297443300037 PM 22078407 ER PT J AU Bray, M Babiuk, S AF Bray, Mike Babiuk, Shawn TI Camelpox: Target for eradication? SO ANTIVIRAL RESEARCH LA English DT Editorial Material ID SMALLPOX; VIRUSES; DISEASES; IRAN; POX C1 [Bray, Mike] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Babiuk, Shawn] Canadian Food Inspect Agcy, Natl Ctr Foreign Anim Dis, Winnipeg, MB, Canada. RP Bray, M (reprint author), NIAID, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov NR 32 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD NOV PY 2011 VL 92 IS 2 BP 164 EP 166 DI 10.1016/j.antiviral.2011.09.006 PG 3 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 853LG UT WOS:000297427200004 PM 21945042 ER PT J AU Kravitz, DJ Behrmann, M AF Kravitz, Dwight J. Behrmann, Marlene TI Space-, object-, and feature-based attention interact to organize visual scenes SO ATTENTION PERCEPTION & PSYCHOPHYSICS LA English DT Article DE Neural attentional mechanisms; Object-based attention; Space-based attention ID SPATIAL ATTENTION; SELECTIVE ATTENTION; BIASED COMPETITION; FOCUSED-ATTENTION; CORTEX; MECHANISMS; LOCATIONS; SYSTEMS; REPRESENTATIONS; DYNAMICS AB Biased-competition accounts of attentional processing propose that attention arises from distributed interactions within and among different types of perceptual representations (e.g., spatial, featural, and object-based). Although considerable research has examined the facilitation in processing afforded by attending selectively to spatial locations, or to features, or to objects, surprisingly little research has addressed a key prediction of the biased-competition account: that attending to any stimulus should give rise to simultaneous interactions across all the types of perceptual representations encompassed by that stimulus. Here we show that, when an object in a visual display is cued, space-, feature-, and object-based forms of attention interact to enhance processing of that object and to create a scene-wide pattern of attentional facilitation. These results provide evidence to support the biased-competition framework and suggest that attention might be thought of as a mechanism by which multiple, disparate bottom-up, and even top-down, visual perceptual representations are coordinated and preferentially enhanced. C1 [Kravitz, Dwight J.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Behrmann, Marlene] Carnegie Mellon Univ, Dept Psychol, Pittsburgh, PA 15213 USA. RP Kravitz, DJ (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM kravitzd@mail.nih.gov RI Kravitz, Dwight/B-8430-2012; OI Behrmann, Marlene/0000-0002-3814-1015 FU National Institute of Mental Health [MH54246] FX This research was supported by a grant from the National Institute of Mental Health (MH54246) to M.B. The authors thank Chris Baker, Linda Moya, Adam Greenberg, and Sarah Shomstein for their helpful comments, and Lauren Lorenzi for help with the data collection. NR 50 TC 14 Z9 14 U1 4 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1943-3921 J9 ATTEN PERCEPT PSYCHO JI Atten. Percept. Psychophys. PD NOV PY 2011 VL 73 IS 8 BP 2434 EP 2447 DI 10.3758/s13414-011-0201-z PG 14 WC Psychology; Psychology, Experimental SC Psychology GA 852ME UT WOS:000297361300007 PM 22006523 ER PT J AU Pietsch, KE Neels, JF Yu, X Gong, JC Sturla, SJ AF Pietsch, Kathryn E. Neels, James F. Yu, Xiang Gong, Jiachang Sturla, Shana J. TI Chemical and Enzymatic Reductive Activation of Acylfulvene to Isomeric Cytotoxic Reactive Intermediates SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ALPHA,BETA-UNSATURATED CARBONYL-COMPOUNDS; BIOREDUCTIVE ALKYLATING-AGENTS; RAT-LIVER CYTOSOL; TUMOR-CELL LINES; MITOMYCIN-C; HYDROXYMETHYLACYLFULVENE HMAF; ALKENAL/ONE OXIDOREDUCTASE; HISTIOSPECIFIC TOXICITY; PRECLINICAL EVALUATION; CONJUGATE REDUCTION AB Acylfulvenes (AFs), a class of semisynthetic analogues of the sesquiterpene natural product illudin S, are cytotoxic toward cancer cells. The minor structural changes between illudin S and AFs translate to an improved therapeutic window in preclinical cell-based assays and xenograft models. AFs are, therefore, unique tools for addressing the chemical and biochemical basis of cytotoxic selectivity. AFs elicit cytotoxic responses by alkylation of biological targets, including DNA. While AFs are capable of direct alkylation, cytosolic reductive bioactivation to an electrophilic intermediate is correlated with enhanced cytotoxicity. Data obtained in this study illustrate chemical aspects of the process of AF activation. By tracking reaction mechanisms with stable isotope-labeled reagents, enzymatic versus chemical activation pathways for AF were compared for reactions involving the NADPH-dependent enzyme prostaglandin reductase 1 (PTGR1) or sodium borohydride, respectively. These two processes resulted in isomeric products that appear to give rise to similar patterns of DNA modification. The chemically activated isomer has been newly isolated and chemically characterized in this study, including an assessment of its relative stereochemistry and stability at varying pH and under bioassay conditions. In mammalian cancer cells, this chemically activated analogue was shown to not rely on further cellular activation to significantly enhance cytotoxic potency, in contrast to the requirements of AF. On the basis of this study, we anticipate that the chemically activated form of AF will serve as a useful chemical probe for evaluating biomolecular interactions independent of enzyme-mediated activation. C1 [Pietsch, Kathryn E.; Sturla, Shana J.] ETH, Inst Food Nutr & Hlth, CH-8092 Zurich, Switzerland. [Pietsch, Kathryn E.; Neels, James F.; Gong, Jiachang] Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55455 USA. [Yu, Xiang] NCI, Canc Cell & Biol Branch, NIH, Bethesda, MD 20814 USA. RP Sturla, SJ (reprint author), ETH, Inst Food Nutr & Hlth, CH-8092 Zurich, Switzerland. EM sturlas@ethz.ch RI Sturla, Shana/B-4028-2015 FU National Cancer Institute [R01 CA123007]; Masonic Cancer Center Analytical Biochemistry Facility, University of Minnesota [CA 77598]; University of Minnesota Medical School; Minnesota Medical Foundation; National Science Foundation [BIR 961477] FX We acknowledge the National Cancer Institute (R01 CA123007) for support of this research. The Masonic Cancer Center Analytical Biochemistry Facility, University of Minnesota, is supported in part by the Cancer Center Support Grant (CA 77598). The MN Structural Biology NMR Facility, University of Minnesota, is supported by the University of Minnesota Medical School, the Minnesota Medical Foundation, and funding from the National Science Foundation (BIR 961477). NR 42 TC 9 Z9 9 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD NOV PY 2011 VL 24 IS 11 BP 2044 EP 2054 DI 10.1021/tx200401u PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 848VF UT WOS:000297082500029 PM 21939268 ER PT J AU Li, M Gustchina, A Matuz, K Tozser, J Namwong, S Goldfarb, NE Dunn, BM Wlodawer, A AF Li, Mi Gustchina, Alla Matuz, Krisztina Toezser, Jozsef Namwong, Sirilak Goldfarb, Nathan E. Dunn, Ben M. Wlodawer, Alexander TI Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease SO FEBS JOURNAL LA English DT Article DE aspartic protease; enzyme inhibition; inhibitor binding; retrovirus ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC-FATIGUE-SYNDROME; CRYSTAL-STRUCTURE; HIV-1 PROTEASE; TYPE-1 PROTEASE; RETROVIRUS XMRV; FIV PROTEASE; PEPSTATIN-A; PROTEINASE; AMPRENAVIR AB Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus and a number of potential inhibitors have been investigated by biochemical and structural techniques. It was observed that several inhibitors used clinically against HIV PR exhibit nanomolar or even subnanomolar values of Ki, depending on the exact experimental conditions. Both TL-3, a universal inhibitor of retroviral PRs, and some inhibitors originally shown to inhibit plasmepsins were also quite potent, whereas inhibition by pepstatin A was considerably weaker. Crystal structures of the complexes of xenotropic murine leukemia virus-related virus PR with TL-3, amprenavir and pepstatin A were solved at high resolution and compared with the structures of complexes of these inhibitors with other retropepsins. Whereas TL-3 and amprenavir bound in a predictable manner, spanning the substrate-binding site of the enzyme, two molecules of pepstatin A bound simultaneously in an unprecedented manner, leaving the catalytic water molecule in place. C1 [Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, MCL, Prot Struct Sect, Frederick, MD 21702 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Matuz, Krisztina; Toezser, Jozsef] Univ Debrecen, Dept Biochem & Mol Biol, Fac Med, Debrecen, Hungary. [Namwong, Sirilak] Suan Sunandha Rajabhat Univ, Fac Sci & Technol, Dept Biotechnol, Bangkok, Thailand. [Goldfarb, Nathan E.; Dunn, Ben M.] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Wlodawer, A (reprint author), NCI, MCL, Prot Struct Sect, Bldg 536,Rm 5, Frederick, MD 21702 USA. EM wlodawer@nih.gov RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; TAMOP [4.2.1./B-09/1/KONV-2010-0007]; Hungarian Science and Research Fund [OTKA K68288]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIAID [R37 AI28571]; Ruth L. Kirschstein National Research Service Award [5T32 CA009126-33] FX The help of B. Farkas with kinetic and inhibition measurements is greatly appreciated. We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team, located at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. The work of K. Matuz and J. Tozser was supported by the TAMOP 4.2.1./B-09/1/KONV-2010-0007 project and by the Hungarian Science and Research Fund (OTKA K68288). This work was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E, and by grant R37 AI28571 from NIAID to B. M. Dunn. N. E. Goldfarb was supported by a Ruth L. Kirschstein National Research Service Award 5T32 CA009126-33 Training Grant in Cancer Biology. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, and nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 52 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD NOV PY 2011 VL 278 IS 22 BP 4413 EP 4424 DI 10.1111/j.1742-4658.2011.08364.x PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 849WI UT WOS:000297155600024 PM 21951660 ER PT J AU Nemunaitis, G Jay, CM Maples, PB Gahl, WA Huizing, M Yardeni, T Tong, AW Phadke, AP Pappen, BO Bedell, C Allen, H Hernandez, C Templeton, NS Kuhn, J Senzer, N Nemunaitis, J AF Nemunaitis, Gregory Jay, Chris M. Maples, Phillip B. Gahl, William A. Huizing, Marjan Yardeni, Tal Tong, Alex W. Phadke, Anagha P. Pappen, Beena O. Bedell, Cynthia Allen, Henry Hernandez, Cathy Templeton, Nancy S. Kuhn, Joseph Senzer, Neil Nemunaitis, John TI Hereditary Inclusion Body Myopathy: Single Patient Response to Intravenous Dosing of GNE Gene Lipoplex SO HUMAN GENE THERAPY LA English DT Article ID DUCHENNES MUSCULAR-DYSTROPHY; MUSCLE STRENGTH; SIALIC ACIDS; CELL-SURFACE; BREAK TESTS; RELIABILITY; MUTATIONS; SCALE AB Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE gene function through liposomal delivery of the wild-type GNE gene. Results were verified in a single patient treated by intravenous infusion of GNE gene lipoplex. A single patient (patient 001) with severe HIBM treated with a compassionate investigational new drug received seven doses of GNE gene lipoplex via intravenous infusion at the following doses: 0.4, 0.4, 1.0, 4.0, 5.0, 6.0, and 7.0 mg of DNA. GNE transgene expression, downstream induction of sialic acid, safety, and muscle function were evaluated. Transient low-grade fever, myalgia, tachycardia, transaminase elevation, hyponatremia, and hypotension were observed after infusion of each dose of GNE gene lipoplex. Quadriceps muscle expression of the delivered GNE, plasmid, and RNA was observed 24 hr after the 5.0-mg dose and at significantly greater levels 72 hr after the 7.0-mg infusion in comparison with expression in quadriceps muscle immediately before infusion. Sialic acid-related proteins were increased and stabilization in the decline of muscle strength was observed. We conclude that clinical safety and activity have been demonstrated with intravenous infusion of GNE gene lipoplex. Further assessment will involve a phase I trial of intravenous administration of GNE gene lipoplex in individuals with less advanced HIBM with more muscle function. C1 [Nemunaitis, Gregory; Bedell, Cynthia; Senzer, Neil; Nemunaitis, John] Mary Crowley Canc Res Ctr, Dallas, TX 75201 USA. [Nemunaitis, Gregory] MetroHlth Med Ctr, Cleveland, OH 44109 USA. [Jay, Chris M.; Maples, Phillip B.; Tong, Alex W.; Phadke, Anagha P.; Pappen, Beena O.; Templeton, Nancy S.; Senzer, Neil; Nemunaitis, John] Gradalis Inc, Dallas, TX 75201 USA. [Gahl, William A.; Huizing, Marjan; Yardeni, Tal] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Allen, Henry; Hernandez, Cathy] Hospitalist Internists Associates, Dallas, TX 75251 USA. [Kuhn, Joseph] WLS Surg Associates, Dallas, TX 75246 USA. [Senzer, Neil; Nemunaitis, John] Texas Oncol, Dallas, TX 75251 USA. RP Nemunaitis, J (reprint author), 1700 Pacific,Suite 1100, Dallas, TX 75201 USA. EM jnemunaitis@marycrowley.org FU National Human Genome Research Institute, National Institutes of Health (Bethesda, MD); Mary Crowley Cancer Research Centers (Dallas, TX); Neuromuscular Disease Foundation (Beverly Hills, CA) FX The authors thank Susan Mill for competent and knowledgeable assistance in the preparation of this manuscript. Samir Sliheet is also acknowledged for transport support. The authors thank Dr. Gregory Bevels, M. D., of Primary Care Specialists (Alexandria, LA) for assistance with weekly physical assessments during the study period. This work was partially supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (Bethesda, MD). The authors are also grateful for the financial support of the Mary Crowley Cancer Research Centers (Dallas, TX) and the Neuromuscular Disease Foundation (Beverly Hills, CA). NR 29 TC 15 Z9 15 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD NOV PY 2011 VL 22 IS 11 BP 1331 EP 1341 DI 10.1089/hum.2010.192 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 852QS UT WOS:000297373100005 PM 21517694 ER PT J AU Agarwal, MM Weigl, B Hod, M AF Agarwal, Mukesh M. Weigl, Bernhard Hod, Moshe TI Gestational diabetes screening: The low-cost algorithm SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Fasting glucose; Gestational diabetes; Low-resource countries; Screening ID FASTING PLASMA-GLUCOSE; HIGH-RISK POPULATION; DIAGNOSTIC ALGORITHM; MELLITUS; SIMPLIFY; CRITERIA AB The American Diabetes Association has endorsed the demanding recommendation by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) that every pregnant woman should undergo the oral glucose tolerance test (OGTT) for the screening of gestational diabetes mellitus (GDM). The aim of this study was to find out if the fasting plasma glucose (FPG) and newer emerging technologies could simplify the cumbersome IADPSG algorithm. Two FPG thresholds (of the OGTT) were used to rule in and rule out GDM in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort (n = 23 316) and a population at high risk for GDM (n =10 283). For the HAPO cohort and the high-risk population, respectively, FPG thresholds of: (a) >= 5.1 mmol/L (specificity 100%) independently ruled in GDM in 1769 (8.3%) women and 2975 (28.9%) women; and (b) <= 4.4 mmol/L ruled out GDM in 11 526 (49.4%) women (84.1% sensitivity) and 2228 (21.7%) women (95.4% sensitivity). Use of the FPG independently could have avoided 13 295 (57.0%) and 5203 (50.6%) OGTTs in the 2 groups. The initial FPG by significantly reducing the number of cumbersome OGTTs needed can make the IADPSG recommendations more acceptable worldwide. The number of GDM women missed is population dependent. For low-resource countries, alternative newer and cheaper tests in development hold an exciting future. (C) 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Agarwal, Mukesh M.] UAE Univ, Fac Med, Dept Pathol, Al Ain, U Arab Emirates. [Weigl, Bernhard] NIBIB Ctr POC Diagnost Global Hlth, PATH, Seattle, WA USA. [Hod, Moshe] Tel Aviv Univ, Sackler Fac Med, Div Maternal Fetal Med, Rabin Med Ctr, IL-69978 Tel Aviv, Israel. RP Hod, M (reprint author), Helen Schneider Hosp Women, Rabin Med Ctr, Div Maternal Fetal Med, IL-49100 Petah Tiqwa, Israel. EM mhod@clalit.org.il NR 24 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD NOV PY 2011 VL 115 SU 1 BP S30 EP S33 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 852XJ UT WOS:000297390500008 PM 22099438 ER PT J AU Li, Y Kim, DJ Ma, WY Lubet, RA Bode, AM Dong, ZG AF Li, Yan Kim, Dong Joon Ma, Weiya Lubet, Ronald A. Bode, Ann M. Dong, Zigang TI Discovery of Novel Checkpoint Kinase 1 Inhibitors by Virtual Screening Based on Multiple Crystal Structures SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID LIGAND DOCKING; RECEPTOR CONFORMATIONS; CHK1 INHIBITORS; BIOLOGICAL EVALUATION; PROTEIN STRUCTURES; ENSEMBLE DOCKING; BINDING-SITE; NORMAL-MODES; POTENT; CANCER AB Incorporating receptor flexibility is considered crucial for improvement of docking-based virtual screening. With an abundance of crystallographic structures freely available, docking with multiple crystal structures is believed to be a practical approach to cope with protein flexibility. Here we describe a successful application of the docking of multiple structures to discover novel and potent Chk1 inhibitors. Forty-six Chk1 structures were first compared in single structure docking by predicting the binding mode and recovering known ligands. Combinations of different protein structures were then compared by recovery of known ligands and an optimal ensemble of Chk1 structures were selected. The chosen structures were used in the virtual screening of over 60 000 diverse compounds for Chk1 inhibitors. Six novel compounds ranked at the top of the hits list were tested experimentally, and two of these compounds inhibited Chk1 activity-the best with an IC(50) value of 9.6 mu M. Further study indicated that achieving a better enrichment and identifying more diverse compounds was more likely using multiple structures than using only a single structure even when protein structures were randomly selected. Taking into account conformational energy difference did not help to improve enrichment in the top ranked list. C1 [Li, Yan; Kim, Dong Joon; Ma, Weiya; Bode, Ann M.; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lubet, Ronald A.] NCI, Bethesda, MD 20892 USA. RP Dong, ZG (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM zgdong@hi.umn.edu RI Li, Yan/L-2129-2013 FU Hormel Foundation; National Institutes of Health [R37 CA081064]; NCI [HHSN-261200533001C-NO1-CN-53301] FX This work was supported by The Hormel Foundation, National Institutes of Health Grant R37 CA081064, and NCI Contract Number HHSN-261200533001C-NO1-CN-53301. NR 56 TC 16 Z9 16 U1 0 U2 5 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 NOV PY 2011 VL 51 IS 11 BP 2904 EP 2914 DI 10.1021/ci200257b PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 851MM UT WOS:000297275000012 PM 21955044 ER PT J AU Huijben, S Sim, DG Nelson, WA Read, AF AF Huijben, S. Sim, D. G. Nelson, W. A. Read, A. F. TI The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection SO JOURNAL OF EVOLUTIONARY BIOLOGY LA English DT Article DE competition; competitive release; complexity of infection; drug resistance; malaria; multiplicity of infection; Plasmodium chabaudi; selection coefficient; within-host dynamics ID PLASMODIUM-FALCIPARUM INFECTIONS; WITHIN-HOST COMPETITION; REVERSE-TRANSCRIPTION PCR; CHABAUDI INFECTIONS; ARTEMISININ RESISTANCE; POPULATION-DYNAMICS; HOLOENDEMIC AREA; STAGE MALARIA; TRANSMISSION; EVOLUTION AB Malaria infections normally consist of more than one clonally replicating lineage. Within-host interactions between sensitive and resistant parasites can have profound effects on the evolution of drug resistance. Here, using the Plasmodium chabaudi mouse malaria model, we ask whether the costs and benefits of resistance are affected by the number of co-infecting strains competing with a resistant clone. We found strong competitive suppression of resistant parasites in untreated infections and marked competitive release following treatment. The magnitude of competitive suppression depended on competitor identity. However, there was no overall effect of the diversity of susceptible parasites on the extent of competitive suppression or release. If these findings generalize, then transmission intensity will impact on resistance evolution because of its effect on the frequency of mixed infections, not because of its effect on the distribution of clones per host. This would greatly simplify the computational problems of adequately capturing within-host ecology in models of drug resistance evolution in malaria. C1 [Huijben, S.; Sim, D. G.; Read, A. F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Huijben, S.; Sim, D. G.; Read, A. F.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Huijben, S.] Univ Edinburgh, Sch Biol Sci, Edinburgh, Midlothian, Scotland. [Nelson, W. A.] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Read, A. F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Huijben, S (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM silviehuijben@gmail.com RI Nelson, William/D-1405-2013 FU National Institute of General Medical Sciences, and Penn State [R01GM089932]; National Institute of Allergy And Infectious Diseases [R01AI089819, U19AI089676] FX We thank R. Hallett, S. Reece, W. Snyder, members of the Read group and members of the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, for stimulating discussion. Sarah Knowles and an anonymous reviewer provided stimulating comments that greatly helped to improve the manuscript. The empirical work reported here was supported by Award Number R01GM089932 from the National Institute of General Medical Sciences, and Penn State. Work under awards R01AI089819 and U19AI089676 from the National Institute of Allergy And Infectious Diseases contributed to conceptual and analytical developments. 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 General Medical Sciences, the National Institute of Allergy and Infectious Diseases, or the National Institutes of Health. NR 93 TC 17 Z9 17 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1010-061X J9 J EVOLUTION BIOL JI J. Evol. Biol. PD NOV PY 2011 VL 24 IS 11 BP 2410 EP 2422 DI 10.1111/j.1420-9101.2011.02369.x PG 13 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 852CU UT WOS:000297325600011 PM 21883612 ER PT J AU Smith, SB Maixner, DW Greenspan, JD Dubner, R Fillingim, RB Ohrbach, R Knott, C Slade, GD Bair, E Gibson, DG Zaykin, DV Weir, BS Maixner, W Diatchenko, L AF Smith, Shad B. Maixner, Dylan W. Greenspan, Joel D. Dubner, Ronald Fillingim, Roger B. Ohrbach, Richard Knott, Charles Slade, Gary D. Bair, Eric Gibson, Dustin G. Zaykin, Dmitri V. Weir, Bruce S. Maixner, William Diatchenko, Luda TI Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study SO JOURNAL OF PAIN LA English DT Article DE Pain genetics; temporomandibular joint disorders (TMD); association study; HTR2A; COMT; NR3C1; CAMK4; CHRM2; IFRD1; GRK5 ID TEMPOROMANDIBULAR DISORDERS; PAIN PERCEPTION; RECEPTOR; POLYMORPHISM; DYSFUNCTION; HERITABILITY; SENSITIVITY; MULTILOCUS; ANALGESIA; HAPLOTYPE AB Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1,442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3,295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously reported associations between TMD and 2 genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD, and they identify potential targets for therapeutic intervention. Perspective: Genetic risk factors for TMD pain were explored in the case-control component of the OPPERA cooperative agreement, a large population-based prospective cohort study. Over 350 candidate pain genes were assessed using a candidate gene panel, with several genes displaying preliminary evidence for association with TMD status. Published by Elsevier Inc. on behalf of the American Pain Society C1 [Diatchenko, Luda] Univ N Carolina, Sch Dent, Ctr Neurosensory Disorders, Chapel Hill, NC 27514 USA. [Slade, Gary D.] Univ N Carolina, Dept Dent Ecol, Chapel Hill, NC USA. [Slade, Gary D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Bair, Eric; Maixner, William; Diatchenko, Luda] Univ N Carolina, Dept Endodont, Chapel Hill, NC USA. [Bair, Eric] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Maixner, William] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. [Greenspan, Joel D.; Dubner, Ronald] Univ Maryland, Sch Dent, Dept Neural & Pain Sci, Baltimore, MD 21201 USA. [Greenspan, Joel D.; Dubner, Ronald] Univ Maryland, Sch Dent, Brotman Facial Pain Ctr, Baltimore, MD 21201 USA. [Fillingim, Roger B.] Univ Florida, Dept Community Dent & Behav Sci, Gainesville, FL USA. [Ohrbach, Richard] SUNY Buffalo, Dept Oral Diagnost Serv, Buffalo, NY 14260 USA. [Knott, Charles] Battelle Mem Inst, Durham, NC USA. [Zaykin, Dmitri V.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Weir, Bruce S.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Diatchenko, Luda] Carolina Ctr Genome Sci Chapel Hill, Chapel Hill, NC USA. RP Diatchenko, L (reprint author), Univ N Carolina, Sch Dent, Ctr Neurosensory Disorders, CB 7450, Chapel Hill, NC 27514 USA. EM lbdiatch@email.unc.edu RI Weir, Bruce/A-2894-2013; OI Bair, Eric/0000-0001-8733-7869; Greenspan, Joel/0000-0003-4062-9797; Gibson, Dustin/0000-0002-9073-3376 FU NIH [U01DE017018, DE016558, P01NS045685, R01DE016155, F32DE019057]; NIH, National Institute of Environmental Health Sciences (DZ) FX Supported by NIH grants U01DE017018, DE016558, P01NS045685, R01DE016155, and F32DE019057, and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (DZ). The OPPERA program also acknowledges resources specifically provided for this project by the respective host universities: University at Buffalo, University of Florida, University of Maryland-Baltimore, and University of North Carolina-Chapel Hill. NR 45 TC 56 Z9 58 U1 1 U2 16 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD NOV PY 2011 VL 12 IS 11 SU 3 BP T92 EP T101 DI 10.1016/j.jpain.2011.08.005 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 852TI UT WOS:000297380000008 PM 22074755 ER PT J AU Petzold, A Worthington, V Appleby, I Kerr, ME Kitchen, N Smith, M AF Petzold, Axel Worthington, Viki Appleby, Ian Kerr, Mary E. Kitchen, Neil Smith, Martin TI Cerebrospinal Fluid Ferritin Level, a Sensitive Diagnostic Test in Late-Presenting Subarachnoid Hemorrhage SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Biomarker; protein biomaker; longitudinal; central nervous system; bleed ID NEGATIVE PATIENTS; BILIRUBIN; SCALE AB The workup of patients with suspected subarachnoid hemorrhage (SAH) presenting late is complicated by a loss of diagnostic sensitivity of computed tomography (CT) brain imaging and cerebrospinal fluid (CSF) bilirubin levels. In this prospective longitudinal study of CSF ferritin levels in SAN, serial CSF samples from 14 patients with aneurysmal SAH requiring extraventricular drainage (EVD) were collected. The control group comprised 44 patients presenting with headache suspicious of SAH. Nine patients underwent a traumatic spinal tap. CSF ferritin levels were significantly higher in the patients with SAH compared with controls (P < .0001). The upper reference range of CSF ferritin is 12 ng/mL, and there was no significant difference between the traumatic and normal spinal taps (mean, 9.0 ng/mL vs 3.9 ng/mL; P = .59). CSF ferritin levels increased after SAH, from an average of 65 ng/mL on day 1 to 1750 ng/mL on day 11 (P < .01). Both the Fisher and Columbia CT scores were significantly correlated with CSF ferritin level. The increas in CSF ferritin level after SAH and possibly may provide additional diagnostic information in patients with suspected SAH who present late to the clinic. C1 [Petzold, Axel; Worthington, Viki] UCL, Inst Neurol, Dept Neuroimmunol, London WC1N 3BG, England. [Petzold, Axel; Appleby, Ian; Smith, Martin] Natl Hosp Neurol & Neurosurg, Tavistock Intens Care Unit, London WC1N 3BG, England. [Kitchen, Neil] Natl Hosp Neurol & Neurosurg, Dept Neurosurg, London WC1N 3BG, England. [Kerr, Mary E.] NINR, NIH, Bethesda, MD 20892 USA. RP Petzold, A (reprint author), UCL, Inst Neurol, Dept Neuroimmunol, Queen Sq, London WC1N 3BG, England. EM a.petzold@ion.ucl.ac.uk RI Petzold, Axel/C-1090-2009 OI Petzold, Axel/0000-0002-0344-9749 FU Department of Health's National Institute for Health Research Centres; National Institutes of Health [RO1NR0433] FX This work was undertaken at University College London Hospitals and was funded in part by the Department of Health's National Institute for Health Research Centres funding scheme. Cerebrospinal fluid samples at the University of Pittsburgh Medical Center were collected in conjunction with a National Institutes of Health funded project (Grant RO1NR0433). The authors have no conflicts of interest to disclose. NR 15 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD NOV-DEC PY 2011 VL 20 IS 6 BP 489 EP 493 DI 10.1016/j.jstrokecerebrovasdis.2010.02.021 PG 5 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 852VX UT WOS:000297386700001 PM 20719531 ER PT J AU Bielekova, B Richert, N Herman, ML Ohayon, J Waldmann, TA McFarland, H Martin, R Blevins, G AF Bielekova, B. Richert, N. Herman, M. L. Ohayon, J. Waldmann, T. A. McFarland, H. Martin, R. Blevins, G. TI Intrathecal effects of daclizumab treatment of multiple sclerosis SO NEUROLOGY LA English DT Article ID BIOLOGICALLY INACTIVE MOLECULE; T-CELLS; CEREBROSPINAL-FLUID; INTERFERON-BETA; P40 HOMODIMER; NITRIC-OXIDE; IMMUNE CELLS; THERAPY; NATALIZUMAB; ANTIBODY AB Objectives: We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS) who were suboptimal responders to interferon-beta and that this response correlated with expansion of CD56(bright) NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system. Methods: Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and CSF. Results: The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56bright NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. Conclusions: Daclizumab monotherapy inhibits formation of MS plaques in patients with RRMS and immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment. Classification of evidence: The study provides Class III evidence that daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period. Neurology (R) 2011; 77: 1877-1886 C1 [Bielekova, B.; Richert, N.; Herman, M. L.; Ohayon, J.; McFarland, H.; Martin, R.; Blevins, G.] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Waldmann, T. A.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Martin, R.] Univ Zurich Hosp, Dept Neuroimmunol, CH-8091 Zurich, Switzerland. [Blevins, G.] Univ Alberta, Div Neurol, Edmonton, AB, Canada. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Branch NIB, NIH, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov FU NIH/NINDS; Cumming Foundation; Biogen Idec; Teva Pharmaceutical Industries Ltd.; Merck Serono FX Supported by the Intramural Research Program of the NIH/NINDS. Daclizumab was provided free of charge by Roche, under collaborative agreement with T.A.W., NCI.; Dr. Bielekova is coinventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH. Dr. Richert is a full-time employee of and receives stock options in Biogen Idec; she became employee of Biogen Idec after study conclusion and after data analysis was finalized. M. L. Herman and J. Ohayon report no disclosures. Dr. Waldmann is coinventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH. Dr. McFarland is coinventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH. Dr. Martin has served on scientific advisory boards for Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., and sanofi-aventis; has received speaker honoraria from Biogen Idec and Merck Serono; is coinventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH; and serves as a consultant for the Myelin Repair Foundation, The Weatherall Institute for Molecular Studies, University of Oxford, and the Hertie Foundation. Dr. Blevins serves on scientific advisory boards and as a consultant for Biogen Idec, Teva Pharmaceutical Industries Ltd., and Merck Serono; and has received funding for travel from the Cumming Foundation, Biogen Idec, Teva Pharmaceutical Industries Ltd., and Merck Serono. NR 30 TC 41 Z9 42 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD NOV PY 2011 VL 77 IS 21 BP 1877 EP 1886 DI 10.1212/WNL.0b013e318239f7ef PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 852CD UT WOS:000297322600014 PM 22076546 ER PT J AU Waddell, LB Tran, J Zheng, XF Bonnemann, CG Hu, Y Evesson, FJ Lek, M Arbuckle, S Wang, MX Smith, RL North, KN Clarke, NF AF Waddell, Leigh B. Tran, Jenny Zheng, Xi F. Boennemann, Carsten G. Hu, Ying Evesson, Frances J. Lek, Monkol Arbuckle, Susan Wang, Min-Xia Smith, Robert L. North, Kathryn N. Clarke, Nigel F. TI A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients SO NEUROMUSCULAR DISORDERS LA English DT Article DE Muscular dystrophy; Diagnosis; FHL1; BAG3; MATR3; PTRF; TCAP ID DOMINANT DISTAL MYOPATHY; REDUCING BODY MYOPATHY; NEUROMUSCULAR DISORDERS; SARCOMERIC PROTEIN; GENE-MUTATIONS; TELETHONIN; MUSCLE; POPULATION; DEFICIENCY; PHENOTYPES AB FHL1, BAG3, MATR3 and PTRF are recently identified myopathy genes associated with phenotypes that overlap muscular dystrophy. TCAP is a rare reported cause of muscular dystrophy not routinely screened in most centres. We hypothesised that these genes may account for patients with undiagnosed forms of muscular dystrophy in Australia. We screened a large cohort of muscular dystrophy patients for abnormalities in FHL1 (n = 102) and TCAP (n = 100) and selected patients whose clinical features overlapped the phenotypes previously described for BAG3 (n = 9), MATR3 (n = 15) and PTRF (n = 7). We found one FHL1 mutation (c.311G>A, p.C104Y) in a boy with rapidly progressive muscle weakness and reducing body myopathy who was initially diagnosed with muscular dystrophy. We identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP. In conclusion, we have excluded these five genes as common causes of muscular dystrophy in Australia. Patients with reducing body myopathy may be initially diagnosed as muscular dystrophy. (C) 2011 Elsevier B.V. All rights reserved. C1 [Waddell, Leigh B.; Tran, Jenny; Zheng, Xi F.; Evesson, Frances J.; Lek, Monkol; North, Kathryn N.; Clarke, Nigel F.] Univ Sydney, Discipline Paediat & Child Hlth, Childrens Hosp Westtnead, Inst Neurosci & Muscle Res, Sydney, NSW 2006, Australia. [Boennemann, Carsten G.; Hu, Ying] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Wang, Min-Xia] Univ Sydney, Dept Neurol, Sydney, NSW 2006, Australia. [Smith, Robert L.] John Hunter Childrens Hosp & Univ, Discipline Paediat & Child Hlth, Newcastle, NSW, Australia. RP Clarke, NF (reprint author), Childrens Hosp, Neurogenet Res Unit, Locked Bag 4001, Westmead, NSW 2145, Australia. EM nigelc@chw.edu.au RI North, Kathryn/K-6476-2012 OI North, Kathryn/0000-0003-0841-8009 FU National Health and Medical Research Council of Australia [505004, 206529, 571287, 301946, 403941] FX We thank the families involved for their invaluable contribution to this research. L.W., N.C. and K.N. are supported by the National Health and Medical Research Council of Australia (L.W. Grant 505004, N.C. Grant 206529 and 571287 and K.N. Grant 301946 and 403941). NR 34 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 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD NOV PY 2011 VL 21 IS 11 BP 776 EP 781 DI 10.1016/j.nmd.2011.05.007 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 853BX UT WOS:000297402300002 PM 21683594 ER PT J AU Lal, A Thomas, MP Altschuler, G Navarro, F O'Day, E Li, XL Concepcion, C Han, YC Thiery, J Rajani, DK Deutsch, A Hofmann, O Ventura, A Hide, W Lieberman, J AF Lal, Ashish Thomas, Marshall P. Altschuler, Gabriel Navarro, Francisco O'Day, Elizabeth Li, Xiao Ling Concepcion, Carla Han, Yoon-Chi Thiery, Jerome Rajani, Danielle K. Deutsch, Aaron Hofmann, Oliver Ventura, Andrea Hide, Winston Lieberman, Judy TI Capture of MicroRNA-Bound mRNAs Identifies the Tumor Suppressor miR-34a as a Regulator of Growth Factor Signaling SO PLOS GENETICS LA English DT Article ID DOWN-REGULATION; CELL-CYCLE; HEPATOCELLULAR-CARCINOMA; TARGET RECOGNITION; CANCER; GENES; EXPRESSION; APOPTOSIS; PROTEIN; P53 AB A simple biochemical method to isolate mRNAs pulled down with a transfected, biotinylated microRNA was used to identify direct target genes of miR-34a, a tumor suppressor gene. The method reidentified most of the known miR-34a regulated genes expressed in K562 and HCT116 cancer cell lines. Transcripts for 982 genes were enriched in the pull-down with miR-34a in both cell lines. Despite this large number, validation experiments suggested that similar to 90% of the genes identified in both cell lines can be directly regulated by miR-34a. Thus miR-34a is capable of regulating hundreds of genes. The transcripts pulled down with miR-34a were highly enriched for their roles in growth factor signaling and cell cycle progression. These genes form a dense network of interacting gene products that regulate multiple signal transduction pathways that orchestrate the proliferative response to external growth stimuli. Multiple candidate miR-34a-regulated genes participate in RAS-RAF-MAPK signaling. Ectopic miR-34a expression reduced basal ERK and AKT phosphorylation and enhanced sensitivity to serum growth factor withdrawal, while cells genetically deficient in miR-34a were less sensitive. Fourteen new direct targets of miR-34a were experimentally validated, including genes that participate in growth factor signaling (ARAF and PIK3R2) as well as genes that regulate cell cycle progression at various phases of the cell cycle (cyclins D3 and G2, MCM2 and MCM5, PLK1 and SMAD4). Thus miR-34a tempers the proliferative and pro-survival effect of growth factor stimulation by interfering with growth factor signal transduction and downstream pathways required for cell division. C1 [Lal, Ashish; Thomas, Marshall P.; Navarro, Francisco; O'Day, Elizabeth; Thiery, Jerome; Rajani, Danielle K.; Deutsch, Aaron; Lieberman, Judy] Childrens Hosp Boston, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA 02115 USA. [Lal, Ashish; Thomas, Marshall P.; Navarro, Francisco; O'Day, Elizabeth; Thiery, Jerome; Rajani, Danielle K.; Deutsch, Aaron; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Lal, Ashish; Li, Xiao Ling] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Altschuler, Gabriel; Hofmann, Oliver; Hide, Winston] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Concepcion, Carla; Han, Yoon-Chi; Ventura, Andrea] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10021 USA. RP Lal, A (reprint author), Childrens Hosp Boston, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA 02115 USA. EM lalas@mail.nih.gov; lieberman@idi.harvard.edu RI Hofmann, Oliver/F-1800-2013; Hide, Winston Hide/C-7217-2009; Lieberman, Judy/A-2717-2015; OI Hofmann, Oliver/0000-0002-7738-1513; Hide, Winston Hide/0000-0002-8621-3271; Deutsch, Aaron/0000-0001-6750-5335; Ventura, Andrea/0000-0003-4320-9907 FU GSK-IDI Alliance; NSF FX This work was supported by a research grant (JL) and fellowship (FN) from the GSK-IDI Alliance and by NSF predoctoral fellowships (MPT, DKR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 91 Z9 92 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2011 VL 7 IS 11 AR e1002363 DI 10.1371/journal.pgen.1002363 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 851JM UT WOS:000297264500018 PM 22102825 ER PT J AU Arnvig, KB Comas, I Thomson, NR Houghton, J Boshoff, HI Croucher, NJ Rose, G Perkins, TT Parkhill, J Dougan, G Young, DB AF Arnvig, Kristine B. Comas, Inaki Thomson, Nicholas R. Houghton, Joanna Boshoff, Helena I. Croucher, Nicholas J. Rose, Graham Perkins, Timothy T. Parkhill, Julian Dougan, Gordon Young, Douglas B. TI Sequence-Based Analysis Uncovers an Abundance of Non-Coding RNA in the Total Transcriptome of Mycobacterium tuberculosis SO PLOS PATHOGENS LA English DT Article ID GLOBAL GENE-EXPRESSION; BOVIS BCG; LISTERIA-MONOCYTOGENES; ESCHERICHIA-COLI; HYPOXIC RESPONSE; PROTEIN FAMILY; VIRULENCE; BACTERIA; IDENTIFICATION; GENOME AB RNA sequencing provides a new perspective on the genome of Mycobacterium tuberculosis by revealing an extensive presence of non-coding RNA, including long 5' and 3' untranslated regions, antisense transcripts, and intergenic small RNA (sRNA) molecules. More than a quarter of all sequence reads mapping outside of ribosomal RNA genes represent non-coding RNA, and the density of reads mapping to intergenic regions was more than two-fold higher than that mapping to annotated coding sequences. Selected sRNAs were found at increased abundance in stationary phase cultures and accumulated to remarkably high levels in the lungs of chronically infected mice, indicating a potential contribution to pathogenesis. The ability of tubercle bacilli to adapt to changing environments within the host is critical to their ability to cause disease and to persist during drug treatment; it is likely that novel post-transcriptional regulatory networks will play an important role in these adaptive responses. C1 [Arnvig, Kristine B.; Comas, Inaki; Houghton, Joanna; Rose, Graham; Young, Douglas B.] MRC Natl Inst Med Res, Div Mycobacterial Res, London, England. [Thomson, Nicholas R.; Croucher, Nicholas J.; Perkins, Timothy T.; Parkhill, Julian; Dougan, Gordon] Wellcome Trust Sanger Inst, Cambridge, England. [Boshoff, Helena I.] NIAID, NIH, Bethesda, MD 20892 USA. RP Arnvig, KB (reprint author), MRC Natl Inst Med Res, Div Mycobacterial Res, London, England. EM karnvig@nimr.mrc.ac.uk RI Parkhill, Julian/G-4703-2011; Perkins, Timothy/G-1791-2010; Comas, Inaki/F-1185-2011; OI Parkhill, Julian/0000-0002-7069-5958; Comas, Inaki/0000-0001-5504-9408; Arnvig, Kristine/0000-0002-6850-2547; Rose, Graham/0000-0002-5097-5426 FU Wellcome Trust under its Functional Genomics Resources Initiative; MRC [U117581288]; NIH, NIAID FX We would like to thank Roger Buxton and David Sherman for providing M. tuberculosis CRP [45] and DosR [5] knockout strains. We are grateful to the Core library making and sequencing teams at the Wellcome Trust Sanger Institute for preparing libraries and for sequencing. We acknowledge the B mu G@S (the Bacterial Microarray Group at St. George's, University of London) for the supply of the M. tuberculosis microarrays and advice, and the Wellcome Trust funding of the multicollaborative microbial pathogen microarray facility under its Functional Genomics Resources Initiative. We would also like to thank Paul Gardner for helpful suggestions and Finn Werner for critical reading of the manuscript.; This work was supported by the MRC core funds (U117581288, The Wellcome Trust and in part by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 83 Z9 86 U1 0 U2 37 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 NOV PY 2011 VL 7 IS 11 AR e1002342 DI 10.1371/journal.ppat.1002342 PG 16 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 852EZ UT WOS:000297337300011 PM 22072964 ER PT J AU McCubbin, JA Merritt, MM Sollers, JJ Evans, MK Zonderman, AB Lane, RD Thayer, JF AF McCubbin, James A. Merritt, Marcellus M. Sollers, John J., III Evans, Michele K. Zonderman, Alan B. Lane, Richard D. Thayer, Julian F. TI Cardiovascular-Emotional Dampening: The Relationship Between Blood Pressure and Recognition of Emotion SO PSYCHOSOMATIC MEDICINE LA English DT Article DE emotion regulation; blood pressure; hemodynamics; hypertension development; central nervous system; stress ID PAIN SENSITIVITY; SEX-DIFFERENCES; FACIAL AFFECT; HYPERTENSION; RISK; PERCEPTION; DISEASE; HUMANS; COMMON; NORMOTENSIVES AB Objective: Persons with elevated blood pressure (BP) show dampened emotional responses to affect-laden stimuli. We sought to further examine cardiovascular-emotional dampening by examination of the relationship between resting hemodynamic measures and recognition of emotion in an African American community-based sample. Methods: Participants were 106 African American men and women (55 women; mean age = 52.8 years), mainly low in socioeconomic status, and part of the Healthy Aging in Nationally Diverse Longitudinal Samples pilot study. Participants evaluated emotional expressions in faces and sentences using the Perception of Affect Test (PAT). Resting BP, total peripheral resistance (TPR), cardiac output, and heart rate were obtained continuously using a Portapres BP monitor. Results: Total PAT scores were inversely related to systolic (r = -0.30) and diastolic (r = -0.24) BPs, TPR (r = -0.36), and age (r = -0.31; p values < .01) and were positively related to cardiac output (r = 0.27) and education (r = 0.38; p values < .01), as well as with mental state (r = 0.25) and body mass index (r = -0.20; p values < .05). Accuracy of emotion recognition on the PAT tasks remained inversely related to TPR and BP after adjustment for demographic variables, medication, mental state, and body mass index. Conclusions: Elevated BP and TPR were associated with reduced perception of affect. TPR was the most consistent independent hemodynamic correlate of emotional dampening for the PAT scores. These results suggest potentially important links among central nervous system regulation of emotions, hemodynamic processes, and hypertension development. C1 [McCubbin, James A.] Clemson Univ, Dept Psychol, Clemson, SC 29634 USA. [Merritt, Marcellus M.] Univ Wisconsin, Dept Psychol, Milwaukee, WI 53201 USA. [Sollers, John J., III] Univ Auckland, Dept Psychol Med, Auckland 1, New Zealand. [Evans, Michele K.] NIA, Immunol Lab, Bethesda, MD 20892 USA. [Zonderman, Alan B.] NIA, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Lane, Richard D.] Univ Arizona, Dept Psychiat, Tucson, AZ USA. [Thayer, Julian F.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. RP McCubbin, JA (reprint author), Clemson Univ, Dept Psychol, 418 Brackett Hall, Clemson, SC 29634 USA. EM jmccubb@clemson.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, National Institutes of Health [R01 NR007952]; National Center on Minority Health and Health Disparities, National Institutes of Health FX The Healthy Aging in Neighborhoods of Diversity across the Life Span study is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (Grant R01 NR007952). Support was also provided by the National Center on Minority Health and Health Disparities, National Institutes of Health. NR 38 TC 16 Z9 19 U1 1 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD NOV-DEC PY 2011 VL 73 IS 9 BP 743 EP 750 DI 10.1097/PSY.0b013e318235ed55 PG 8 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 850OT UT WOS:000297205700004 PM 22042880 ER PT J AU Pineda-Alvarez, DE Solomon, BD Roessler, E Balog, JZ Hadley, DW Zein, WM Hadsall, CK Brooks, BP Muenke, M AF Pineda-Alvarez, Daniel E. Solomon, Benjamin D. Roessler, Erich Balog, Joan Z. Hadley, Donald W. Zein, Wadih M. Hadsall, Casey K. Brooks, Brian P. Muenke, Maximilian TI A Broad Range of Ophthalmologic Anomalies Is Part of the Holoprosencephaly Spectrum SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE holoprosencephaly; SHH; SIX3; ZIC2; FGF8; ocular; microphthalmia; coloboma; strabismus; microcornea ID SONIC HEDGEHOG MUTATIONS; LOSS-OF-FUNCTION; HUMAN SIX3 GENE; PHENOTYPE; HUMANS; ZIC2; MANAGEMENT; GENOTYPE; CHILDREN; PROTEIN AB Holoprosencephaly (HPE) is the most common disorder of the developing forebrain in humans, and is characterized by failed or incomplete cleavage of the cerebral hemispheres and deep brain structures. HPE includes wide phenotypic variability, with a continuum of both brain and craniofacial anomalies. While "classic'' eye findings, including the spectrum of midline anomalies ranging from cyclopia to hypotelorism, as well as chorioretinal coloboma and microphthalmia, have been frequently described in patients with HPE, other subtle eye anomalies may also occur. In our study we prospectively analyzed a small cohort of 10 patients in whom we identified mutations in SHH, SIX3, ZIC2, or FGF8, the latter of which is a very recently described HPE-associated gene. We found that 9 of 10 patients had at least two ophthalmologic anomalies, including refractive errors, microcornea, microphthalmia, blepharoptosis, exotropia, and uveal coloboma. These findings contribute to the understanding of the phenotypic variability of the HPE spectrum, and highlight findings in one medically important but often incompletely investigated system. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. C1 [Pineda-Alvarez, Daniel E.; Solomon, Benjamin D.; Roessler, Erich; Balog, Joan Z.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20814 USA. [Hadley, Donald W.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20814 USA. [Zein, Wadih M.; Hadsall, Casey K.; Brooks, Brian P.] NEI, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,Bldg 35,Room 1B202, Bethesda, MD 20814 USA. EM mamuenke@mail.nih.gov FU Division of Intramural Research of the National Human Genome Research Institute; National Institutes of Health FX Grant sponsor: Division of Intramural Research of the National Human Genome Research Institute; Grant sponsor: National Institutes of Health. NR 38 TC 11 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD NOV PY 2011 VL 155A IS 11 BP 2713 EP 2720 DI 10.1002/ajmg.a.34261 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 850MU UT WOS:000297199700015 PM 21976454 ER PT J AU Bianconi, SE Conley, SK Keil, MF Sinaii, N Rother, KI Porter, FD Stratakis, CA AF Bianconi, Simona E. Conley, Sandra K. Keil, Meg F. Sinaii, Ninet Rother, Kristina I. Porter, Forbes D. Stratakis, Constantine A. TI Adrenal Function in Smith-Lemli-Opitz Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE adrenal gland; adrenocortical insufficiency; pituitary gland; adrenocorticotropin (ACTH); cortisol; Smith-Lemli-Opitz syndrome (SLOS); inborn error of cholesterol synthesis; corticotropin releasing hormone (CRH) ID CORTICOTROPIN-RELEASING HORMONE; DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; DELTA-7-STEROL REDUCTASE GENE; MULTIPLE CONGENITAL-ANOMALIES; STIMULATION TEST; CUSHINGS-SYNDROME; INSUFFICIENCY; PHENOTYPE; DELINEATION; MUTATIONS AB Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation syndrome due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7), which leads to a deficiency of cholesterol synthesis and an accumulation of 7-dehydrocholesterol. The SLOS clinical spectrum ranges from multiple major malformations to a mild phenotype with minor anomalies and intellectual disability. Several children with SLOS and adrenal insufficiency have been described. We performed ovine corticotropin (oCRH) testing in 35 SLOS patients and 16 age-and gender-matched controls. We reviewed prior adrenocorticotropin (ACTH) stimulation tests of our SLOS patients (19 of 35 available) and reviewed results of ACTH stimulation tests from 10 additional SLOS patients. Results from oCRH testing showed that patients with SLOS had significantly higher ACTH baseline values than healthy controls (24.8 +/- 15.3 pg/ml vs. 17.8 +/- 7.5 pg/ml, P=0.034). However, no statistically significant differences were noted for peak ACTH values (74.4 +/- 35.0 pg/ml vs. 64.0 +/- 24.9 pg/ml, P=0.303) and for baseline (14.2 +/- 7.8 mcg/dl vs. 14.2 +/- 6.3 mcg/dl, P=0.992) and peak cortisol values (28.2 +/- 7.9 mcg/dl vs. 24.8 +/- 8.1 mcg/dl, P=0.156). The area-under-the-curve (AUC) was not significantly different in SLOS patients compared to controls for both ACTH (250.1 +/- 118.7 pg/ml vs. 195.3 +/- 96.6 pg/ml, P=0.121) as well as cortisol secretion (83.1 +/- 26.1 mcg/dl vs. 77.8 +/- 25.9 mcg/dl, P=0.499). ACTH stimulation test results were normal in 28 of 29 tests. The individual with the abnormal test results had subsequent normal oCRH tests. The slightly increased baseline ACTH level seen during oCRH testing may be due to compensated adrenocortical insufficiency. However, we were able to show that our patients with SLOS had an adequate glucocorticoid response, and thus, in mild to moderate cases of SLOS stress steroid coverage may not be warranted. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. C1 [Bianconi, Simona E.; Conley, Sandra K.; Keil, Meg F.; Porter, Forbes D.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD USA. [Bianconi, Simona E.; Porter, Forbes D.; Stratakis, Constantine A.] NIH, Interinst Med Genet Training Program, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIH, Biostat & Clin Epidemiol Serv, NIH Clin Ctr, Bethesda, MD 20892 USA. [Rother, Kristina I.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD USA. [Rother, Kristina I.; Stratakis, Constantine A.] NIH, Interinst Training Program Pediat Endocrinol, Bethesda, MD 20892 USA. RP Bianconi, SE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet PDEGEN, NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. FU U.S. National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD-000642-04, HD-008825-04]; National Institutes of Health (NIH); National Institutes of Health (NIH), Bethesda, MD, USA FX Grant sponsor: U.S. National Institutes of Health; Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Grant numbers: HD-000642-04, HD-008825-04; Grant sponsor: National Institutes of Health (NIH).; This study was supported by U.S. National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural project HD-000642-04 (to Dr. C. A. Stratakis) and HD-008825-04 (to Dr. F. D. Porter), and National Institutes of Health (NIH), Bethesda, MD, USA. NR 46 TC 6 Z9 8 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD NOV PY 2011 VL 155A IS 11 BP 2732 EP 2738 DI 10.1002/ajmg.a.34271 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 850MU UT WOS:000297199700017 PM 21990131 ER PT J AU Motegi, S Garfield, S Feng, X Sardy, M Udey, MC AF Motegi, Sei-ichiro Garfield, Susan Feng, Xu Sardy, Miklos Udey, Mark C. TI Potentiation of Platelet-Derived Growth Factor Receptor-beta Signaling Mediated by Integrin-Associated MFG-E8 SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE MFG-E8; PDGF receptor beta; PDGF-BB; integrin; pericyte ID FOCAL ADHESION KINASE; SMOOTH-MUSCLE-CELLS; DISCOIDIN-DOMAIN PROTEIN; ALPHA(V)BETA(3) INTEGRIN; NEGATIVE REGULATION; EGF REPEAT; PDGFR-BETA; C-CBL; MIGRATION; BINDING AB Objective-Pericytes/pericyte precursors produce milk fat globule-associated protein with epidermal growth factor and factor VIII-like domains (MFG-E8) in vivo, and this alpha(v) integrin ligand enhances angiogenesis in tumors and in oxygen-induced retinopathy in mice. Inhibition of MFG-E8 production or function attenuates platelet-derived growth factor-BB (PDGF-BB)-induced migration of pericyte/pericyte precursor-like 10T1/2 cells in vitro. Herein, we describe mechanisms by which MFG-E8 modulates PDGF-BB: PDGF receptor beta (PDGFR beta) signaling in 10T1/2 cells. Methods and Results-Small interfering RNA depletion of MFG-E8 from 10T1/2 cells or antibody inhibition of MFG-E8 action enhanced PDGF-BB-dependent degradation of PDGFR beta and attenuated signaling. Coimmunoprecipitation revealed transient association of MFG-E8 with PDGFR beta in PDGF-BB-treated 10T1/2 cells and reduced PDGFR beta-focal adhesion kinase association in MFG-E8-depleted cells. Confocal microscopy demonstrated that MFG-E8 binding to 10T1/2 cells was RGD motif and alpha(v) dependent but PDGF-BB treatment independent, whereas colocalization of MFG-E8 with PDGFR beta was enhanced by PDGF-BB. Ubiquitination of PDGFR beta was also increased in MFG-E8 small interfering RNA-transfected cells. Conclusion-Integrin alpha(v)-bound MFG-E8 associates with PDGFR beta and focal adhesion kinase after PDGF-BB treatment, results in cell surface retention of PDGFR beta, delays receptor degradation, potentiates downstream signaling, and enhances migration of 10T1/2 cells. MFG-E8 may promote angiogenesis, in part, via cell autonomous actions on pericytes or pericyte precursors that result in enhanced PDGF-BB:PDGFR beta signaling mediated via integrin-growth factor receptor cross-talk. (Arterioscler Thromb Vasc Biol. 2011;31:2653-2664.) C1 [Motegi, Sei-ichiro; Feng, Xu; Sardy, Miklos; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20802 USA. [Garfield, Susan] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20802 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Rm 12N238, Bethesda, MD 20802 USA. EM udeym@mail.nih.gov FU National Institutes of Health, Center for Cancer Research, National Cancer Institute; Japan Foundation for Aging and Health; Japan Society for Promotion of Science at the National Institutes of Health FX This work was supported by the Intramural Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. Dr Motegi was supported, in part, by project grants from the Japan Foundation for Aging and Health and by a Japan Society for Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health. NR 40 TC 14 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2011 VL 31 IS 11 BP 2653 EP U747 DI 10.1161/ATVBAHA.111.233619 PG 20 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 842NE UT WOS:000296605400040 PM 21868707 ER PT J AU Liu, JK Fox, CS Hickson, D Bidulescu, A Carr, JJ Taylor, HA AF Liu, Jiankang Fox, Caroline S. Hickson, DeMarc Bidulescu, Aurelian Carr, J. Jeffery Taylor, Herman A. TI Fatty Liver, Abdominal Visceral Fat, and Cardiometabolic Risk Factors The Jackson Heart Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE Jackson Heart Study; abdominal visceral fat; cardiometabolic risk factors; fatty liver ID SUBCUTANEOUS ADIPOSE-TISSUE; INSULIN-RESISTANCE; HEPATIC STEATOSIS; UNITED-STATES; OBESITY; HUMANS; DISEASE; IMPACT; ASSOCIATION; SECRETION AB Objective-The goal of this study was to examine whether fatty liver and abdominal visceral adipose tissue (VAT) are jointly associated with cardiometabolic abnormalities. Methods and Results-Black participants were from the Jackson Heart Study (n = 2882, 65% women) who underwent computed tomography. Fatty liver was measured by liver attenuation in Hounsfield units (LA), and VAT was quantified volumetrically. Cross-sectional associations between LA, VAT, and cardiometabolic risk factors were assessed using linear and logistic regression, and their joint associations were further examined in 4 subgroups: high-LA/low-VAT (n = 1704), low-LA/low-VAT (n = 422), high-LA/high-VAT (n = 436), and low-LA/high-VAT (n = 320). Both LA and VAT were associated with most cardiometabolic traits (all P < 0.0001), which persisted after additional adjustment for each other (LA, P < 0.01-0.0001; VAT, P < 0.0001). In bootstrap analyses, the regression coefficient of VAT was significantly greater than LA for triglycerides, high-density lipoprotein cholesterol, impaired glucose, and metabolic syndrome (P = 0.009-0.0001). The interaction between LA and VAT was significant for high-density lipoprotein cholesterol (P = 0.002), impaired glucose (P = 0.003), and metabolic syndrome (P = 0.04). Among 4 subgroups, participants with higher VAT and lower LA had higher prevalence of cardiometabolic traits than those with each condition alone. Conclusion-Both fatty liver and VAT are independent correlates of cardiometabolic risk, but the associations are stronger for VAT than for fatty liver. (Arterioscler Thromb Vasc Biol. 2011;31:2715-2722.) C1 [Liu, Jiankang; Hickson, DeMarc; Taylor, Herman A.] Jackson State Univ, Univ Mississippi Med Ctr, Jackson Heart Study, Jackson, MS 39213 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Bidulescu, Aurelian] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Carr, J. Jeffery] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. RP Liu, JK (reprint author), Jackson State Univ, Univ Mississippi Med Ctr, Jackson Heart Study, 350 W Woodrow Wilson Dr, Jackson, MS 39213 USA. EM jliu@umc.edu RI Bidulescu, Aurelian/N-2617-2014; Carr, John/A-1938-2012 OI Bidulescu, Aurelian/0000-0001-8211-8309; Carr, John/0000-0002-4398-8237 FU National Heart, Lung, and Blood Institute [N01-HC-95170, N01-HC-95171, N01-C-95172]; National Center on Minority Health and Health Disparities FX The Jackson Heart Study is supported by the National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities. Funding for Dr Taylor was provided under contracts N01-HC-95170, N01-HC-95171, and N01-C-95172 from the National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities. NR 31 TC 40 Z9 42 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2011 VL 31 IS 11 BP 2715 EP 2722 DI 10.1161/ATVBAHA.111.234062 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 842NE UT WOS:000296605400047 PM 21885852 ER PT J AU Alger, HM Raben, N Pistilli, E Francia, DL Rawat, R Getnet, D Ghimbovschi, S Chen, YW Lundberg, IE Nagaraju, K AF Alger, Heather M. Raben, Nina Pistilli, Emidio Francia, Dwight L. Rawat, Rashmi Getnet, Derese Ghimbovschi, Svetlana Chen, Yi-Wen Lundberg, Ingrid E. Nagaraju, Kanneboyina TI The Role of TRAIL in Mediating Autophagy in Myositis Skeletal Muscle A Potential Nonimmune Mechanism of Muscle Damage SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; MHC CLASS-I; NF-KAPPA-B; CELL-DEATH; INFLAMMATORY MYOPATHIES; AUTOIMMUNE MYOSITIS; GOLGI-COMPLEX; UP-REGULATION; APOPTOSIS; DERMATOMYOSITIS AB Objective. Multinucleated cells are relatively resistant to classic apoptosis, and the factors initiating cell death and damage in myositis are not well defined. We hypothesized that nonimmune autophagic cell death may play a role in muscle fiber damage. Recent reports indicate that TRAIL may induce both NF-kappa B activation and autophagic cell death in other systems. We undertook this study to investigate the role of TRAIL in cell death and pathogenesis in vitro and in vivo, using myositis muscle tissues from humans and mice. Methods. Gene expression profiling was performed in myositis patient and control muscle specimens. Immunohistochemistry analysis was performed to confirm the gene array findings. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NF-kappa B activation in vitro in cultured cells. Results. TRAIL was expressed predominantly in myositis muscle fibers, but not in biopsy specimens from normal or other dystrophic-diseased muscle. Autophagy markers were up-regulated in humans with myositis and in mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NF-kappa B activation and I kappa B degradation in cultured cells that are resistant to TRAIL-induced apoptosis but that undergo autophagic cell death. Conclusion. Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NF-kappa B and autophagic cell death in myositis. Thus, this nonimmune pathway may be an attractive target for therapeutic intervention in myositis. C1 [Nagaraju, Kanneboyina] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [Alger, Heather M.; Francia, Dwight L.; Ghimbovschi, Svetlana; Chen, Yi-Wen; Nagaraju, Kanneboyina] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Raben, Nina] NIAMSD, NIH, Bethesda, MD 20892 USA. [Pistilli, Emidio] Univ Penn, Philadelphia, PA 19104 USA. [Rawat, Rashmi] FDA, Silver Spring, MD USA. [Getnet, Derese] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lundberg, Ingrid E.] Karolinska Univ Hosp Solna, Stockholm, Sweden. [Lundberg, Ingrid E.] Karolinska Inst, Stockholm, Sweden. RP Nagaraju, K (reprint author), Childrens Natl Med Ctr, Med Genet Res Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM knagaraju@cnmcresearch.org RI Getnet, Derese/C-5421-2012 FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [1-R01-AR-052027-01A2]; National Institute of Child Health and Human Development [1-U54-HD-053177-01A1, 1-R24-HD-050846-01]; Myositis Association; Association Francaise contre les Myopathies; NIH [R01-AR-050478, 5-U54-HD-053177] FX Dr. Chen's work was supported in part by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant 1-R01-AR-052027-01A2 and National Institute of Child Health and Human Development grants 1-U54-HD-053177-01A1 and 1-R24-HD-050846-01). Dr. Lundberg's work was supported by the Myositis Association and the Association Francaise contre les Myopathies. Dr. Nagaraju's work was supported by the NIH (grants R01-AR-050478 and 5-U54-HD-053177). NR 47 TC 11 Z9 12 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD NOV PY 2011 VL 63 IS 11 BP 3448 EP 3457 PG 10 WC Rheumatology SC Rheumatology GA 850TC UT WOS:000297221100029 PM 21769834 ER PT J AU Tanaka, N Izawa, K Saito, MK Sakuma, M Oshima, K Ohara, O Nishikomori, R Morimoto, T Kambe, N Goldbach-Mansky, R Aksentijevich, I de Saint Basile, G Neven, B van Gijn, M Frenkel, J Arostegui, JI Yague, J Merino, R Ibanez, M Pontillo, A Takada, H Imagawa, T Kawai, T Yasumi, T Nakahata, T Heike, T AF Tanaka, Naoko Izawa, Kazushi Saito, Megumu K. Sakuma, Mio Oshima, Koichi Ohara, Osamu Nishikomori, Ryuta Morimoto, Takeshi Kambe, Naotomo Goldbach-Mansky, Raphaela Aksentijevich, Ivona de Saint Basile, Genevieve Neven, Benedicte van Gijn, Marielle Frenkel, Joost Arostegui, Juan I. Yaguee, Jordi Merino, Rosa Ibanez, Mercedes Pontillo, Alessandra Takada, Hidetoshi Imagawa, Tomoyuki Kawai, Tomoki Yasumi, Takahiro Nakahata, Tatsutoshi Heike, Toshio TI High Incidence of NLRP3 Somatic Mosaicism in Patients With Chronic Infantile Neurologic, Cutaneous, Articular Syndrome Results of an International Multicenter Collaborative Study SO ARTHRITIS AND RHEUMATISM LA English DT Article ID MULTISYSTEM INFLAMMATORY DISEASE; LOW-LEVEL MOSAICISM; CIAS1 MUTATIONS; AUTOINFLAMMATORY DISEASES; GENE AB Objective. Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in similar to 40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. Methods. An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations. Results. Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean +/- SD 12.1 +/- 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. Conclusion. Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome. C1 [Ohara, Osamu] Kazusa DNA Res Inst, Dept Human Genome Res, Kisarazu, Chiba 2920818, Japan. [Tanaka, Naoko; Izawa, Kazushi; Nishikomori, Ryuta; Kawai, Tomoki; Yasumi, Takahiro; Heike, Toshio] Kyoto Univ, Grad Sch Med, Kyoto 6068507, Japan. [Saito, Megumu K.; Nakahata, Tatsutoshi] Ctr iPS Cell Res & Applicat, Kyoto, Japan. [Oshima, Koichi; Ohara, Osamu] RIKEN Yokohama Inst, Yokohama, Kanagawa, Japan. [Kambe, Naotomo] Chiba Univ, Grad Sch Med, Chiba, Japan. [Goldbach-Mansky, Raphaela; Aksentijevich, Ivona] NIAMSD, NIH, Bethesda, MD 20892 USA. [de Saint Basile, Genevieve] Paris Descartes Univ, Paris, France. [de Saint Basile, Genevieve] INSERM, U768, Paris, France. [Neven, Benedicte] Necker Hosp Sick Children, AP HP, Paris, France. [van Gijn, Marielle; Frenkel, Joost] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Arostegui, Juan I.; Yaguee, Jordi] Hosp Clin Barcelona, Barcelona, Spain. [Merino, Rosa] Hosp La Paz, Madrid, Spain. [Ibanez, Mercedes] Hosp Nino Jesus, Madrid, Spain. [Pontillo, Alessandra] IRCCS Burlo Garofalo, Trieste, Italy. [Takada, Hidetoshi] Kyushu Univ, Grad Sch Med Sci, Fukuoka 812, Japan. [Imagawa, Tomoyuki] Yokohama City Univ, Sch Med, Yokohama, Kanagawa 232, Japan. RP Ohara, O (reprint author), Kazusa DNA Res Inst, Dept Human Genome Res, 2-6-7 Kazusakamatari Kisarazu, Kisarazu, Chiba 2920818, Japan. EM ohara@kazusa.or.jp; rnishiko@kuhp.kyoto-u.ac.jp RI Ohara, Osamu/A-9119-2012; PONTILLO, ALESSANDRA/D-4352-2012; Ohara, Osamu/G-5448-2015; OI Ohara, Osamu/0000-0002-3328-9571; Arostegui, Juan Ignacio/0000-0003-4757-504X; Kambe, Naotomo/0000-0001-9610-4952 FU Mitsubishi Pharma Research Foundation; Japanese Ministry of Education, Science, Sports, and Culture; Japanese Ministry of Health, Labor, and Welfare FX Supported by Mitsubishi Pharma Research Foundation, the Japanese Ministry of Education, Science, Sports, and Culture, and the Japanese Ministry of Health, Labor, and Welfare. NR 16 TC 89 Z9 99 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD NOV PY 2011 VL 63 IS 11 BP 3625 EP 3632 DI 10.1002/art.30512 PG 8 WC Rheumatology SC Rheumatology GA 850TC UT WOS:000297221100051 PM 21702021 ER PT J AU Allen, JA Peterson, A Sufit, R Hinchcliff, ME Mahoney, JM Wood, TA Miller, FW Whitfield, ML Varga, J AF Allen, Jeffrey A. Peterson, Alicia Sufit, Robert Hinchcliff, Monique E. Mahoney, J. Matthew Wood, Tammara A. Miller, Frederick W. Whitfield, Michael L. Varga, John TI Post-Epidemic Eosinophilia-Myalgia Syndrome Associated With L-Tryptophan SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SCLERODERMA; INGESTION; CONTAMINANTS; EXPRESSION; FASCIITIS AB Eosinophilia-myalgia syndrome (EMS) is characterized by subacute onset of myalgias and peripheral eosinophilia, followed by chronic neuropathy and skin induration. An epidemic of EMS in 1989 was linked to consumption of L-tryptophan that had originated from a single source. Following the ban by the Food and Drug Administration (FDA) on the sale of L-tryptophan, the incidence of EMS declined rapidly. Moreover, no new cases have been described since the FDA ban was lifted in 2005. We report the clinical, histopathologic, and immunogenetic features of a new case of L-tryptophan-associated EMS, along with evidence of activated transforming growth factor beta and interleukin-4 signaling in the lesional skin. C1 [Varga, John] Northwestern Univ, Div Rheumatol, Feinberg Sch Med, Chicago, IL 60612 USA. [Mahoney, J. Matthew; Wood, Tammara A.; Whitfield, Michael L.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. [Miller, Frederick W.] NIEHS, NIH, Bethesda, MD USA. RP Varga, J (reprint author), Northwestern Univ, Div Rheumatol, Feinberg Sch Med, 240 E Huron St, Chicago, IL 60612 USA. EM J-varga@northwestern.edu OI Miller, Frederick/0000-0003-2831-9593 FU Scleroderma Research Foundation; Arthritis Foundation; National Institute of Arthritis and Musculoskeletal and Skin Diseases [U01-AR-055063]; National Human Genome Research Institute [R01-HG-004499]; National Cancer Institute [R01-CA-077485, R25-CA-134286]; NIH (National Institute of Environmental Health Sciences) [Z01-ES-101074-DIR]; NIH [AR-42309] FX The work of Dr. Mahoney, Ms Wood, and Dr. Whitfield was supported by grants from the Scleroderma Research Foundation, the Arthritis Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U01-AR-055063), the National Human Genome Research Institute (R01-HG-004499), and the National Cancer Institute (R01-CA-077485). Dr. Mahoney's work was also supported by an individual grant from the National Cancer Institute (R25-CA-134286). Dr. Miller's work was supported by the NIH (National Institute of Environmental Health Sciences Z01-ES-101074-DIR). Dr. Vargas' work was supported by the NIH (grant AR-42309). NR 20 TC 15 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD NOV PY 2011 VL 63 IS 11 BP 3633 EP 3639 DI 10.1002/art.30514 PG 7 WC Rheumatology SC Rheumatology GA 850TC UT WOS:000297221100052 PM 21702023 ER PT J AU Rider, LG Werth, VP Huber, AM Alexanderson, H Rao, AP Ruperto, N Herbelin, L Barohn, R Isenberg, D Miller, FW AF Rider, Lisa G. Werth, Victoria P. Huber, Adam M. Alexanderson, Helene Rao, Anand Prahalad Ruperto, Nicolino Herbelin, Laura Barohn, Richard Isenberg, David Miller, Frederick W. TI Measures of Adult and Juvenile Dermatomyositis, Polymyositis, and Inclusion Body Myositis Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), Physician Global Damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI) SO ARTHRITIS CARE & RESEARCH LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; MUSCULAR-DYSTROPHY FSHD; RANDOMIZED PILOT TRIAL; HOME EXERCISE PROGRAM; OF-LIFE; PEDIATRIC RHEUMATOLOGY; NATURAL-HISTORY; PROGNOSTIC-FACTORS; INTERNATIONAL CONSENSUS C1 [Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH, Bethesda, MD 20892 USA. [Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Werth, Victoria P.] Univ Penn, Philadelphia, PA 19104 USA. [Huber, Adam M.] Dalhousie Univ, Halifax, NS, Canada. [Huber, Adam M.] IWK Hlth Ctr, Halifax, NS, Canada. [Alexanderson, Helene] Karolinska Inst, Stockholm, Sweden. [Alexanderson, Helene] Karolinska Univ Hosp, Stockholm, Sweden. [Rao, Anand Prahalad; Ruperto, Nicolino] IRCCS G Gaslini, Paediat Rheumatol Int Trials Org, Genoa, Italy. [Herbelin, Laura; Barohn, Richard] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Isenberg, David] UCL, London, England. RP Rider, LG (reprint author), NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH, CRC 4-2352,MSC 1301,10 Ctr Dr, Bethesda, MD 20892 USA. EM rider1@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458 FU NIH National Institute of Environmental Health Sciences FX Supported in part by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences. NR 112 TC 51 Z9 54 U1 2 U2 10 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD NOV PY 2011 VL 63 SU 11 BP S118 EP S157 DI 10.1002/acr.20532 PG 40 WC Rheumatology SC Rheumatology GA 850SR UT WOS:000297219500011 PM 22588740 ER PT J AU Gadalla, SM Savage, SA AF Gadalla, Shahinaz M. Savage, Sharon A. TI Telomere biology in hematopoiesis and stem cell transplantation SO BLOOD REVIEWS LA English DT Review DE Telomeres; Bone marrow failure disorders; Hematopoietic stem cell transplant; Dyskeratosis congenita; Myelodysplastic syndrome; Pluripotent stem cells ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; IN-SITU HYBRIDIZATION; HUMAN SOMATIC-CELLS; MEMORY T-CELLS; DYSKERATOSIS-CONGENITA; MYELODYSPLASTIC SYNDROMES; APLASTIC-ANEMIA AB Telomeres are long (TTAGGG), nucleotide repeats and an associated protein complex located at the end of the chromosomes. They shorten with every cell division and, thus are markers for cellular aging, senescence, and replicative capacity. Telomere dysfunction is linked to several bone marrow disorders, including dyskeratosis congenita, aplastic anemia, myelodysplastic syndrome, and hematopoietic malignancies. Hematopoietic stem cell transplantation (HSCT) provides an opportunity in which to study telomere dynamics in a high cell proliferative environment. Rapid telomere shortening of donor cells occurs in the recipient shortly after HSCT; the degree of telomere attrition does not appear to differ by graft source. As expected, telomeres are longer in recipients of grafts with longer telomeres (e.g., cord blood). Telomere attrition may play a role in, or be a marker of, long term outcome after HSCT, but these data are limited. In this review, we discuss telomere biology in normal and abnormal hematopoiesis, including HSCT. Published by Elsevier Ltd. C1 [Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Gadalla, Shahinaz M.] NCI, Canc Prevent Fellowship Program, Rockville, MD 20852 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7018, Rockville, MD 20852 USA. EM gadallas@mail.nih.gov; savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 156 TC 17 Z9 17 U1 0 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0268-960X J9 BLOOD REV JI Blood Rev. PD NOV PY 2011 VL 25 IS 6 BP 261 EP 269 DI 10.1016/j.blre.2011.06.004 PG 9 WC Hematology SC Hematology GA 851AB UT WOS:000297239600004 PM 21764192 ER PT J AU Carol, H Boehm, I Reynolds, CP Kang, MH Maris, JM Morton, CL Gorlick, R Kolb, EA Keir, ST Wu, JR Wozniak, AE Yang, Y Manfredi, M Ecsedy, J Wang, JM Neale, G Houghton, PJ Smith, MA Lock, RB AF Carol, Hernan Boehm, Ingrid Reynolds, C. Patrick Kang, Min H. Maris, John M. Morton, Christopher L. Gorlick, Richard Kolb, E. Anders Keir, Stephen T. Wu, Jianrong Wozniak, Amy E. Yang, Yu Manfredi, Mark Ecsedy, Jeffrey Wang, Jianmin Neale, Geoffrey Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Preclinical testing; Developmental therapeutics; MLN8237; Pediatric cancer ID TESTING PROGRAM; COPY NUMBER; HUMAN NEUROBLASTOMA; DRUG TARGETS; CELL-DEATH; HISTONE H3; A KINASE; IN-VIVO; N-MYC; SPINDLE AB To gain a greater understanding of the potential of the Aurora kinase A inhibitor MLN8237 in the treatment of pediatric malignancies. The activity of MLN8237 was evaluated against 28 neuroblastoma and Ewing sarcoma cell lines, and its in vivo efficacy was studied over a range of doses against 12 pediatric tumor xenograft models. Pharmacokinetic, pharmacodynamic, and genomic studies were undertaken. In vitro neuroblastoma cell lines were generally more sensitive to MLN8237 than Ewing sarcoma lines. MLN8237 demonstrated significant activity in vivo against solid tumor models at the maximum tolerated dose (MTD); however, only 2 of 6 neuroblastoma models had objective responses at 0.25MTD. In contrast, MLN8237 induced objective responses at its MTD and at 0.5MTD in three ALL models and in two out of three at 0.25MTD. Pharmacokinetic studies at 0.5MTD demonstrated a T (max) of 0.5 h, C (max) of 24.8 mu M, AUC((0-24)) of 60.3 mu M h, and 12 h trough level of 1.2 mu M. Mitotic indices increased 6-12 h after MLN8237 administration. AURKA copy number variation was frequent in xenografts, and expression was highly correlated with copy number. Objective responses were more frequent in tumors with decreased AURKA copy number (5/8) compared to those with increased gene copy number (2/14). This report confirms the significant activity against both solid tumor and ALL xenografts at the MTD, with a steep dose response. These data support clinical development of MLN8237 in childhood cancer. Because of the steep dose-response relationship, such studies should target achieving trough levels of 1 mu M or higher for sustained periods of treatment. C1 [Carol, Hernan; Boehm, Ingrid; Lock, Richard B.] UNSW, Leukaemia Biol Program, Childrens Canc Inst Australia Med Res, Lowy Canc Res Ctr, Randwick, NSW 2031, Australia. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Morton, Christopher L.; Wu, Jianrong; Wozniak, Amy E.; Wang, Jianmin; Neale, Geoffrey] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Yang, Yu; Manfredi, Mark; Ecsedy, Jeffrey] Millennium Pharmaceut Inc, Cambridge, MA USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), UNSW, Leukaemia Biol Program, Childrens Canc Inst Australia Med Res, Lowy Canc Res Ctr, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au 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 [NO1-CM-42216, NO1-CM91001-03, CA21765, CA108786] FX This work was supported by NO1-CM-42216, NO1-CM91001-03, CA21765, and CA108786 from the National Cancer Institute and used MLN8237 supplied by Millennium Pharmaceuticals, Inc. Sherry Ansher, Catherine A. Billups, Joshua Courtright, Mila Dolotin, Edward Favours, Henry S. Friedman, Debbie Payne-Turner, Charles Stopford, Chandra Tucker, Joe Zeidner, Ellen Zhang, and Jian Zhang contributed to this work in addition to the authors. Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital. NR 46 TC 48 Z9 48 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD NOV PY 2011 VL 68 IS 5 BP 1291 EP 1304 DI 10.1007/s00280-011-1618-8 PG 14 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 849KM UT WOS:000297124400022 PM 21448591 ER PT J AU Sasaki, T Hansford, R Zviman, MM Kolandaivelu, A Bluemke, DA Berger, RD Calkins, H Halperin, HR Nazarian, S AF Sasaki, Takeshi Hansford, Rozann Zviman, Menekhem M. Kolandaivelu, Aravindan Bluemke, David A. Berger, Ronald D. Calkins, Hugh Halperin, Henry R. Nazarian, Saman TI Quantitative Assessment of Artifacts on Cardiac Magnetic Resonance Imaging of Patients With Pacemakers and Implantable Cardioverter-Defibrillators SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE MRI; artifacts; pacemakers; implantable cardioverter-defibrillator ID NONISCHEMIC CARDIOMYOPATHY; VENTRICULAR-ARRHYTHMIA; ABSORPTION RATE; 1.5 TESLA; SAFETY; MRI; ENHANCEMENT; SUBSTRATE; DEVICES; UTILITY AB Background-The safety and clinical utility of MRI at 1.5 T in patients with cardiac implantable devices such as pacemakers (PM) and implantable cardioverter-defibrillators (ICD) have been reported. This study aims to evaluate the extent of artifacts on cardiac magnetic resonance (CMR) in patients with PM and ICD (PM/ICD). Methods and Results-A total of 71 CMR studies were performed with an established safety protocol in patients with prepectoral PM/ICD. The artifact area around the PM/ICD generator was measured in all short-axis (SA), horizontal (HLA), and vertical long-axis (VLA) SSFP cine planes. The location and extent of artifacts were also assessed in all SA (20 sectors per plane), HLA, and VLA (6 sectors per plane) late gadolinium-enhanced CMR (LGE-CMR) planes. The artifact area on cine CMR was significantly larger with ICD versus PM generators in each plane (P<0.001, respectively). In patients with left-sided ICD or biventricular ICD systems, the percentages of sectors with any artifacts on LGE-CMR were 53.7%, 48.0%, and 49.2% in SA, HLA, and VLA planes, respectively. Patients with left-sided PM or right-sided PM/ICD had fewer artifacts. Anterior and apical regions were severely affected by artifact caused by left-sided PM/ICD generators. Conclusions-In contrast to patients with right-sided PM/ICD and left-sided PM, the anterior and apical left ventricle can be affected by susceptibility artifacts in patients with left-sided ICD. Artifact reduction methodologies will be necessary to improve the performance of CMR in patients with left sided ICD systems. (Circ Cardiovasc Imaging. 2011;4:662-670.) C1 [Sasaki, Takeshi] Johns Hopkins Univ, Div Cardiol, Sch Med, Dept Med Cardiol, Baltimore, MD 21287 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. RP Sasaki, T (reprint author), Johns Hopkins Univ, Div Cardiol, Sch Med, Dept Med Cardiol, Carnegie 592C,600 N Wolfe St, Baltimore, MD 21287 USA. EM tsasaki1@jhu.edu OI Bluemke, David/0000-0002-8323-8086 FU Francis Chiaramonte MD Private Foundation; Career Development Award [K23HL089333]; National Institutes of Health [R01-HL65795]; Zoll Circulation Inc; St Jude Medical Inc; Medtronic Inc; Boston Scientific Corp; Cameron Health Inc. FX Dr Sasaki is funded by the Francis Chiaramonte MD Private Foundation. Dr Nazarian is supported by Career Development Award K23HL089333 and Dr Halperin by grant R01-HL65795 from the National Institutes of Health.; Dr Nazarian received honoraria for lectures from St Jude Medical Inc, Boston Scientific Inc, and Biotronic Inc. Dr Halperin received research grant and consultant fees from Zoll Circulation Inc and has ownership interests in MRI International Inc and IMRICOR Medical Systems Inc. Dr Calkins received honoraria from Biosense Webster Inc and Medtronic Inc. Dr Berger received research grants from St Jude Medical Inc and Medtronic Inc and consultant fees from Boston Scientific Corp and Cameron Health Inc. The Johns Hopkins University Conflict of Interest Committee manages all commercial arrangements. NR 28 TC 30 Z9 34 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD NOV PY 2011 VL 4 IS 6 BP 662 EP U104 DI 10.1161/CIRCIMAGING.111.965764 PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 850AZ UT WOS:000297168100011 PM 21946701 ER PT J AU Payne, AR Berry, C Kellman, P Anderson, R Hsu, LY Chen, MY McPhaden, AR Watkins, S Schenke, W Wright, V Lederman, RJ Aletras, AH Arai, AE AF Payne, Alexander R. Berry, Colin Kellman, Peter Anderson, Rachel Hsu, Li-Yueh Chen, Marcus Y. McPhaden, Allan R. Watkins, Stuart Schenke, William Wright, Victor Lederman, Robert J. Aletras, Anthony H. Arai, Andrew E. TI Bright-Blood T-2-Weighted MRI Has High Diagnostic Accuracy for Myocardial Hemorrhage in Myocardial Infarction A Preclinical Validation Study in Swine SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE myocardial infarction; MRI; hemorrhage ID CARDIAC MAGNETIC-RESONANCE; AUTOMATED FEATURE ANALYSIS; DELAYED ENHANCEMENT MRI; IRON OVERLOAD; INVERSION-RECOVERY; SIZING ALGORITHM; 1.5 T; REPERFUSION; THALASSEMIA; RISK AB Background-Myocardial hemorrhage after myocardial infarction (MI) usually goes undetected. We investigated the diagnostic accuracy of bright-blood T-2-weighted cardiac MRI for myocardial hemorrhage in experimental MI. Methods and Results-MI was created in swine by occluding the left anterior descending (n=10) or circumflex (n=5) coronary arteries for 90 minutes followed by reperfusion for <3 days (n=2), 10 days (n=7), or 60 days (n=6). MRI was performed at 1.5 T, using bright-blood T-2-prepared steady-state free-precession, T-2* and early (1 minute) and late (10-15 minutes) gadolinium enhancement (EGE, LGE, respectively) MRI. Left ventricular sections and histology were assessed for hemorrhage by an experienced cardiac pathologist blinded to the MRI data. Hypointense regions on T-2-weighted and contrast-enhanced MRI were independently determined by 3 cardiologists experienced in MRI who were also blinded to the pathology results. Eighty ventricular pathological sections were matched with MRI (n=68 for EGE MRI). All sections with evidence of MI (n=63, 79%) also exhibited hyperintense zones consistent with edema on T-2-weighted MRI and infarct on LGE MRI. Myocardial hemorrhage occurred in 49 left ventricular sections (61%) and corresponded with signal voids on 48 T-2-weighted (98%) and 26 LGE-MRI (53%). Alternatively, signal voids occurred in the absence of hemorrhage in 3 T-2-weighted (90% specificity) and 5 LGE MRI (84% specificity). On EGE MRI, 27 of 43 cases of early microvascular obstruction corresponded with hemorrhage (63% sensitivity), whereas 5 of 25 defects occurred in the absence of hemorrhage (80% specificity). The positive and negative predictive values for pathological evidence of hemorrhage were 94% and 96% for T-2-weighted, 84% and 55% for LGE MRI, and 85% and 56% for EGE MRI. Conclusions-Bright-blood T-2-weighted MRI has high diagnostic accuracy for myocardial hemorrhage. (Circ Cardiovasc Imaging. 2011;4:738-745.) C1 [Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Payne, Alexander R.; Berry, Colin; McPhaden, Allan R.; Watkins, Stuart] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, DHHS, Bldg 10,Room B1D 416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov OI Aletras, Anthony/0000-0002-3786-3817 FU Division of Intramural Research of the National Institutes of Health [Z01-HL004607-12, Z01-HL005062-08]; Chief Scientist Office, Scotland; Scottish Funding Council FX This research was funded by the Division of Intramural Research of the National Institutes of Health (Z01-HL004607-12 to Dr Arai; Z01-HL005062-08 to Dr Lederman). Dr Payne was supported by a project grant from the Chief Scientist Office, Scotland. Professor Berry is employed in the Institute of Cardiovascular and Medical Sciences, University of Glasgow, and holds a Senior Clinical Fellowship from the Scottish Funding Council. NR 27 TC 25 Z9 27 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD NOV PY 2011 VL 4 IS 6 BP 738 EP 745 DI 10.1161/CIRCIMAGING.111.965095 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 850AZ UT WOS:000297168100020 PM 21930836 ER PT J AU Kanbe, K Chen, Q Nakamura, A Hobo, K AF Kanbe, Katsuaki Chen, Qian Nakamura, Atsushi Hobo, Kaori TI Inhibition of MAP kinase in synovium by treatment with tocilizumab in rheumatoid arthritis SO CLINICAL RHEUMATOLOGY LA English DT Article DE Histology; MAPK; Rheumatoid arthritis; Synovium; Tocilizumab ID DOUBLE-BLIND; INTERLEUKIN-6; EFFICACY; SAFETY AB To investigate the histological changes of mitogen-activated protein kinase (MAPK) in synovium with tocilizumab in rheumatoid arthritis (RA), synovial tissue samples were assessed from ten methotrexate (MTX)-treated RA patients for control and ten tocilizumab with MTX-treated RA patients. The synovium was observed using hematoxylin and eosin (H&E) stain and analyzed immunohistochemically for the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cell), CD20 (B cell), CD68 (macrophage), vascular endothelial growth factor (VEGF), CD29 (beta-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK [extracellular signal-regulated kinase (ERK) 1/ERK2], and phospho-c-Jun N-terminal kinase (JNK). H&E staining showed that there is a significant difference of cell proliferation; however, there is no change of hypervascularity in the synovium between both groups. An immunohistochemical examination showed that the decrease of CD29 (beta-1 integrin) and JNK was found significant, while ERK was increased in the tocilizumab group. CD20, B-lymphocyte, was decreased in the tocilizumab group compared with the MTX group significantly. IL-6 was completely blocked in the patients who received tocilizumab. TNF-alpha was similarly expressed in the interstitial cells of synovium of patients in both groups. MMP-3 and CD68 were similarly expressed on the surface of synovium. VEGF was less expressed in both groups. These findings indicate that the inhibition of CD20, CD29, and JNK in MAPK may be involved in the efficacy of tocilizumab compared with MTX treatment in RA. C1 [Kanbe, Katsuaki; Nakamura, Atsushi; Hobo, Kaori] Tokyo Womens Med Univ, Dept Orthopaed Surg, Med Ctr E, Arakawa, Tokyo 1168567, Japan. [Chen, Qian] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Orthopaed,NIH Ctr Biomed Res Excellence Skel, Providence, RI 02903 USA. RP Kanbe, K (reprint author), Tokyo Womens Med Univ, Dept Orthopaed Surg, Med Ctr E, 2-1-10 Nishiogu, Arakawa, Tokyo 1168567, Japan. EM kanbeor@dnh.twmu.ac.jp RI Chen, Qian/C-4354-2011 OI Chen, Qian/0000-0003-4406-5618 NR 14 TC 11 Z9 11 U1 1 U2 2 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0770-3198 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD NOV PY 2011 VL 30 IS 11 BP 1407 EP 1413 DI 10.1007/s10067-011-1833-z PG 7 WC Rheumatology SC Rheumatology GA 850NK UT WOS:000297201300003 PM 21909699 ER PT J AU Miura, S Mishina, Y AF Miura, Shigeto Mishina, Yuji TI Hepatocyte Growth Factor-Regulated Tyrosine Kinase Substrate (Hgs) Is Involved in BMP Signaling Through Phosphorylation of SMADs and TAK1 in Early Mouse Embryo SO DEVELOPMENTAL DYNAMICS LA English DT Article DE gastrulation; signal transduction; endosome ID EARLY ENDOSOMES; MESODERM FORMATION; MAMMALIAN EMBRYO; FYVE DOMAIN; STEM-CELLS; IN-VITRO; KAPPA-B; RECEPTOR; PROTEIN; HRS AB Hepatocyte growth factor-regulated tyrosine kinase substrate that is encoded by Hgs promotes degradation of ubiquitinated signaling molecule in the early endosome. We previously reported that a targeted mutation in Hgs results in embryonic lethality soon after gastrulation in the mouse. Here, we report that downstream target genes for BMP signaling were highly down-regulated in the Hgs mutant embryos. We also showed that Hgs is required for phosphorylation of SMAD1/5/8 and TAK1/p38 to transduce BMP signaling. Furthermore, we found that HGS functions to localize TAK1 in early endosome for its activation. These results suggest that HGS is critical to localize TAK1 to early endosome for transducing BMP signaling for proper development. Our data revealed a new mechanism to modify BMP signaling by Hgs during early mouse development. Developmental Dynamics 240: 2474-2481, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Miura, Shigeto; Mishina, Yuji] Natl Inst Environm Hlth Sci, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC USA. RP Mishina, Y (reprint author), Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. EM mishina@umich.edu FU National Institute of Environmental Health Sciences [ES071003-11] FX Grant sponsor: Intramural Research Program of the National Institute of Environmental Health Sciences; Grant number: ES071003-11. NR 47 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD NOV PY 2011 VL 240 IS 11 BP 2474 EP 2481 DI 10.1002/dvdy.22750 PG 8 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 847KL UT WOS:000296971700007 PM 21953618 ER PT J AU Behl, M Nyska, A Chhabra, RS Travlos, GS Fomby, LM Sparrow, BR Hejtmancik, MR Chan, PC AF Behl, Mamta Nyska, Abraham Chhabra, Rajendra S. Travlos, Gregory S. Fomby, Laurene M. Sparrow, Barney R. Hejtmancik, Milton R. Chan, Po C. TI Liver toxicity and carcinogenicity in F344/N rats and B6C3F1 mice exposed to Kava Kaya SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Kaya; Gavage; Liver; Toxicity; Rats; Mice ID FULMINANT HEPATIC-FAILURE; HERB-DRUG INTERACTIONS; ZERO-DOSE CONTROL; PIPER-METHYSTICUM; NATURAL THERAPY; SAFETY CONCERNS; ORAL TREATMENT; CYTOCHROME-P450; EXTRACT; HEPATOTOXICITY AB Kava Kava is an herbal supplement used as an alternative to antianxiety drugs. Although some reports suggest an association of Kaya Kava with hepatotoxicity, it continues to be used in the United States due to lack of toxicity characterization. In these studies F344/N rats and B6C3F1 mice were administered Kava Kava extract orally by gavage in corn oil for two weeks, thirteen weeks or two years. Results from prechronic studies administered Kava Kava at 0.125 to 2 g/kg body weight revealed dose-related increases in liver weights and incidences of hepatocellular hypertrophy. In the chronic studies, there were dose-related increases in the incidences of hepatocellular hypertrophy in rats and mice administered Kava Kava for up to 1 g/kg body weight. This was accompanied by significant increases in incidences of centrilobular fatty change. There was no treatment- related increase in carcinogenic activity in the livers of male or female rats in the chronic studies. Male mice showed a significant dose-related increase in the incidence of hepatoblastomas. In female mice, there was a significant increase in the combined incidence of hepatocellular adenoma and carcinoma in the low and mid dose groups but not in the high dose group. These findings were accompanied by several nonneoplastic hepatic lesions. Published by Elsevier Ltd. C1 [Behl, Mamta; Chhabra, Rajendra S.; Travlos, Gregory S.; Chan, Po C.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Nyska, Abraham] Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. [Fomby, Laurene M.; Sparrow, Barney R.; Hejtmancik, Milton R.] Battelle Mem Inst, Columbus, OH 43201 USA. RP Chhabra, RS (reprint author), NIEHS, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM chhabrar@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences [IZIAES045004-14] FX We thank Drs. Matthew Stout and Michelle Hooth, NTP/NIEHS for their helpful review of this manuscript and Dr. Peter Fu, NCTR, for his input during the planning of these studies. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences under Research Project Number IZIAES045004-14. NR 92 TC 4 Z9 5 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD NOV PY 2011 VL 49 IS 11 BP 2820 EP 2829 DI 10.1016/j.fct.2011.07.067 PG 10 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 843OM UT WOS:000296681600013 PM 21871523 ER PT J AU Yeung, ML Jeang, KT AF Yeung, Man Lung Jeang, Kuan-Teh TI Roles of miRNAs in virus-mediated cellular transformation: lessons from human T-cell leukemia virus type 1 SO FUTURE VIROLOGY LA English DT Review DE antagomir; ATL; cancer; HTLV-1; miRNA; RNAi; Tax ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MICRORNA EXPRESSION PROFILES; SMALL NONCODING RNAS; HEPATITIS-C VIRUS; NUCLEAR-PROTEIN 1; ENCODED MICRORNAS; MESSENGER-RNA; GENE-EXPRESSION; TUMOR-SUPPRESSOR; TRANSLATIONAL REPRESSION AB miRNAs are small noncoding RNAs of similar to 18-25 nucleotides that contribute to the regulation of a diverse variety of biological pathways. Perturbed miRNA expression is seen in many diseases, including cancers. Here, we first discuss the oncogenic and tumor suppressor roles of miRNA, including the roles played by miRNAs in the replication of some oncogenic viruses. Next, using human T-cell leukemia virus type 1 as an example, we discuss the contributions of virus-induced miRNAs in human T-cell leukemia virus type 1-transformation of human cells. Finally, we briefly survey the therapeutic potential of miRNA mimics or anti-miRNAs, antagomirs, to reverse cancer phenotypes. C1 [Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Yeung, Man Lung] Univ Hong Kong, State Key Lab Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China. [Yeung, Man Lung] Univ Hong Kong, Res Ctr Infect & Immunol, Hong Kong, Hong Kong, Peoples R China. [Yeung, Man Lung] Univ Hong Kong, Dept Microbiol, Hong Kong, Hong Kong, Peoples R China. [Yeung, Man Lung] Univ Hong Kong, Carol Yu Ctr Infect, Hong Kong, Hong Kong, Peoples R China. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 138 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0794 J9 FUTURE VIROL JI Future Virol. PD NOV PY 2011 VL 6 IS 11 BP 1351 EP 1360 DI 10.2217/FVL.11.109 PG 10 WC Virology SC Virology GA 850SO UT WOS:000297219000013 ER PT J AU Rahimi, Z Nourozi-Rad, R Vaisi-Raygani, A Saidi, MR Rahimi, Z Ahmadi, R Yarani, R Hamzehee, K Parsian, A AF Rahimi, Zohreh Nourozi-Rad, Reza Vaisi-Raygani, Asad Saidi, Mohammad-Reza Rahimi, Ziba Ahmadi, Reza Yarani, Reza Hamzehee, Koorosh Parsian, Abbas TI Association Between Cholesteryl Ester Transfer Protein TaqIB Variants and Risk of Coronary Artery Disease and Diabetes Mellitus in the Population of Western Iran SO GENETIC TESTING AND MOLECULAR BIOMARKERS LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; FUTURE CARDIOVASCULAR DEATH; TURKISH POPULATION; GENE POLYMORPHISM; JAPANESE PATIENTS; APOLIPOPROTEIN-E; HEART-DISEASE; CETP; ATHEROSCLEROSIS; PREVALENCE AB Aims: To shed light on the previously inconsistent results about the association of cholesteryl ester transfer protein TaqIB (CETP TaqIB) variants, high-density lipoprotein cholesterol (HDL-C) levels, and the risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). Methods: To determine the frequency of CETP TaqIB variants and to examine the possible association between CETP TaqIB polymorphism with CAD and T2DM, we studied 207 unrelated patients with CAD, 101 patients with T2DM, and 92 controls. The CETP TaqIB variants were detected by polymerase chain reaction-restriction fragment length polymorphism. Results: Logistic regression analysis indicated that the B1 allele of CETP was significantly associated with increased risk of CAD (odds ratio, OR 1.65 [95% confidence interval, CI 1.2-2.3, p = 0.005]) and T2DM (OR 1.7 [95% CI 1.13-2.54, p = 0.005]). Adjusted logistic regression analysis for the effects of age, sex, hypertension, diabetes, and hyperlipidemia was performed; and a significant association was found between the B1 allele and risk of CAD (OR 1.9 [95% CI 1-3.6, p = 0.049]) in patients with CAD. There were no associations between the CETP alleles and the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, and HDL-C in studied groups. Conclusions: The results of the present study revealed that the CETP B1 allele is associated with increased risk of CAD and T2DM independent of plasma HDL-C level in our population. C1 [Rahimi, Zohreh] Kermanshah Univ Med Sci, Med Biol Res Ctr, Sch Med, Kermanshah 6714869914, Iran. [Rahimi, Zohreh; Nourozi-Rad, Reza; Vaisi-Raygani, Asad; Ahmadi, Reza] Kermanshah Univ Med Sci, Dept Biochem, Sch Med, Kermanshah 6714869914, Iran. [Saidi, Mohammad-Reza] Kermanshah Univ Med Sci, Dept Cardiol, Sch Med, Kermanshah 6714869914, Iran. [Parsian, Abbas] NIAAA, Div Neurosci & Behav, NIH, Rockville, MD 20852 USA. RP Rahimi, Z (reprint author), Kermanshah Univ Med Sci, Med Biol Res Ctr, Sch Med, Daneshgah Ave, Kermanshah 6714869914, Iran. EM zrahimi@kums.ac.ir; zrahimi@kums.ac.ir RI Norouzirad, Reza/L-7475-2015; OI Norouzirad, Reza/0000-0002-5046-057X; Saidi, Mohammad Reza/0000-0003-4570-5314; Rahimi, Zohreh/0000-0001-7589-3307; Vaisi-Raygani, Asad/0000-0002-3042-2832 FU Kermanshah University of Medical Sciences, Kermanshah, Iran FX This work was financially supported by a grant from Vice Chancellor for Research of Kermanshah University of Medical Sciences, Kermanshah, Iran. NR 28 TC 4 Z9 5 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1945-0265 J9 GENET TEST MOL BIOMA JI Genet. Test. Mol. Biomark. PD NOV PY 2011 VL 15 IS 11 BP 813 EP 819 DI 10.1089/gtmb.2011.0037 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 851JE UT WOS:000297263500012 PM 21689002 ER PT J AU Kaufmann, SH Karp, JE Litzow, MR Mesa, RA Hogan, W Steensma, DP Flatten, KS Loegering, DA Schneider, PA Peterson, KL Maurer, MJ Smith, BD Greer, J Chen, YH Reid, JM Ivy, SP Ames, MM Adjei, AA Erlichman, C Karnitz, LM AF Kaufmann, Scott H. Karp, Judith E. Litzow, Mark R. Mesa, Ruben A. Hogan, William Steensma, David P. Flatten, Karen S. Loegering, David A. Schneider, Paula A. Peterson, Kevin L. Maurer, Matthew J. Smith, B. Douglas Greer, Jacqueline Chen, Yuhong Reid, Joel M. Ivy, S. Percy Ames, Matthew M. Adjei, Alex A. Erlichman, Charles Karnitz, Larry M. TI Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE cytarabine; tanespimycin; phase I study; pharmacological study; acute leukemia ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; BCR-ABL; HEAT-SHOCK-PROTEIN-90 INHIBITION; KINASE INHIBITOR; TARGETING HSP90; DOWN-REGULATION; HUMAN CHK1; CELLS; PROTEIN AB Background In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and Methods Patients received cytarabine 400 mg/m(2)/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. Results Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m(2)/day for 5 days along with tanespimycin 300 mg/m(2) on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. Conclusions Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. C1 [Kaufmann, Scott H.; Litzow, Mark R.; Mesa, Ruben A.; Hogan, William; Steensma, David P.] Mayo Clin, Coll Med, Dept Med, Div Hematol, Rochester, MN 55905 USA. [Kaufmann, Scott H.; Flatten, Karen S.; Loegering, David A.; Schneider, Paula A.; Peterson, Kevin L.; Chen, Yuhong; Reid, Joel M.; Ames, Matthew M.; Karnitz, Larry M.] Mayo Clin, Coll Med, Dept Oncol, Div Oncol Res, Rochester, MN 55905 USA. [Adjei, Alex A.; Erlichman, Charles] Mayo Clin, Coll Med, Dept Oncol, Div Med Oncol, Rochester, MN 55905 USA. [Maurer, Matthew J.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Karp, Judith E.; Smith, B. Douglas; Greer, Jacqueline] Sidney Kimmel Canc Ctr Johns Hopkins, Div Hematol Malignancies, Baltimore, MD USA. [Ivy, S. Percy] NCI, Invest Drug Branch, Canc Treatment Evaluat Program, Rockville, MD USA. RP Kaufmann, SH (reprint author), Mayo Clin, Coll Med, Dept Med, Div Hematol, Gonda 19-212,200 1st St SW, Rochester, MN 55905 USA. EM kaufmann.scott@mayo.edu OI Steensma, David/0000-0001-5130-9284 FU National Center for Research Resources [M01 RR0052]; General Clinical Research Center; Leukemia & Lymphoma Society of America; [U01 CA69912]; [U01 CA70095]; [P30 CA06973] FX this work was supported in part by U01 CA69912 (to CE), U01 CA70095 (to JEK), P30 CA06973 (JEK, BDS), National Center for Research Resources grant M01 RR0052 supporting the Johns Hopkins University School of Medicine, General Clinical Research Center, and a Translational Research Grant from the Leukemia & Lymphoma Society of America (to SHK, JEK, and LMK). NR 47 TC 21 Z9 21 U1 0 U2 3 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD NOV PY 2011 VL 96 IS 11 BP 1619 EP 1626 DI 10.3324/haematol.2011.049551 PG 8 WC Hematology SC Hematology GA 851BR UT WOS:000297243800011 PM 21791475 ER PT J AU Lee, J Romero, R Dong, Z Xu, Y Qureshi, F Jacques, S Yoo, W Chaiworapongsa, T Mittal, P Hassan, SS Kim, CJ AF Lee, JoonHo Romero, Roberto Dong, Zhong Xu, Yi Qureshi, Faisal Jacques, Suzanne Yoo, Wonsuk Chaiworapongsa, Tinnakorn Mittal, Pooja Hassan, Sonia S. Kim, Chong Jai TI Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies SO HISTOPATHOLOGY LA English DT Article DE amniotic fluid; CXCL10; panel-reactive antibody; placenta; pregnancy ID PLACENTAL REACTION PATTERNS; PRETRANSPLANT SERUM CXCL10; UNKNOWN ETIOLOGY; NEONATAL THROMBOCYTOPENIA; ANGIOGENIC FACTORS; ENDOTHELIAL-CELLS; PREDICTIVE ROLE; HLA ANTIBODIES; STILLBIRTH; COMPLEMENT AB Aims: Chronic chorioamnionitis is a histological manifestation of maternal anti-fetal cellular rejection. As failure of graft survival is the most catastrophic event in organ transplantation, we hypothesized that fetal death could be a consequence of maternal rejection. The aim of this study was to assess whether there is evidence of cellular and antibody-mediated rejection in fetal death. Methods and results: Placental histology was reviewed for the presence of chronic chorioamnionitis in unexplained preterm fetal death (n = 30) and preterm live birth (n = 103). Amniotic fluid CXCL10 concentrations were measured with a specific immunoassay. Chronic chorioamnionitis was more frequent in fetal death than in live birth (60.0% versus 37.9%; P < 0.05) and fetal death had a higher median amniotic fluid CXCL10 concentration than live birth (2.0 versus 1.8 ng/ml, P < 0.05), after adjusting for gestational age at amniocentesis. Maternal anti- human leucocyte antigen class II panelreactive seropositivity determined by flow cytometry was higher in fetal death compared to live birth (35.7% versus 10.9%; P < 0.05). Conclusions: Chronic chorioamnionitis is a common pathologic feature in unexplained preterm fetal death. This novel finding suggests that cellular and antibodymediated anti- fetal rejection of the mother is associated with fetal death (graft failure) in human pregnancy. C1 [Romero, Roberto; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Yoo, Wonsuk] Wayne State Univ, Sch Med, Dept Internal Med, Detroit, MI 48201 USA. [Lee, JoonHo; Romero, Roberto; Dong, Zhong; Xu, Yi; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Hassan, Sonia S.; Kim, Chong Jai] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RP Kim, CJ (reprint author), Wayne State Univ, Sch Med, Dept Pathol, Hutzel Womens Hosp, 3990 John R St, Detroit, MI 48201 USA. EM cjkim@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This work was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 52 TC 22 Z9 24 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 J9 HISTOPATHOLOGY JI Histopathology PD NOV PY 2011 VL 59 IS 5 BP 928 EP 938 DI 10.1111/j.1365-2559.2011.04038.x PG 11 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 851CC UT WOS:000297244900014 PM 22092404 ER PT J AU Jager, J AF Jager, Justin TI Convergence and nonconvergence in the quality of adolescent relationships and its association with adolescent adjustment and young-adult relationship quality SO INTERNATIONAL JOURNAL OF BEHAVIORAL DEVELOPMENT LA English DT Article DE adolescent development; latent class analysis; relationship quality; social capital ID ROMANTIC RELATIONSHIPS; FRIENDS; PARTNERS; COMPETENCE; NETWORKS; MIXTURE; PARENTS; MOTHERS; STYLES; NUMBER AB With the aim of identifying and examining both convergence (matched relationship quality across one's set of relationships) and nonconvergence (mixed relationship quality across one's set of relationships), the present study used a pattern-centered approach to examine the different ways adolescent relationships pattern together among a large, national sample of U.S. adolescents (aged 13-19). The study also examined how adolescent adjustment and young-adult relationship quality varied across the different relationship patterns or constellations. The current study used latent class analysis and data from Add Health (n = 4,233), a national U.S. longitudinal study that spans adolescence and young adulthood, to uncover heterogeneity in adolescent relations with parents, friends, romantic partners, peers, and teachers. As predicted, patterns of both convergence and nonconvergence were found, though patterns of nonconvergence were more common than expected. Some patterns of nonconvergence appear more stable (i.e., similar pattern found during both adolescence and young adulthood) than others. Also, no "high" converging pattern was found, indicating that few adolescents have "first-rate" relations in every relational domain. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Jager, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM jagerjo@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 42 TC 4 Z9 4 U1 0 U2 8 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0165-0254 J9 INT J BEHAV DEV JI Int. J. Behav. Dev. PD NOV PY 2011 VL 35 IS 6 BP 497 EP 506 DI 10.1177/0165025411422992 PG 10 WC Psychology, Developmental SC Psychology GA 851ZV UT WOS:000297312300005 PM 22334764 ER PT J AU Yang, JD Seol, SY Leem, SH Kim, YH Sun, ZF Lee, JS Thorgeirsson, SS Chu, IS Roberts, LR Kang, KJ AF Yang, Ju Dong Seol, So-Young Leem, Sun-Hee Kim, Yong Hoon Sun, Zhifu Lee, Ju-Seog Thorgeirsson, Snorri S. Chu, In-Sun Roberts, Lewis R. Kang, Koo Jeong TI Genes Associated with Recurrence of Hepatocellular Carcinoma: Integrated Analysis by Gene Expression and Methylation Profiling SO JOURNAL OF KOREAN MEDICAL SCIENCE LA English DT Article DE Carcinoma; Hepatocellular; Gene Expression Profiling; Microarray analysis; DNA methylation; Survival ID DNA METHYLATION; BREAST-CANCER; TARGET DDA3; CYTOGLOBIN; DAMAGE; CELLS; P53; AUTOPHAGY; INTERACTS; FIBROSIS AB Gene expression is suppressed by DNA methylation. The goal of this study was to identify genes whose CpG site methylation and mRNA expression are associated with recurrence after surgical resection for hepatocellular carcinoma (HCC). Sixty-two HCCs were examined by both whole genome DNA methylation and transcriptome analysis. The Cox model was used to select genes associated with recurrence. A validation was performed in an independent cohort of 66 HCC patients. Among fifty-nine common genes, increased CpG site methylation and decreased mRNA expression were associated with recurrence for 12 genes (Group A), whereas decreased CpG site methylation and increased mRNA expression were associated with recurrence for 25 genes (Group B). The remaining 22 genes were defined as Group C. Complement factor H (CFH) and myosin VIIA and Rab interacting protein (MYRIP) in Group A; proline/serine-rich coiled-coil 1 (PSRC1), meiotic recombination 11 homolog A (MRE11A), and myosin IE (MYO1E) in Group B; and autophagy-related protein LC3 A (MAP1LC3A), and NADH dehydrogenase 1 alpha subcomplex assembly factor 1 (NDUFAF1) in Group C were validated. In conclusion, potential tumor suppressor (CFH, MYRIP) and oncogenes (PSRC1, MRE11A, MYO1E) in HCC are reported. The regulation of individual genes by methylation in hepatocarcinogenesis needs to be validated. C1 [Kang, Koo Jeong] Keimyung Univ, Dong San Med Ctr, Dept Surg, Sch Med, Taegu 700712, South Korea. [Yang, Ju Dong; Roberts, Lewis R.; Kang, Koo Jeong] Mayo Clin, Coll Med, Miles & Shirley Fiterman Ctr Digest Dis, Rochester, MN USA. [Seol, So-Young; Leem, Sun-Hee] Dong A Univ, Dept Biol Sci, Pusan, South Korea. [Sun, Zhifu] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Rochester, MN USA. [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. [Chu, In-Sun] Korea Res Inst Biosci & Biotechnol, Korean Bioinformat Ctr, Taejon, South Korea. RP Kang, KJ (reprint author), Keimyung Univ, Dong San Med Ctr, Dept Surg, Sch Med, 56 Dalseong Ro, Taegu 700712, South Korea. EM kjkang@dsmc.or.kr OI Sun, Zhifu/0000-0001-8461-7523; Roberts, Lewis/0000-0001-7885-8574 FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology (MEST), Republic of Korea [2009-0063260]; KRIBB; Shared Research Equipment Assistance Program; Korea Basic Science Institute; MEST; NIH [CA100882, CA128633] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea (2009-0063260, S.-H. L.) and the intramural program of KRIBB (I.-S.C.). Microarray study was supported by Shared Research Equipment Assistance Program (S.-H. L.) by Korea Basic Science Institute, MEST, and NIH grants CA100882 and CA128633 (to LRR). NR 30 TC 15 Z9 16 U1 1 U2 8 PU KOREAN ACAD MEDICAL SCIENCES PI SEOUL PA 302 75 DONG DU ICHON, DONG YONGSAN KU, SEOUL 140 031, SOUTH KOREA SN 1011-8934 J9 J KOREAN MED SCI JI J. Korean Med. Sci. PD NOV PY 2011 VL 26 IS 11 BP 1428 EP 1438 DI 10.3346/jkms.2011.26.11.1428 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 851BF UT WOS:000297242600005 PM 22065898 ER PT J AU Liu, L Chen, C Gong, W Li, YJ Edin, ML Zeldin, DC Wang, DW AF Liu, Liu Chen, Chen Gong, Wei Li, Yuanjing Edin, Matthew L. Zeldin, Darryl C. Wang, Dao Wen TI Epoxyeicosatrienoic Acids Attenuate Reactive Oxygen Species Level, Mitochondrial Dysfunction, Caspase Activation, and Apoptosis in Carcinoma Cells Treated with Arsenic Trioxide SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; EPOXYGENASE-DERIVED EICOSANOIDS; PROTEIN-KINASE PATHWAY; CERVICAL-CANCER CELLS; SIGNALING PATHWAYS; ENDOTHELIAL-CELLS; OXIDATIVE STRESS; P38 MAPK; DEATH; ROS AB Epoxyeicosatrienoic acids (EETs) and the cytochrome P450 epoxygenase CYP2J2 promote tumorogenesis in vivo and in vitro via direct stimulation of tumor cell growth and inhibition of tumor cell apoptosis. Herein, we describe a novel mechanism of inhibition of tumor cell apoptosis by EETs. In Tca-8113 cancer cells, the antileukemia drug arsenic trioxide (ATO) led to the generation of reactive oxygen species (ROS), impaired mitochondrial function, and induced apoptosis. 11,12-EET pretreatment increased expression of the antioxidant enzymes superoxide dismutase and catalase and inhibited ATO-induced apoptosis. 11,12-EET also prevented the ATO-induced activation of p38 mitogen-activated protein kinase, c-Jun NH(2)-terminal kinase, caspase-3, and caspase-9. Therefore, 11,12-EET-pretreatment attenuated the ROS generation, loss of mitochondrial function, and caspase activation observed after ATO treatment. Moreover, the CYP2J2-specific inhibitor compound 26 enhanced arsenic cytotoxicity to a clinically relevant concentration of ATO (1-2 mu M). Both the thiol-containing antioxidant, N-acetyl-cysteine, and 11,12-EET reversed the synergistic effect of the two agents. Taken together, these data indicate that 11,12-EET inhibits apoptosis induced by ATO through a mechanism that involves induction of antioxidant proteins and attenuation of ROS-mediated mitochondrial dysfunction. C1 [Liu, Liu; Chen, Chen; Gong, Wei; Li, Yuanjing; Wang, Dao Wen] Huazhong Univ Sci & Technol, Dept Internal Med, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Peoples R China. [Liu, Liu; Chen, Chen; Gong, Wei; Li, Yuanjing; Wang, Dao Wen] Huazhong Univ Sci & Technol, Gene Therapy Ctr, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Peoples R China. [Edin, Matthew L.; Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Dept Internal Med, Tongji Hosp, Tongji Med Coll, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.cn OI Edin, Matthew/0000-0002-7042-500X FU China Natural Science Foundation Committee [30700377, 30770882, 30430320]; 973 Project [2007 CB512004]; National Institutes of Health National Institute of Environmental Health Sciences [Z01-ES025034] FX This work was supported by the China Natural Science Foundation Committee [Grants 30700377, 30770882, 30430320]; the 973 Project [Grant 2007 CB512004]; and the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01-ES025034]. NR 44 TC 34 Z9 37 U1 2 U2 8 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 NOV PY 2011 VL 339 IS 2 BP 451 EP 463 DI 10.1124/jpet.111.180505 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 840TS UT WOS:000296464800015 PM 21846841 ER PT J AU Uehara, S Murayama, N Nakanishi, Y Zeldin, DC Yamazaki, H Uno, Y AF Uehara, Shotaro Murayama, Norie Nakanishi, Yasuharu Zeldin, Darryl C. Yamazaki, Hiroshi Uno, Yasuhiro TI Immunochemical Detection of Cytochrome P450 Enzymes in Liver Microsomes of 27 Cynomolgus Monkeys SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DRUG-METABOLISM; MACACA-FASCICULARIS; IN-VITRO; RHESUS-MONKEY; PHASE-I; EXPRESSION; IDENTIFICATION; CYP2C76; HUMANS; POLYMORPHISMS AB The cynomolgus monkey is widely used as a primate model in preclinical studies because of its evolutionary closeness to humans. Despite their importance in drug metabolism, the content of each cytochrome P450 (P450) enzyme has not been systematically determined in cynomolgus monkey livers. In this study, liver microsomes of 27 cynomolgus monkeys were analyzed by immunoblotting using selective P450 antibodies. The specificity of each antibody was confirmed by analyzing the cross-reactivity against 19 CYP1-3 subfamily enzymes using recombinant proteins. CYP2A, CYP2B6, CYP2C9/19, CYP2C76, CYP2D, CYP2E, CYP3A4, and CYP3A5 were detected in all 27 animals. In contrast, CYP1A, CYP1D, and CYP2J were below detectable levels in all liver samples. The average content of each P450 showed that among the P450s analyzed CYP3A (3A4 and 3A5) was the most abundant (40% of total immunoquantified P450), followed by CYP2A (25%), CYP2C (14%), CYP2B6 (13%), CYP2E1 (11%), and CYP2D (3%). No apparent sex differences were found for any P450. Interanimal variations ranged from 2.6-fold (CYP3A) to 11-fold (CYP2C9/19), and most P450s (CYP2A, CYP2D, CYP2E, CYP3A4, and CYP3A5) varied 3- to 4-fold. To examine the correlations of P450 content with enzyme activities, metabolic assays were performed in 27 cynomolgus monkey livers using 7-ethoxyresorufin, coumarin, pentoxyresorufin, flurbiprofen, bufuralol, dextromethorphan, and midazolam. CYP2D and CYP3A4 contents were significantly correlated with typical reactions of human CYP2D (bufuralol 1'-hydroxylation and dextromethorphan O-deethylation) and CYP3A (midazolam 1'-hydroxylation and 4-hydroxylation). The results presented in this study provide useful information for drug metabolism studies using cynomolgus monkeys. C1 [Uno, Yasuhiro] Shin Nippon Biomed Labs Ltd, Genome Res Grp, Pharmacokinet & Bioanal Ctr, Wakayama 6420017, Japan. [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, Res Triangle Pk, NC USA. [Murayama, Norie; Yamazaki, Hiroshi] Showa Pharmaceut Univ, Lab Drug Metab & Pharmacokinet, Tokyo, Japan. RP Uno, Y (reprint author), Shin Nippon Biomed Labs Ltd, Genome Res Grp, Pharmacokinet & Bioanal Ctr, 16-1 Minami Akasaka, Wakayama 6420017, Japan. EM uno-yasuhiro@snbl.co.jp OI Yamazaki, Hiroshi/0000-0002-1068-4261 FU National Institutes of Health National Institute of Environmental Health Sciences FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences. NR 47 TC 28 Z9 28 U1 0 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 NOV PY 2011 VL 339 IS 2 BP 654 EP 661 DI 10.1124/jpet.111.185009 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 840TS UT WOS:000296464800035 PM 21849623 ER PT J AU Hiranita, T Soto, PL Kohut, SJ Kopajtic, T Cao, JJ Newman, AH Tanda, G Katz, JL AF Hiranita, Takato Soto, Paul L. Kohut, Stephen J. Kopajtic, Theresa Cao, Jianjing Newman, Amy H. Tanda, Gianluigi Katz, Jonathan L. TI Decreases in Cocaine Self-Administration with Dual Inhibition of the Dopamine Transporter and sigma Receptors SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CONDITIONED PLACE PREFERENCE; RIMCAZOLE ANALOGS; RAT; BINDING; AGONISTS; LIGANDS; ALTERS; DRUG; SIGMA(1)-RECEPTORS; CONFORMATION AB Sigma receptor (sigma R) antagonists attenuate many behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the sigma R antagonist rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl] diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of sigma R antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100)] had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective sigma R antagonists in their dual affinities for sigma Rs and the dopamine transporter (DAT) assessed with radio-ligand binding. Selective DAT inhibitors and sigma R antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both sigma Rs and the DAT were sufficient to reproduce the effects of rimcazole analogs. Typical DAT inhibitors [2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and sigma R antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical sigma R antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the unique effects of rimcazole analogs are due to dual actions at the DAT and sigma Rs and that a combined target approach may have utility in development of medical treatments for cocaine abuse. C1 [Hiranita, Takato; Soto, Paul L.; Kohut, Stephen J.; Kopajtic, Theresa; Tanda, Gianluigi; Katz, Jonathan L.] Natl Inst Drug Abuse, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. [Cao, Jianjing; Newman, Amy H.] Natl Inst Drug Abuse, Med Chem Sect, Medicat Discovery Res Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. [Hiranita, Takato] NIH, Bethesda, MD 20892 USA. RP Katz, JL (reprint author), Natl Inst Drug Abuse, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov RI Hiranita, Takato/G-6567-2011; Tanda, Gianluigi/B-3318-2009 OI Tanda, Gianluigi/0000-0001-9526-9878 FU National Institutes of Health National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse. NR 41 TC 25 Z9 26 U1 0 U2 6 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 NOV PY 2011 VL 339 IS 2 BP 662 EP 677 DI 10.1124/jpet.111.185025 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 840TS UT WOS:000296464800036 PM 21859929 ER PT J AU Zhang, L Li, CT Su, TP Hu, XZ Lanius, RA Webster, MJ Chung, MY Chen, YS Bai, YM Barker, JL Barrett, JE Li, XX Li, H Benedek, DM Ursano, R AF Zhang, Lei Li, Cheng-Ta Su, Tung-Ping Hu, Xian-Zhang Lanius, Ruth A. Webster, Maree J. Chung, Ming-Yi Chen, Ying-Sheue Bai, Ya-Mei Barker, Jeffery L. Barrett, James E. Li, Xiao-Xia Li, He Benedek, David M. Ursano, Robert TI P11 expression and PET in bipolar disorders SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE p11; PET; Bipolar disorder-I; Bipolar disorder-II; Biomarker; Amygdala ID BRAIN GLUCOSE-METABOLISM; ANTERIOR CINGULATE; MOOD DISORDERS; DEPRESSION; REMISSION; SUBTYPE; STATES; SCANS AB Background: Bipolar disorder (BD) is a common mental disorder, subdivided into BD-I and BD-II. Currently, few biomarkers differentiate BD-I from BD-II. However, it is suggested that peripheral blood mononuclear cell (PBMC) mRNA levels of p11 and positron emission tomography (PET) might be potential biomarkers for BD. Methods: Healthy controls (HCs), BD-I, and BD-II patients in remission (n = 20 in each group) underwent a resting PET study with the radiotracer [F-18]-2-deoxy-2-fluoro-D-glucose (F-18-FDG). PBMC p11 mRNA levels were determined by quantitative real-time PCR. Results: Comparing BD patients to HCs, normalized glucose metabolism (NGM) was higher in the hippocampus, parahippocampus, and amygdala, but lower in the anterior cingulate cortex (aCC), medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (dIPFC), insula and thalamus. Compared to BD-II, BD-I had hypometabolism of glucose in the aCC, bilateral middle and inferior gyrus, insula and striatum, and hypermetabolism of glucose in the left parahippocampus. PBMC p11 mRNA was over-expressed in both BD-I and BD-II, although there was no significant difference in its expression levels between BD-I and B-II patients. Further, there were significant positive correlations between PBMC p11 mRNA and NGM in the mPFC, aCC, left insula, bilateral orbitofrontal cortex (OFC), and left middle, inferior and superior temporal gyri. Also, PBMC p11 mRNA was positively correlated to the number of depressive episodes in BD patients, especially in BD-I patients. Discussion: This study demonstrates that PBMC p11 mRNA expression is associated with neural activation in the brain of BD patients and warrants a larger translational study to determine its clinical utility. Published by Elsevier Ltd. C1 [Zhang, Lei; Hu, Xian-Zhang; Li, Xiao-Xia; Li, He; Benedek, David M.; Ursano, Robert] Uniformed Serv Univ Hlth Sci, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD 20814 USA. [Li, Cheng-Ta; Su, Tung-Ping; Chen, Ying-Sheue; Bai, Ya-Mei] Natl Yang Ming Univ, Div Psychiat, Fac Med, Taipei 112, Taiwan. [Li, Cheng-Ta; Su, Tung-Ping; Chen, Ying-Sheue; Bai, Ya-Mei] Natl Yang Ming Univ, Inst Brian Sci, Taipei 112, Taiwan. [Li, Cheng-Ta; Su, Tung-Ping] Taipei Vet Gen Hosp, Dept Psychiat, Taipei, Taiwan. [Lanius, Ruth A.] Univ Western Ontario, Dept Psychiat, Traumat Stress Serv, London Hlth Sci Ctr, London, ON N6A 3K7, Canada. [Chung, Ming-Yi] Natl Yang Ming Univ, Inst Genome Sci, Taipei 112, Taiwan. [Barker, Jeffery L.] NINDS, NIH, Neurophysiol Lab, Bethesda, MD 20892 USA. [Barrett, James E.] Drexel Univ, Coll Med, Dept Physiol & Pharmacol, Philadelphia, PA 19102 USA. RP Zhang, L (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD 20814 USA. EM Lezhang@USUHS.mil RI Lanius, Ruth/J-6961-2015 OI Lanius, Ruth/0000-0002-3758-1393 FU Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences; National Science Council, Taiwan [NSC 96-2752-B-010-006-PAE, 97-2752-B-010-002-PAE] FX This research was supported in part by the Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences and National Science Council, Taiwan (NSC 96-2752-B-010-006-PAE & 97-2752-B-010-002-PAE). NR 22 TC 11 Z9 11 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD NOV PY 2011 VL 45 IS 11 BP 1426 EP 1431 DI 10.1016/j.jpsychires.2011.06.006 PG 6 WC Psychiatry SC Psychiatry GA 843QU UT WOS:000296688100003 PM 21722919 ER PT J AU Rocco, MV Lockridge, RS Beck, GJ Eggers, PW Gassman, JJ Greene, T Larive, B Chan, CT Chertow, GM Copland, M Hoy, CD Lindsay, RM Levin, NW Ornt, DB Pierratos, A Pipkin, MF Rajagopalan, S Stokes, JB Unruh, ML Star, RA Kliger, AS AF Rocco, Michael V. Lockridge, Robert S., Jr. Beck, Gerald J. Eggers, Paul W. Gassman, Jennifer J. Greene, Tom Larive, Brett Chan, Christopher T. Chertow, Glenn M. Copland, Michael Hoy, Christopher D. Lindsay, Robert M. Levin, Nathan W. Ornt, Daniel B. Pierratos, Andreas Pipkin, Mary F. Rajagopalan, Sanjay Stokes, John B. Unruh, Mark L. Star, Robert A. Kliger, Alan S. CA Frequent Hemodialysis Network FHN TI The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial SO KIDNEY INTERNATIONAL LA English DT Article DE hemodialysis; left ventricular mass; nocturnal hemodialysis; RAND physical health composite (PHC) SF-36; randomized clinical trial; vascular access ID LEFT-VENTRICULAR HYPERTROPHY; QUALITY-OF-LIFE; MEMBRANE FLUX; DIALYSIS PATIENTS; BLOOD-PRESSURE; FOLLOW-UP; HEMO; UREA; EXPERIENCE; DISEASE AB Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome. Kidney International (2011) 80, 1080-1091; doi:10.1038/ki.2011.213; published online 20 July 2011 C1 [Rocco, Michael V.] Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC 27157 USA. [Lockridge, Robert S., Jr.; Pipkin, Mary F.] Univ Virginia, Lynchburg Nephrol Phys, Lynchburg, VA USA. [Beck, Gerald J.; Gassman, Jennifer J.; Larive, Brett] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Eggers, Paul W.; Star, Robert A.] NIDDK, Bethesda, MD USA. [Greene, Tom] Univ Utah, Salt Lake City, UT USA. [Chan, Christopher T.] Univ Toronto, Univ Hlth Network, Toronto, ON M5S 1A1, Canada. [Chertow, Glenn M.] Stanford Univ, Palo Alto, CA 94304 USA. [Chertow, Glenn M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Copland, Michael] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Hoy, Christopher D.] Rubin Dialysis Ctr, Saratoga Springs, NY USA. [Lindsay, Robert M.] Univ Western Ontario, London, ON, Canada. [Levin, Nathan W.] Renal Res Inst, New York, NY USA. [Ornt, Daniel B.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Pierratos, Andreas] Univ Toronto, Humber River Reg Hosp, Toronto, ON, Canada. [Rajagopalan, Sanjay] Ohio State Univ, Columbus, OH 43210 USA. [Stokes, John B.] Univ Iowa, Iowa City, IA USA. [Stokes, John B.] Iowa City VA Med Ctr, Iowa City, IA USA. [Unruh, Mark L.] Univ Pittsburgh, Pittsburgh, PA USA. [Kliger, Alan S.] Yale Univ, Hosp St Raphael, New Haven, CT USA. RP Rocco, MV (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mrocco@wakehealth.edu RI Suri, Rita/G-3348-2011 OI Suri, Rita/0000-0002-0519-3927 FU National Institute of Diabetes and Digestive and Kidney Diseases; Centers for Medicare and Medicaid Services; NIH Research Foundation; Fresenius Medical Care FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the Centers for Medicare and Medicaid Services, and the NIH Research Foundation. The investigators and sponsors are grateful for the support of contributors to the NIH Foundation: Amgen, Baxter, and Dialysis Clinics, and support from Fresenius Medical Care. We are indebted to the patients who participated in the study, and to the United States Renal Data System for providing additional hospitalization data. This trial was registered at Clinical Trials.gov #NCT 00271999. NR 36 TC 201 Z9 203 U1 2 U2 17 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 NOV PY 2011 VL 80 IS 10 BP 1080 EP 1091 DI 10.1038/ki.2011.213 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 842OW UT WOS:000296609800012 PM 21775973 ER PT J AU Smith, MD Patterson, E Wahed, AS Belle, SH Berk, PD Courcoulas, AP Dakin, GF Flum, DR Machado, L Mitchell, JE Pender, J Pomp, A Pories, W Ramanathan, R Schrope, B Staten, M Ude, A Wolfe, BM AF Smith, Mark D. Patterson, Emma Wahed, Abdus S. Belle, Steven H. Berk, Paul D. Courcoulas, Anita P. Dakin, Gregory F. Flum, David R. Machado, Laura Mitchell, James E. Pender, John Pomp, Alfons Pories, Walter Ramanathan, Ramesh Schrope, Beth Staten, Myrlene Ude, Akuezunkpa Wolfe, Bruce M. TI Thirty-day Mortality After Bariatric Surgery: Independently Adjudicated Causes of Death in the Longitudinal Assessment of Bariatric Surgery SO OBESITY SURGERY LA English DT Article DE Mortality; Cause of death; Bariatric surgery; Gastric bypass ID GASTRIC BYPASS; UNITED-STATES; DIABETES-MELLITUS; OBESITY SURGERY; MORBID-OBESITY; US ADULTS; PREVALENCE; MULTICENTER; OVERWEIGHT; OUTCOMES AB Mortality following bariatric surgery is a rare event in contemporary series, making it difficult for any single center to draw meaningful conclusions as to cause of death. Nevertheless, much of the published mortality data come from single-center case series and reviews of administrative databases. These sources tend to produce lower mortality estimates than those obtained from controlled clinical trials. Furthermore, information about the causes of death and how they were determined is not always available. The aim of the present report is to describe in detail all deaths occurring within 30 days of surgery in the Longitudinal Assessment of Bariatric Surgery (LABS). LABS is a ten-center observational cohort study of bariatric surgical outcomes. Data were collected prospectively for bariatric surgeries performed between March 2005 and April 2009. All deaths occurring within 30-days of surgery were identified, and cause of death assigned by an independent Adjudication Subcommittee, blinded to operating surgeon and site. Six thousand one hundred eighteen patients underwent primary bariatric surgery. Eighteen deaths (0.3%) occurred within 30-days of surgery. The most common cause of death was sepsis (33% of deaths), followed by cardiac causes (28%), and pulmonary embolism (17%). For one patient cause of death could not be determined despite examination of all available information. This study confirms the low 30-day mortality rate following bariatric surgery. The recognized complications of anastomotic leak, cardiac events, and pulmonary emboli accounted for the majority of 30-day deaths. C1 [Smith, Mark D.; Patterson, Emma] Legacy Good Samaritan Hosp, Portland, OR 97210 USA. [Wahed, Abdus S.; Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Data Coordinating Ctr, Pittsburgh, PA USA. [Berk, Paul D.; Schrope, Beth; Ude, Akuezunkpa] Columbia Univ, Med Ctr, New York, NY USA. [Courcoulas, Anita P.; Ramanathan, Ramesh] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Dakin, Gregory F.; Pomp, Alfons] Weill Cornell Med Coll, New York, NY USA. [Flum, David R.] Univ Washington, Seattle, WA 98195 USA. [Machado, Laura] Sacramento Bariatr Med Associates, Sacramento, CA USA. [Mitchell, James E.] Neuropsychiat Res Inst, Fargo, ND USA. [Pender, John; Pories, Walter] E Carolina Med Ctr, Greenville, NC USA. [Staten, Myrlene] NIDDK, Iowa City, IA USA. [Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Smith, MD (reprint author), Legacy Good Samaritan Hosp, 1040 NW 22nd Ave,Suite 500, Portland, OR 97210 USA. EM mdsmith2@mac.com OI Wahed, Abdus/0000-0001-6911-7221 FU National Institute of Diabetes and Digestive and Kidney Diseases [DCC -U01 DK066557]; Cornell University Medical Center CTSC, [Columbia-U01-DK66667, UL1-RR024996]; University of Washington (CTRC) [U01-DK66568, M01RR-00037]; Neuropsychiatric Research Institute [U01-DK66471]; East Carolina University [U01-DK66526]; University of Pittsburgh Medical Center (CTRC) [U01-DK66585, UL1-RR024153]; Oregon Health and Science University [U01-DK66555]; Transenterix; Allergan Health; Reshape Medical; Covidien; Sanofi Aventis; Ethicon; GlaxoSmithKline; EnteroMedics; Crospon/Wellcome FX This clinical study was a cooperative agreement funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Grant numbers: DCC -U01 DK066557; Columbia-U01-DK66667 (in collaboration with Cornell University Medical Center CTSC, Grant UL1-RR024996); University of Washington-U01-DK66568 (in collaboration with CTRC, Grant M01RR-00037); Neuropsychiatric Research Institute-U01-DK66471; East Carolina University-U01-DK66526; University of Pittsburgh Medical Center-U01-DK66585 (in collaboration with CTRC, Grant UL1-RR024153); Oregon Health and Science University-U01-DK66555.; Mark D. Smith, Abdus S. Wahed, Steven H. Belle, Paul D. Berk, Anita P. Courcoulas, Gregory F. Dakin, Laura Machado, James E. Mitchell, John Pender, Alfons Pomp, Ramesh Ramanathan, Beth Schrope, Myrlene Staten, and Akuezunkpa Ude have no relevant financial interests to disclose. Emma Patterson discloses that she is an owner and co-founder of Doctors of Weight Loss, and receives consulting fees from Transenterix, Allergan Health, and Reshape Medical. David R. Flum discloses that he receives research grant support from Covidien and Sanofi Aventis. Walter Pories discloses that he receives research grant support from Ethicon and GlaxoSmithKline. Bruce M. Wolfe discloses that he receives consulting fees from EnteroMedics and Crospon/Wellcome. NR 41 TC 31 Z9 32 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 J9 OBES SURG JI Obes. Surg. PD NOV PY 2011 VL 21 IS 11 BP 1687 EP 1692 DI 10.1007/s11695-011-0497-8 PG 6 WC Surgery SC Surgery GA 849MD UT WOS:000297128700008 PM 21866378 ER PT J AU Erby, LAH Roter, DL Biesecker, BB AF Erby, Lori A. H. Roter, Debra L. Biesecker, Barbara B. TI Examination of standardized patient performance: Accuracy and consistency of six standardized patients over time SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Standardized patient; Genetic counseling; Provider-patient communication; Accuracy; Consistency ID STRUCTURED CLINICAL EXAMINATION; COMMUNICATION; COMPETENCE; SKILLS AB Objective: To explore the accuracy and consistency of standardized patient (SP) performance in the context of routine genetic counseling, focusing on elements beyond scripted case items including general communication style and affective demeanor. Methods: One hundred seventy-seven genetic counselors were randomly assigned to counsel one of six SPs. Videotapes and transcripts of the sessions were analyzed to assess consistency of performance across four dimensions. Results: Accuracy of script item presentation was high; 91% and 89% in the prenatal and cancer cases. However, there were statistically significant differences among SPs in the accuracy of presentation, general communication style, and some aspects of affective presentation. All SPs were rated as presenting with similarly high levels of realism. SP performance over time was generally consistent, with some small but statistically significant differences. Conclusion and practice implications: These findings demonstrate that well-trained SPs can not only perform the factual elements of a case with high degrees of accuracy and realism; but they can also maintain sufficient levels of uniformity in general communication style and affective demeanor over time to support their use in even the demanding context of genetic counseling. Results indicate a need for an additional focus in training on consistency between different SPs. (C) 2010 Published by Elsevier Ireland Ltd. C1 [Erby, Lori A. H.; Roter, Debra L.] Johns Hopkins Bloomberg Sch Publ Hlth Hlth Behav, Baltimore, MD 21205 USA. [Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Erby, LAH (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth Hlth Behav, 624 N Broadway,Room 755, Baltimore, MD 21205 USA. EM lerby@jhsph.edu RI Roter, Debra/N-8830-2014 FU National Human Genome Research Institute of the NIH; [1R01HG002688-01A1] FX This research was supported by grant 1R01HG002688-01A1, Genetic Counseling Processes and Analogue Client Outcomes, funded by the National Human Genome Research Institute of the NIH. This study was performed in partial fulfillment of the requirements for Dr. Erby's doctoral dissertation at the Johns Hopkins Bloomberg School of Public Health. The authors thank Rita Johnson for her transcription services, Erin McDonald for assistance in transcript coding, Mary Catherine Beach, Peter Zandi, and Ada Hamosh for their early insights, and the anonymous reviewers whose suggestions have considerably improved our manuscript. We would also like to thank the Johns Hopkins Bloomberg School of Public Health biostatistics consulting service for their helpful insights on the statistical modeling in this most recent version of the manuscript. NR 31 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD NOV PY 2011 VL 85 IS 2 BP 194 EP 200 DI 10.1016/j.pec.2010.10.005 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 850WX UT WOS:000297231400012 PM 21094590 ER PT J AU Case, LB Waterman, CM AF Case, Lindsay B. Waterman, Clare M. TI Adhesive F-actin Waves: A Novel Integrin-Mediated Adhesion Complex Coupled to Ventral Actin Polymerization SO PLOS ONE LA English DT Article ID ARP2/3 COMPLEX; CELL LOCOMOTION; MATRIX ADHESION; OSCILLATIONS; INVADOPODIA; ACTIVATION; MATURATION; PODOSOMES; DYNAMICS AB At the leading lamellipodium of migrating cells, protrusion of an Arp2/3-nucleated actin network is coupled to formation of integrin-based adhesions, suggesting that Arp2/3-mediated actin polymerization and integrin-dependent adhesion may be mechanistically linked. Arp2/3 also mediates actin polymerization in structures distinct from the lamellipodium, in "ventral F-actin waves'' that propagate as spots and wavefronts along the ventral plasma membrane. Here we show that integrins engage the extracellular matrix downstream of ventral F-actin waves in several mammalian cell lines as well as in primary mouse embryonic fibroblasts. These "adhesive F-actin waves'' require a cycle of integrin engagement and disengagement to the extracellular matrix for their formation and propagation, and exhibit morphometry and a hierarchical assembly and disassembly mechanism distinct from other integrin-containing structures. After Arp2/3-mediated actin polymerization, zyxin and VASP are co-recruited to adhesive F-actin waves, followed by paxillin and vinculin, and finally talin and integrin. Adhesive F-actin waves thus represent a previously uncharacterized integrin-based adhesion complex associated with Arp2/3-mediated actin polymerization. C1 [Case, Lindsay B.] Univ N Carolina, Sch Med, Dept Cell & Dev Biol, Chapel Hill, NC 27515 USA. [Case, Lindsay B.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Case, LB (reprint author), Univ N Carolina, Sch Med, Dept Cell & Dev Biol, Chapel Hill, NC 27515 USA. EM watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) FX Funding provided by the Intramural program of the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 29 TC 31 Z9 31 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 1 PY 2011 VL 6 IS 11 AR e26631 DI 10.1371/journal.pone.0026631 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 849UN UT WOS:000297150900021 PM 22069459 ER PT J AU Stenholm, S Kronholm, E Bandinelli, S Guralnik, JM Ferrucci, L AF Stenholm, Sari Kronholm, Erkki Bandinelli, Stefania Guralnik, Jack M. Ferrucci, Luigi TI Self-Reported Sleep Duration and Time in Bed as Predictors of Physical Function Decline: Results from the InCHIANTI Study SO SLEEP LA English DT Article DE Aging; disability; epidemiology; follow-up studies; gerontology; physical performance; sleep; sleep duration; time in bed ID LOWER-EXTREMITY FUNCTION; ALL-CAUSE MORTALITY; LARGE US SAMPLE; SUBSEQUENT DISABILITY; PERFORMANCE BATTERY; MEANINGFUL CHANGE; OLDER-ADULTS; RISK-FACTOR; GAIT SPEED; LONG-SLEEP AB Study Objectives: To characterize elderly persons into sleep/rest groups based on their self-reported habitual total sleeping time (TST) and habitual time in bed (TIB) and to examine the prospective association between sleep/rest behavior on physical function decline. Design: Population-based InCHIANTI study with 6 years follow-up (Tuscany, Italy). Setting: Community. Participants: Men and women aged >= 65 years (n = 751). Measurements and Results: At baseline, participants were categorized into 5 sleep/rest behavior groups according to their self-reported TST and TIB, computed from bedtime and wake-up time Physical function was assessed at baseline and at 3- and 6-year follow-ups as walking speed, the Short Physical Performance Battery (SPPB), and self-reported mobility disability (ability to walk 400 m or climb one flight of stairs). Both long (>= 9 h) TST and long TIB predicted accelerated decline in objectively measured physical performance and greater incidence in subjectively assessed mobility disability, but short (<= 6 h) TST did not. After combining TST and TIB, long sleepers (TST and TIB >= 9 h) experienced the greatest decline in physical performance and had the highest risk for incident mobility disability in comparison to mid-range sleepers with 7-8 h TST and TIB. Subjective short sleepers reporting short (<= 6 h) TST but long (>= 9 h) TIB showed a greater decline in SPPB score and had a higher risk of incident mobility disability than true short sleepers with short (<= 6 h) TST and TIB <= 8 hours. Conclusions: Extended time in bed as well as long total sleeping time is associated with greater physical function decline than mid-range or short sleep. TIB offers important additive information to the self-reported sleep duration when evaluating the consequences of sleep duration on health and functional status. C1 [Stenholm, Sari] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Funct Capac Unit, FI-20720 Turku, Finland. [Kronholm, Erkki] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Populat Studies Unit, FI-20720 Turku, Finland. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Stenholm, S (reprint author), Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Funct Capac Unit, Peltolantie 3, FI-20720 Turku, Finland. EM sari.stenholm@thl.fi RI Stenholm, Sari/G-6940-2011 FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; National Institute on Aging, National Institutes of Health, Baltimore, Maryland FX 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); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-up 2 study (2004-2006) was financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. The authors have no financial or personal conflicts of interest. None of the sponsoring institutions interfered with the design, methods, subject recruitment, data collections, analysis and preparation of paper. NR 39 TC 21 Z9 21 U1 1 U2 6 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD NOV 1 PY 2011 VL 34 IS 11 BP 1583 EP 1593 DI 10.5665/sleep.1402 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844DF UT WOS:000296727200019 PM 22043129 ER PT J AU Keefer, LK AF Keefer, Larry K. TI Fifty Years of Diazeniumdiolate Research. From Laboratory Curiosity to Broad-Spectrum Biomedical Advances SO ACS CHEMICAL BIOLOGY LA English DT Review ID NITRIC-OXIDE DONOR; CONTROLLED BIOLOGICAL RELEASE; IN-VIVO; JS-K; RELAXING FACTOR; NITROSAMINO ACIDS; AMINE ADDUCTS; NO DONOR; CHEMISTRY; HNO AB Here I show that a "pure" research project, seemingly totally lacking in practical application when it was first published, can years later spark a whole new scientific field with the potential to revolutionize clinical practice. A 1961 publication describing adducts of nitric oxide (NO) with certain nucleophiles attracted little notice at the time, but later work showing that the adducts could be hydrolyzed to regenerate the NO in bioactive form has provided the foundation for a host of biomedical applications Crucial to the discovery of widely used tools for studying NO'S chemical biology as well as for the design of a variety of promising therapeutic advances has been the increasingly detailed understanding of the physicochemical properties of these "diazeniumdiolates" (also known as NONOates). C1 NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Keefer, LK (reprint author), NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. EM keeferl@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 65 TC 47 Z9 47 U1 1 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD NOV PY 2011 VL 6 IS 11 BP 1147 EP 1155 DI 10.1021/cb200274r PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848GM UT WOS:000297038800001 PM 21932836 ER PT J AU Jedrzejczak, R Wang, JW Dauter, M Szczesny, RJ Stepien, PP Dauter, Z AF Jedrzejczak, Robert Wang, Jiawei Dauter, Miroslawa Szczesny, Roman J. Stepien, Piotr P. Dauter, Zbigniew TI Human Suv3 protein reveals unique features among SF2 helicases SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID YEAST MITOCHONDRIAL DEGRADOSOME; RNA HELICASE; RNA/DNA HELICASE; MODEL; SURVEILLANCE; HYDROLYSIS; REFINEMENT; METABOLISM; MECHANISM; PATHWAY AB Suv3 is a helicase that is involved in efficient turnover and surveillance of RNA in eukaryotes. In vitro studies show that human Suv3 (hSuv3) in complex with human polynucleotide phosphorylase has RNA degradosome activity. The enzyme is mainly localized in mitochondria, but small fractions are found in cell nuclei. Here, two X-ray crystallographic structures of human Suv3 in complex with AMPPNP, a nonhydrolysable analog of ATP, and with a short five-nucleotide strand of RNA are presented at resolutions of 2.08 and 2.9 angstrom, respectively. The structure of the enzyme is very similar in the two complexes and consists of four domains. Two RecA-like domains form the tandem typical of all helicases from the SF2 superfamily which together with the C-terminal all-helical domain makes a ring structure through which the nucleotide strand threads. The mostly helical N-terminal domain is positioned externally with respect to the core of the enzyme. Most of the typical helicase motifs are present in hSuv3, but the protein shows certain unique characteristics, suggesting that Suv3 enzymes may constitute a separate subfamily of helicases. C1 [Szczesny, Roman J.; Stepien, Piotr P.] Warsaw Univ, Dept Genet & Biotechnol, PL-02106 Warsaw, Poland. [Jedrzejczak, Robert; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Argonne Natl Lab, Argonne, IL 60439 USA. [Jedrzejczak, Robert] Argonne Natl Lab, Midw Ctr Struct Genom, Biosci Div, Argonne, IL 60439 USA. [Wang, Jiawei; Dauter, Miroslawa] SAIC Frederick Inc, Basic Res Program, Argonne Natl Lab, Argonne, IL 60439 USA. [Wang, Jiawei] Tsinghua Univ, Struct Biol Ctr, Sch Life Sci, Beijing 100084, Peoples R China. [Wang, Jiawei] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China. [Szczesny, Roman J.; Stepien, Piotr P.] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. RP Stepien, PP (reprint author), Warsaw Univ, Dept Genet & Biotechnol, Pawinskiego 5A, PL-02106 Warsaw, Poland. EM stepien@ibb.waw.pl; dauter@anl.gov FU Polish National Centre for Research and Development [NR 13004704]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported in part by the Polish National Centre for Research and Development (NR 13004704) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800001). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 38 TC 7 Z9 7 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD NOV PY 2011 VL 67 BP 988 EP 996 DI 10.1107/S0907444911040248 PN 11 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 844XW UT WOS:000296787400011 PM 22101826 ER PT J AU Fradley, MG Larson, MG Cheng, S McCabe, E Coglianese, E Shah, RV Levy, D Vasan, RS Wang, TJ AF Fradley, Michael G. Larson, Martin G. Cheng, Susan McCabe, Elizabeth Coglianese, Erin Shah, Ravi V. Levy, Daniel Vasan, Rarnachandran S. Wang, Thomas J. TI Reference Limits for N-Terminal-pro-B-Type Natriuretic Peptide in Healthy Individuals (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID BIOLOGICAL VARIATION; AGE; FAILURE; BNP; DYSFUNCTION; GENDER; ADULTS; IMPACT; SEX AB N-terminal pro B-type natriuretic peptide (NT-pro-BNP) is a commonly measured cardiovascular biomarker in ambulatory and hospital settings. Nonetheless, there are limited data regarding "normal" ranges for NT-pro-BNP in healthy subjects, despite the importance of such information for interpreting natriuretic peptide measurements. In this study, a healthy reference sample free of cardiovascular disease from the Framingham Heart Study Generation 3 cohort was examined; there were 2,285 subjects (mean age 38 years, 56% women). Plasma NT-pro-BNP levels were measured using the Roche Diagnostics Elecsys 2010 assay, and reference values (2.5th, 50th, and 97.5th quantiles) were determined using empiric and quantile regression methods. Gender, age, blood pressure, and body mass index accounted for approximately 33% of the interindividual variability in NT-pro-BNP in the reference sample. NT-pro-BNP values were substantially higher in women compared to men at every age, and levels increased with increasing age for both genders. Using quantile regression, the upper reference values (97.5th quantile) for NT proBNP were 42.5 to 106.4 pg/ml in men (depending on age) and 111.0 to 215.9 pg/ml in women. Intraindividual variability was assessed in an additional 12 healthy subjects, who had serial NT-pro-BNP measurements over 1 month. Intraclass correlation was 0.85, indicating that most of the variability in NT-pro-BNP concentrations was among rather than within subjects. However, the reference change value was 100%, suggesting that small proportional differences in NT-pro-BNP could be attributable to analytic variability. In conclusion, the reference limits obtained from this large, healthy, community-based sample may aid in the evaluation of NT-pro-BNP concentrations measured for clinical and research purposes. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1341-1345) C1 [Fradley, Michael G.; McCabe, Elizabeth; Coglianese, Erin; Shah, Ravi V.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02215 USA. [Larson, Martin G.; Cheng, Susan; Levy, Daniel; Vasan, Rarnachandran S.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Cheng, Susan] Harvard Univ, Sch Med, Div Cardiovasc Med, Brigham & Womens Hosp, Boston, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Levy, Daniel; Vasan, Rarnachandran S.] Boston Univ, Sch Med, Prevent Med & Cardiol Sect, Boston, MA 02118 USA. RP Wang, TJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02215 USA. EM tjwang@partners.org OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute's Framingham Heart Study [NO1-HC-25195]; Siemens Healthcare Diagnostics, Deerfield, Illinois; Brahms AG, Hennigsdorf, Germany; [R01-HL086875] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (NO1-HC-25195) and grant R01-HL086875.; Dr. Wang has been a coinvestigator on studies that have received assay support from Siemens Healthcare Diagnostics, Deerfield, Illinois, and Brahms AG, Hennigsdorf, Germany. NR 20 TC 34 Z9 36 U1 0 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD NOV 1 PY 2011 VL 108 IS 9 BP 1341 EP 1345 DI 10.1016/j.amjcard.2011.06.057 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 846YM UT WOS:000296939100023 PM 21864812 ER PT J AU Jefferson, AL Himali, JJ Au, R Seshadri, S DeCarli, C O'Donnell, CJ Wolf, PA Manning, WJ Beiser, AS Benjamin, EJ AF Jefferson, Angela L. Himali, Jayandra J. Au, Rhoda Seshadri, Sudha DeCarli, Charles O'Donnell, Christopher J. Wolf, Philip A. Manning, Warren J. Beiser, Alexa S. Benjamin, Emelia J. TI Relation of Left Ventricular Ejection Fraction to Cognitive Aging (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CHRONIC CEREBRAL HYPOPERFUSION; WHITE-MATTER LESIONS; ALZHEIMERS-DISEASE; CARDIAC TRANSPLANTATION; BRAIN MORPHOLOGY; BLOOD-FLOW; FAILURE; IMPAIRMENT; ISCHEMIA; MEMORY AB Heart failure is a risk factor for Alzheimer's disease and cerebrovascular disease. In the absence of heart failure, it was hypothesized that left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected from 1,114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (aged 40 to 89 years, mean age 67 +/- 9 years, 54% women). Neuropsychological and neuroimaging markers of brain aging were related to cardiac MRI assessed LVEF. In multivariable-adjusted linear regressions, LVEF was not associated with any brain aging variable (p values >0.15). However, LVEF quintile analyses yielded several U-shaped associations. Compared to the referent (quintile 2 to 4), the lowest quintile (quintile 1) LVEF was associated with lower mean cognitive performance, including Visual Reproduction Delayed Recall (beta = -0.27, p<0.001) and Hooper Visual Organization Test (beta = -0.27, p<0.001). Compared to the referent, the highest quintile (quintile 5) LVEF values also were associated with lower mean cognitive performance, including Logical Memory Delayed Recall (beta = -0.18, p = 0.03), Visual Reproduction Delayed Recall (beta = -0.17, p = 0.03), Trail Making Test Part B - Part A (beta = -0.22, p = 0.02), and Hooper Visual Organization Test (beta = -0.20, p = 0.02). Findings were similar when analyses were repeated excluding prevalent cardiovascular disease. In conclusion, although these observational cross-sectional data cannot establish causality, they suggest a nonlinear association between LVEF and measures of accelerated cognitive aging. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1346-1351) C1 [Jefferson, Angela L.; Himali, Jayandra J.; Au, Rhoda; Seshadri, Sudha; Wolf, Philip A.; Beiser, Alexa S.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02215 USA. [Jefferson, Angela L.; Seshadri, Sudha] Boston Univ, Alzheimers Dis Ctr, Boston, MA 02215 USA. [Jefferson, Angela L.; Benjamin, Emelia J.] Boston Univ, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. [Himali, Jayandra J.; Au, Rhoda; Seshadri, Sudha; O'Donnell, Christopher J.; Wolf, Philip A.; Beiser, Alexa S.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Himali, Jayandra J.; Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Ctr Neurosci, Davis, CA 95616 USA. [DeCarli, Charles] Univ Calif Davis, Imaging Dementia & Aging Lab, Davis, CA 95616 USA. [Manning, Warren J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Cardiovasc Div, Boston, MA USA. [Manning, Warren J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA USA. RP Jefferson, AL (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. EM angelaj@bu.edu OI Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Benjamin, Emelia/0000-0003-4076-2336; Beiser, Alexa/0000-0001-8551-7778; /0000-0003-1391-9481 FU NHLBI's Framingham Heart Study [N01-HC25195]; Paul B. Beeson Career Development Award in Aging Program [AG027480, AG030962]; Alzheimer's Association [IIRG-08-88733]; [P30-AG013846]; [AG08122]; [NS017950]; [AG033040]; [AG16495]; [AG033193]; [AG031287]; [AG021028]; [AG010129]; [HL070279]; [AG028321]; [HL092577] FX This study was supported by NHLBI's Framingham Heart Study N01-HC25195; AG027480, AG030962 (Paul B. Beeson Career Development Award in Aging Program), Alzheimer's Association IIRG-08-88733 (A.L.J.); P30-AG013846 (Boston University Alzheimer's Disease Core Center); AG08122, NS017950, AG033040, AG16495 (P.A.W.); AG028321, HL092577 (E.J.B.); AG033193, AG031287 (S.S.); AG021028 (CD), AG010129 (University of California, Davis, Alzheimer's Disease Core Center); and HL070279 (W.J.M.). NR 29 TC 42 Z9 42 U1 0 U2 13 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD NOV 1 PY 2011 VL 108 IS 9 BP 1346 EP 1351 DI 10.1016/j.amjcard.2011.06.056 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 846YM UT WOS:000296939100024 PM 21880293 ER PT J AU Chen, X AF Chen, Xiaoyuan TI Protein and peptide probes for molecular imaging SO AMINO ACIDS LA English DT Editorial Material C1 NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, X (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, 31 Ctr Dr,1C22, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [ZIA EB000073-01] NR 16 TC 1 Z9 1 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD NOV PY 2011 VL 41 IS 5 BP 1009 EP 1012 DI 10.1007/s00726-011-0945-8 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840VJ UT WOS:000296469100001 PM 21643775 ER PT J AU Lin, X Xie, J Chen, XY AF Lin, Xin Xie, Jin Chen, Xiaoyuan TI Protein-based tumor molecular imaging probes SO AMINO ACIDS LA English DT Review DE Tumor targeting; Antibody; Human epidermal growth factor receptor (HER); Vascular endothelial growth factor (VEGF) ID EPIDERMAL-GROWTH-FACTOR; SINGLE-CHAIN FV; SITE-SPECIFIC MODIFICATION; BREAST-CANCER CELLS; RECOMBINANT ANTIBODY FRAGMENTS; POSITRON-EMISSION-TOMOGRAPHY; PLASMA-MEMBRANE ASYMMETRY; BINDING AFFIBODY MOLECULE; XENOGRAFT-BEARING MICE; FLUORESCENT AMINO-ACID AB Molecular imaging is an emerging discipline which plays critical roles in diagnosis and therapeutics. It visualizes and quantifies markers that are aberrantly expressed during the disease origin and development. Protein molecules remain to be one major class of imaging probes, and the option has been widely diversified due to the recent advances in protein engineering techniques. Antibodies are part of the immunosystem which interact with target antigens with high specificity and affinity. They have long been investigated as imaging probes and were coupled with imaging motifs such as radioisotopes for that purpose. However, the relatively large size of antibodies leads to a half-life that is too long for common imaging purposes. Besides, it may also cause a poor tissue penetration rate and thus compromise some medical applications. It is under this context that various engineered protein probes, essentially antibody fragments, protein scaffolds, and natural ligands have been developed. Compared to intact antibodies, they possess more compact size, shorter clearance time, and better tumor penetration. One major challenge of using protein probes in molecular imaging is the affected biological activity resulted from random labeling. Site-specific modification, however, allows conjugation happening in a stoichiometric fashion with little perturbation of protein activity. The present review will discuss protein-based probes with focus on their application and related site-specific conjugation strategies in tumor imaging. C1 [Lin, Xin; Xie, Jin; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, X (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bldg 31,Room 1C22, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-01] NR 217 TC 8 Z9 8 U1 3 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD NOV PY 2011 VL 41 IS 5 BP 1013 EP 1036 DI 10.1007/s00726-010-0545-z PG 24 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840VJ UT WOS:000296469100002 PM 20232092 ER PT J AU Yan, YJ Chen, XY AF Yan, Yongjun Chen, Xiaoyuan TI Peptide heterodimers for molecular imaging SO AMINO ACIDS LA English DT Review DE Peptide; Heterodimer; Molecular imaging ID INTEGRIN ALPHA(V)BETA(3) EXPRESSION; RGD-BOMBESIN HETERODIMER; SMALL-ANIMAL PET; HETEROBIVALENT LIGANDS; RECEPTORS; DESIGN; TUMORS; MICROPET; THERAPY; MULTIVALENCY AB One main issue with peptide-based molecular imaging probes is their relatively low tumor affinity and short retention time. To improve peptide binding affinity, multivalency approach has been introduced. Traditionally, this approach involves the use of peptide homodimers or homomultimers in which peptide ligands of the same type are constructed with suitable linkers. Recently, a new approach using peptide heterodimers has emerged as a promising method for targeting multi-receptor over-expressed tumor cells. Significant affinity enhancements have been observed with peptide heterodimers compared with their parent peptide monomers. In a peptide heterodimer, two different peptide ligands capable of targeting two different receptors are covalently linked. The binding modes of peptide heterodimers can be monovalent or bivalent depending on whether simultaneous binding of two ligands can be achieved. Increased local ligand concentration and improved binding kinetics contribute to enhanced binding in both monovalent- and bivalent binding modes, while multivalency effect also plays an important role in bivalent binding mode. As many tumors overexpress multiple receptors, more peptide heterodimer-based molecular imaging probes are expected to be developed in future. This review article will discuss the peptide homodimers and heterodimers for molecular imaging with special emphasis on peptide heterodimers. C1 [Yan, Yongjun; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, X (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bldg 31,Room 1C22, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-01] NR 32 TC 17 Z9 17 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD NOV PY 2011 VL 41 IS 5 BP 1081 EP 1092 DI 10.1007/s00726-010-0546-y PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840VJ UT WOS:000296469100007 PM 20232091 ER PT J AU Cao, QZ Liu, SL Niu, G Chen, K Yan, YJ Liu, ZF Chen, XY AF Cao, Qizhen Liu, Shuanglong Niu, Gang Chen, Kai Yan, Yongjun Liu, Zhaofei Chen, Xiaoyuan TI Phage display peptide probes for imaging early response to bevacizumab treatment SO AMINO ACIDS LA English DT Article DE Phage display; Angiogenesis; Therapy response; Bevacizumab; Molecular imaging ID ENDOTHELIAL GROWTH-FACTOR; IN-VIVO; ANTIANGIOGENIC THERAPY; TUMOR VASCULATURE; INTEGRIN ALPHA(V)BETA(3); PROSTATE-CANCER; DRUG-DELIVERY; MOUSE MODEL; CELLS; NORMALIZATION AB Early evaluation of cancer response to a therapeutic regimen can help increase the effectiveness of treatment schemes and, by enabling early termination of ineffective treatments, minimize toxicity, and reduce expenses. Biomarkers that provide early indication of tumor therapy response are urgently needed. Solid tumors require blood vessels for growth, and new anti-angiogenic agents can act by preventing the development of a suitable blood supply to sustain tumor growth. The purpose of this study is to develop a class of novel molecular imaging probes that will predict tumor early response to an anti-angiogenic regimen with the humanized vascular endothelial growth factor antibody bevacizumab. Using a bevacizumab-sensitive LS174T colorectal cancer model and a 12-mer bacteriophage (phage) display peptide library, a bevacizumab-responsive peptide (BRP) was identified after six rounds of biopanning and tested in vitro and in vivo. This 12-mer peptide was metabolically stable and had low toxicity to both endothelial cells and tumor cells. Near-infrared dye IRDye800-labeled BRP phage showed strong binding to bevacizumab-treated tumors, but not to untreated control LS174T tumors. In addition, both IRDye800- and (18)F-labeled BRP peptide had significantly higher uptake in tumors treated with bevacizumab than in controls treated with phosphate-buffered saline. Ex vivo histopathology confirmed the specificity of the BRP peptide to bevacizumab-treated tumor vasculature. In summary, a novel 12-mer peptide BRP selected using phage display techniques allowed non-invasive visualization of early responses to anti-angiogenic treatment. Suitably labeled BRP peptide may be potentially useful pre-clinically and clinically for monitoring treatment response. C1 [Niu, Gang; Chen, Kai; Yan, Yongjun; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Cao, Qizhen; Liu, Shuanglong; Liu, Zhaofei; Chen, Xiaoyuan] Stanford Univ, Sch Med, Mol Imaging Program Stanford MIPS, Dept Radiol, Stanford, CA 94305 USA. [Cao, Qizhen; Liu, Shuanglong; Liu, Zhaofei; Chen, Xiaoyuan] Stanford Univ, Sch Med, Biox Program, Stanford, CA 94305 USA. RP Chen, X (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU National Cancer Institute (NCI) [P50 CA114747, U54 CA119367, R24 CA93862]; NIBIB, NIH; Radiology and Imaging Sciences Department, Clinical Center FX This project was supported, in part, by National Cancer Institute (NCI) (P50 CA114747, U54 CA119367, and R24 CA93862) and the Intramural Research Program, NIBIB, NIH. G. Niu is an Imaging Sciences Training Fellowship jointly supported by the Radiology and Imaging Sciences Department, Clinical Center and the Intramural Research Program, NIBIB, NIH. We acknowledge Dr. Henry S. Eden for proof-reading this manuscript. NR 38 TC 6 Z9 6 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD NOV PY 2011 VL 41 IS 5 BP 1103 EP 1112 DI 10.1007/s00726-010-0548-9 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840VJ UT WOS:000296469100009 PM 20232090 ER PT J AU Samuni, Y Baum, BJ AF Samuni, Yuval Baum, Bruce J. TI Gene delivery in salivary glands: From the bench to the clinic SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Gene therapy; Salivary gland; Translational research ID HUMAN AQUAPORIN-1 CDNA; PIG PAROTID-GLANDS; TRANSGENIC SECRETORY PROTEINS; ADENOVIRAL-MEDIATED TRANSFER; INCREASED FLUID SECRETION; IN-VIVO; MINIATURE PIG; SJOGRENS-SYNDROME; GROWTH-HORMONE; ACINAR-CELLS AB In vivo gene delivery has long been seen as providing opportunities for the development of novel treatments for disorders refractory to existing therapies. Over the last two decades, salivary glands have proven to be a useful, if somewhat unconventional, target tissue for studying several potential clinical applications of therapeutic gene delivery. Herein, we follow the progress, address some problems and assess the outlook for clinical applications of salivary gland gene delivery. Our experience with these tissues provides a roadmap for the process of moving an idea from the laboratory bench to patients. Published by Elsevier B.V. C1 [Samuni, Yuval; Baum, Bruce J.] NIDCR, MPTB, NIH, Bethesda, MD 20892 USA. [Samuni, Yuval] Barzilai Govt Hosp, Dept Oral & Maxillofacial Surg, Ashqelon, Israel. RP Baum, BJ (reprint author), NIDCR, MPTB, NIH, Bldg 10,Rm 1N113,MSC-1190, Bethesda, MD 20892 USA. EM bbaum@mail.nih.gov FU Division of Intramural Research of the National Institute of Dental and Craniofacial Research FX The Division of Intramural Research of the National Institute of Dental and Craniofacial Research supported all of the research upon which this review is based, and we are extremely grateful for the stability this research support has allowed. We also are most appreciative of the many wonderful colleagues who have worked with us over the years on the projects described herein. We also wish to thank Dr. Changyu Zheng for providing us with the photograph shown in Fig. 1a, and Dr. Nikolay Nikolov for providing us with the photo shown in Fig. 1b. NR 88 TC 16 Z9 17 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD NOV PY 2011 VL 1812 IS 11 BP 1515 EP 1521 DI 10.1016/j.bbadis.2011.06.014 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 847DR UT WOS:000296952600019 PM 21763423 ER PT J AU McInerney, JO Martin, WF Koonin, EV Allen, JF Galperin, MY Lane, N Archibald, JM Embley, TM AF McInerney, James O. Martin, William F. Koonin, Eugene V. Allen, John F. Galperin, Michael Y. Lane, Nick Archibald, John M. Embley, T. Martin TI Planctomycetes and eukaryotes: A case of analogy not homology SO BIOESSAYS LA English DT Article DE eukaryote origins; horizontal gene transfer; Planctomycetes; phylogeny reconstruction ID HORIZONTAL GENE-TRANSFER; CELL COMPARTMENTALIZATION; PHYLUM VERRUCOMICROBIA; ARCHAEBACTERIAL ORIGIN; GEMMATA-OBSCURIGLOBUS; COMPARATIVE GENOMICS; PSI-BLAST; EVOLUTION; PROTEIN; BACTERIUM AB Planctomycetes, Verrucomicrobia and Chlamydia are prokaryotic phyla, sometimes grouped together as the PVC superphylum of eubacteria. Some PVC species possess interesting attributes, in particular, internal membranes that superficially resemble eukaryotic endomembranes. Some biologists now claim that PVC bacteria are nucleus-bearing prokaryotes and are considered evolutionary intermediates in the transition from prokaryote to eukaryote. PVC prokaryotes do not possess a nucleus and are not intermediates in the prokaryote-to-eukaryote transition. Here we summarise the evidence that shows why all of the PVC traits that are currently cited as evidence for aspiring eukaryoticity are either analogous (the result of convergent evolution), not homologous, to eukaryotic traits; or else they are the result of horizontal gene transfers. C1 [McInerney, James O.] Natl Univ Ireland Maynooth, Dept Biol, Maynooth, Kildare, Ireland. [Martin, William F.] Univ Dusseldorf, Inst Bot 3, Dusseldorf, Germany. [Koonin, Eugene V.; Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Allen, John F.] Univ London, Sch Biol & Chem Sci, London, England. [Lane, Nick] UCL, Dept Genet Evolut & Environm, London, England. [Archibald, John M.] Dalhousie Univ, Dept Biochem & Mol Biol, Canadian Inst Adv Res, Program Integrated Microbial Biodivers, Halifax, NS, Canada. [Embley, T. Martin] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP McInerney, JO (reprint author), Natl Univ Ireland Maynooth, Dept Biol, Maynooth, Kildare, Ireland. EM james.o.mcinerney@nuim.ie RI Galperin, Michael/B-5859-2013; McInerney, James/B-5108-2012; Martin, William /O-5446-2015; OI Galperin, Michael/0000-0002-2265-5572; McInerney, James/0000-0003-1885-2503; Martin, William /0000-0003-1478-6449; Embley, Thomas Martin/0000-0002-1484-340X; Allen, John/0000-0002-0950-0429 FU Science Foundation Ireland; DFG; ERC; NIH; The Leverhulme Trust; NIH at the National Library of Medicine; UCL Provost's Venture Research Fellowship; Canadian Institute for Advanced Research; The Royal Society FX We thank the following funding sources for support: JOM, Science Foundation Ireland Research Frontiers Programme; WFM, DFG, ERC; EVK, NIH; JFA, The Leverhulme Trust; EVK and MYG, NIH Intramural research Program at the National Library of Medicine; NL, UCL Provost's Venture Research Fellowship; JMA, Canadian Institute for Advanced Research, Program in Integrated Microbial Biodiversity; TME, The Royal Society. NR 103 TC 43 Z9 44 U1 1 U2 27 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD NOV PY 2011 VL 33 IS 11 BP 810 EP 817 DI 10.1002/bies.201100045 PG 8 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 847XZ UT WOS:000297010300005 PM 21858844 ER PT J AU Schmidt, H Zeginigg, M Wiltgen, M Freudenberger, P Petrovic, K Cavalieri, M Gider, P Enzinger, C Fornage, M Debette, S Rotter, JI Ikram, MA Launer, LJ Schmidt, R AF Schmidt, Helena Zeginigg, Marion Wiltgen, Marco Freudenberger, Paul Petrovic, Katja Cavalieri, Margherita Gider, Pierre Enzinger, Christian Fornage, Myriam Debette, Stephanie Rotter, Jerome I. Ikram, Mohammad A. Launer, Lenore J. Schmidt, Reinhold CA CHARGE Consortium Neurology Workin TI Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease SO BRAIN LA English DT Article DE NOTCH3; cerebral small vessel disease; genetics; MRI; ageing ID AUSTRIAN STROKE PREVENTION; SMOOTH-MUSCLE-CELLS; MATTER HYPERINTENSITY VOLUME; WHITE-MATTER; COGNITIVE DECLINE; FOLLOW-UP; CADASIL; BRAIN; HAPLOTYPE; MUTATION AB Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association. C1 [Schmidt, Helena; Zeginigg, Marion; Freudenberger, Paul; Gider, Pierre] Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, A-8010 Graz, Austria. [Schmidt, Helena; Petrovic, Katja; Cavalieri, Margherita; Enzinger, Christian; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, A-8036 Graz, Austria. [Wiltgen, Marco] Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria. [Enzinger, Christian] Med Univ Graz, Dept Radiol, Neuroradiol Sect, A-8036 Graz, Austria. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. [Debette, Stephanie] Boston Univ, Dept Neurol, Sch Med, Boston, MA 02114 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Ikram, Mohammad A.] Erasmus MC Univ, Dept Epidemiol, Med Ctr, NL-3000 CA Rotterdam, Netherlands. [Ikram, Mohammad A.] Erasmus MC Univ, Dept Radiol, Med Ctr, NL-3000 CA Rotterdam, Netherlands. [Ikram, Mohammad A.] Netherlands Consortium Healthy Ageing, NL-2300 RC Leiden, Netherlands. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Schmidt, H (reprint author), Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, Harrachgasse 21, A-8010 Graz, Austria. EM helena.schmidt@medunigraz.at RI Cavalieri, Margherita/G-8053-2012; OI Ikram, Mohammad Arfan/0000-0003-0372-8585 FU Austrian Science Fund (FWF) [P20545-P05, P13180]; NIA [N01-AG-12100, AG08122, AG16495, AG033193, AG031287]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641, R01-HL093029, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01-HL087652, N01-HC-25195]; National Human Genome Research Institute [U01-HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; National Centre for Research Resources [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Affymetrix Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Institute of Neurological Disorders and Stroke [NS17950]; Netherlands Organization of Scientific Research (NWO) [175.010.2005.011]; Netherlands Genomics Initiative (NGI)/ NWO [050-060-810]; Erasmus Medical Centre and University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; NEI; NIDCD FX The Austrian Stroke Prevention Study: This work was supported by the Austrian Science Fund (FWF) grant number P20545-P05 to HS and P13180 to RS. The Medical University of Graz supports the database of the Austrian Stroke Prevention Study. Aging Gene-Environment Susceptibility - Reykjavik Study: The research has been funded by NIA contract N01-AG-12100 with contributions from NEI, NIDCD and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study: The research is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and grants R01-HL087641 and R01-HL093029; National Human Genome Research Institute contract U01-HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study: The research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01-HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Centre for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Centre Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Centre. Framingham Heart Study: From the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Ageing (AG08122, AG16495, AG033193, AG031287). Rotterdam Study: The GWA database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research (NWO; nr. 175.010.2005.011). This study was further supported by the Netherlands Genomics Initiative (NGI)/ NWO project 050-060-810. The Rotterdam Study is supported by the Erasmus Medical Centre and University, Rotterdam; the NWO, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. NR 52 TC 40 Z9 43 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD NOV PY 2011 VL 134 BP 3384 EP 3397 DI 10.1093/brain/awr252 PN 11 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 847MH UT WOS:000296976500030 PM 22006983 ER PT J AU Mitchell, GF van Buchem, MA Sigurdsson, S Gotal, JD Jonsdottir, MK Kjartansson, O Garcia, M Aspelund, T Harris, TB Gudnason, V Launer, LJ AF Mitchell, Gary F. van Buchem, Mark A. Sigurdsson, Sigurdur Gotal, John D. Jonsdottir, Maria K. Kjartansson, Olafur Garcia, Melissa Aspelund, Thor Harris, Tamara B. Gudnason, Vilmundur Launer, Lenore J. TI Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility - Reykjavik Study SO BRAIN LA English DT Article DE haemodynamics; aortic stiffness; magnetic resonance imaging; brain structure; cognitive function ID PULSE-WAVE VELOCITY; AORTIC INPUT IMPEDANCE; WHITE-MATTER LESIONS; SMALL-VESSEL DISEASE; INDEPENDENT PREDICTOR; HYPERTENSIVE PATIENTS; COGNITIVE PERFORMANCE; CARDIOVASCULAR MORTALITY; ADVANCING AGE; RISK AB Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid-femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility - Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69-93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta-carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta-carotid reflection coefficient (R = -0.66, P < 0.001). Carotid pulse pressure, pulsatility index and carotid-femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62-1.71 per standard deviation, P < 0.002). Carotid-femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 +/- 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (-0.127 +/- 0.037 SD/SD, P < 0.001), grey matter (-0.079 +/- 0.038 SD/SD, P = 0.038) and white matter (-0.128 +/- 0.039 SD/SD, P < 0.001) volumes. Carotid-femoral pulse wave velocity (-0.095 +/- 0.043 SD/SD, P = 0.028) and carotid pulse pressure (-0.114 +/- 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (-0.165 +/- 0.039 SD/SD, P < 0.001), slower processing speed (-0.118 +/- 0.033 SD/SD, P < 0.001) and worse performance on tests assessing executive function (-0.155 +/- 0.041 SD/SD, P < 0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains. C1 [Mitchell, Gary F.; Gotal, John D.] Cardiovasc Engn Inc, Norwood, MA 02062 USA. [van Buchem, Mark A.] Leiden Univ, Dept Radiol, Med Ctr, NL-2300 RC Leiden, Netherlands. [Sigurdsson, Sigurdur; Jonsdottir, Maria K.; Kjartansson, Olafur; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Jonsdottir, Maria K.] Univ Iceland, Fac Psychol, IS-101 Reykjavik, Iceland. [Garcia, Melissa; Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edgewater Dr,Suite 201A, Norwood, MA 02062 USA. EM garyfmitchell@mindspring.com RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health [N01-AG-12100]; National Institute on Ageing; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Institutes of Health, National Heart, Lung and Blood Institute [HL094898] FX National Institutes of Health (contract N01-AG-12100); National Institute on Ageing Intramural Research Programme; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Institutes of Health, National Heart, Lung and Blood Institute (HL094898). NR 46 TC 188 Z9 188 U1 4 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD NOV PY 2011 VL 134 BP 3398 EP 3407 DI 10.1093/brain/awr253 PN 11 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 847MH UT WOS:000296976500031 PM 22075523 ER PT J AU Medic, N Desai, A Komarow, H Burch, LH Bandara, G Beaven, MA Metcalfe, DD Gilfillan, AM AF Medic, Nevenka Desai, Avanti Komarow, Hirsh Burch, Lauranell H. Bandara, Geethani Beaven, Michael A. Metcalfe, Dean D. Gilfillan, Alasdair M. TI Examination of the role of TRPM8 in human mast cell activation and its relevance to the etiology of cold-induced urticaria SO CELL CALCIUM LA English DT Article DE TRPM8; Calcium; Mast cells; Cold-induced urticaria; Fc epsilon RI; Degranulation ID HISTAMINE-RELEASE; MEDIATOR RELEASE; PROSTAGLANDIN-D2; RECEPTORS; INDUCTION; MICE AB Mast cells are considered the primary initiators of allergic diseases as a consequence of the release of multiple inflammatory mediators on activation. Although predominately activated through antigen-mediated aggregation of IgE-occupied-Fc epsilon RI, they can also be induced to release mediators by other receptors and environmental stimuli. Based on studies conducted in the RBL 2H3 rodent mast cell line, the transient receptor potential melastatin 8 (TRPM8) cation channel has been implicated in the activation of mast cells in response to cold and, by inference, the development of urticaria. Here we investigated the expression and role of TRPM8 receptor, in both human and mouse non-transformed cells, with the aim of exploring the potential link between TRPM8 and the pathology of cold urticaria in humans. Although expressed in mouse mast cells, we found no evidence of TRPM8 expression in human mast cells or functional mutations in TRPM8 in cold urticaria patients. Furthermore, neither mouse nor human primary cultured mast cells degranulated in response to cold challenge or TRPM8 agonists and mast cell reactivity was unaffected in Trpm8(-/-) mice. From these data, we conclude that TRPM8 is unlikely to directly regulate mast cell activation in cold urticaria. Thus, alternative mechanisms likely exist for the pathogenesis of this disease. Published by Elsevier Ltd. C1 [Medic, Nevenka; Desai, Avanti; Komarow, Hirsh; Bandara, Geethani; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Burch, Lauranell H.] Natl Inst Environm Hlth Sci, Mol Genet Core Facil, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C206,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov FU Division of Intramural Research of NIAID; NHLBI within National Institutes of Health FX Financial support for this work was provided by the Division of Intramural Research of NIAID and NHLBI within the National Institutes of Health. The authors would like to thank Joel Abramowitz (NIEHS, NIH) who coordinated the effort and Dr. Ajay Dhaka (University of Washington, Seattle) and Dr. Ardem Patapoutian (The Scripps Research Institute) for supplying the Trpm8-/- mice; and Dr. Kirshenbaum and the LAD clinical staff for the provision of CD34+ cells. NR 38 TC 12 Z9 12 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD NOV PY 2011 VL 50 IS 5 BP 473 EP 480 DI 10.1016/j.ceca.2011.08.003 PG 8 WC Cell Biology SC Cell Biology GA 848GI UT WOS:000297038300008 PM 21906810 ER PT J AU Scher, HI Nasso, SF Rubin, EH Simon, R AF Scher, Howard I. Nasso, Shelley Fuld Rubin, Eric H. Simon, Richard TI Adaptive Clinical Trial Designs for Simultaneous Testing of Matched Diagnostics and Therapeutics SO CLINICAL CANCER RESEARCH LA English DT Article ID RESISTANT PROSTATE-CANCER; ABIRATERONE ACETATE; ANTITUMOR-ACTIVITY; SIGNATURE DESIGN; EXPRESSION; DOCETAXEL; CHALLENGES; THERAPY; SUBSET; GENES AB A critical challenge in the development of new molecularly targeted anticancer drugs is the identification of predictive biomarkers and the concurrent development of diagnostics for these biomarkers. Developing matched diagnostics and therapeutics will require new clinical trial designs and methods of data analysis. The use of adaptive design in phase III trials may offer new opportunities for matched diagnosis and treatment because the size of the trial can allow for subpopulation analysis. We present an adaptive phase III trial design that can identify a suitable target population during the early course of the trial, enabling the efficacy of an experimental therapeutic to be evaluated within the target population as a later part of the same trial. The use of such an adaptive approach to clinical trial design has the potential to greatly improve the field of oncology and facilitate the development of personalized medicine. Clin Cancer Res; 17(21); 6634-40. (C)2011 AACR. C1 [Scher, Howard I.] Mem Sloan Kettering Canc Ctr, Dept Med, Sidney Kimmel Ctr Prostate & Urol Canc, Genitourinary Oncol Serv, New York, NY 10021 USA. [Scher, Howard I.] Weill Cornell Med Coll, New York, NY USA. [Nasso, Shelley Fuld] Susan G Komen Cure Advocacy Alliance, Washington, DC USA. [Rubin, Eric H.] Merck Res Labs, Oncol Clin Res, Whitehouse Stn, NJ USA. [Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Scher, HI (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Sidney Kimmel Ctr Prostate & Urol Canc, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10021 USA. EM scherh@mskcc.org FU Ortho Biotech Oncology Research and Development; MSKCC SPORE in Prostate Cancer [P50 CA92629]; Department of Defense [PC051382]; Research and Therapeutics Program for Prostate Cancer; Prostate Cancer Foundation; Medivation FX Dr. Scher has received research funding from Ortho Biotech Oncology Research and Development and Medivation. He has served as a consultant or in an advisory role for Ortho Biotech Oncology Research and Development and Medivation. No potential conflicts of interest were disclosed by the other authors.; This work was supported in part by the MSKCC SPORE in Prostate Cancer (P50 CA92629), the Department of Defense Prostate Cancer Research Program (PC051382), The Research and Therapeutics Program for Prostate Cancer, and The Prostate Cancer Foundation. NR 29 TC 24 Z9 25 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2011 VL 17 IS 21 BP 6634 EP 6640 DI 10.1158/1078-0432.CCR-11-1105 PG 7 WC Oncology SC Oncology GA 842TS UT WOS:000296624000006 PM 22046024 ER PT J AU Turteltaub, KW Davis, MA Burns-Naas, LA Lawton, MP Clark, AM Reynolds, JA AF Turteltaub, Kenneth W. Davis, Myrtle A. Burns-Naas, Leigh Ann Lawton, Michael P. Clark, Adam M. Reynolds, Jack A. TI Identification and Elucidation of the Biology of Adverse Events: The Challenges of Safety Assessment and Translational Medicine SO CLINICAL CANCER RESEARCH LA English DT Article ID INDUCED VASCULAR INJURY; SYSTEMS BIOLOGY; CARDIOTOXICITY; INHIBITOR; BIOMARKERS AB There has been an explosion of technology-enabled scientific insight into the basic biology of the causes of adverse events. This has been driven, in part, by the development of the various "omics" tools (e. g., genomics, proteomics, and metabolomics) and associated bioinformatics platforms. Meanwhile, for decades, changes in preclinical testing protocols and guidelines have been limited. Preclinical safety testing currently relies heavily on the use of outdated animal models. Application of systems biology methods to evaluation of toxicities in oncology treatments can accelerate the introduction of safe, effective drugs. Systems biology adds insights regarding the causes and mechanisms of adverse effects, provides important and actionable information to help understand the risks and benefits to humans, focuses testing on methods that add value to the safety testing process, and leads to modifications of chemical entities to reduce liabilities during development. Leveraging emerging technologies, such as genomics and proteomics, may make preclinical safety testing more efficient and accurate and lead to better safety decisions. The development of a U. S. Food and Drug Administration guidance document on the use of systems biology in clinical testing would greatly benefit the development of drugs for oncology by communicating the potential application of specific methodologies, providing a framework for qualification and application of systems biology outcomes, and providing insight into the challenges and limitations of systems biology in the regulatory decision-making process. Clin Cancer Res; 17(21); 6641-5. (C)2011 AACR. C1 [Turteltaub, Kenneth W.] Battelle Mem Inst, Livermore, CA 94550 USA. [Turteltaub, Kenneth W.] Lawrence Livermore Natl Lab, Biosci & Biotechnol Div, Ctr Accelerator, Livermore, CA 94550 USA. [Burns-Naas, Leigh Ann; Lawton, Michael P.] Pfizer Inc, Drug Safety Res & Dev, San Diego, CA USA. [Davis, Myrtle A.] NCI, Pharmacol Branch, Bethesda, MD 20892 USA. [Clark, Adam M.] FasterCures, Sci & Fed Affairs, Washington, DC USA. [Reynolds, Jack A.] AnaBios Corp, San Diego, CA USA. RP Turteltaub, KW (reprint author), Battelle Mem Inst, 7000 East Ave,L-452, Livermore, CA 94550 USA. EM turteltaub2@llnl.gov NR 27 TC 10 Z9 10 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2011 VL 17 IS 21 BP 6641 EP 6645 DI 10.1158/1078-0432.CCR-11-1106 PG 5 WC Oncology SC Oncology GA 842TS UT WOS:000296624000007 PM 22046025 ER PT J AU Cleeland, CS O'Mara, A Zagari, M Baas, C AF Cleeland, Charles S. O'Mara, Ann Zagari, Martin Baas, Carole TI Integrating Pain Metrics into Oncology Clinical Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID MITOXANTRONE PLUS PREDNISONE; ADVANCED PROSTATE-CANCER; IMMPACT RECOMMENDATIONS; RANDOMIZED-TRIAL; CHEMOTHERAPY; SURVIVAL; SYMPTOMS; ADULTS AB Cancer-related pain is highly prevalent and often severe, and as a result is often one of the defining experiences for patients with malignancy. Patients and patients' families almost always live with the ever-present reality that cancer treatment and progression may be accompanied by pain. For patients nearing the end of life, most fear that their final days will be spent living with the terrible effects of the disease, the most important of which is pain. Despite this, there is far less systematic research on the mechanisms of cancer-related pain or on the development of new agents to reduce or eliminate pain in cancer patients compared with research to combat the disease itself. Further, even when the focus of research is treatment of the tumor, the effects of anticancer treatments on pain are often under-reported in publications and other forums. To illustrate the relative drought in the cancer pain control area, there have been no new drugs approved for cancer-related pain in recent years. A number of methodologic and logistical challenges that hinder the ability to assess pain response in clinical trials are discussed in this article. Possible ways to address these challenges are also discussed. Clin Cancer Res; 17(21); 6646-50. (C)2011 AACR. C1 [Cleeland, Charles S.] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Unit 1450, Houston, TX 77030 USA. [O'Mara, Ann] NCI, NIH, Bethesda, MD 20892 USA. [Zagari, Martin] Amgen Inc, Hlth Econ & Outcome Res, Thousand Oaks, CA 91320 USA. RP Cleeland, CS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Unit 1450, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM ccleeland@mdanderson.org FU AstraZeneca Pharmaceuticals FX Dr. Cleeland has received a commercial research grant from AstraZeneca Pharmaceuticals and has served as a consultant on the advisory board of Amgen Inc. and Abbott Laboratories. No potential conflicts of interest were disclosed by the other authors. NR 26 TC 9 Z9 9 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2011 VL 17 IS 21 BP 6646 EP 6650 DI 10.1158/1078-0432.CCR-11-1109 PG 5 WC Oncology SC Oncology GA 842TS UT WOS:000296624000008 PM 22046026 ER PT J AU Ambrose, LF Freedman, J Buetow, K Friend, S Schilsky, RL AF Ambrose, Laurie Fenton Freedman, Jamie Buetow, Kenneth Friend, Stephen Schilsky, Richard L. TI Using Patient-Initiated Study Participation in the Development of Evidence for Personalized Cancer Therapy SO CLINICAL CANCER RESEARCH LA English DT Article AB Personalized cancer therapy offers the promise of delivering the right treatments to the right patients to improve patient outcomes and quality of life, while reducing exposure to ineffective therapies and the cost of cancer care. Realizing this promise depends in large part on our ability to generate timely and sufficiently detailed information regarding factors that influence treatment response. Generating this evidence through the traditional physician investigator-initiated clinical trial system has proved to be challenging, given poor recruitment rates and low compliance with requests for biospecimen collection. As a result, our current understanding of treatment response is inadequate, particularly for cancer therapies that have been in use for many years. Patient-initiated study participation may offer a new model for evidence generation that capitalizes on strong patient interest in furthering research to inform better and more tailored cancer therapies. In this approach, patients are engaged and recruited directly by the sponsor of an Institutional Review Board-approved study, and patients subsequently drive the participation of their health care providers to facilitate collection of required data and tissue samples. The ultimate goal of these studies is to generate evidence of sufficient quality to inform regulatory decisions (i.e., labeling changes for marketed therapies to reflect populations most likely to respond) and treatment selection. Here, we describe a hypothetical prospective observational study in non-small cell lung cancer that could serve as a model for patient-initiated study participation applied to understand molecular determinants of treatment response. Key elements discussed include study design, patient engagement, and data/biospecimen collection and management principles. Clin Cancer Res; 17(21); 6651-7. (C)2011 AACR. C1 [Schilsky, Richard L.] Univ Chicago, Med Ctr, Div Biol Sci, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Ambrose, Laurie Fenton] Lung Canc Alliance, Washington, DC USA. [Freedman, Jamie] GlaxoSmithKline Inc, Collegeville, PA USA. [Buetow, Kenneth] NCI, Bethesda, MD 20892 USA. [Friend, Stephen] Sage Bionetworks, Seattle, WA USA. RP Schilsky, RL (reprint author), Univ Chicago, Med Ctr, Div Biol Sci, Ctr Comprehens Canc, 5841 S Maryland Ave,MC 2115, Chicago, IL 60637 USA. EM rschilsk@medicine.bsd.uchicago.edu NR 17 TC 4 Z9 4 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2011 VL 17 IS 21 BP 6651 EP 6657 DI 10.1158/1078-0432.CCR-11-1110 PG 7 WC Oncology SC Oncology GA 842TS UT WOS:000296624000009 PM 22046027 ER PT J AU Rajan, A Kelly, RJ Trepel, JB Kim, YS Alarcon, SV Kummar, S Gutierrez, M Crandon, S Zein, WM Jain, L Mannargudi, B Figg, WD Houk, BE Shnaidman, M Brega, N Giaccone, G AF Rajan, Arun Kelly, Ronan J. Trepel, Jane B. Kim, Yeong Sang Alarcon, Sylvia V. Kummar, Shivaani Gutierrez, Martin Crandon, Sonja Zein, Wadih M. Jain, Lokesh Mannargudi, Baskar Figg, William D. Houk, Brett E. Shnaidman, Michael Brega, Nicoletta Giaccone, Giuseppe TI A Phase I Study of PF-04929113 (SNX-5422), an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Patients with Refractory Solid Tumor Malignancies and Lymphomas SO CLINICAL CANCER RESEARCH LA English DT Article ID CHAPERONE MACHINERY; SIGNALING PATHWAYS; HSP90 INHIBITION; ADULT PATIENTS; CANCER; 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN; RESISTANCE; SNX-2112; GROWTH; CELLS AB Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. Methods: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response. Results: Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m(2) administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction. Conclusions: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study. Clin Cancer Res; 17(21); 6831-9. (C)2011 AACR. C1 [Rajan, Arun; Kelly, Ronan J.; Trepel, Jane B.; Kim, Yeong Sang; Alarcon, Sylvia V.; Kummar, Shivaani; Gutierrez, Martin; Crandon, Sonja; Jain, Lokesh; Mannargudi, Baskar; Figg, William D.; Giaccone, Giuseppe] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Zein, Wadih M.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Houk, Brett E.; Shnaidman, Michael; Brega, Nicoletta] Pfizer, Milan, Italy. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Figg Sr, William/M-2411-2016; Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Mannargudi, Baskar/0000-0001-6430-0641 FU National Cancer Institute; NIH; Pfizer Oncology; La Jolla Laboratories, San Diego, CA; NIH at the 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, NIH. This work was supported by Pfizer Oncology, La Jolla Laboratories, San Diego, CA, and the Intramural Research Program of the NIH at the National Cancer Institute, Center for Cancer Research. NR 29 TC 57 Z9 58 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2011 VL 17 IS 21 BP 6831 EP 6839 DI 10.1158/1078-0432.CCR-11-0821 PG 9 WC Oncology SC Oncology GA 842TS UT WOS:000296624000026 PM 21908572 ER PT J AU Hardy, NM Mossoba, ME Steinberg, SM Fellowes, V Yan, XY Hakim, FT Babb, RR Avila, D Gea-Banacloche, J Sportes, C Levine, BL June, CH Khuu, HM Carpenter, AE Krumlauf, MC Dwyer, AJ Gress, RE Fowler, DH Bishop, MR AF Hardy, Nancy M. Mossoba, Miriam E. Steinberg, Seth M. Fellowes, Vicki Yan, Xiao-Yi Hakim, Frances T. Babb, Rebecca R. Avila, Daniele Gea-Banacloche, Juan Sportes, Claude Levine, Bruce L. June, Carl H. Khuu, Hahn M. Carpenter, Ashley E. Krumlauf, Michael C. Dwyer, Andrew J. Gress, Ronald E. Fowler, Daniel H. Bishop, Michael R. TI Phase I Trial of Adoptive Cell Transfer with Mixed-Profile Type-I/Type-II Allogeneic T Cells for Metastatic Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; DONOR TH2 CELLS; EX-VIVO; CD3/CD28 COSTIMULATION; GRAFT-REJECTION; CLINICAL-TRIAL; IMMUNOTHERAPY; CONSENSUS; DEPLETION AB Purpose: Metastatic breast cancer (MBC) response to allogeneic lymphocytes requires donor T-cell engraftment and is limited by graft-versus-host disease (GVHD). In mice, type-II-polarized T cells promote engraftment and modulate GVHD, whereas type-I-polarized T cells mediate more potent graft-versus-tumor (GVT) effects. This phase I translational study evaluated adoptive transfer of ex vivo costimulated type-I/type-II (T1/T2) donor T cells with T-cell-depleted (TCD) allogeneic stem cell transplantation (AlloSCT) for MBC. Experimental Design: Patients had received anthracycline, taxane, and antibody therapies, and been treated for metastatic disease and a human leukocyte antigen (HLA)-identical-sibling donor. Donor lymphocytes were costimulated ex vivo with anti-CD3/anti-CD28 antibody-coated magnetic beads in interleukin (IL)-2/IL-4-supplemented media. Patients received reduced intensity conditioning, donor stem cells and T1/T2 cells, and monitoring for toxicity, engraftment, GVHD, and tumor response; results were compared with historical controls, identically treated except for T1/T2 product infusions. Results: Mixed type-I/type-II CD4(+) T cells predominated in T1/T2 products. Nine patients received T1/T2 cells at dose level 1 (5 x 10(6) cells/kg). T-cell donor chimerism reached 100% by a median of 28 days. Seven (78%) developed acute GVHD. At day +28, five patients had partial responses (56%) and none had MBC progression; thereafter, two patients had continued responses. Donor T-cell engraftment and tumor responses appeared faster than in historical controls, but GVHD rates were similar and responders progressed early, often following treatment of acute GVHD. Conclusion: Allogeneic T1/T2 cells were safely infused with TCD-AlloSCT, appeared to promote donor engraftment, and may have contributed to transient early tumor responses. Clin Cancer Res; 17(21); 6878-87. (C)2011 AACR. RP Hardy, NM (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH,Hatfield Clin Res Ctr, 10 Ctr Dr,Room 3E-3330, Bethesda, MD 20892 USA. EM hardyn@mail.nih.gov RI Levine, Bruce/D-1688-2009 FU Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD. NR 41 TC 3 Z9 4 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2011 VL 17 IS 21 BP 6878 EP 6887 DI 10.1158/1078-0432.CCR-11-1579 PG 10 WC Oncology SC Oncology GA 842TS UT WOS:000296624000031 PM 21948234 ER PT J AU Berger, VW AF Berger, Vance W. TI Different name, same problems SO CONTEMPORARY CLINICAL TRIALS LA English DT Letter DE Allocation concealment; Clinical trial; Masking; Selection bias ID MINIMIZATION C1 [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, 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 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2011 VL 32 IS 6 BP 785 EP 785 DI 10.1016/j.cct.2011.08.002 PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 841CE UT WOS:000296489100002 PM 21864720 ER PT J AU Marcus, PM Gareen, IF Miller, AB Rosenbaum, J Keating, K Aberle, DR Berg, CD AF Marcus, Pamela M. Gareen, Ilana F. Miller, Anthony B. Rosenbaum, Jennifer Keating, Kristen Aberle, Denise R. Berg, Christine D. TI The National Lung Screening Trial's Endpoint Verification Process: Determining the cause of death SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Randomized controlled trials; Adjudication committee; Lung cancer; Cause of death; Mass screening ID CANCER MORTALITY; CERTIFICATES; PROJECT AB Background: Randomized controlled trials (RCTs) evaluating cancer screening modalities usually employ cause-specific mortality as their primary endpoint. Because death certificate cause of death can be inaccurate, RCTs frequently use review committees to assign an underlying cause of death. We describe the National Lung Screening Trial's (NLST's) death review approach, the Endpoint Verification Process (EVP), which strives to minimize errors in assignment of cause of death due to lung cancer. Methods: Deaths selected for review include those with a notation of lung cancer on the death certificate and those occurring among participants ever diagnosed with lung cancer. Other criteria that trigger death review include, but are not limited to, death within 6 months of a screen suspicious for lung cancer and death within 60 days of certain diagnostic evaluation procedures associated with a screen suspicious for lung cancer or a lung cancer diagnosis. EVP requires concordance on whether death was due to lung cancer. Deaths are first reviewed by the EVP chair. If concordance is not achieved, the death is next reviewed by an Endpoint Verification Team (EVT) member. If concordance between the chair- and member-assigned cause of death is not achieved, the death is next reviewed by a group of at least three EVT members. Cause of death is assigned at the step in which concordance was achieved, or if necessary, at the team review. Conclusions: NLSTs EVP is designed to produce a highly accurate count of lung cancer deaths. Published by Elsevier Inc. C1 [Marcus, Pamela M.; Berg, Christine D.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Gareen, Ilana F.] Brown Univ, Ctr Stat Sci, Providence, RI 02912 USA. [Gareen, Ilana F.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. [Rosenbaum, Jennifer; Keating, Kristen] WESTAT Corp, Rockville, MD 20850 USA. [Aberle, Denise R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. RP Marcus, PM (reprint author), NCI, Canc Prevent Div, 6130 Execut Blvd,Suite 3131, Bethesda, MD 20892 USA. EM marcusp@mail.nih.gov; igareen@stat.brown.edu; Ab.miller@sympatico.ca; Rosenbj1@westat.com; kristenkeating@westat.com; daberle@mednet.ucla.edu; bergc@mail.nih.gov RI Gareen, Ilana/I-2816-2014; Berg , Christine/K-1047-2014; OI Gareen, Ilana/0000-0002-0457-5595; Aberle, Denise/0000-0002-8858-3401 FU Division of Cancer Prevention, National Cancer Institute, NIH, DHHS [N01CN25476, N01CN25511, N01CN25512, N01CN25513, N01CN25514, N01CN25515, N01CN25516, N01CN25518, N01CN25522, N01CN25524, N01CN75022]; Division of Cancer Treatment and Diagnosis, NCI; [U01 80098]; [CA79778] FX This research was supported by contracts (N01CN25476, N01CN25511, N01CN25512, N01CN25513, N01CN25514, N01CN25515, N01CN25516, N01CN25518, N01CN25522, N01CN25524, N01CN75022) from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS, and by grants (U01 80098 and CA79778) to the American College of Radiology Imaging Network (ACRIN) under a cooperative agreement with the Cancer Imaging Program, Division of Cancer Treatment and Diagnosis, NCI. NR 13 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2011 VL 32 IS 6 BP 834 EP 840 DI 10.1016/j.cct.2011.07.003 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 841CE UT WOS:000296489100010 PM 21782037 ER PT J AU Diamond, MP Mitwally, M Casper, R Ager, J Legro, RS Brzyski, R Casson, P Eisenberg, E Zhang, HP AF Diamond, Michael P. Mitwally, Mohamed Casper, Robert Ager, Joel Legro, Richard S. Brzyski, Robert Casson, Peter Eisenberg, Esther Zhang, Heping CA NICHD Cooperative Reprod Med TI Estimating rates of multiple gestation pregnancies: Sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Multiple gestation; Ovulation induction; Gonadotropins; Aromatase inhibitor; Unexplained infertility ID IN-VITRO FERTILIZATION; UNEXPLAINED INFERTILITY; OVULATION INDUCTION; TRIPLET PREGNANCIES; SELECTIVE REDUCTION; CLOMIPHENE CITRATE; RANDOMIZED-TRIAL; UNITED-STATES; INSEMINATION; SUPEROVULATION AB Infertility afflicts 15% of couples who wish to conceive. Despite intensive evaluation of both male and female partners, the etiology may remain unknown leading to a diagnosis of unexplained infertility. For such couples, treatment often entails ovulation induction (OI) with fertility medications coupled with intrauterine insemination. Complications of this therapy include ovarian hyperstimulation syndrome and creation of multiple gestation pregnancies, which can be complicated by preterm labor and delivery, and the associated neonatal morbidity and expense of care for preterm infants. The Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) study is designed to assess whether OI in couples with unexplained infertility with an aromatase inhibitor produces mono-follicular development in most cycles, thereby reducing multiple gestations while maintaining a comparable pregnancy success rate to that achieved by OI with either gonadotropins or clomiphene citrate. These results will provide future guidance of therapy for couples with unexplained infertility, and if comparable pregnancy rates are achieved with a substantial reduction in multiple gestations, the public health benefit will be considerable. (C) 2011 Elsevier Inc. All rights reserved. C1 [Diamond, Michael P.] Wayne State Univ, Sch Med, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Mitwally, Mohamed] Canadian Amer Reprod Med, Toronto, ON M5S 2X9, Canada. [Casper, Robert] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5S 2X9, Canada. [Ager, Joel] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA. [Legro, Richard S.] RM C3604 Penn State Univ, Coll Med, MS Hershey Med Ctr, Dept Obstet & Gynecol, Hershey, PA 17033 USA. [Brzyski, Robert] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Casson, Peter] Univ Vermont, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Burlington, VT 05401 USA. [Eisenberg, Esther] CPR Eunice Kennedy Shriver Natl Inst Child Hlth &, Reprod Med Network, Reprod Sci Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Heping] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. RP Diamond, MP (reprint author), Wayne State Univ, Sch Med, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, 60 W Hancock, Detroit, MI 48201 USA. EM mdiamond@med.wayne.edu; mmitwally@yahoo.com; casper@lunenfeld.ca; jager@med.wayne.edu; rsl1@psu.edu; brzyski@uthscsa.edu; peter.casson@vtmednet.org; eisenbes@mail.nih.gov; heping.zhang@yale.edu OI Diamond, Michael/0000-0001-6353-4489 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [5U10 HD 039005, 3U10 HD 039005-S1, 5U10 HD 038992, 3U10 HD 038992-S1, 5U10 HD 055942, 3U10 HD 055942-S1, 5U10 HD 055944, 3U10 HD 055944-S1, 5U10HD055925, 5U10HD055925-S1] FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5U10 HD 039005, 3U10 HD 039005-S1, 5U10 HD 038992, 3U10 HD 038992-S1, 5U10 HD 055942, 3U10 HD 055942-S1, 5U10 HD 055944, 3U10 HD 055944-S1, 5U10HD055925, 5U10HD055925-S1). NR 47 TC 20 Z9 20 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2011 VL 32 IS 6 BP 902 EP 908 DI 10.1016/j.cct.2011.07.009 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 841CE UT WOS:000296489100018 PM 21787883 ER PT J AU Negishi, M AF Negishi, Masahiko TI CAR and PXR at the Cross-Roads of Xenobiotic-Cell Signal Interactions SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional ISSX Meeting CY OCT 16-20, 2011 CL Atlanta, GA C1 [Negishi, Masahiko] NIEHS, Pharmacogenet Sect, LRDT, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 17 EP 18 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400037 ER PT J AU Goldstein, JA Rana, R Surapureddi, S AF Goldstein, Joyce A. Rana, Ritu Surapureddi, Sailesh TI Applications of siRNA to resolve mechanisms of regulation of drug metabolizing enzmes through nuclear receptors and coactivators SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional ISSX Meeting CY OCT 16-20, 2011 CL Atlanta, GA C1 [Goldstein, Joyce A.; Rana, Ritu; Surapureddi, Sailesh] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 20 EP 21 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400044 ER PT J AU Li, LH Li, HS Sueyoshi, T Negishi, M Wang, HB AF Li, Linhao Li, Haishan Sueyoshi, Tatsuya Negishi, Masahiko Wang, Hongbing TI The inductive expression of citrate transporter SLC13A5 gene is regulated by the xenobiotic receptor CAR and PXR in human liver SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional ISSX Meeting CY OCT 16-20, 2011 CL Atlanta, GA C1 [Li, Linhao; Wang, Hongbing] Univ Maryland, Baltimore, MD 21201 USA. [Li, Haishan] Chinese Acad Inspect & Quarantine, Beijing, Peoples R China. [Sueyoshi, Tatsuya; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, LRDT, NIH, Res Triangle Pk, NC 27709 USA. RI Li, Linhao/A-6348-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 35 EP 36 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400070 ER PT J AU Lee, JS Ward, WO Ren, HZ Vallanat, B DeVito, MJ Corton, JC AF Lee, Janice S. Ward, William O. Ren, Hongzu Vallanat, Beena DeVito, Michael J. Corton, Jon C. TI Characterization of the impact of life stage on xenobiotic metabolizing enzyme expression and gene - chemical interactions in the liver SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional ISSX Meeting CY OCT 16-20, 2011 CL Atlanta, GA C1 [Lee, Janice S.; Ward, William O.; Ren, Hongzu; Vallanat, Beena; Corton, Jon C.] US EPA, Res Triangle Pk, NC 27711 USA. [DeVito, Michael J.] NIEHS NTP, Toxicol Branch, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 72 EP 72 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400140 ER PT J AU Richardson, VM Sey, YM DeVito, MJ AF Richardson, Vicki M. Sey, Yusupha M. DeVito, Michael J. TI Thyroxine (T-4) catabolism in human and rat hepatocytes increases following exposure to prototypical hepatic enzyme inducers SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 16-20, 2011 CL Atlanta, GA SP Int Soc Study Xenobiot (ISSX) C1 [Richardson, Vicki M.; Sey, Yusupha M.] US EPA, ORD Nheerl Istd PB, Res Triangle Pk, NC USA. [Richardson, Vicki M.] Univ N Carolina, Res Triangle Pk, NC USA. [DeVito, Michael J.] NIEHS NTP, Toxicol Branch, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 148 EP 148 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400283 ER PT J AU Osabe, M Negishi, M AF Osabe, Makoto Negishi, Masahiko TI Phospho-ERK1/2 interacts with the nuclear receptor CAR and represses de-phosphorylation of threonine 38 to inactive CAR in Huh-7 cells SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional ISSX Meeting CY OCT 16-20, 2011 CL Atlanta, GA C1 [Osabe, Makoto; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, LRDT, NIH, Res Triangle Pk, NC 27709 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 185 EP 185 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400351 ER PT J AU Shindo, S Squires, J Sakuma, T Kanayama, T Moore, R Negishi, M AF Shindo, Sawako Squires, James Sakuma, Tsutomu Kanayama, Tomohiko Moore, Rick Negishi, Masahiko TI Phosphorylation of estrogen receptor in reproductive organs of female mice SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional ISSX Meeting CY OCT 16-20, 2011 CL Atlanta, GA C1 [Shindo, Sawako; Squires, James; Sakuma, Tsutomu; Kanayama, Tomohiko; Moore, Rick; Negishi, Masahiko] Natl Inst Environm Hlth Sci, Pharmacogenet Sect, LRDT, NIH, Res Triangle Pk, NC USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 186 EP 186 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400352 ER PT J AU Cheng, J AF Cheng, Jie TI Rifaximin toxicity on hepatocellular fatty degeneration via activation of human pregnane X receptor SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 17th North American Regional ISSX Meeting CY OCT 16-20, 2011 CL Atlanta, GA C1 [Cheng, Jie] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2011 VL 43 SU 2 SI SI BP 187 EP 187 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848MT UT WOS:000297056400354 ER PT J AU Velma, V Tchounwou, PB AF Velma, Venkatramreddy Tchounwou, Paul B. TI Hexavalent Chromium-Induced Multiple Biomarker Responses in Liver and Kidney of Goldfish, Carassius auratus SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE hexavalent chromium; goldfish; subchronic exposure; catalase; superoxide dismutase; glutathione peroxidase; metallothionein; protein expression; oxidative stress ID OXIDATIVE STRESS; LIPID-PEROXIDATION; SODIUM DICHROMATE; ACUTE TOXICITY; RAINBOW-TROUT; ANTIOXIDANT; WATER; FISH; METALLOTHIONEIN; EXPOSURE AB Hexavalent chromium [Cr (VI)] is a constituent of chromite ore. Although it is known to have several industrial and technological applications, its release into the aquatic environment as a result of chemical spill or inadequate waste discharge may hamper the health of aquatic organisms. In this study, we have investigated the effects of Cr (VI) on multiple biomarkers responses in goldfish under subchronic exposure conditions. Laboratory-acclimatized fish were exposed to 4.25 ppm and 8.57 ppm Cr (VI) for four weeks using a continuous flow-through system. During exposure, fish samples were collected on a weekly basis and analyzed for multiple biomarkers including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), metallothionein (MT), and total protein in liver and kidney. Study results indicated that the CAT activity and total protein levels in Cr (VI) - treated goldfish did not significantly differ (P > 0.05) from their respective controls during experimentation. However, highly significant up-regulations (P < 0.05) of SOD, GPx, and MT expression in Cr (VI) - treated goldfish were recorded at different exposure times depending on Cr (VI) concentration, test organ, and/or biomarker of interest. For example, significantly higher liver GPx levels were found at weeks 2 and 3 in the 4.25 ppm concentration, and at weeks 3 and 4 in the 8.57 ppm, while kidney GPx levels were significantly higher at weeks 1, 2 and 3 in the 4.25 ppm concentration, and at weeks 2, 3 and 4 in the 8.57 ppm concentration. In summary, Cr (VI)-induced oxidative stress was characterized by statistically significant increases in SOD, GPx, and MT expression in goldfish tissues; with the kidney showing a relatively higher sensitivity to Cr (VI) toxicity compared with the liver. (C) 2010 Wiley Periodicals, Inc. Environ Toxicol 26: 649-656, 2011. C1 [Velma, Venkatramreddy; Tchounwou, Paul B.] Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Environm Toxicol Res Lab, Jackson, MS USA. RP Tchounwou, PB (reprint author), Jackson State Univ, Coll Sci Engn & Technol, NIH RCMI Ctr Environm Hlth, Environm Toxicol Res Lab, 1400 Lynch St,Box 18750, Jackson, MS USA. EM paul.b.tchounwou@jsums.edu FU National Institutes of Health RCMI [2G12RR013459]; National Oceanic and Atmospheric Administration ECSC [NA06OAR4810164, 000953] FX Contract grant sponsor: National Institutes of Health RCMI; Contract grant number: 2G12RR013459; Contract grant sponsor: National Oceanic and Atmospheric Administration ECSC; Contract grant number: NA06OAR4810164, 000953 NR 39 TC 10 Z9 14 U1 1 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1520-4081 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD NOV PY 2011 VL 26 IS 6 BP 649 EP 656 DI 10.1002/tox.20602 PG 8 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA 849CJ UT WOS:000297102800009 PM 20549632 ER PT J AU Pang, ALY Clark, J Chan, WY Rennert, OM AF Pang, Alan L. Y. Clark, Jessica Chan, Wai-Yee Rennert, Owen M. TI Expression of human NAA11 (ARD1B) gene is tissue-specific and is regulated by DNA methylation SO EPIGENETICS LA English DT Article DE arrest defective 1; N(alpha)-acetyltransferase; spermatogenesis; testis; placenta; methylation-specific polymerase chain reaction; CpG island methylation; promoter assay; retrogene ID CANCER-CELL-PROLIFERATION; ACETYLTRANSFERASE COMPLEX; TERMINAL ACETYLTRANSFERASES; ACETYLATION; PROTEINS; YEAST; MECHANISM; PROMOTER; HARD1; NATA AB NAA10 gene encodes the catalytic subunit of N(alpha)-acetyltransferase NatA that catalyzes the acetylation of the N-termini of many eukaryotic proteins. A homologous gene called NAA11 is also present in mammalian cells. hNaa10p and hNaa11p are reported to be co-expressed in human cell cultures. In mouse tissues, however, Naa11 transcripts can only be detected in gonadal tissues whereas Naa10 transcripts are present in various tissues. We re-examined the expression of NAA11 in human cell lines and expanded the test to normal as well as cancerous human tissues. Surprisingly, we did not detect the expression of NAA11 in human cell lines that previously were reported to express it. Similar to its mouse ortholog, NAA10 displayed widespread expression in human tissues. NAA11 transcripts, however, were only detected in testicular and placental tissues. The lack of NAA11 expression was also demonstrated in eight different types of human cancerous tissues. By methylation-specific polymerase chain reaction and bisulfite sequencing, we found that the absence of NAA11 expression correlated with hypermethylation of the CpG island located at the proximal promoter of NAA11 gene. We also found that the cloned NAA11 gene promoter fragment was active when introduced into non NAA11-expressing human cells and its promoter activity was lost upon in vitro DNA methylation. Taken together, our results indicate NAA11 expression is tissue-specific and is epigenetically regulated by DNA methylation. C1 [Pang, Alan L. Y.; Clark, Jessica; Chan, Wai-Yee; Rennert, Owen M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, NIH, Bethesda, MD USA. [Chan, Wai-Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. RP Pang, ALY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, NIH, Bethesda, MD USA. EM panga@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 37 TC 3 Z9 3 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 J9 EPIGENETICS-US JI Epigenetics PD NOV PY 2011 VL 6 IS 11 BP 1391 EP 1399 DI 10.4161/epi.6.11.18125 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 849ZD UT WOS:000297163200012 PM 22048246 ER PT J AU Ansenberger-Fricano, K Mao, M Stadler, K Mason, RP Santos, JH Bonini, M AF Ansenberger-Fricano, Kristine Mao, Mao Stadler, Krisztian Mason, Ronald P. Santos, Janine H. Bonini, Marcelo TI Manganese Superoxide Dismutase Overexpression Leads To Cancer Cell Survival SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Ansenberger-Fricano, Kristine; Mao, Mao; Bonini, Marcelo] Univ Illinois, Chicago, IL USA. [Mason, Ronald P.] NIEHS, NIH, Res Triangle Pk, NC USA. [Santos, Janine H.] UMDNJ, Piscataway, NJ USA. RI Mao, Mao/E-3783-2013 OI Mao, Mao/0000-0003-1524-8853 NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S119 EP S119 DI 10.1016/j.freeradbiomed.2011.10.307 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600301 ER PT J AU Chatterjee, S Tokar, EJ Kadiiska, M Waalkes, M Diehl, AM Mason, RP AF Chatterjee, Saurabh Tokar, Erik J. Kadiiska, Maria Waalkes, Michael Diehl, Anna Mae Mason, Ronald P. TI Leptin is Key To Macrophage-Dependent Free Radical Formation in Ccl(4)-Induced Exacerbation of Steatohepatitis of Obesity SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Chatterjee, Saurabh; Tokar, Erik J.; Kadiiska, Maria; Waalkes, Michael; Mason, Ronald P.] NIEHS, NIH, Bethesda, MD 20892 USA. [Diehl, Anna Mae] Duke Univ, Div Gastroenterol, Durham, NC 27706 USA. NR 0 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S26 EP S27 DI 10.1016/j.freeradbiomed.2011.10.061 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600055 ER PT J AU Cho, HY Jedlicka, AE Gladwell, W Marzec, J Kleeberger, SR AF Cho, Hye-Youn Jedlicka, Anne E. Gladwell, Wesley Marzec, Jacqui Kleeberger, Steven R. TI Nrf2 Polymorphisms and Association With Susceptibility To Oxidative Lung Injury in Mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Cho, Hye-Youn; Gladwell, Wesley; Marzec, Jacqui; Kleeberger, Steven R.] Natl Inst Environm Hlth Sci, NIH, Bethesda, MD USA. [Jedlicka, Anne E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. NR 0 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S110 EP S110 DI 10.1016/j.freeradbiomed.2011.10.346 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600281 ER PT J AU Das, DK Gurusamy, N Mukhopadhyay, P AF Das, Dipak K. Gurusamy, Narasimman Mukhopadhyay, Partha TI Resveratrol-Modified Stem Cell in Cardiac Regeneration: Role of Micro RNA 20b SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Das, Dipak K.; Gurusamy, Narasimman] Univ Connecticut, Sch Med, Storrs, CT 06269 USA. [Mukhopadhyay, Partha] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S39 EP S40 DI 10.1016/j.freeradbiomed.2011.10.096 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600089 ER PT J AU Hwang, P AF Hwang, Paul TI p53, AEROBIC METABOLISM AND CANCER SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Hwang, Paul] NHLBI, NIH, Bethesda, MD USA. NR 0 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S7 EP S7 DI 10.1016/j.freeradbiomed.2011.10.015 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600012 ER PT J AU Joseph, J Zielonka, J Pacher, P Kalyanaraman, B AF Joseph, Joy Zielonka, Jacek Pacher, Pal Kalyanaraman, Balaraman TI Syntheses and Applications of Mitochondria-Targeted Antioxidants SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Joseph, Joy; Zielonka, Jacek; Kalyanaraman, Balaraman] Med Coll Wisconsin, Milwaukee, WI USA. [Pacher, Pal] NIH, Bethesda, MD 20892 USA. RI Zielonka, Jacek/N-9546-2014 OI Zielonka, Jacek/0000-0002-2524-0145 NR 0 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S88 EP S88 DI 10.1016/j.freeradbiomed.2011.10.406 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600220 ER PT J AU Leinisch, F Ranguelova, K DeRose, E Jiang, J Mason, RP AF Leinisch, Fabian Ranguelova, Kalina DeRose, Eugene Jiang, JinJie Mason, Ronald P. TI Determination of ESR Spin-Trapping Artifacts Originating from the Forrester-Hepburn Mechanism SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Leinisch, Fabian; DeRose, Eugene; Jiang, JinJie; Mason, Ronald P.] NIEHS, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S146 EP S146 DI 10.1016/j.freeradbiomed.2011.10.249 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600381 ER PT J AU Mukhopadhyay, P Horvath, B Kechrid, M Tanchian, G Rajesh, M Boulares, H Pacher, P AF Mukhopadhyay, Partha Horvath, Bela Kechrid, Malek Tanchian, Galin Rajesh, Mohanraj Boulares, Hamid Pacher, Pal TI Poly(ADP-ribose)Polymerase-1 is a Key Mediator of Cisplatin-Induced Kidney Inflammation And SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Mukhopadhyay, Partha; Horvath, Bela; Kechrid, Malek; Tanchian, Galin; Rajesh, Mohanraj; Pacher, Pal] NIAAA, NIH, Bethesda, MD 20892 USA. RI Horvath, Bela/A-7368-2009 NR 0 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S93 EP S93 DI 10.1016/j.freeradbiomed.2011.10.456 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600235 ER PT J AU Nagababu, E AF Nagababu, Enika TI Reaction of Nitric Oxide With Glutathionylcobalamin Forms a Ternary Complex SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Nagababu, Enika] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S160 EP S160 DI 10.1016/j.freeradbiomed.2011.10.221 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600422 ER PT J AU Park, JW Piknova, B Schechter, AN AF Park, Ji Won Piknova, Barbora Schechter, Alan N. TI Effect of Nitrite Level On Platelet Function in Mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Park, Ji Won; Piknova, Barbora; Schechter, Alan N.] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. NR 0 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S161 EP S162 DI 10.1016/j.freeradbiomed.2011.10.225 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600426 ER PT J AU Piknova, B Schechter, AN AF Piknova, Barbora Schechter, Alan N. TI Variation of NO Production From Arterial and Venous Endothelium - Base for Artery-To-Vein Nitrite Gradient? SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Piknova, Barbora; Schechter, Alan N.] NIDDK, NIH, Bethesda, MD USA. NR 0 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S162 EP S162 DI 10.1016/j.freeradbiomed.2011.10.226 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600427 ER PT J AU Salmon, A Van Remmen, H Pulliam, D Liu, YH Styskal, J Bhattacharya, A Kim, G Zhao, H Levine, R Richardson, A AF Salmon, Adam Van Remmen, Holly Pulliam, Daniel Liu, Yuhong Styskal, JennaLynn Bhattacharya, Arunabh Kim, Geumsoo Zhao, Hang Levine, Rodney Richardson, Arlan TI Mitochondria-Generated Oxidative Stress is Altered by Subcellular Localization of MsrA Overexpression SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Salmon, Adam; Van Remmen, Holly; Pulliam, Daniel; Liu, Yuhong; Styskal, JennaLynn; Bhattacharya, Arunabh; Richardson, Arlan] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Kim, Geumsoo; Zhao, Hang; Levine, Rodney] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S139 EP S139 DI 10.1016/j.freeradbiomed.2011.10.297 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600363 ER PT J AU Welsh, J Wagner, B Zehr, P Berg, D Halfdanarson, T Yee, N Bodeker, K Bhatia, S Buettner, G Levine, M Cullen, J AF Welsh, Jessemae Wagner, Brett Zehr, Pamela Berg, Daniel Halfdanarson, Thorvardur Yee, Nelson Bodeker, Kellie Bhatia, Sundershan Buettner, Garry Levine, Mark Cullen, Joseph TI A Phase I Clinical Trial of Ascorbic Acid and Gemcitabine for the Treatment of Metastatic Pancreatic Cancer SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract CT 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM) CY NOV 16-20, 2011 CL Atlanta, GA SP Soc Free Rad Biol & Med (SFRBM) C1 [Welsh, Jessemae; Wagner, Brett; Zehr, Pamela; Berg, Daniel; Halfdanarson, Thorvardur; Yee, Nelson; Bodeker, Kellie; Bhatia, Sundershan; Buettner, Garry; Cullen, Joseph] Univ Iowa, Iowa City, IA 52242 USA. [Levine, Mark] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 SU 1 BP S130 EP S130 DI 10.1016/j.freeradbiomed.2011.10.342 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 848FS UT WOS:000297036600336 ER PT J AU Cirulli, ET Heinzen, EL Dietrich, FS Shianna, KV Singh, A Maia, JM Goedert, JJ Goldstein, DB AF Cirulli, Elizabeth T. Heinzen, Erin L. Dietrich, Fred S. Shianna, Kevin V. Singh, Abanish Maia, Jessica M. Goedert, James J. Goldstein, David B. TI A whole-genome analysis of premature termination codons SO GENOMICS LA English DT Article DE Nonsense-mediated decay; Whole-genome sequencing; RNA-Seq; Premature termination codons ID MESSENGER-RNA DECAY; NONSENSE-MEDIATED DECAY; GENE; NMD; POSITION AB We sequenced the genomes of ten unrelated individuals and identified heterozygous stop codon-gain variants in protein-coding genes: we then sequenced their transcriptomes and assessed the expression levels of the stop codon-gain alleles. An ANOVA showed statistically significant differences between their expression levels (p = 4 x 10(-16)). This difference was almost entirely accounted for by whether the stop codon-gain variant had a second, non-protein-truncating function in or near an alternate transcript: stop codon-gains without alternate functions were generally not found in the cDNA (p = 3 x 10(-5)). Additionally, stop colon-gain variants in two intronless genes were not expressed, an unexpected outcome given previous studies. In this study, stop codon-gain variants were either well expressed in all individuals or were never expressed. Our finding that stop codon-gain variants were generally expressed only when they had an alternate function suggests that most naturally occurring stop codon-gain variants in protein-coding genes are either not transcribed or have their transcripts destroyed. (C) 2011 Elsevier Inc. All rights reserved. C1 [Cirulli, Elizabeth T.; Heinzen, Erin L.; Shianna, Kevin V.; Singh, Abanish; Maia, Jessica M.; Goldstein, David B.] Duke Univ, Ctr Human Genome Variat, Sch Med, Durham, NC 27708 USA. [Dietrich, Fred S.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Goedert, James J.] US Natl Canc Inst Hlth, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Goldstein, DB (reprint author), Duke Univ, Ctr Human Genome Variat, Sch Med, Box 91009, Durham, NC 27708 USA. EM d.goldstein@duke.edu OI Cirulli Rogers, Liz/0000-0001-7808-2809 FU NIAID Center for HIV/AIDS Vaccine Immunology [UO1AI067854]; Bill & Melinda Gates Foundation; NIMH [RC2MH089915]; NINDS [RC2NS070344] FX Funding was provided by the NIAID Center for HIV/AIDS Vaccine Immunology grant UO1AI067854 and the Bill & Melinda Gates Foundation. We also acknowledge C. Gumbs, K. Cronin and L. Little for DNA and RNA extraction. Sequencing of control genomes and exomes was funded by NIMH GrantRC2MH089915 and NINDS Award# RC2NS070344, and the control samples were provided by G Cavalleri, S Sisodiya, C Depondt, R Radtke, A Husain, M Mikati, N Walley, JP McEvoy, AC Need, J Silver, M Silver, and R Ottman. NR 25 TC 2 Z9 2 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 0888-7543 J9 GENOMICS JI Genomics PD NOV PY 2011 VL 98 IS 5 BP 337 EP 342 DI 10.1016/j.ygeno.2011.07.001 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 849PS UT WOS:000297138200003 PM 21803148 ER PT J AU Krishnadev, N Forooghian, F Cukras, C Wong, W Saligan, L Chew, EY Nussenblatt, R Ferris, F Meyerle, C AF Krishnadev, Nupura Forooghian, Farzin Cukras, Catherine Wong, Wai Saligan, Leorey Chew, Emily Y. Nussenblatt, Robert Ferris, Frederick, III Meyerle, Catherine TI Subconjunctival sirolimus in the treatment of diabetic macular edema SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE Sirolimus; Diabetic retinopathy; Macular edema; mTOR ID RANDOMIZED-TRIAL; STANDARD STENT; ELUTING STENT; RETINOPATHY; PHOTOCOAGULATION; RAPAMYCIN; MECHANISM AB Diabetic macular edema (DME) is a leading cause of blindness in the developed world. Sirolimus has been shown to inhibit the production, signaling, and activity of many growth factors relevant to the development of diabetic retinopathy. This phase I/II study assesses the safety of multiple subconjunctival sirolimus injections for the treatment of DME, with some limited efficacy data. In this phase I/II prospective, open-label pilot study, five adult participants with diabetic macular edema involving the center of the fovea and best-corrected ETDRS visual acuity score of a parts per thousand currency sign74 letters (20/32 or worse) received 20 mu l (440 mu g) of subconjunctival sirolimus at baseline, month 2 and every 2 months thereafter, unless there was resolution of either retinal thickening on OCT or leakage on fluorescein angiography. Main outcome measures included best-corrected visual acuity and central retinal thickness on OCT at 6 months and 1 year, as well as safety outcomes. Repeated subconjunctival sirolimus injections were well-tolerated, with no significant drug-related adverse events. There was no consistent treatment effect related to sirolimus; one participant experienced a 2-line improvement in visual acuity and 2 log unit decrease in retinal thickness at 6 months and 1 year, two remained essentially stable, one had stable visual acuity but improvement of central retinal thickness of 1 and 3 log units at 6 months and 1 year respectively, and one had a 2-line worsening of visual acuity and a 1 log unit increase in retinal thickness at 6 months and 1 year. Results in the fellow eyes with diabetic macular edema, not treated with sirolimus, were similar. Subconjunctival sirolimus appears safe to use in patients with DME. Assessment of possible treatment benefit will require a randomized trial. C1 [Krishnadev, Nupura; Forooghian, Farzin; Cukras, Catherine; Wong, Wai; Saligan, Leorey; Chew, Emily Y.; Nussenblatt, Robert; Ferris, Frederick, III; Meyerle, Catherine] NEI, NIH, Bethesda, MD 20892 USA. RP Meyerle, C (reprint author), NEI, NIH, Bldg 10 Magnuson,Rm 10S-235, Bethesda, MD 20892 USA. EM meyerlec@nei.nih.gov OI Wong, Wai/0000-0003-0681-4016 FU Intramural NIH HHS [ZIA EY000494-01] NR 12 TC 16 Z9 18 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X EI 1435-702X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD NOV PY 2011 VL 249 IS 11 BP 1627 EP 1633 DI 10.1007/s00417-011-1694-9 PG 7 WC Ophthalmology SC Ophthalmology GA 838NP UT WOS:000296299600003 PM 21567211 ER PT J AU Wallace, GL Case, LK Harms, MB Silvers, JA Kenworthy, L Martin, A AF Wallace, Gregory L. Case, Laura K. Harms, Madeline B. Silvers, Jennifer A. Kenworthy, Lauren Martin, Alex TI Diminished Sensitivity to Sad Facial Expressions in High Functioning Autism Spectrum Disorders is Associated with Symptomatology and Adaptive Functioning SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Emotion; Face; Symptomatology; Adaptive functioning ID PERVASIVE DEVELOPMENTAL DISORDERS; DIAGNOSTIC INTERVIEW; EMOTION-RECOGNITION; ASPERGER-SYNDROME; NORMAL-CHILDREN; BASIC EMOTIONS; AMYGDALA; PERCEPTION; INDIVIDUALS; ADOLESCENTS AB Prior studies implicate facial emotion recognition (FER) difficulties among individuals with autism spectrum disorders (ASD); however, many investigations focus on FER accuracy alone and few examine ecological validity through links with everyday functioning. We compared FER accuracy and perceptual sensitivity (from neutral to full expression) between 42 adolescents with high functioning (IQ > 80) ASD and 31 typically developing adolescents (matched on age, IQ, sex ratio) across six basic emotions and examined links between FER and symptomatology/adaptive functioning within the ASD group. Adolescents with ASD required more intense facial expressions for accurate emotion identification. Controlling for this overall group difference revealed particularly diminished sensitivity to sad facial expressions in ASD, which was uniquely correlated with ratings of autism-related behavior and adaptive functioning. C1 [Wallace, Gregory L.; Case, Laura K.; Harms, Madeline B.; Silvers, Jennifer A.; Kenworthy, Lauren; Martin, Alex] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Kenworthy, Lauren] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. RP Wallace, GL (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Room 4C104,MSC 1366, Bethesda, MD 20892 USA. EM gregwallace@mail.nih.gov RI martin, alex/B-6176-2009; OI Case, Laura/0000-0003-3730-2451; Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS [ZIA MH002920-03] NR 69 TC 31 Z9 32 U1 7 U2 32 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD NOV PY 2011 VL 41 IS 11 BP 1475 EP 1486 DI 10.1007/s10803-010-1170-0 PG 12 WC Psychology, Developmental SC Psychology GA 850BA UT WOS:000297168200004 PM 21347615 ER PT J AU Wang, H Park, O Gao, B AF Wang, Hua Park, Ogyi Gao, Bin TI NKT cells in liver fibrosis: Controversies or complexities SO JOURNAL OF HEPATOLOGY LA English DT Letter ID KILLER T-CELLS; INJURY C1 [Wang, Hua; Park, Ogyi; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Wang, H (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. EM whua@mail.nih.gov FU Intramural NIH HHS [ZIA AA000368-11, ZIA AA000369-11, Z99 AA999999] NR 7 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2011 VL 55 IS 5 BP 1166 EP 1166 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 846BN UT WOS:000296872300035 PM 21763666 ER PT J AU Yao, ZB Fanslow, WC Seldin, MF Rousseau, AM Painter, SL Comeau, MR Cohen, JI Spriggs, MK AF Yao, Zhengbin Fanslow, William C. Seldin, Michael F. Rousseau, Anne-Marie Painter, Sally L. Comeau, Michael R. Cohen, Jeffrey I. Spriggs, Melanie K. TI Herpesvirus Saimiri Encodes a New Cytokine, IL-17, Which Binds to a Novel Cytokine Receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; HUMAN-IMMUNODEFICIENCY-VIRUS; OPEN READING FRAME; T-CELL; VACCINIA VIRUS; BIOLOGICAL CHARACTERIZATION; INTERSPECIFIC CROSS; SIGNAL-TRANSDUCTION; MOUSE CHROMOSOME-6 AB Herpesvirus Saimiri gene 13 (HVS13) exhibits 57% identity with the predicted sequences of a T cell-derived molecule termed CTLA8. Recombinant HVS13 and CTLAB stimulate transcriptional factor NF-kappa B activity and interleukin-6 (IL-6) secretion in fibroblaste, and costimulate T cell proliferation. An HVS13.Fe fusion protein was used to isolate a cDNA encoding a novel receptor that also binds CTLAB. This receptor is unrelated to previously identified cytokine receptor families. A recombinant soluble raceptor inhibited T cell proliferation and IL-2 production induced by PHA, con-canavalin A(conA), and anti TCR MAb. These results define CTLAB and HVS13 as novel cytokines that bind to a novel cytokine receptor. We propose to call these molecules IL-17, vIL-17, and IL-17R, respectively. C1 [Yao, Zhengbin; Fanslow, William C.; Rousseau, Anne-Marie; Painter, Sally L.; Comeau, Michael R.; Spriggs, Melanie K.] Immunex Corp, Seattle, WA 98101 USA. [Seldin, Michael F.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Seldin, Michael F.] Duke Univ, Med Ctr, Dept Microbiol, Durham, NC 27710 USA. [Cohen, Jeffrey I.] NIH, Clin Invest Lab, Bethesda, MD 20892 USA. RP Yao, ZB (reprint author), Immunex Corp, 51 Univ St, Seattle, WA 98101 USA. FU National Institutes of Health [HG00734, AR41053] FX We would like to thank T. Hollingworth and C.-P. Huang for DNA seqencing. We also with to thank Dr. D. Cosman for critical reading of the manuscript and helpful suggestions. Drs. D. Williams, K. Mohler, and M. Widmer for critical reading of manuscript and A.C. Bannister for expert editorial assistance. This work was supported in part by National Institutes of Health grants HG00734 and AR41053 (M. F. S.) NR 70 TC 10 Z9 11 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2011 VL 187 IS 9 BP 4392 EP 4402 PG 11 WC Immunology SC Immunology GA 841ET UT WOS:000296496000002 PM 22013205 ER PT J AU McPhee, CG Sproule, TJ Shin, DM Bubier, JA Schott, WH Steinbuck, MP Avenesyan, L Morse, HC Roopenian, DC AF McPhee, Caroline G. Sproule, Thomas J. Shin, Dong-Mi Bubier, Jason A. Schott, William H. Steinbuck, Martin P. Avenesyan, Lia Morse, Herbert C., III Roopenian, Derry C. TI MHC Class I Family Proteins Retard Systemic Lupus Erythematosus Autoimmunity and B Cell Lymphomagenesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; NEONATAL FC-RECEPTOR; NATURAL-KILLER-CELLS; MEDIATED PRESENTATION; MONOCLONAL-ANTIBODY; MURINE LUPUS; CHAIN GENE; SJL MICE; DISEASE; BETA(2)-MICROGLOBULIN AB Dysregulation of the T cell-dependent Ab response can lead to numerous immunological disorders, ranging from systemic lupus erythematosus to B cell lymphomas. Cellular processes governed by MHC class II proteins play a major role in this response and its dysregulation. The extent to which processes controlled by the diverse family of MHC class I proteins impact such autoimmune and neoplastic disorders, however, is less clear. In this study, we genetically dissect the contributions of individual MHC class I family members and the pathological processes under their control in the systemic lupus erythematosus-like disease of BXSB.Yaa mice and B cell lymphomagenesis of SJL mice. This study reveals a powerful repressive regulatory axis comprised of MHC class I-dependent CD8(+) T cells and NK cells. These results indicate that the predominant role of the MHC class I protein family in such immunological disorders is to protect from more aggressive diseases. The Journal of Immunology, 2011, 187: 4695-4704. C1 [McPhee, Caroline G.; Sproule, Thomas J.; Bubier, Jason A.; Schott, William H.; Steinbuck, Martin P.; Avenesyan, Lia; Roopenian, Derry C.] Jackson Lab, Bar Harbor, ME 04609 USA. [Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Roopenian, DC (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM hmorse@niaid.nih.gov; dcr@jax.org OI Morse, Herbert/0000-0002-9331-3705; Bubier, Jason/0000-0001-5013-1234 FU National Institutes of Health; Alliance for Lupus Research; Arthritis Foundation; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by grants from the National Institutes of Health and the Alliance for Lupus Research (to D.C.R.). C.G.M. was supported partially by a National Institutes of Health training grant. J.A.B. was supported by the Arthritis Foundation. This work was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to D.-M.S. and H.C.M.). NR 57 TC 18 Z9 18 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 NOV 1 PY 2011 VL 187 IS 9 BP 4695 EP 4704 DI 10.4049/jimmunol.1101776 PG 10 WC Immunology SC Immunology GA 841ET UT WOS:000296496000035 PM 21964024 ER PT J AU Liang, QM Deng, HY Li, XJ Wu, XF Tang, QY Chang, TH Peng, HZ Rauscher, FJ Ozato, K Zhu, FX AF Liang, Qiming Deng, Hongying Li, Xiaojuan Wu, Xianfang Tang, Qiyi Chang, Tsung-Hsien Peng, Hongzhuang Rauscher, Frank J., III Ozato, Keiko Zhu, Fanxiu TI Tripartite Motif-Containing Protein 28 Is a Small Ubiquitin-Related Modifier E3 Ligase and Negative Regulator of IFN Regulatory Factor 7 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; TRIM FAMILY PROTEINS; TRANSCRIPTION FACTOR; I INTERFERON; RETROVIRAL RESTRICTION; IRF-7 PHOSPHORYLATION; MEDIATED DEGRADATION; ANTIVIRAL DEFENSE; PIAS PROTEINS; SUMO AB IFN regulatory factor 7 (IRF7) is a potent transcription factor of type I IFNs and IFN-stimulated genes and is known as the master regulator of type I IFN-dependent immune responses. Because excessive responses could harm the host, IRF7 itself is delicately regulated at the transcriptional, translational, and posttranslational levels. Modification of IRF7 by small ubiquitin-related modifiers (SUMOs) has been shown to regulate IFN expression and antiviral responses negatively, but the specific E3 ligase needed for IRF7 SUMOylation has remained unknown. As reported in this article, we have identified the tripartite motif-containing protein 28 (TRIM28) as a binding partner of IRF7. We have demonstrated that TRIM28 also interacts with the SUMO E2 enzyme and increases SUMOylation of IRF7 both in vivo and in vitro, suggesting it acts as a SUMO E3 ligase of IRF7. Unlike the common SUMO E3 ligase, protein inhibitor of activated STAT1, the E3 activity of TRIM28 is specific to IRF7, because it has little effect on IRF7's close relative IRF3. TRIM28 is therefore, so far as we know, the first IRF7-specific SUMO E3 reported. TRIM28-mediated SUMOylation of IRF7 is increased during viral infection, and SUMOylation of transcription factors usually results in transcriptional repression. Overexpression of TRIM28 therefore inhibits IRF7 transactivation activity, whereas knockdown of TRIM28 has the opposite effect and potentiates IFN production and antiviral responses. Collectively, our results suggest that TRIM28 is a specific SUMO E3 ligase and negative regulator of IRF7. The Journal of Immunology, 2011, 187: 4754-4763. C1 [Liang, Qiming; Deng, Hongying; Li, Xiaojuan; Wu, Xianfang; Zhu, Fanxiu] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Tang, Qiyi] Ponce Sch Med, AIDS Program, Dept Microbiol, Ponce, PR 00716 USA. [Chang, Tsung-Hsien; Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Peng, Hongzhuang; Rauscher, Frank J., III] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Zhu, FX (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. EM fzhu@bio.fsu.edu FU National Institutes of Health [R01DE016680] FX This work was supported by National Institutes of Health Grant R01DE016680. NR 63 TC 42 Z9 44 U1 1 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2011 VL 187 IS 9 BP 4754 EP 4763 DI 10.4049/jimmunol.1101704 PG 10 WC Immunology SC Immunology GA 841ET UT WOS:000296496000041 PM 21940674 ER PT J AU Dalloneau, E Pereira, PL Brault, V Nabel, EG Herault, Y AF Dalloneau, Emilie Pereira, Patricia Lopes Brault, Veronique Nabel, Elizabeth G. Herault, Yann TI Prmt2 Regulates the Lipopolysaccharide-Induced Responses in Lungs and Macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; TOLL-LIKE RECEPTORS; IN-VIVO; INFLAMMATORY RESPONSE; ARGININE METHYLATION; SIGNALING PATHWAY; GENE-EXPRESSION; INNATE IMMUNITY; ENDOTOXIN; METHYLTRANSFERASE AB Precise control of the LPS stimulation in the lung modulates inflammation and airway hyperresponsiveness involving the well-known TLR4/NF-kappa B pathway. As a consequence, the expression and secretion of proinflammatory cytokines is tightly regulated with the recruitment of neutrophils. Changes in the LPS-induced responses have been observed in the Prmt2-Col6a1 monosomic model, suggesting the presence of dosage-sensitive genes controlling LPS pathway in the mouse. In this article, we report that the Prmt2 regulates the LPS-induced lung responses in lungs and macrophages. We demonstrate that Prmt2 gene dosage influences the lung airway hyperresponsiveness, the recruitment of neutrophils, and the expression of proinflammatory cytokines, such as IL-6 and TNF-alpha. In addition, Prmt2 loss of function also altered the nuclear accumulation of NF-kappa B in stimulated macrophages. Prmt2 should be considered as a new member of the NF-kappa B pathway controlling LPS-induced inflammatory and lung responses in a dosage-dependent manner, certainly through regulating nuclear accumulation of NF-kappa B as shown already in fibroblasts. The Journal of Immunology, 2011, 187: 4826-4834. C1 [Dalloneau, Emilie; Pereira, Patricia Lopes; Brault, Veronique; Herault, Yann] Univ Strasbourg, Inst Genet Biol Mol & Cellulaire, CNRS, INSERM,UMR7104,UMR964, F-67404 Illkirch Graffenstaden, France. [Nabel, Elizabeth G.] NHLBI, NIH, Bethesda, MD 20892 USA. [Herault, Yann] Inst Clin Souris, F-67404 Illkirch Graffenstaden, France. RP Herault, Y (reprint author), Univ Strasbourg, Inst Genet Biol Mol & Cellulaire, CNRS, INSERM,UMR7104,UMR964, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France. EM herault@igbmc.fr RI Herault, Yann/B-5500-2012 OI Herault, Yann/0000-0001-7049-6900 FU National Centre for Scientific Research; European commission [LSHG-CT-2006-037627] FX This work was supported by the National Centre for Scientific Research and the European commission with the AnEUploidy project (LSHG-CT-2006-037627). NR 56 TC 3 Z9 4 U1 2 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2011 VL 187 IS 9 BP 4826 EP 4834 DI 10.4049/jimmunol.1101087 PG 9 WC Immunology SC Immunology GA 841ET UT WOS:000296496000048 PM 21957146 ER PT J AU Sakakibara, S Tosato, G AF Sakakibara, Shuhei Tosato, Giovanna TI Viral Interleukin-6: Role in Kaposi's Sarcoma-Associated Herpesvirus-Associated Malignancies SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Review ID MULTICENTRIC CASTLEMANS-DISEASE; PRIMARY EFFUSION LYMPHOMA; RHESUS MACAQUE RHADINOVIRUS; SIGNAL TRANSDUCER GP130; AIDS-RELATED MALIGNANCIES; GENE-EXPRESSION; GROWTH-FACTOR; LYTIC REPLICATION; DNA-SEQUENCES; HUMAN IL-6 AB Viral interleukin-6 (vIL-6) is a product of Kaposi's sarcoma-associated herpesvirus (KSHV) expressed in latently infected cells and to a higher degree during viral replication. A distinctive feature of vIL-6 is the ability to directly bind and activate gp130 signaling in the absence of other receptor subunits. Secretion of vIL-6 is generally poor, but vIL-6 can activate gp130 from inside the cell. Due to the wide cell distribution of gp130, vIL-6 has the potential to induce a wide range of biological effects. Expression of vIL-6 is variable in KSHV-associated Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and in a newly described MCD-like systemic inflammatory syndrome observed in human immunodeficiency virus-positive patients. PEL effusions usually contain vIL-6 at high concentrations; since vIL-6 induces vascular endothelial growth factor, vIL-6 likely contributes to vascular permeability and formation of PEL effusions. Lymph nodes affected with MCD contain vIL-6-positive cells, and vIL-6 levels rise in conjunction with flares of the disease and likely contribute to symptoms of inflammation. The development of vIL-6 inhibitors is a potentially important advance in the treatment of KSHV-associated malignancies where vIL-6 is expressed. C1 [Sakakibara, Shuhei; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Rm 4124, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD FX This work was supported by the intramural research program at Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. The authors thank Dr. R. Yarchoan for his comments. NR 109 TC 21 Z9 29 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD NOV PY 2011 VL 31 IS 11 BP 791 EP 801 DI 10.1089/jir.2011.0043 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 846MI UT WOS:000296906900001 PM 21767154 ER PT J AU Ehler, M AF Ehler, Martin TI Shrinkage rules for variational minimization problems and applications to analytical ultracentrifugation SO JOURNAL OF INVERSE AND ILL-POSED PROBLEMS LA English DT Article DE Shrinkage; variational optimization; sparsity; frames; Fredholm integral equations ID LINEAR INVERSE PROBLEMS; SPARSITY CONSTRAINTS; WAVELET SHRINKAGE; BI-FRAMES; OPERATOR-EQUATIONS; GRADIENT-METHOD; REPRESENTATIONS; SEDIMENTATION; RECOVERY; NOISE AB Finding a sparse representation of a noisy signal can be modeled as a variational minimization with l(q)-sparsity constraints for q less than one. Especially for real-time, online, or iterative applications, in which problems of this type have to be solved multiple times, one needs fast algorithms to compute these minimizers. However, identifying the exact minimizers is computationally expensive. We consider minimization up to a constant factor to circumvent this limitation. We verify that q-dependent modifications of shrinkage rules provide closed formulas for such minimizers. Therefore, their computation is extremely fast. We also introduce a new shrinkage rule which is adapted to q. To support the theoretical results, the proposed method is applied to Landweber iteration with shrinkage used at each iteration step. This approach is utilized to solve the ill-posed problem of analytic ultracentrifugation, a method to determine the size distribution of macromolecules. For relatively pure solutes, our proposed scheme leads to sparser solutions with sharper peaks, higher resolution, and smaller residuals than standard regularization for this problem. C1 [Ehler, Martin] Helmholtz Zentrum Munchen, Inst Biomath & Biometry, D-85764 Neuherberg, Germany. [Ehler, Martin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Biophys, NIH, Bethesda, MD 20892 USA. RP Ehler, M (reprint author), Helmholtz Zentrum Munchen, Inst Biomath & Biometry, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. EM martin.ehler@helmholtz-muenchen.de FU National Institutes of Child Health and Human Development; National Institutes of Health [575910]; German Science Foundation FX The research was funded by the Intramural Research Program of the National Institutes of Child Health and Human Development and by the Research Career Transition Awards Program 575910 of the National Institutes of Health and the German Science Foundation. NR 45 TC 6 Z9 6 U1 0 U2 0 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0928-0219 EI 1569-3945 J9 J INVERSE ILL-POSE P JI J. Inverse Ill-Posed Probl. PD NOV PY 2011 VL 19 IS 4-5 BP 593 EP 614 DI 10.1515/JIIP.2011.057 PG 22 WC Mathematics, Applied; Mathematics SC Mathematics GA 846IV UT WOS:000296891400003 ER PT J AU Zhang, JH Pandey, M Seigneur, EM Panicker, LM Koo, L Schwartz, OM Chen, WP Chen, CK Simonds, WF AF Zhang, Jian-Hua Pandey, Mritunjay Seigneur, Erica M. Panicker, Leelamma M. Koo, Lily Schwartz, Owen M. Chen, Weiping Chen, Ching-Kang Simonds, William F. TI Knockout of G protein beta 5 impairs brain development and causes multiple neurologic abnormalities in mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE dendrite; dentate gyrus; limbic cortex; Purkinje cell; R7BP; regulator of G protein signaling ID MEMBRANE ANCHOR R7BP; ON-BIPOLAR CELLS; TIME RT-PCR; IMMUNOHISTOCHEMICAL LOCALIZATION; MOTOR COORDINATION; RGS PROTEINS; MUTANT MICE; RAT-BRAIN; SUBUNIT; COMPLEX AB G beta 5 is a divergent member of the signal-transducing G protein beta subunit family encoded by GNB5 and expressed principally in brain and neuronal tissue. Among heterotrimeric G beta isoforms, G beta 5 is unique in its ability to heterodimerize with members of the R7 subfamily of the regulator of G protein signaling proteins that contain G protein-gamma like domains. Previous studies employing Gnb5 knockout (KO) mice have shown that G beta 5 is an essential stabilizer of such regulator of G protein signaling proteins and regulates the deactivation of retinal phototransduction and the proper functioning of retinal bipolar cells. However, little is known of the function of G beta 5 in the brain outside the visual system. We show here that mice lacking G beta 5 have a markedly abnormal neurologic phenotype that includes impaired development, tiptoe-walking, motor learning and coordination deficiencies, and hyperactivity. We further show that G beta 5-deficient mice have abnormalities of neuronal development in cerebellum and hippocampus. We find that the expression of both mRNA and protein from multiple neuronal genes is dysregulated in Gnb5 KO mice. Taken together with previous observations from Gnb5 KO mice, our findings suggest a model in which G beta 5 regulates dendritic arborization and/or synapse formation during development, in part by effects on gene expression. C1 [Zhang, Jian-Hua; Pandey, Mritunjay; Seigneur, Erica M.; Panicker, Leelamma M.; Simonds, William F.] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Koo, Lily; Schwartz, Owen M.] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Ching-Kang] Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA. RP Simonds, WF (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 8C-101,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. EM wfs@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; NIH [EY013811] FX The authors thank Kimya Davani and William Jou of the NIDDK Mouse Metabolism Core for their expert assistance. This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Allergy and Infectious Diseases. C-KC is supported in part by an NIH grant EY013811. NR 40 TC 20 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2011 VL 119 IS 3 BP 544 EP 554 DI 10.1111/j.1471-4159.2011.07457.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 848AS UT WOS:000297019300011 PM 21883221 ER PT J AU Nanavati, D Austin, DR Catapano, LA Luckenbaugh, DA Dosemeci, A Manji, HK Chen, G Markey, SP AF Nanavati, Dhaval Austin, Daniel R. Catapano, Lisa A. Luckenbaugh, David A. Dosemeci, Ayse Manji, Husseini K. Chen, Guang Markey, Sanford P. TI The effects of chronic treatment with mood stabilizers on the rat hippocampal post-synaptic density proteome SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE ankyrin 3; Grm3; hippocampus; lithium; post-synapse; valproate ID TERM LITHIUM TREATMENT; BIPOLAR DISORDER; HUNTINGTONS-DISEASE; PREFRONTAL CORTEX; GENE-EXPRESSION; NEURODEGENERATIVE DISEASES; MASS-SPECTROMETRY; NERVOUS-SYSTEM; VALPROIC ACID; SCHIZOPHRENIA AB Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. There is growing evidence that the disease is correlated with disruptions in synaptic plasticity cascades involved in cognition and mood regulation. Alleviating the symptoms of bipolar disorder involves chronic treatment with mood stabilizers like lithium or valproate. These two structurally dissimilar drugs are known to alter prominent signaling cascades in the hippocampus, but their effects on the post-synaptic density complex remain undefined. In this work, we utilized mass spectrometry for quantitative profiling of the rat hippocampal post-synaptic proteome to investigate the effects of chronic mood stabilizer treatment. Our data show that in response to chronic treatment of mood stabilizers there were not gross qualitative changes but rather subtle quantitative perturbations in post-synaptic density proteome linked to several key signaling pathways. Our data specifically support the changes in action dynamics on valproate treatment. Using label-free quantification methods, we report that lithium and valproate significantly altered the abundance of 21 and 43 proteins, respectively. Seven proteins were affected similarly by both lithium and valproate: Ank3, glutamate receptor 3 dynein heavy chain 1, and four isoforms of the 14-3-3 family. Immunoblotting the same samples confirmed the changes in Ank3 and glutamate receptor 3 abundance. Our findings support the hypotheses that BPD is a synaptic disorder and that mood stabilizers modulate the protein signaling complex in the hippocampal post-synaptic density. C1 [Nanavati, Dhaval; Markey, Sanford P.] NIMH, Lab Neurotoxicol, NIH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Austin, Daniel R.; Catapano, Lisa A.; Luckenbaugh, David A.; Manji, Husseini K.; Chen, Guang] NIMH, Lab Mol Pathophysiol & Expt Therapeut, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Dosemeci, Ayse] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Markey, SP (reprint author), NIMH, Lab Neurotoxicol, NIH, Mood & Anxiety Disorders Program, 10 Ctr Dr,Bldg 10,Rm 3D-42, Bethesda, MD 20892 USA. EM markeys@mail.nih.gov RI Chen, Guang/A-2570-2017 FU National Institute of Mental Health, NIH [MH000274, MH000279] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, NIH (MH000274 and MH000279). The authors received significant advice and assistance from staff in LNT, especially Dr Jeffrey Kowalak, Anthony J. Makusky, Jason Harrington, and Ronald Finnegan. NR 81 TC 24 Z9 25 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2011 VL 119 IS 3 BP 617 EP 629 DI 10.1111/j.1471-4159.2011.07424.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 848AS UT WOS:000297019300017 PM 21838781 ER PT J AU Susarla, BTS Laing, ED Yu, PP Katagiri, Y Geller, HM Symes, AJ AF Susarla, Bala T. S. Laing, Eric D. Yu, Panpan Katagiri, Yasuhiro Geller, Herbert M. Symes, Aviva J. TI Smad proteins differentially regulate transforming growth factor-beta-mediated induction of chondroitin sulfate proteoglycans SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE astrocytes; cell culture; glial scar; Smad3; Smad2; transforming growth factor-beta ID SPINAL-CORD-INJURY; OLIGODENDROCYTE LINEAGE CELLS; CENTRAL-NERVOUS-SYSTEM; MOLECULAR-CLONING; MESSENGER-RNA; RAT-BRAIN; FUNCTIONAL RECOVERY; SCAR TISSUE; CNS INJURY; EXPRESSION AB Traumatic injury to the CNS results in increased expression and deposition of chondroitin sulfate proteoglycans (CSPGs) that are inhibitory to axonal regeneration. Transforming growth factor-beta (TGF-beta) has been implicated as a major mediator of these changes, but the mechanisms through which TGF-beta regulates CSPG expression are not known. Using lentiviral expressed Smad-specific ShRNA we show that TGF-beta induction of CSPG expression in astrocytes is Smad-dependent. However, we find a differential dependence of the synthetic machinery on Smad2 and/or Smad3. TGF-beta induction of neurocan and xylosyl transferase 1 required both Smad2 and Smad3, whereas induction of phosphacan and chondroitin synthase 1 required Smad2 but not Smad3. Smad3 knockdown selectively reduced induction of chondroitin-4-sulfotransferase 1 and the amount of 4-sulfated CSPGs secreted by astrocytes. Additionally, Smad3 knockdown in astrocytes was more efficacious in promoting neurite outgrowth of neurons cultured on the TGF-beta-treated astrocytes. Our data implicate TGF-beta Smad3-mediated induction of 4-sulfation as a critical determinant of the permissiveness of astrocyte secreted CSPGs for axonal growth. C1 [Susarla, Bala T. S.; Laing, Eric D.; Symes, Aviva J.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Yu, Panpan; Katagiri, Yasuhiro; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Symes, AJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pharmacol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM asymes@usuhs.mil RI Yu, Panpan/A-4962-2013; Symes, Aviva/S-7471-2016 OI Symes, Aviva/0000-0003-2557-9939 FU Maryland Spinal Cord Injury Research Board; National Heart, Lung and Blood Institute FX This work was supported by a grant from the Maryland Spinal Cord Injury Research Board (AJS) and the Intramural Research Program of the National Heart, Lung and Blood Institute (PY, YK and HMG). We thank Dr Dours Zimmermann (Zurich, Switzerland) for the generous gift of neurocan antibody. We are grateful to past and present members of the Symes and Geller laboratories for their helpful comments and suggestions. The opinions and assertions contained herein are the private opinions of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences or the US Department of Defense. The authors report no conflicts of interest. NR 51 TC 26 Z9 27 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2011 VL 119 IS 4 BP 868 EP 878 DI 10.1111/j.1471-4159.2011.07470.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 848AZ UT WOS:000297020300019 PM 21895657 ER PT J AU Swain, JE Kim, P Ho, SS AF Swain, J. E. Kim, P. Ho, S. S. TI Neuroendocrinology of Parental Response to Baby-Cry SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Review DE parent-child relationships; brain imaging; functional magnetic resonance imaging; attachment; parenting; caregiving; cortisol; dopamine; opioids ID MATERNAL BRAIN; POSTPARTUM DEPRESSION; OXYTOCIN; INFANT; MOTHERS; HUMANS; CORTISOL; REWARD; FEAR; ATTACHMENT AB This overview attempts to synthesise current understandings of the neuroendocrine basis of parenting. The parent-infant bond is central to the human condition, contributes to risks for mood and anxiety disorders, and provides the potential for resiliency and protection against the development of psychopathology. Animal models of parenting provide compelling evidence that biological mechanisms may be studied in humans. This has led to brain imaging and endocrine system studies of human parents using baby stimuli and concerted psychological and behavioural measures. Certain brain circuits and related hormonal systems, including subcortical regions for motivation (striatum, amygdala, hypothalamus and hippocampus) and cortical regions for social cognition (anterior cingulate, insula, medial frontal and orbitofrontal cortices), appear to be involved. These brain circuits work with a range of endocrine systems to manage stress and motivate appropriate parental caring behaviour with a flexibility appropriate to the environment. Work in this field promises to link evolving models of parental brain performance with resilience, risk and treatment toward mother-infant mental health. C1 [Swain, J. E.; Ho, S. S.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Kim, P.] NIMH, Bethesda, MD 20892 USA. RP Swain, JE (reprint author), Univ Michigan, Dept Psychiat, 4250 Plymouth Rd, Ann Arbor, MI 48109 USA. EM jamesswa@med.umich.edu RI Swain, James/F-7270-2013 OI Swain, James/0000-0001-8440-0658 FU Institute for Research on Unlimited Love; National Alliance for Research on Schizophrenia and Depression; Klingenstein Third Generation Foundation; Yale Center for Risk, Resilience, and Recovery, Associates of the Yale Child Study Center; Department of Psychiatry of the University of Michigan; MICHR [UL1RR024986]; Science of Generosity Initiative; NICHD [IRC2MD004767-01] FX This work was supported by the Institute for Research on Unlimited Love (http://unlimitedloveinstitute.org); the National Alliance for Research on Schizophrenia and Depression (http://narsad.org); the Klingenstein Third Generation Foundation (http://ktgf.org); Yale Center for Risk, Resilience, and Recovery, Associates of the Yale Child Study Center; the Department of Psychiatry of the University of Michigan, MICHR High Tech grant UL1RR024986; the Science of Generosity Initiative (http://generosityresearch.nd.edu/); and the NICHD (IRC2MD004767-01). Drs P. Kim and S. S. Ho contributed to this work equally. Dr J. E. Swain would especially like to acknowledge the inestimable collegial support of many individuals, including Drs Ruth Feldman, James F. Leckman Jeffrey Lorberbaum, Linda C. Mayes, Robert T. Schultz and Lane Strathearn. NR 73 TC 37 Z9 37 U1 1 U2 31 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD NOV PY 2011 VL 23 IS 11 SI SI BP 1036 EP 1041 DI 10.1111/j.1365-2826.2011.02212.x PG 6 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 848CB UT WOS:000297024600009 PM 21848646 ER PT J AU Snow, J Ingeholm, JE Levy, IF Caravella, RA Case, LK Wallace, GL Martin, A AF Snow, Joseph Ingeholm, John E. Levy, Ilana F. Caravella, Rachel A. Case, Laura K. Wallace, Gregory L. Martin, Alex TI Impaired Visual Scanning and Memory for Faces in High-Functioning Autism Spectrum Disorders: It's Not Just the Eyes SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Autistic disorder; Asperger's syndrome; Face processing; Memory; Eye tracking; Domain-specificity ID DIAGNOSTIC INTERVIEW; CHILDREN; ATTENTION; INDIVIDUALS; RECOGNITION; INFORMATION; TRACKING; EMOTION; MOUTH AB Prior studies suggest that autism spectrum disorders (ASD) are associated with a domain-specific memory impairment for faces. The underlying cause of this problem and its relation to impaired visual scanning of faces-particularly of the eyes-remains to be determined. We recorded eye movements while 22 high-functioning ASD and 21 typically developing (TD) adolescents encoded and later recognized faces and objects from a single, nonsocial object category (electric fans). Relative to TD subjects, ASD individuals had poorer memory for faces, but not fans. Correlational analyses showed significant relationships between recognition memory and fixations. Eye tracking during encoding revealed that TD subjects made more fixations to faces than fans, whereas ASD individuals did not differ in number of fixations made to each stimulus type. Moreover, although both the TD and ASD groups showed a strong preference for fixating the eyes more than the mouth, the ASD subjects were less likely than TD subjects to scan regions of the face outside of the primary facial features (i.e., eyes, nose, and mouth). We concluded that ASD individuals have a domain-specific memory impairment for faces relative to mechanical objects and that this impairment may be related to abnormal scanning during encoding. (JINS, 2011, 17, 1021-1029) C1 [Snow, Joseph; Ingeholm, John E.; Levy, Ilana F.; Caravella, Rachel A.; Case, Laura K.; Wallace, Gregory L.; Martin, Alex] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Snow, J (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Room 3N222, Bethesda, MD 20892 USA. EM joseph.snow@nih.gov RI martin, alex/B-6176-2009; OI Case, Laura/0000-0003-3730-2451; Caravella, Rachel/0000-0003-1136-5913; Wallace, Gregory/0000-0003-0329-5054 FU NIH, National Institute of Mental Health FX This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health. There are no financial or other relationships that could be interpreted as a conflict of interest affecting this manuscript. We thank the participants and their families for the time and energy they gave in completing this research. We also thank Laura Dolan and Madeline Harms for their assistance with data collection and management. NR 31 TC 12 Z9 12 U1 6 U2 22 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD NOV PY 2011 VL 17 IS 6 BP 1021 EP 1029 DI 10.1017/S1355617711000981 PG 9 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 848DF UT WOS:000297028500009 PM 21892988 ER PT J AU Dowsett, M Nielsen, TO A'Hern, R Bartlett, J Coombes, RC Cuzick, J Ellis, M Henry, NL Hugh, JC Lively, T McShane, L Paik, S Penault-Llorca, F Prudkin, L Regan, M Salter, J Sotiriou, C Smith, IE Viale, G Zujewski, JA Hayes, DF AF Dowsett, Mitch Nielsen, Torsten O. A'Hern, Roger Bartlett, John Coombes, R. Charles Cuzick, Jack Ellis, Matthew Henry, N. Lynn Hugh, Judith C. Lively, Tracy McShane, Lisa Paik, Soon Penault-Llorca, Frederique Prudkin, Ljudmila Regan, Meredith Salter, Janine Sotiriou, Christos Smith, Ian E. Viale, Giuseppe Zujewski, Jo Anne Hayes, Daniel F. TI Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PATHOLOGISTS GUIDELINE RECOMMENDATIONS; IMPROVED SURGICAL OUTCOMES; PHASE-II TRIAL; POSTMENOPAUSAL WOMEN; CELL PROLIFERATION; AMERICAN SOCIETY; PROGNOSTIC VALUE; CLINICAL ONCOLOGY/COLLEGE; NEOADJUVANT CHEMOTHERAPY; PROGESTERONE-RECEPTORS AB Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice. C1 [Dowsett, Mitch; Salter, Janine] Royal Marsden Hosp, Acad Dept Biochem, London SW3 6JJ, England. [Dowsett, Mitch; Salter, Janine] Breakthrough Breast Canc Ctr, London, England. [Nielsen, Torsten O.] Univ British Columbia, Vancouver Hosp, Vancouver, BC V5Z 1M9, Canada. [A'Hern, Roger] Inst Canc Res, Canc Res UK Clin Trials & Stat Unit, Surrey, England. [Bartlett, John] Univ Edinburgh, Western Gen Hosp, Edinburgh Canc Res Ctr, Edinburgh, Midlothian, Scotland. [Coombes, R. Charles] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Div Canc, London, England. [Cuzick, Jack] Univ London, Barts & London Sch Med & Dent, Wolfson Inst Prevent Med, London, England. [Ellis, Matthew] Washington Univ, Sch Med, Siteman Canc Ctr, Breast Canc Program, St Louis, MO USA. [Henry, N. Lynn; Hayes, Daniel F.] Univ Michigan, Ctr Comprehens Canc, Breast Oncol Program, Ann Arbor, MI 48109 USA. [Hugh, Judith C.] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. [Lively, Tracy] NCI, Diagnost Evaluat Branch, Canc Diag Program, Rockville, MD USA. [McShane, Lisa] NCI, Biometr Res Branch, DCTD, Bethesda, MD 20892 USA. [Paik, Soon] NSABP Fdn, Div Pathol, Pittsburgh, PA USA. [Penault-Llorca, Frederique] Univ Auvergne, Dept Biopathol, Clermont Ferrand, France. [Prudkin, Ljudmila] Hosp Univ Vall Hebron, Lab Patol Mol, Barcelona, Spain. [Regan, Meredith] Dana Farber Canc Inst, IBCSG Stat Ctr, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Regan, Meredith] Harvard Univ, Sch Med, Boston, MA USA. [Sotiriou, Christos] Inst Jules Bordet, Dept Med Oncol, B-1000 Brussels, Belgium. [Sotiriou, Christos] Breast Canc Translat Res Lab BCTL, Brussels, Belgium. [Smith, Ian E.] Royal Marsden Hosp, Breast Unit, London SW3 6JJ, England. [Viale, Giuseppe] Univ Milan, European Inst Oncol, Dept Pathol, Milan, Italy. [Zujewski, Jo Anne] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Dowsett, M (reprint author), Royal Marsden Hosp, Dept Biochem, Fulham Rd, London SW3 6JJ, England. EM mitch.dowsett@icr.ac.uk FU Cancer Research UK NR 55 TC 500 Z9 525 U1 3 U2 36 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 NOV PY 2011 VL 103 IS 22 BP 1656 EP 1664 DI 10.1093/jnci/djr393 PG 9 WC Oncology SC Oncology GA 850PV UT WOS:000297209000007 PM 21960707 ER PT J AU Folio, L Fischer, T Shogan, PJ Frew, M Bunger, R Provenzale, JM AF Folio, Les Fischer, Tatjana Shogan, Paul J. Frew, Michael Bunger, Rolf Provenzale, James M. TI Cartesian Positioning System for Localization of Blast and Ballistic Fragments: A Phantom-Based Pilot Study SO MILITARY MEDICINE LA English DT Article ID BULLET AB Our purpose was to demonstrate the consistency of radiologists' three-dimensional measurements of simulated blast fragment locations in vitro in an effort to objectively localize retained fragments and wound paths. We designed a phantom consisting of 10 nail heads (simulating blast fragments) glued to wooden pegs that were randomly situated at distances from a reference point within a plastic tub. The x, y, and z coordinates of simulated fragments were recorded in Cartesian 3-space relative to the reference point. Computed tomography images of the phantom were acquired. Differences in x, y, and z positions as determined by three observers were summed for each fragment. Agreement between recordings of coordinates across readers was assessed using the intraclass correlation coefficient. Summed differences in coordinate positions as determined by readers ranged between 0.00 and 1.204 cm (mean: 0.732 cm). Across readers, the intraclass correlation coefficient for each dimension was >0.99. We found excellent agreement among readers with minimal discrepancy of measured locations of simulated fragments. Our results provide a foundation for trajectory analysis necessary to lead to automated organ damage reporting for immediate assessment in the emergency department and for forensic investigation and long-term epidemiological analysis. C1 [Folio, Les] NIH, Bethesda, MD 20892 USA. [Fischer, Tatjana] Tech Univ Munich, D-80333 Munich, Germany. [Shogan, Paul J.] Walter Reed Army Med Ctr, Natl Capital Consortium, Dept Radiol, Washington, DC 20307 USA. [Shogan, Paul J.] Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. [Provenzale, James M.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27705 USA. [Provenzale, James M.] Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. [Provenzale, James M.] Emory Univ, Sch Med, Dept Biomed Engn, Atlanta, GA 30322 USA. [Provenzale, James M.] Emory Univ, Sch Med, Dept Oncol, Atlanta, GA 30322 USA. RP Folio, L (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 13 TC 3 Z9 3 U1 0 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD NOV PY 2011 VL 176 IS 11 BP 1300 EP 1305 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 845NR UT WOS:000296830300016 PM 22165660 ER PT J AU Proescholdt, MA Merrill, M Storr, EM Lohmeier, A Brawanski, A AF Proescholdt, Martin A. Merrill, Marsha Stoerr, Eva Maria Lohmeier, Annette Brawanski, Alexander TI KNOCKDOWN OF CARBONIC ANHYDRASE IX EXPRESSION IN MALIGNANT GLIOMA CELLS AUGMENTS EFFICACY OF RADIATION AND CHEMOTHERAPY SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Proescholdt, Martin A.; Stoerr, Eva Maria; Lohmeier, Annette; Brawanski, Alexander] Univ Regensburg, Med Ctr, Regensburg, Germany. [Merrill, Marsha] NIH, Bethesda, MD 20892 USA. NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 11 EP 11 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600044 ER PT J AU Chu, WT Lee, HT Huang, FJ Aldape, K Yao, J Steeg, PS Lu, ZM Xie, KP Huang, SY AF Chu, Wen-Tai Lee, Hsueh-Te Huang, Feng-Ju Aldape, Kenneth Yao, Jun Steeg, Patricia S. Lu, Zhimin Xie, Keping Huang, Suyun TI TARGETED DISRUPTION OF STAT3 SIGNALING INHIBITS TUMOR GROWTH AND BRAIN METASTASES BY CAVEOLIN-1 UPREGULATION SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Chu, Wen-Tai; Lee, Hsueh-Te; Aldape, Kenneth; Yao, Jun; Lu, Zhimin; Xie, Keping; Huang, Suyun] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Huang, Feng-Ju] Univ Texas Grad Sch Biomed Sci Houston, Program Canc Biol, Houston, TX USA. [Steeg, Patricia S.] NCI, Mol Pharmacol Lab, Womens Canc Sect, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 14 EP 15 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600059 ER PT J AU Mann, BS Yabroff, R Harlan, L Zeruto, C Abrams, J AF Mann, Bhupinder S. Yabroff, Robin Harlan, Linda Zeruto, Christopher Abrams, Jeffrey TI CLINICAL MANAGEMENT AND SURVIVAL IN THE PATTERNS OF CARE STUDY OF PATIENTS DIAGNOSED WITH GLIOBLASTOMA MULTIFORME AND REPORTED TO THE SURVEILLANCE, EPIDEMIOLOGY AND END RESULTS PROGRAM IN 2006 SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Mann, Bhupinder S.; Yabroff, Robin; Harlan, Linda; Abrams, Jeffrey] NCI, Bethesda, MD 20892 USA. [Zeruto, Christopher] Informat Management Serv Inc, Silver Spring, MD USA. NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 26 EP 26 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600109 ER PT J AU Nayak, L Iwamoto, FM Rudnick, JD Norden, AD Omuro, A Kaley, TJ AF Nayak, Lakshmi Iwamoto, Fabio M. Rudnick, Jeremy D. Norden, Andrew D. Omuro, Antonio Kaley, Thomas J. TI BEVACIZUMAB IN MULTIPLY RECURRENT AGGRESSIVE MENINGIOMAS SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Nayak, Lakshmi; Omuro, Antonio; Kaley, Thomas J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Iwamoto, Fabio M.] NCI, NIH, Bethesda, MD 20892 USA. [Rudnick, Jeremy D.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Norden, Andrew D.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 61 EP 61 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600248 ER PT J AU Lassman, AB Wang, MH Gilbert, MR Aldape, KD Beumer, JJ Wright, J Takebe, N Puduvalli, VK Hormigo, A Gaur, R Werner-Wasik, M Mehta, MP AF Lassman, Andrew B. Wang, Meihua Gilbert, Mark R. Aldape, Kenneth D. Beumer, Jan J. Wright, John Takebe, Naoko Puduvalli, Vinay K. Hormigo, Adilia Gaur, Rakesh Werner-Wasik, Maria Mehta, Minesh P. TI PHASE II TRIAL OF DASATINIB IN TARGET SELECTED PATIENTS WITH RECURRENT GLIOBLASTOMA (RTOG 0627) SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Lassman, Andrew B.; Hormigo, Adilia] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wang, Meihua] RTOG Stat Ctr, Philadelphia, PA USA. [Gilbert, Mark R.; Aldape, Kenneth D.; Puduvalli, Vinay K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Beumer, Jan J.] Univ Pittsburgh, Pittsburgh, PA USA. [Wright, John; Takebe, Naoko] NCI, Invest Drug Branch, CTEP, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Gaur, Rakesh] Kansas City CCOP, Kansas City, MO USA. [Werner-Wasik, Maria] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Mehta, Minesh P.] NW Mem Hosp, Chicago, IL 60611 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 0 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 64 EP 64 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600263 ER PT J AU Gephart, MH Lee, E Kyriazopoulou-Panagiotopoulou, S Milenkovic, L Xun, X Hou, Y Kui, W Edwards, M Batzoglou, S Jun, W Scott, M AF Gephart, Melanie Hayden Lee, Eunice Kyriazopoulou-Panagiotopoulou, Sofia Milenkovic, Ljiljana Xun, Xu Hou, Yong Kui, Wu Edwards, Michael Batzoglou, Serafim Jun, Wang Scott, Matthew TI CANCER PATHWAY DISCOVERY IN A MOUSE MODEL OF MEDULLOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Gephart, Melanie Hayden; Kyriazopoulou-Panagiotopoulou, Sofia; Milenkovic, Ljiljana; Edwards, Michael; Batzoglou, Serafim; Scott, Matthew] Stanford Univ, Stanford, CA 94305 USA. [Lee, Eunice; Jun, Wang] NIH, Stanford, CA USA. [Xun, Xu; Hou, Yong; Kui, Wu] Beijing Genom Inst, Shenzhen, Peoples R China. NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 78 EP 78 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600315 ER PT J AU Groves, MD DeGroot, J Tremont, I Forman, A Kang, S Pei, BL Julie, W Schultz, D Yuan, Y Guha, N Hwu, WJ Papadopoulos, N Camphausen, K Yung, WKA AF Groves, Morris D. DeGroot, John Tremont, Ivo Forman, Arthur Kang, Sanghee Pei, Be-Lian Julie, Walker Schultz, Diana Yuan, Ying Guha, Nandita Hwu, Wen-Jen Papadopoulos, Nicholas Camphausen, Kevin Yung, W. K. Alfred TI A PILOT STUDY OF SYSTEMICALLY ADMINISTERED BEVACIZUMAB IN PATIENTS WITH NEOPLASTIC MENINGITIS: IMAGING, CLINICAL, CSF, AND BIOMARKER OUTCOMES SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Groves, Morris D.; DeGroot, John; Tremont, Ivo; Forman, Arthur; Kang, Sanghee; Pei, Be-Lian; Julie, Walker; Schultz, Diana; Yuan, Ying; Guha, Nandita; Hwu, Wen-Jen; Papadopoulos, Nicholas; Yung, W. K. Alfred] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Camphausen, Kevin] NCI, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 85 EP 85 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600345 ER PT J AU Lassman, AB Kaley, TJ DeAngelis, LM Hormigo, A Mellinghoff, IK Otap, DD Seger, J Doyle, LA Ludwig, E Lacouture, ME Panageas, KS AF Lassman, Andrew B. Kaley, Thomas J. DeAngelis, Lisa M. Hormigo, Adilia Mellinghoff, Ingo K. Otap, Daniel D. Seger, Jennifer Doyle, L. A. Ludwig, Emmy Lacouture, Mario E. Panageas, Katherine S. TI PHASE I TRIAL OF TEMSIROLIMUS AND PERIFOSINE FOR RECURRENT OR PROGRESSIVE MALIGNANT GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Lassman, Andrew B.; Kaley, Thomas J.; DeAngelis, Lisa M.; Hormigo, Adilia; Mellinghoff, Ingo K.; Otap, Daniel D.; Seger, Jennifer; Ludwig, Emmy; Lacouture, Mario E.; Panageas, Katherine S.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Doyle, L. A.] NCI, Invest Drug Branch, CTEP, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 90 EP 90 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600364 ER PT J AU Qi, XY Cuttitta, F Chu, ZT Celerier, J Pakradouni, J Rixe, O AF Qi, Xiaoyang Cuttitta, Franck Chu, Zhengtao Celerier, Jerome Pakradouni, Jihane Rixe, Olivier TI NOV C-TER: A NOVEL ANTIANGIOGENIC AND ANTITUMOR AGENT SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Qi, Xiaoyang; Chu, Zhengtao; Rixe, Olivier] Univ Cincinnati, Inst Canc, Cincinnati, OH USA. [Cuttitta, Franck] NCI, Gaithersburg, MD USA. [Celerier, Jerome; Pakradouni, Jihane] Sisene Biotechnol, Paris, France. [Rixe, Olivier] UC Brain Tumor Ctr, Cincinnati, OH USA. RI Cuttitta, Frank/B-4758-2016 NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 113 EP 113 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600447 ER PT J AU Kil, WJ Ko, C Kaushal, A Warran, K Ning, H Camphausen, K Smart, D AF Kil, Whoon Jong Ko, Christine Kaushal, Aradhana Warran, Kathy Ning, Holly Camphausen, Kevin Smart, DeeDee TI PAROTID GLAND IRRADIATION DURING CRANIOSPINAL PLUS BOOST TREATMENT OF PEDIATRIC BRAIN TUMORS: A DOSIMETRIC EVALUATION SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Kil, Whoon Jong; Ko, Christine; Kaushal, Aradhana; Warran, Kathy; Ning, Holly; Camphausen, Kevin; Smart, DeeDee] NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 127 EP 127 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600500 ER PT J AU Yong, RM Yang, CZ Lonser, R Zhuang, ZP AF Yong, Raymund Yang, Chunzhang Lonser, Russell Zhuang, Zhengping TI SCRATCH-INJURED NORMAL HUMAN ASTROCYTES EXHIBIT PREFERENTIAL DNA DAMAGE AT SOMATIC MUTATIONAL HOTSPOTS IDENTIFIED IN GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Yong, Raymund; Yang, Chunzhang; Lonser, Russell; Zhuang, Zhengping] NIH, Bethesda, MD 20892 USA. NR 0 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 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 SU 3 BP 134 EP 134 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CP UT WOS:000297026600526 ER PT J AU Iwamoto, FM Hottinger, AF Karimi, S Riedel, E Dantis, J Jahdi, M Panageas, KS Lassman, AB Abrey, LE Fleisher, M DeAngelis, LM Holland, EC Hormigo, A AF Iwamoto, Fabio M. Hottinger, Andreas F. Karimi, Sasan Riedel, Elyn Dantis, Jocelynn Jahdi, Maryam Panageas, Katherine S. Lassman, Andrew B. Abrey, Lauren E. Fleisher, Martin DeAngelis, Lisa M. Holland, Eric C. Hormigo, Adilia TI Serum YKL-40 is a marker of prognosis and disease status in high-grade gliomas SO NEURO-ONCOLOGY LA English DT Article DE glioblastoma; glioma; serum marker YKL-40 ID PHASE-III TRIAL; RESPONSE CRITERIA; PLASMA YKL-40; CANCER; GLIOBLASTOMA; SURVIVAL; TEMOZOLOMIDE; EXPRESSION; SUBTYPES; RADIOTHERAPY AB The objective of this study was to evaluate whether longitudinal levels of serum YKL-40 correlate with disease status or survival in adults with gliomas. Patients with histologically confirmed gliomas were eligible for this longitudinal study. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. YKL-40 levels determined by ELISA were correlated with radiographic disease status and survival. We performed a multivariate survival analysis including well-known prognostic factors such as age, performance status, and extent of surgical resection. Three hundred and forty-three patients with gliomas (41 low-grade, 105 anaplastic, and 197 glioblastoma) were accrued. Two-year survival from registration was 29% for glioblastomas, 62% for anaplastic gliomas, and 83% for low-grade gliomas. A total of 1740 serum samples were collected, and 95.6% of samples had matching MRI scans. Serum YKL-40 level was significantly lower in patients with no radiographic disease compared with patients with radiographic disease in both the anaplastic glioma (P = .0008) and the glioblastoma (P = .0006) cohorts. Serum levels of YKL-40 in patients with low-grade gliomas were not associated with radiographic disease status. Increases in YKL-40 were independently associated with worse survival in anaplastic gliomas (hazard ratio [HR] = 1.4, P = .01) and glioblastomas (HR 5 1.4, P < .0001). Longitudinal increases in serum YKL-40 are associated with increased risk of death in patients with glioblastomas and anaplastic gliomas. YKL-40 is also a putative indicator of disease status in these patients. C1 [Hormigo, Adilia] Mem Sloan Kettering Canc Ctr, Dept Neurol, Brain Tumor Ctr, New York, NY 10065 USA. [Karimi, Sasan] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA. [Riedel, Elyn; Panageas, Katherine S.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol Biostat, New York, NY 10065 USA. [Fleisher, Martin] Mem Sloan Kettering Canc Ctr, Dept Clin Labs, New York, NY 10065 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA. [Iwamoto, Fabio M.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Iwamoto, Fabio M.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Hottinger, Andreas F.] Univ Hosp Geneva, Dept Oncol, Geneva, Switzerland. RP Hormigo, A (reprint author), Mem Sloan Kettering Canc Ctr, Dept Neurol, Brain Tumor Ctr, 1275 York Ave, New York, NY 10065 USA. EM hormigoa@mskcc.org FU Society for Memorial Sloan-Kettering Cancer Center FX Adilia Hormigo received a grant from the Society for Memorial Sloan-Kettering Cancer Center. NR 36 TC 34 Z9 35 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2011 VL 13 IS 11 BP 1244 EP 1251 DI 10.1093/neuonc/nor117 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 848CH UT WOS:000297025500009 PM 21831900 ER PT J AU Hambidge, KM Sheng, XY Mazariegos, M Jiang, TJ Garces, A Li, DH Westcott, J Tshefu, A Sami, N Pasha, O Chomba, E Lokangaka, A Goco, N Manasyan, A Wright, LL Koso-Thomas, M Bose, C Goldenberg, RL Carlo, WA McClure, EM Krebs, NF AF Hambidge, K. Michael Sheng, Xiaoyang Mazariegos, Manolo Jiang, Tianjiang Garces, Ana Li, Dinghua Westcott, Jamie Tshefu, Antoinette Sami, Neelofar Pasha, Omrana Chomba, Elwyn Lokangaka, Adrien Goco, Norman Manasyan, Albert Wright, Linda L. Koso-Thomas, Marion Bose, Carl Goldenberg, Robert L. Carlo, Waldemar A. McClure, Elizabeth M. Krebs, Nancy F. TI Evaluation of meat as a first complementary food for breastfed infants: impact on iron intake SO NUTRITION REVIEWS LA English DT Review DE complementary feeding; infants; iron; meat ID ANIMAL SOURCE FOODS; KENYAN SCHOOL-CHILDREN; DIETARY INTERVENTION; CONSUMPTION; ABSORPTION; NUTRITION; TODDLERS; BIOAVAILABILITY; EVOLUTION; SURVIVAL AB The rationale for promoting the availability of local, affordable, non-fortified food sources of bioavailable iron in developing countries is considered in this review. Intake of iron from the regular consumption of meat from the age of 6 months is evaluated with respect to physiological requirements. Two major randomized controlled trials evaluating meat as a first and regular complementary food are described in this article. These trials are presently in progress in poor communities in Guatemala, Pakistan, Zambia, Democratic Republic of the Congo, and China. (C) 2011 International Life Sciences Institute C1 [Hambidge, K. Michael; Westcott, Jamie; Krebs, Nancy F.] Univ Colorado, Aurora, CO 80045 USA. [Sheng, Xiaoyang; Jiang, Tianjiang; Li, Dinghua] Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China. [Mazariegos, Manolo] Inst Nutr Cent Amer & Panama, Guatemala City, Guatemala. [Garces, Ana] Inst Multidisciplinario Salud, Guatemala City, Guatemala. [Tshefu, Antoinette; Lokangaka, Adrien] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Sami, Neelofar; Pasha, Omrana] Aga Khan Univ, Karachi, Pakistan. [Chomba, Elwyn; Manasyan, Albert] Univ Teaching Hosp, Lusaka, Zambia. [Goco, Norman; McClure, Elizabeth M.] RTI Int, Res Triangle Pk, NC USA. [Wright, Linda L.; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Bose, Carl] Univ N Carolina, Chapel Hill, NC USA. [Goldenberg, Robert L.] Drexel Univ, Philadelphia, PA 19104 USA. [Carlo, Waldemar A.] Univ Alabama, Birmingham, AL USA. RP Hambidge, KM (reprint author), Univ Colorado, 12700 E 19th Ave,Box C225, Aurora, CO 80045 USA. EM Michael.Hambidge@ucdenver.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD040657, HD043464, HD040607, HD043475, HD040636]; Office of Dietary Supplements, NIH NIDDK [K24 DK083772]; Thrasher Research Fund [02827-4] FX The work reported on here was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD040657 [UCD], HD043464 [UAB], HD040607 [Drexel], HD043475 [UNC], HD040636 [RTI]), the Office of Dietary Supplements, NIH NIDDK K24 DK083772, and the Thrasher Research Fund (02827-4). The National Cattlemen's Beef Association partially supported the analyses of biomarkers for this project. NR 37 TC 5 Z9 8 U1 3 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD NOV PY 2011 VL 69 SU 1 SI SI BP S57 EP S63 DI 10.1111/j.1753-4887.2011.00434.x PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 847GW UT WOS:000296961400009 PM 22043884 ER PT J AU Burstein, M Ameli-Grillon, L Merikangas, KR AF Burstein, Marcy Ameli-Grillon, Leila Merikangas, Kathleen R. TI Shyness Versus Social Phobia in US Youth SO PEDIATRICS LA English DT Article DE social phobia; shyness; adolescents; epidemiology; National Comorbidity Survey-Adolescent Supplement ID COMORBIDITY SURVEY REPLICATION; SUPPLEMENT NCS-A; NATIONAL COMORBIDITY; MENTAL-DISORDERS; CIGARETTE USE; TEENAGE DRUG; YOUNG-ADULTS; SELF-ESTEEM; 1ST GRADE; PREVALENCE AB OBJECTIVES: Scholars and the popular press have suggested that the diagnostic entity of social phobia "medicalizes" normal human shyness. In this study we examined the plausibility of this hypothesis by (1) determining the frequency of shyness and its overlap with social phobia in a nationally representative adolescent sample, (2) investigating the degree to which shyness and social phobia differ with regard to sociodemographic characteristics, functional impairment, and psychiatric comorbidity, and (3) examining differences in rates of prescribed medication use among youth with shyness and/or social phobia. METHODS: The National Comorbidity Survey-Adolescent Supplement is a nationally representative, face-to-face survey of 10 123 adolescents, aged 13 to 18 years, in the continental United States. Lifetime social phobia was assessed by using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview. Adolescents and parents also provided information on youth shyness and prescribed medication use. RESULTS: Only 12% of the youth who identified themselves as shy also met the criteria for lifetime social phobia. Relative to adolescents who were characterized as shy, adolescents affected with social phobia displayed significantly greater role impairment and were more likely to experience a multitude of psychiatric disorders, including disorders of anxiety, mood, behavior, and substance use. However, those adolescents were no more likely than their same-age counterparts to be taking prescribed medications. CONCLUSIONS: The results of this study provide evidence that social phobia is an impairing psychiatric disorder, beyond normal human shyness. Such findings raise questions concerning the "medicalization" hypothesis of social phobia. Pediatrics 2011;128:917-925 C1 [Burstein, Marcy; Ameli-Grillon, Leila; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Bldg 35,Room 1A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU National Institutes of Health (NIH); National Institute of Mental Health [Z01 MH002808-08, U01-MH60220] FX Funded by the National Institutes of Health (NIH).; This work was supported by the Intramural Research Program of the National Institute of Mental Health (grant Z01 MH002808-08). The National Comorbidity Survey-Adolescent Supplement and the larger program of related National Comorbidity Surveys are supported by the National Institute of Mental Health (grant U01-MH60220). NR 58 TC 11 Z9 11 U1 2 U2 14 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 NOV PY 2011 VL 128 IS 5 BP 917 EP 925 DI 10.1542/peds.2011-1434 PG 9 WC Pediatrics SC Pediatrics GA 843YO UT WOS:000296714000059 PM 22007009 ER PT J AU Wolraich, M Brown, L Brown, RT DuPaul, G Earls, M Feldman, HM Ganiats, TG Kaplanek, B Meyer, B Perrin, J Pierce, K Reiff, M Stein, MT Visser, S AF Wolraich, Mark Brown, Lawrence Brown, Ronald T. DuPaul, George Earls, Marian Feldman, Heidi M. Ganiats, Theodore G. Kaplanek, Beth Meyer, Bruce Perrin, James Pierce, Karen Reiff, Michael Stein, Martin T. Visser, Susanna TI ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents SO PEDIATRICS LA English DT Article DE attention-deficit/hyperactivity disorder; children; adolescents; preschool; behavioral therapy; medication ID DEFICIT-HYPERACTIVITY DISORDER; GUANFACINE EXTENDED-RELEASE; IMPROVING PRIMARY-CARE; LONG-TERM; PRESCHOOL-CHILDREN; PSYCHOSOCIAL TREATMENTS; STIMULANT MEDICATION; CHRONIC ILLNESS; PARENT; METHYLPHENIDATE AB Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood and can profoundly affect the academic achievement, well-being, and social interactions of children; the American Academy of Pediatrics first published clinical recommendations for the diagnosis and evaluation of ADHD in children in 2000; recommendations for treatment followed in 2001. Pediatrics 2011;128:1007-1022 C1 [Wolraich, Mark] Eli Lilly & Co, Indianapolis, IN USA. [Brown, Lawrence] NIH, Safety Monitoring Board Best Pharmaceut Children, Bethesda, MD 20892 USA. NR 72 TC 382 Z9 390 U1 31 U2 124 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2011 VL 128 IS 5 BP 1007 EP 1022 DI 10.1542/peds.2011-2654 PG 16 WC Pediatrics SC Pediatrics GA 843YO UT WOS:000296714000069 ER PT J AU Ambalavanan, N Carlo, WA McDonald, SA Yao, Q Das, A Higgins, RD AF Ambalavanan, Namasivayam Carlo, Waldemar A. McDonald, Scott A. Yao, Qing Das, Abhik Higgins, Rosemary D. CA Generic Database Follow-Up Subcomm Eunice Kennedy TI Identification of Extremely Premature Infants at High Risk of Rehospitalization SO PEDIATRICS LA English DT Article DE logistic models; infant; premature; predictive value of tests ID BIRTH-WEIGHT INFANTS; NEONATAL RESEARCH NETWORK; PRETERM INFANTS; BRONCHOPULMONARY DYSPLASIA; GESTATIONAL-AGE; OUTCOMES; HOSPITALIZATION; DISEASE; HYDROCEPHALUS; TRIAL AB OBJECTIVE: Extremely low birth weight infants often require rehospitalization during infancy. Our objective was to identify at the time of discharge which extremely low birth weight infants are at higher risk for rehospitalization. METHODS: Data from extremely low birth weight infants in Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers from 2002-2005 were analyzed. The primary outcome was rehospitalization by the 18- to 22-month follow-up, and secondary outcome was rehospitalization for respiratory causes in the first year. Using variables and odds ratios identified by stepwise logistic regression, scoring systems were developed with scores proportional to odds ratios. Classification and regression-tree analysis was performed by recursive partitioning and automatic selection of optimal cutoff points of variables. RESULTS: A total of 3787 infants were evaluated (mean +/- SD birth weight: 787 +/- 136 g; gestational age: 26 +/- 2 weeks; 48% male, 42% black). Forty-five percent of the infants were rehospitalized by 18 to 22 months; 14.7% were rehospitalized for respiratory causes in the first year. Both regression models (area under the curve: 0.63) and classification and regression-tree models (mean misclassification rate: 40%-42%) were moderately accurate. Predictors for the primary outcome by regression were shunt surgery for hydrocephalus, hospital stay of > 120 days for pulmonary reasons, necrotizing enterocolitis stage II or higher or spontaneous gastrointestinal perforation, higher fraction of inspired oxygen at 36 weeks, and male gender. By classification and regression-tree analysis, infants with hospital stays of > 120 days for pulmonary reasons had a 66% rehospitalization rate compared with 42% without such a stay. CONCLUSIONS: The scoring systems and classification and regression-tree analysis models identified infants at higher risk of rehospitalization and might assist planning for care after discharge. Pediatrics 2011; 128: e1216-e1225 C1 [Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama, Dept Pediat, Birmingham, AL 35249 USA. [McDonald, Scott A.; Yao, Qing] RTI Int, Res Triangle Pk, NC USA. [Das, Abhik] RTI Int, Rockville, MD USA. [Higgins, Rosemary D.] NICHD Neonatal Res Network, NIH, Bethesda, MD USA. RP Ambalavanan, N (reprint author), Univ Alabama, Dept Pediat, 176F Suite 9380,619 S 20th St, Birmingham, AL 35249 USA. EM ambal@uab.edu RI Myers , Gary /I-4901-2013; OI Myers , Gary /0000-0003-4317-015X; Ambalavanan, Namasivayam/0000-0003-0731-9092 FU National Institutes of Health (NIH); NICHD; Department of Health and Human Services [U10 HD21364, U10 HD21385, U10 HD40689, U10 HD27871, U10 HD21373, U10 HD36790, U10 HD40498, U10 HD40461, U10 HD34216, U10 HD21397, U10 HD27904, U10 HD40492, U10 HD27856, U10 HD40521, U10 HD27853, U10 HD27880, U10 HD27851, R03 HD054420]; National Institutes of Health [M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR70, M01 RR80, M01 RR125, M01 RR750, M01 RR633, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, KL2 RR24149, UL1 RR24139, UL1 RR24148, UL1 RR24160]; University of Cincinnati [20012006]; Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island [U10 HD27904]; Rainbow Babies & Children's Hospital [U10 HD21364, M01 RR80]; Cincinnati Children's Hospital Medical Center, University Hospital; Good Samaritan Hospital [U10 HD27853, M01 RR8084] FX The National Institutes of Health and the NICHD provided grant support for the NRN's Generic Database and Follow-up Studies. This research was supported by grants from the NICHD and the Department of Health and Human Services (U10 HD21364, U10 HD21385, U10 HD40689, U10 HD27871, U10 HD21373, U10 HD36790, U10 HD40498, U10 HD40461, U10 HD34216, U10 HD21397, U10 HD27904, U10 HD40492, U10 HD27856, U10 HD40521, U10 HD27853, U10 HD27880, U10 HD27851, and R03 HD054420) and from the National Institutes of Health (M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR70, M01 RR80, M01 RR125, M01 RR750, M01 RR633, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, KL2 RR24149, UL1 RR24139, UL1 RR24148, and UL1 RR24160).; Myriam The following investigators, in addition to those listed as authors, participated in this study (grant numbers are shown in parentheses). NRN steering committee chairs: Alan H. Jobe, MD, PhD (University of Cincinnati [20012006]), and Michael S. Caplan, MD (University of Chicago, Pritzker School of Medicine [2006 - present]); Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904): Abbot R. Laptook, MD, William Oh, MD, Betty R. Vohr, MD, Angelita Hensman, BSN, RNC, Theresa M. Leach, Med, CAES, Martha R. Leonard, BA, BS, James R. Moore, MD, Lucy Noel, RN, Bonnie E. Stephens, MD, Robert Burke, MD, Yvette Yatchmink, MD, Rachel V. Walden, MD, and Victoria E. Watson, MS, CAS; Case Western Reserve University, Rainbow Babies & Children's Hospital (U10 HD21364, M01 RR80): Michele C. Walsh, MD, MS, Avroy A. Fanaroff, MD, Deanne Wilson-Costello, MD, Nancy S. Newman, RN, and Bonnie S. Siner, RN; Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084): Kurt Schibler, MD, Edward F. Donovan, MD, Jean J. Steichen, MD, Kate Bridges, MD, Barbara Alexander, RN, Cathy Grisby, RN, Marcia Worley Mersmann, RN, CCRC, Holly L. Mincey, RN, BSN, Jody Hessling, RN, and Teresa L. Gratton, PA; Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492, M01 RR30): Ronald N. Goldberg, MD, C. Michael Cotten, MD, MHS, Ricki F. Goldstein, MD, Kathy J. Auten, MSHS, Kimberley A. Fisher, PhD, FNPBC, IBCLC, and Melody B. Lohmeyer, RN, MSN; Emory University, Children's Health Care of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39): Barbara J. Stoll, MD, David P. Carlton, MD, Ira Adams-Chapman, MD, and Ellen C. Hale, RN, BS, CCRC; NICHD: Linda L. Wright, MD, and Elizabeth M. McClure, Med; Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750): Brenda B. Poindexter, MD, MS, James A. Lemons, MD, Anna M. Dusick, MD, Diana D. Appel, RN, BSN, Dianne E. Herron, RN, Lucy C. Miller, RN, BSN, CCRC, and Leslie Dawn Wilson, BSN, CCRC; RTI International (U10 HD36790): W. Kenneth Poole, PhD, Betty Hastings, Elizabeth N. McClure, MEd, Jamie E. Newman, PhD, MPH, Jeanette O'Donnell Auman, BS, Carolyn M. Petrie Huitema, MS, and Kristin M. Zaterka-Baxter, RN, BSN; Stanford University, Lucile Packard Children's Hospital (U10 HD27880, M01 RR70): Krisa P. Van Meurs, MD, Susan R. Hintz, MD, MSEpi, David K. Stevenson, MD, M. Bethany Ball, BS, CCRC, Joan M. Baran, PhD, Lori E. Bond, PhD, Ginger K. Brudos, PhD, S. Davis, MD, MS Epi, Anne M. DeBattista, RN, PNP, Barry E. Fleisher, MD, Jean G. Kohn, MD, MPH, Julie C. Lee-Ancajas, PhD, Renee P. Pyle, PhD, Dharshi Sivakumar, MD, MRCP, and Nicholas H. St John, PhD; University of Alabama at Birmingham Health System and Children's Hospital of Alabama (U10 HD34216, M01 RR32): Myriam Peralta-Carcelen, MD, MPH, Monica V. Collins, RN, BSN MaEd, Shirley S. Cosby, RN, BSN, and Vivien A. Phillips, RN, BSN; University of California-San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461): Neil N. Finer, MD, Yvonne E. Vaucher, MD, MPH, Maynard R. Rasmussen, MD, David Kaegi, MD, Kathy Arnell, RNC, Clarence Demetrio, RN, Martha G. Fuller, RN, MSN, Chris Henderson, RCP, CRTT, and Wade Rich, BSHS, RRT; University of Miami Holtz Children's Hospital (U10 HD21397, M01 RR16587): Charles R.; Bauer, MD, Shahnaz Duara, M, Silvia Hiriart-Fajardo, MD, Ruth Everett-Thomas, RN, BSN, Mary Allison, RN, Alexis N. Diaz, BA, Silvia Frade Eguaras, MS, Yamiley C. Gideon, BA, Arielle Riguard, MD, Alexandra Stoerger, BA, Andrea Garcia, MA, Helina Pierre, BA, and Kasey Hamlin-Smith, PhD; University of Rochester Medical Center, Golisano Children's Hospital (U10 HD40521, M01 RR44, UL1 RR24160): Dale L. Phelps, MD, Gary J. Myers, MD, Linda J. Reubens, RN, CCRC, Mary Rowan, RN, Erica Burnell, RN, Diane Hust, MS, RN, CS, Rosemary L. Jensen, Lauren Zwetsch, RN, MS, PNP, Julie Babish Johnson, MSW, Emily Kushner, MA, Joan Merzbach, LMSW, and Kelly Yost, PhD; University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children's Medical Center Dallas (U10 HD40689, M01 RR633): Walid A. Salhab, MD, Pablo J. S~nchez, MD, Charles R. Rosenfeld, MD, Abbot R. Laptook, MD, Roy J. Heyne, MD, Sally S. Adams, MS, RN, CPNP, Cristin Dooley, PhD, LSSP, Alicia Guzman, Gaynelle Hensley, RN, Jackie F. Hickman, RN, Linda A. Madden, RN, CPNP, Susie Madison, RN, Nancy A. Miller, RN, Janet S. Morgan, RN, Catherine Twell Boatman, MS CIMI, and Elizabeth Heyne, PsyD PA-C; University of Texas Health Science Center at Houston Medical School, Children's Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373, KL2 RR24149, UL1 RR24148): Kathleen A. Kennedy, MD, MPH, Jon E. Tyson, MD, MPH, Brenda H. Morris, MD, Pamela J. Bradt, MD, MPH, Patricia W. Evans, MD, Esther G. Akpa, RN, BSN, Nora I. Alaniz, BS, Patty A. Cluff, RN, Maegan Currence, RN, Claudia I. Franco, RNC, MSN, Anna E. Lis, RN, BSN, Georgia E. McDavid, RN, Patti L. Pierce Tate, RCP, Laura L. Whiteley, MD, and Sharon L. Wright, MT (ASCP); Wake Forest University, Baptist Medical Center, Brenner Children's Hospital, and Forsyth Medical Center NR 23 TC 18 Z9 18 U1 0 U2 4 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 NOV PY 2011 VL 128 IS 5 BP E1216 EP E1225 DI 10.1542/peds.2011-1142 PG 10 WC Pediatrics SC Pediatrics GA 843YO UT WOS:000296714000022 PM 22007016 ER PT J AU Bley, AE Giannikopoulos, OA Hayden, D Kubilus, K Tifft, CJ Eichler, FS AF Bley, Annette E. Giannikopoulos, Ourania A. Hayden, Doug Kubilus, Kim Tifft, Cynthia J. Eichler, Florian S. TI Natural History of Infantile G(M2) Gangliosidosis SO PEDIATRICS LA English DT Article DE infantile G(M2) gangliosidosis; natural history; Tay Sachs; Sandhoff; survival; lysosomal disorders; neurodegeneration ID TAY-SACHS-DISEASE; HEXOSAMINIDASE ALPHA-GENE; SANDHOFF DISEASE; NEUTRAL GLYCOSPHINGOLIPIDS; GM2 GANGLIOSIDOSIS; GENERALIZED ACCUMULATION; FINE-STRUCTURE; BRAIN; STORAGE; MUTATION AB OBJECTIVE: GM2 gangliosidoses are caused by an inherited deficiency of lysosomal beta-hexosaminidase and result in ganglioside accumulation in the brain. Onset during infancy leads to rapid neurodegeneration and death before 4 years of age. We set out to quantify the rate of functional decline in infantile GM2 gangliosidosis on the basis of patient surveys and a comprehensive review of existing literature. METHODS: Patients with infantile GM2 gangliosidosis (N = 237) were surveyed via questionnaire by the National Tay Sachs & Allied Diseases Association (NTSAD). These data were supplemented by survival data from the NTSAD database and a literature survey. Detailed retrospective surveys from 97 patients were available. Five patients who had received hematopoietic stem cell transplantation were evaluated separately. The mortality rate of the remaining 92 patients was comparable to that of the 103 patients from the NTSAD database and 121 patients reported in the literature. RESULTS: Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). All 55 patients who had learned to sit without support lost that ability within 1 year. Individual functional measures correlated with each other but not with survival. Gastric tube placement was associated with prolonged survival. Tay Sachs and Sandhoff variants did not differ. Hematopoietic stem cell transplantation was not associated with prolonged survival. CONCLUSIONS: We studied the timing of regression in 97 cases of infantile GM2 gangliosidosis and conclude that clinical disease progression does not correlate with survival, likely because of the impact of improved supportive care over time. However, functional measures are quantifiable and can inform power calculations and study design of future interventions. Pediatrics 2011; 128: e1233-e1241 C1 [Bley, Annette E.; Giannikopoulos, Ourania A.; Eichler, Florian S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hayden, Doug] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Kubilus, Kim] Natl Tay Sachs & Allied Dis Assoc, Boston, MA USA. [Tifft, Cynthia J.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Eichler, FS (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St,ACC 708, Boston, MA 02114 USA. EM feichler@partners.org FU Harvard Catalyst/Harvard Clinical and Translational Science Center (National Institutes of Health) [UL1 RR 025758]; Harvard University; National Institutes of Health [K08NS52550]; National Institutes of Health "Lysosomal Disease Network" [5U54NS065768]; NTSAD FX This work was conducted with support from Harvard Catalyst/Harvard Clinical and Translational Science Center (National Institutes of Health award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers), National Institutes of Health training grant K08NS52550 (to Dr Eichler), and National Institutes of Health "Lysosomal Disease Network" grant 5U54NS065768. Ms. Giannikopoulos, Mrs. Kubilus, and Dr. Eichler were supported by the NTSAD. NR 76 TC 26 Z9 29 U1 2 U2 13 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 NOV PY 2011 VL 128 IS 5 BP E1233 EP E1241 DI 10.1542/peds.2011-0078 PG 9 WC Pediatrics SC Pediatrics GA 843YO UT WOS:000296714000024 PM 22025593 ER PT J AU Kemper, AR Mahle, WT Martin, GR Cooley, WC Kumar, P Morrow, WR Kelm, K Pearson, GD Glidewell, J Grosse, SD Howell, RR AF Kemper, Alex R. Mahle, William T. Martin, Gerard R. Cooley, W. Carl Kumar, Praveen Morrow, W. Robert Kelm, Kellie Pearson, Gail D. Glidewell, Jill Grosse, Scott D. Howell, R. Rodney TI Strategies for Implementing Screening for Critical Congenital Heart Disease SO PEDIATRICS LA English DT Article DE congenital heart defects; neonatal screening; oximetry ID PULSE OXIMETRY; FOLLOW-UP; HIGH-ALTITUDE; NEWBORNS; STATEMENT; DEFECTS; INFANTS; VALUES; IMPACT AB BACKGROUND: Although newborn screening for critical congenital heart disease (CCHD) was recommended by the US Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children to promote early detection, it was deemed by the Secretary of the HHS as not ready for adoption pending an implementation plan from HHS agencies. OBJECTIVE: To develop strategies for the implementation of safe, effective, and efficient screening. METHODS: A work group was convened with members selected by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children, the American Academy of Pediatrics, the American College of Cardiology Foundation, and the American Heart Association. RESULTS: On the basis of published and unpublished data, the work group made recommendations for a standardized approach to screening and diagnostic follow-up. Key issues for future research and evaluation were identified. CONCLUSIONS: The work-group members found sufficient evidence to begin screening for low blood oxygen saturation through the use of pulse-oximetry monitoring to detect CCHD in well-infant and intermediate care nurseries. Research is needed regarding screening in special populations (eg, at high altitude) and to evaluate service infrastructure and delivery strategies (eg, telemedicine) for nurseries without on-site echocardiography. Public health agencies will have an important role in quality assurance and surveillance. Central to the effectiveness of screening will be the development of a national technical assistance center to coordinate implementation and evaluation of newborn screening for CCHD. Pediatrics 2011;128:e1259-e1267 C1 [Kemper, Alex R.] Duke Univ, Duke Clin Res Inst, Durham, NC 27705 USA. [Kemper, Alex R.] Duke Univ, Dept Pediat, Durham, NC 27705 USA. [Mahle, William T.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Martin, Gerard R.] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA. [Cooley, W. Carl] Ctr Med Home Improvement, Concord, NH USA. [Kumar, Praveen] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [Morrow, W. Robert] Univ Arkansas Med Sci, Sch Med, Dept Pediat, Little Rock, AR 72205 USA. [Kelm, Kellie] US Dept HHS, US FDA, Silver Spring, MD USA. [Pearson, Gail D.] NHLBI, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Glidewell, Jill; Grosse, Scott D.] Ctr Dis Control & Prevent, US Dept HHS, Atlanta, GA USA. [Howell, R. Rodney] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. RP Kemper, AR (reprint author), Duke Univ, Duke Clin Res Inst, 2400 Pratt St,Room 0311 Terrace Level, Durham, NC 27705 USA. EM alex.kemper@duke.edu NR 21 TC 111 Z9 116 U1 1 U2 12 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 NOV PY 2011 VL 128 IS 5 BP E1259 EP E1267 DI 10.1542/peds.2011-1317 PG 9 WC Pediatrics SC Pediatrics GA 843YO UT WOS:000296714000027 PM 21987707 ER PT J AU Figueiras, RG Padhani, AR Goh, VJ Vilanova, JC Gonzalez, SB Martin, CV Caamano, AG Naveira, AB Choyke, PL AF Garcia Figueiras, Roberto Padhani, Anwar R. Goh, Vicky J. Vilanova, Joan C. Baleato Gonzalez, Sandra Villalba Martin, Carmen Gomez Caamano, Antonio Bermudez Naveira, Anaberta Choyke, Peter L. TI Novel Oncologic Drugs: What They Do and How They Affect Images SO RADIOGRAPHICS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; APPARENT DIFFUSION-COEFFICIENT; GUIDELINE VERSION 1.1; TUMOR BLOOD-VESSELS; CANCER-THERAPY; PROSTATE-CANCER; CLINICAL-TRIALS; MTOR INHIBITOR; SOLID TUMORS; ANTIANGIOGENIC THERAPY AB Targeted therapies are designed to interfere with specific aberrant biologic pathways involved in tumor development. The main classes of novel oncologic drugs include antiangiogenic drugs, antivascular agents, drugs interfering with EGFR-HER2 or KIT receptors, inhibitors of the PI3K/Akt/mTOR pathway, and hormonal therapies. Cancer cells usurp normal signal transduction pathways used by growth factors to stimulate proliferation and sustain viability. The interaction of growth factors with their receptors activates different intracellular pathways affecting key tumor biologic processes such as neoangiogenesis, tumor metabolism, and tumor proliferation. The response of tumors to anticancer therapy can be evaluated with anatomic response assessment, qualitative response assessment, and response assessment with functional and molecular imaging. Angiogenesis can be measured by means of perfusion imaging with computed tomography and magnetic resonance (MR) imaging. Diffusion-weighted MR imaging allows imaging evaluation of tumor cellularity. The main imaging techniques for studying tumor metabolism in vivo are positron emission tomography and MR spectroscopy. Familiarity with imaging findings secondary to tumor response to targeted therapies may help the radiologist better assist the clinician in accurate evaluation of tumor response to these anticancer treatments. Functional and molecular imaging techniques may provide valuable data and augment conventional assessment of tumor response to targeted therapies. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.317115108/-/DC1. (C) RSNA, 2011 . radiographics.rsna.org C1 [Garcia Figueiras, Roberto; Baleato Gonzalez, Sandra; Villalba Martin, Carmen; Bermudez Naveira, Anaberta] Complexo Hosp Univ Santiago Compostela, Fdn IDI CHUS IDIS, Grp Imagen Mol, Dept Radiol, Santiago De Compostela 15702, Spain. [Gomez Caamano, Antonio] Complexo Hosp Univ Santiago Compostela, Fdn IDI CHUS IDIS, Grp Imagen Mol, Dept Radiotherapy, Santiago De Compostela 15702, Spain. [Padhani, Anwar R.] Mt Vernon Canc Ctr, Paul Strickland Scanner Ctr, Northwood, Middx, England. [Goh, Vicky J.] Kings Coll London, Div Imaging Sci & Biomed Engn, London WC2R 2LS, England. [Vilanova, Joan C.] Clin Girona, Dept Radiol, Girona, Spain. [Vilanova, Joan C.] Hosp Santa Caterina, Girona, Spain. [Choyke, Peter L.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Figueiras, RG (reprint author), Complexo Hosp Univ Santiago Compostela, Fdn IDI CHUS IDIS, Grp Imagen Mol, Dept Radiol, Choupana S-N, Santiago De Compostela 15702, Spain. EM roberto.garcia.figueiras@sergas.es RI Vilanova, Joan C/H-6104-2015 OI Vilanova, Joan C/0000-0003-2148-6751 FU Springer FX A.R.P.: Related financial activities: none. Other financial activities: consultant and speaker for Siemens Healthcare. J.C.V.: Related financial activities: none. Other financial activities: speaker for Bayer; royalties from Springer. V.J.G.: Related financial activities: none. Other financial activities: consultant for Siemens Healthcare and GE Healthcare. NR 103 TC 37 Z9 39 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD NOV-DEC PY 2011 VL 31 IS 7 BP 2059 EP 2091 DI 10.1148/rg.317115108 PG 33 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 848JE UT WOS:000297047000022 PM 22084189 ER PT J AU Switzer, CH Glynn, SA Ridnour, LA Cheng, RYS Vitek, MP Ambs, S Wink, DA AF Switzer, Christopher H. Glynn, Sharon A. Ridnour, Lisa A. Cheng, Robert Y. -S. Vitek, Michael P. Ambs, Stefan Wink, David A. TI Nitric oxide and protein phosphatase 2A provide novel therapeutic opportunities in ER-negative breast cancer SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CARCINOMA; TUMOR-SUPPRESSOR; APOLIPOPROTEIN-E; PROGNOSTIC-SIGNIFICANCE; MOLECULAR-MECHANISMS; TRANSCRIPTION FACTOR; SIGNAL-TRANSDUCTION; SYNTHASE EXPRESSION; REGULATORY SUBUNIT AB Basal-like breast cancer is an aggressive disease with limited therapeutic options because these tumors frequently express the 'triple-negative' phenotype. We have recently reported that inducible nitric oxide synthase (NOS2) is a strong predictor of survival in patients with estrogen receptor negative [ER(-)] breast cancer, and that NOS2 expression is correlated with a basal-like phenotype. Recent reports also describe the pro-tumor effects of NO in breast and many other types of cancer. NO promotes cancer progression by activating several oncogenic signaling pathways such as extracellular signal-regulated kinases (ERK)-1/2, phosphoinositide 3-kinases (PI3K)/Akt, and c-Myc. Protein phosphatase 2A (PP2A) is a tumor suppressor that negatively regulates the same cancer-related signaling pathways that are activated by NO. PP2A activity is suppressed in tumor cells, but potential pharmacological agents have recently been described to increase PP2A activity in ER(-) breast cancer cells. We examine here the various functions of NO and PP2A in breast cancer and propose a novel mechanism by which activation of PP2A antagonizes NO signaling that promotes ER(-) breast cancer. C1 [Switzer, Christopher H.; Glynn, Sharon A.; Ridnour, Lisa A.; Cheng, Robert Y. -S.; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon A.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon A.] Natl Univ Ireland, Prostate Canc Inst, Galway, Ireland. [Vitek, Michael P.] Cognosci Inc, Res Triangle Pk, NC 27709 USA. [Vitek, Michael P.] Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. EM wink@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Switzer, Christopher/D-9203-2013; OI Glynn, Sharon/0000-0003-1459-2580; Cheng, Robert/0000-0003-0287-6439 FU Intramural NIH HHS [Z99 CA999999] NR 118 TC 23 Z9 24 U1 0 U2 2 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 NOV PY 2011 VL 32 IS 11 BP 644 EP 651 DI 10.1016/j.tips.2011.07.001 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848XL UT WOS:000297088300003 PM 21893353 ER PT J AU Vellano, CP Lee, SE Dudek, SM Hepler, JR AF Vellano, Christopher P. Lee, Sarah Emerson Dudek, Serena M. Hepler, John R. TI RGS14 at the interface of hippocampal signaling and synaptic plasticity SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID GUANINE-NUCLEOTIDE EXCHANGE; HETEROTRIMERIC G-PROTEINS; G-ALPHA-I; GI-ALPHA; EXPRESSION ANALYSIS; SURFACE EXPRESSION; GOLOCO MOTIF; CA2 NEURONS; H-RAS; RECEPTOR AB Learning and memory are encoded within the brain as biochemical and physical changes at synapses that alter synaptic transmission, a process known as synaptic plasticity. Although much is known about factors that positively regulate synaptic plasticity, very little is known about factors that negatively regulate this process. Recently, the signaling protein RGS14 (Regulator of G protein Signaling 14) was identified as a natural suppressor of hippocampal-based learning and memory as well as synaptic plasticity within CA2 hippocampal neurons. RGS14 is a multifunctional scaffolding protein that integrates unconventional G protein and mitogen-activated protein (MAP) kinase signaling pathways that are themselves key regulators of synaptic plasticity, learning, and memory. Here, we highlight the known roles for RGS14 in brain physiology and unconventional G protein signaling pathways, and propose molecular models to describe how RGS14 may integrate these diverse signaling pathways to modulate synaptic plasticity in CA2 hippocampal neurons. C1 [Vellano, Christopher P.; Lee, Sarah Emerson; Hepler, John R.] Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. [Dudek, Serena M.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Vellano, CP (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. EM cvellan@emory.edu; jhepler@emory.edu OI Dudek, Serena M./0000-0003-4094-8368 FU Intramural NIH HHS [ZIA ES100221-10]; NINDS NIH HHS [R01 NS037112-10A2, R01 NS037112-11, R01 NS037112, R56 NS037112-10A1, R56 NS037112] NR 71 TC 13 Z9 13 U1 0 U2 2 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 NOV PY 2011 VL 32 IS 11 BP 666 EP 674 DI 10.1016/j.tips.2011.07.005 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 848XL UT WOS:000297088300006 PM 21906825 ER PT J AU Brown, AJ Bates, A AF Brown, Anissa J. Bates, Angela TI The National Institutes of Health Commitment to Research on Women and Girls and AIDS SO WOMENS HEALTH ISSUES LA English DT Editorial Material C1 [Brown, Anissa J.] NIH, Off AIDS Res, Off Director, Bethesda, MD 20892 USA. [Bates, Angela] NIH, Off Res Womens Hlth, Off Director, Bethesda, MD 20892 USA. RP Brown, AJ (reprint author), NIH, Off AIDS Res, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM brownani@mail.nih.gov NR 4 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 1049-3867 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD NOV-DEC PY 2011 VL 21 IS 6 SU S BP S239 EP S240 DI 10.1016/j.whi.2011.05.006 PG 2 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 848FO UT WOS:000297036100005 PM 21724414 ER PT J AU Bailey, RL Fulgoni, VL Keast, DR Dwyer, JT AF Bailey, Regan L. Fulgoni, Victor L., III Keast, Debra R. Dwyer, Johanna T. TI Dietary supplement use is associated with higher intakes of minerals from food sources SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID MULTIVITAMIN-MULTIMINERAL SUPPLEMENTS; NUTRITION EXAMINATION SURVEY; NUTRIENT INTAKE; NATIONAL-HEALTH; ADULTS; ENERGY; COHORT AB Background: Dietary supplement use is extensive in US adults. Some reports suggested that supplement users had higher nutrient intakes from the diet than did nonusers, but to our knowledge this finding has not been examined in nationally representative survey data. Objective: In this analysis, we examined mineral intakes from the diet by supplement-use categories and how these supplements contributed to meeting or exceeding Dietary Reference Intakes for selected minerals. Design: Data from adults (>= 19 y of age; n = 8860) who participated in NHANES 2003-2006, a nationally representative, cross-sectional survey, were examined. Supplement use was defined as the participant's self-reported use of a supplement that contained one or more selected minerals. Results: Dietary intakes of minerals from food sources were higher for magnesium, copper, potassium, and selenium in male supplement users than in nonusers. For women, dietary intakes of minerals from food sources were higher for users than for nonusers for each mineral examined except for selenium. In women, users of calcium-containing dietary supplements were much more likely to meet the Estimated Average Requirement (EAR) than were nonusers. Even after consideration of supplement use, >14% of adults had inadequate intakes for calcium and magnesium on the basis of the percentage of adults with usual intakes less than the EAR. The prevalence of adults who exceeded the tolerable upper intake level (UL) for calcium, zinc, iron, and magnesium was higher in users than in nonusers. Conclusions: Individuals who used mineral-containing dietary supplements had higher mineral intakes from food sources in the diet than did nonusers. For all minerals examined, and particularly for calcium and magnesium in men and women and iron in women, supplement use decreased the prevalence of intake inadequacy for each respective mineral; however, supplements contributed to risk of potentially excessive intakes for calcium, iron, zinc, and magnesium. Am J Clin Nutr 2011;94:1376-81. C1 [Bailey, Regan L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Fulgoni, Victor L., III] Nutr Impact LLC, Battle Creek, MI USA. [Keast, Debra R.] Food & Nutr Database Res Inc, Okemos, MI USA. [Dwyer, Johanna T.] Tufts Univ, Sch Med, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Bailey, RL (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,2B03, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU US Department of Agriculture Research Service [58-1950-7-707]; Office of Dietary Supplements, NIH; Fortification Committee of the International Life Sciences Institute, North American Branch FX Supported in part with resources from the US Department of Agriculture Research Service (agreement 58-1950-7-707) and the Office of Dietary Supplements, NIH. Data generation for the study was funded by the Fortification Committee of the International Life Sciences Institute, North American Branch. NR 26 TC 45 Z9 45 U1 0 U2 24 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2011 VL 94 IS 5 BP 1376 EP 1381 DI 10.3945/ajcn.111.020289 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 837VV UT WOS:000296236100027 PM 21955646 ER PT J AU Glasser, JH Fee, E Brown, TM AF Glasser, Jay H. Fee, Elizabeth Brown, Theodore M. TI Stephen Smith (1823-1922): Founder of the American Public Health Association SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Glasser, Jay H.] Univ Texas Houston, Sch Publ Hlth, Med & Publ Hlth Initiat, Houston, TX USA. [Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. [Brown, Theodore M.] Univ Rochester, Dept Hist, Rochester, NY USA. [Brown, Theodore M.] Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Glasser, JH (reprint author), 5427 Valkeith Dr, Houston, TX 77096 USA. EM jayhglasser@gmail.com NR 4 TC 0 Z9 0 U1 0 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD NOV PY 2011 VL 101 IS 11 BP 2058 EP 2058 DI 10.2105/AJPH.2009.188920 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 835NA UT WOS:000296041900015 PM 21940929 ER PT J AU Yu, S Nikolic, D AF Yu, Shan Nikolic, Danko TI Quantum mechanics needs no consciousness SO ANNALEN DER PHYSIK LA English DT Article DE Measurement problem; wave function collapse; observer; double-slit experiment ID DELAYED CHOICE; INTERFERENCE; FOUNDATIONS; ATTENTION; PHYSICS; ERASER; PHOTON; ATOMS; TASK; SEE AB It has been suggested that consciousness plays an important role in quantum mechanics as it is necessary for the collapse of wave function during the measurement. Here we formulated several predictions that follow from this hypothetical relationship and that can be empirically tested. Experimental results that are already available suggest falsification of these predictions. Thus, the suggested link between human consciousness and collapse of wave function does not seem viable. We discuss the implications of these conclusions on the role of the human observer for quantum mechanics and on the role of quantum mechanics for the observer's consciousness. (C) 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim C1 [Yu, Shan; Nikolic, Danko] Max Planck Inst Brain Res, Dept Neurophysiol, D-60528 Frankfurt, Germany. [Nikolic, Danko] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, D-60438 Frankfurt, Germany. RP Yu, S (reprint author), NIMH, Sect Crit Brain Dynam, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM yushan.mail@gmail.com; danko.nikolic@googlemail.com NR 38 TC 5 Z9 5 U1 2 U2 19 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0003-3804 J9 ANN PHYS-BERLIN JI Ann. Phys.-Berlin PD NOV PY 2011 VL 523 IS 11 BP 931 EP 938 DI 10.1002/andp.201100078 PG 8 WC Physics, Multidisciplinary SC Physics GA 848IJ UT WOS:000297044800007 ER PT J AU Metifiot, M Johnson, B Smith, S Zhao, XZ Marchand, C Burke, T Hughes, S Pommier, Y AF Metifiot, Mathieu Johnson, Barry Smith, Steven Zhao, Xue Zhi Marchand, Christophe Burke, Terrence Hughes, Stephen Pommier, Yves TI MK-0536 Inhibits HIV-1 Integrases Resistant to Raltegravir SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID EXPERIENCED PATIENTS; ELVITEGRAVIR; REGIMENS; INTASOME; MUTANTS AB With the U. S. Food and Drug Administration approval of raltegravir (RAL; MK-0518; Merck & Co.), HIV-1 integrase (IN) is the newest therapeutic target for AIDS and HIV infections. Recent structural analyses show that IN strand transfer inhibitors (INSTIs) share a common binding mode in the enzyme active site. While RAL represents a therapeutic breakthrough, the emergence of IN resistance mutations imposes the development of new INSTIs. We report here the biochemical and antiviral activities of MK-0536, a new IN inhibitor. We demonstrate that, like RAL, MK-0536 is highly potent against recombinant IN and viral replication. It is also effective against INs that carry the three main RAL resistance mutations (Y143R, N155H, and to a lesser extent G140S-Q148H) and against the G118R mutant. Modeling of IN developed from recent prototype foamy virus structures is presented to account for the differences in the drug activities of MK-0536 and RAL against the IN mutants. C1 [Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Johnson, Barry; Smith, Steven; Hughes, Stephen] NCI, HIV Drug Resistance Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Zhao, Xue Zhi; Burke, Terrence] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Zhao, Xue Zhi/N-9594-2014; Burke, Terrence/N-2601-2014 OI Zhao, Xue Zhi/0000-0003-1006-6364; FU National Institutes of Health, National Cancer Institute, Center for Cancer Research [Z01BC007333-09LMP] FX These studies were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (Z01BC007333-09LMP). NR 23 TC 22 Z9 22 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2011 VL 55 IS 11 BP 5127 EP 5133 DI 10.1128/AAC.05288-11 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 839NX UT WOS:000296375600025 PM 21876054 ER PT J AU Hasin, D Fenton, MC Skodol, A Krueger, R Keyes, K Geier, T Greenstein, E Blanco, C Grant, B AF Hasin, Deborah Fenton, Miriam C. Skodol, Andrew Krueger, Robert Keyes, Katherine Geier, Timothy Greenstein, Eliana Blanco, Carlos Grant, Bridget TI Personality Disorders and the 3-Year Course of Alcohol, Drug, and Nicotine Use Disorders SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; SUBSTANCE USE DISORDERS; DSM-IV ALCOHOL; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; MAJOR DEPRESSIVE DISORDER; PSYCHIATRIC DIAGNOSTIC MODULES; COGNITIVE-BEHAVIORAL TREATMENT; DEPENDENCE TREATMENT OUTCOMES; UNITED-STATES AB Context: Little is known about the role of a broad range of personality disorders in the course of substance use disorder (SUD) and whether these differ by substance. The existing literature focuses mostly on antisocial personality disorder and does not come to clear conclusions. Objective: To determine the association between the 10 DSM-IV personality disorders and the persistence of common SUDs in a 3-year prospective study of a national sample. Design: Data were drawn from participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) who had alcohol dependence (n=1172), cannabis use disorder (n=454), or nicotine dependence (n=4017) at baseline and who were reinterviewed 3 years later. Control variables included demographic characteristics, family history of substance disorders, baseline Axis I disorders and treatment status, and prior SUD duration. Main Outcome Measure: Persistent SUD, defined as meeting full criteria for the relevant SUD throughout the 3-year follow-up period. Results: Persistent SUD was found among 30.1% of participants with alcohol dependence, 30.8% with cannabis use disorder, and 56.6% with nicotine dependence at baseline. Axis I disorders did not have strong or consistent associations with persistent SUD. In contrast, antisocial personality disorder was significantly associated with persistent alcohol, cannabis, and nicotine use disorders (adjusted odds ratios, 2.46-3.51), as was borderline personality disorder (adjusted odds ratios, 2.04-2.78) and schizotypal personality disorder (adjusted odds ratios, 1.65-5.90). Narcissistic, schizoid, and obsessive-compulsive personality disorders were less consistently associated with SUD persistence. Conclusions: The consistent findings on the association of antisocial, borderline, and schizotypal personality disorders with persistent SUD indicates the importance of these personality disorders in understanding the course of SUD. Future studies should examine dimensional representations of personality disorders and the role of specific components of these disorders, biological and environmental contributors to these relationships, and potential applications of these findings to treatment development. C1 [Hasin, Deborah; Skodol, Andrew; Blanco, Carlos] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA. [Hasin, Deborah; Fenton, Miriam C.; Keyes, Katherine] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Hasin, Deborah; Fenton, Miriam C.; Keyes, Katherine; Geier, Timothy; Greenstein, Eliana; Blanco, Carlos] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Grant, Bridget] NIAAA, Intramural Lab Epidemiol & Biometry, Rockville, MD 20852 USA. [Skodol, Andrew] Univ Arizona, Dept Psychiat, Coll Med & Sunbelt Collaborat, Tucson, AZ USA. [Krueger, Robert] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Hasin, D (reprint author), Columbia Univ, Dept Psychiat, Coll Phys & Surg, 1051 Riverside Dr,123, New York, NY 10032 USA. EM dsh2@columbia.edu RI Blanco, Carlos/I-4906-2013 OI Blanco, Carlos/0000-0001-6187-3057 FU NIAAA [U01AA018111, R01DA018652, K05AA014223]; National Institute on Drug Abuse [R01DA019606, K02DA023200, F31DA026689]; New York State Psychiatric Institute; NIAAA, National Institutes of Health FX This study was funded by grants U01AA018111, R01DA018652, and K05AA014223 from the NIAAA (Dr Hasin); R01DA019606, K02DA023200 (Dr Blanco), and F31DA026689 (Dr Keyes) from the National Institute on Drug Abuse; and the New York State Psychiatric Institute (Drs Hasin and Blanco). The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the NIAAA and funded in part by the Intramural Program, NIAAA, National Institutes of Health, with additional support from the National Institute on Drug Abuse. NR 112 TC 70 Z9 70 U1 6 U2 29 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD NOV PY 2011 VL 68 IS 11 BP 1158 EP 1167 PG 10 WC Psychiatry SC Psychiatry GA 843CL UT WOS:000296649800011 PM 22065531 ER PT J AU Murphy, LE Mills, JL Molloy, AM Qian, C Carter, TC Strevens, H Wide-Swensson, D Giwercman, A Levine, RJ AF Murphy, Laurel E. Mills, James L. Molloy, Anne M. Qian, Cong Carter, Tonia C. Strevens, Helena Wide-Swensson, Dag Giwercman, Aleksander Levine, Richard J. TI Folate and vitamin B-12 in idiopathic male infertility SO ASIAN JOURNAL OF ANDROLOGY LA English DT Article DE folate; idiopathic male infertility; semen quality; vitamin B-12 ID MTHFR C677T POLYMORPHISM; METHYLENETETRAHYDROFOLATE REDUCTASE; FOLIC-ACID; MICROBIOLOGICAL ASSAY; GSTM1 DELETION; SEMINAL PLASMA; ZINC-SULFATE; MUTATION; GENE; ASSOCIATION AB Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B-12 (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmo and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l(-1); P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility. Asian Journal of Andrology (2011) 13, 856-861; doi: 10.1038/aja.2011.96; published online 22 August 2011 C1 [Murphy, Laurel E.; Mills, James L.; Carter, Tonia C.; Levine, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Molloy, Anne M.] Trinity Coll Dublin, Sch Med, Dublin 2, Ireland. [Qian, Cong] Glotech Inc, Rockville, MD 20850 USA. [Strevens, Helena; Wide-Swensson, Dag] Lund Univ, Skane Univ Hosp Lund, Dept Obstet & Gynecol, S-22185 Lund, Sweden. [Giwercman, Aleksander] Lund Univ, Skane Univ Hosp Malmo, Reprod Med Ctr, S-20502 Malmo, Sweden. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. EM jamesmills@nih.gov OI Molloy, Anne/0000-0002-1688-9049 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, the United States FX This work was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, the United States. NR 25 TC 15 Z9 18 U1 1 U2 10 PU ACTA PHARMACOLOGICA SINICA PI SHANGHAI PA 294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD NOV PY 2011 VL 13 IS 6 BP 856 EP 861 DI 10.1038/aja.2011.96 PG 6 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 844NB UT WOS:000296752900021 PM 21857689 ER PT J AU Maurovich-Horvat, P Kallianos, K Engel, LC Szymonifka, J Fox, CS Hoffmann, U Truong, QA AF Maurovich-Horvat, Pal Kallianos, Kimberly Engel, Leif-Christopher Szymonifka, Jackie Fox, Caroline S. Hoffmann, Udo Truong, Quynh A. TI Influence of pericoronary adipose tissue on local coronary atherosclerosis as assessed by a novel MDCT volumetric method SO ATHEROSCLEROSIS LA English DT Article DE Coronary artery disease; Pericoronary fat; Epicardial fat; Adipose tissue; Inflammation; Computed tomography ID MULTIDETECTOR COMPUTED-TOMOGRAPHY; VISCERAL ABDOMINAL FAT; PUBLIC-HEALTH PRACTICE; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; PERICARDIAL FAT; RISK-FACTORS; ASSOCIATION; ANGIOGRAPHY; INFLAMMATION AB Objective: Pericoronary adipose tissue (PCAT) may create a pro-inflammatory state, contributing to the development of coronary artery disease (CAD). We sought to evaluate the feasibility of a novel volumetric PCAT quantification method using a novel threshold based computed tomography approach. In addition we determined the relation between PCAT volumes and CAD. Methods: In 51 patients (49.5 +/- 5.1 years, 64.8% male) who underwent 64-slice MDCT, we measured threshold-based PCAT volumes using distance and anatomic-based methods. Using the most reproducible method, we performed the proximal 40-mm distance measurement in three groups as stratified by coronary plaque and high-sensitivity C-reactive protein (hs-CRP) levels: Group 1 (presence of coronary plaque, hs-CRP > 2.0 mg/L); an intermediate group (Group 2, no plaque, hs-CRP > 2.0 mg/L); and Group 3 (no plaque, hs-CRP < 1.0 mg/L). We compared PCAT volumes to the presence of coronary plaque on a patient (n = 51) and vessel (n = 153) basis. On a subsegment basis (n = 1224), we compared PCAT volume to the presence of plaque as well as plaque morphology. Results: Distance-based PCAT volume measurements yielded excellent reproducibility with intra-observer intraclass correlation (ICC) of 0.997 and inter-observer ICC of 0.951. On a both a per-patient and per-vessel analysis, adjusted PCAT volume was greater in patients with plaque (Group 1) than without plaque (Groups 2 and 3, p < 0.001). No difference in PCAT volume was seen between high and low hs-CRP groups without plaque (p = 0.51). Adjusted PCAT volumes were higher in subsegments with plaque as compared without (p < 0.001). Additionally, adjusted PCAT volume was greatest in subsegments with mixed plaque followed by non-calcified plaque, calcified plaque, and the lowest volume in segments with no plaque (p < 0.001). Conclusion: In this proof-of-concept study, threshold based PCAT volume assessment is feasible and highly reproducible. PCAT volume is increased in patients and vessels with coronary plaques. Surrounding vessel subsegments with coronary plaque, particularly mixed plaques, have greatest PCAT volume and highlight the effect of local PCAT in the development of coronary atherosclerosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Maurovich-Horvat, Pal; Kallianos, Kimberly; Engel, Leif-Christopher; Hoffmann, Udo; Truong, Quynh A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program,Div Cardiol, Boston, MA 02114 USA. [Maurovich-Horvat, Pal; Kallianos, Kimberly; Engel, Leif-Christopher; Hoffmann, Udo; Truong, Quynh A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Maurovich-Horvat, Pal] Semmelweis Univ, Ctr Heart, Budapest, Hungary. [Szymonifka, Jackie] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Truong, QA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program,Div Cardiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM qtruong@partners.org OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU NIH [R01 HL080053, K23HL098370, L30HL093896]; Siemens Medical Solutions; General Electrics Healthcare; [TAMOP-4.2.2-08/01/KMR-2008-2004] FX Sources of funding: This work was supported by the NIH R01 HL080053, and in part supported by Siemens Medical Solutions and General Electrics Healthcare. Dr. Truong received support from NIH grant K23HL098370 and L30HL093896. Dr. Maurovich-Horvat received support from TAMOP-4.2.2-08/01/KMR-2008-2004. NR 23 TC 12 Z9 13 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD NOV PY 2011 VL 219 IS 1 BP 151 EP 157 DI 10.1016/j.atherosclerosis.2011.06.049 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HK UT WOS:000296587200023 PM 21782176 ER PT J AU Tost, H Kolachana, B Verchinski, BA Bilek, E Goldman, AL Mattay, VS Weinberger, DR Meyer-Lindenberg, A AF Tost, Heike Kolachana, Bhaskar Verchinski, Beth A. Bilek, Edda Goldman, Aaron L. Mattay, Venkata S. Weinberger, Daniel R. Meyer-Lindenberg, Andreas TI Neurogenetic Effects of OXTR rs2254298 in the Extended Limbic System of Healthy Caucasian Adults SO BIOLOGICAL PSYCHIATRY LA English DT Letter ID OXYTOCIN RECEPTOR GENE; SCHIZOPHRENIA; SEGMENTATION; COGNITION; AUTISM; VOLUME; BRAIN C1 [Tost, Heike; Kolachana, Bhaskar; Verchinski, Beth A.; Goldman, Aaron L.; Mattay, Venkata S.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Tost, Heike; Bilek, Edda; Meyer-Lindenberg, Andreas] Univ Heidelberg, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-6800 Mannheim, Germany. RP Tost, H (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM heike.tost@zi-mannheim.de RI Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Intramural NIH HHS NR 15 TC 32 Z9 33 U1 0 U2 15 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 NOV 1 PY 2011 VL 70 IS 9 BP E37 EP E39 DI 10.1016/j.biopsych.2011.07.021 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 837TZ UT WOS:000296228000001 PM 21872215 ER PT J AU Mitchell, SA Jacobsohn, D Powers, KET Carpenter, PA Flowers, MED Cowen, EW Schubert, M Turner, ML Lee, SJ Martin, P Bishop, MR Baird, K Bolanos-Meade, J Boyd, K Fall-Dickson, JM Gerber, LH Guadagnini, JP Imanguli, M Krumlauf, MC Lawley, L Li, L Reeve, BB Clayton, JA Vogelsang, GB Pavletic, SZ AF Mitchell, Sandra A. Jacobsohn, David Powers, Kimberly E. Thormann Carpenter, Paul A. Flowers, Mary E. D. Cowen, Edward W. Schubert, Mark Turner, Maria L. Lee, Stephanie J. Martin, Paul Bishop, Michael R. Baird, Kristin Bolanos-Meade, Javier Boyd, Kevin Fall-Dickson, Jane M. Gerber, Lynn H. Guadagnini, Jean-Pierre Imanguli, Matin Krumlauf, Michael C. Lawley, Leslie Li, Li Reeve, Bryce B. Clayton, Janine Austin Vogelsang, Georgia B. Pavletic, Steven Z. TI A Multicenter Pilot Evaluation of the National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Therapeutic Response Measures: Feasibility, Interrater Reliability, and Minimum Detectable Change SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Response criteria; lnterrater reliability; Minimum detectable change ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; SAMPLE-SIZE REQUIREMENTS; RODNAN SKIN SCORE; SYSTEMIC-SCLEROSIS; CLINICAL-TRIALS; INTEROBSERVER RELIABILITY; LOCALIZED SCLERODERMA; DIAGNOSTIC-TESTS; SEVERITY INDEX AB The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of 4 consecutive pilot trials evaluating the feasibility and estimating the interrater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n = 34) participated in a 2.5-hour training session on response evaluation in cGVHD. Feasibility and interrater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians' impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range: 12-60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median: 9 minutes). Overall, interrater agreement for skin and oral manifestations was modest; however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final 2 trials, the threshold for defining change exceeding measurement error was 19% to 22% body surface area (BSA) for erythema, 18% to 26% BSA for movable sclerosis, 17% to 21% BSA for nonmovable sclerosis, and 2.1 to 2.6 points on the 15-point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that the NIH response criteria are feasible for use, and these reliability estimates are encouraging, because they were observed following a single 2.5-hour training session given at multiple transplant centers, with no opportunity for iterative training and calibration. Research is needed to evaluate inter- and intrarater reliability in larger samples, and to evaluate these response criteria as predictors of outcomes in clinical trials. Biol Blood Marrow Transplant 17: 1619-1629 (2011) Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation C1 [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20892 USA. [Jacobsohn, David] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Powers, Kimberly E. Thormann; Boyd, Kevin; Lawley, Leslie] Childrens Mem Hosp, Chicago, IL 60614 USA. [Carpenter, Paul A.; Flowers, Mary E. D.; Schubert, Mark; Lee, Stephanie J.; Martin, Paul] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Carpenter, Paul A.; Flowers, Mary E. D.; Schubert, Mark; Lee, Stephanie J.; Martin, Paul] Univ Washington, Sch Med, Seattle, WA USA. [Cowen, Edward W.; Turner, Maria L.; Bishop, Michael R.; Baird, Kristin; Imanguli, Matin; Pavletic, Steven Z.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gerber, Lynn H.; Krumlauf, Michael C.; Li, Li] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gerber, Lynn H.; Krumlauf, Michael C.; Li, Li] George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Bolanos-Meade, Javier; Vogelsang, Georgia B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Fall-Dickson, Jane M.] NINR, Symptom Management Branch, NIH, Bethesda, MD 20892 USA. [Guadagnini, Jean-Pierre] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Reeve, Bryce B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Reeve, Bryce B.] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC 27599 USA. [Clayton, Janine Austin] NEI, NIH, Bethesda, MD 20892 USA. RP Mitchell, SA (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci,NIH, 6130 Execut Blvd,MSC 7344,EPN 4020, Bethesda, MD 20892 USA. EM mitchlls@mail.nih.gov FU National Institutes of Health Clinical Center; Center for Cancer Research, National Cancer Institute FX This work was supported by the Intramural Research Program at the National Institutes of Health Clinical Center, and by the Center for Cancer Research, National Cancer Institute. NR 39 TC 21 Z9 21 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2011 VL 17 IS 11 BP 1619 EP 1629 DI 10.1016/j.bbmt.2011.04.002 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 845NF UT WOS:000296829000009 PM 21536143 ER PT J AU Stahl, A Krohne, TU Sapieha, P Chen, J Hellstrom, A Chew, E Holz, FG Smith, LEH AF Stahl, Andreas Krohne, Tim U. Sapieha, Przemyslaw Chen, Jing Hellstrom, Ann Chew, Emily Holz, Frank G. Smith, Lois E. H. TI Lipid metabolites in the pathogenesis and treatment of neovascular eye disease SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Review ID OXYGEN-INDUCED RETINOPATHY; PIGMENT EPITHELIAL-CELLS; RETINAL MICROVASCULAR DEGENERATION; POLYUNSATURATED FATTY-ACIDS; MACULAR DEGENERATION; DIABETIC-RETINOPATHY; PEROXIDATION PRODUCTS; OXIDATIVE STRESS; PROTEIN MODIFICATIONS; NEUROPROTECTIN D1 AB Lipids and lipid metabolites have long been known to play biological roles that go beyond energy storage and membrane structure. In age-related macular degeneration and diabetes, for example, dysregulation of lipid metabolism is closely associated with disease onset and progression. At the same time, some lipids and their metabolites can exert beneficial effects in the same disorders. This review summarises our current knowledge of the contributions of lipids to both the pathogenesis and treatment of neovascular eye disease. The clinical entities covered are exudative age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity, with a special emphasis on the potential therapeutic effects of omega 3- (also known as n-3) polyunsaturated fatty acids. C1 [Stahl, Andreas; Chen, Jing; Smith, Lois E. H.] Harvard Univ, Sch Med, Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. [Stahl, Andreas] Univ Eye Hosp Freiburg, Freiburg, Germany. [Krohne, Tim U.; Holz, Frank G.] Univ Eye Hosp Bonn, Bonn, Germany. [Sapieha, Przemyslaw] Univ Montreal, Dept Ophthalmol, Maisonneuve Rosemont Hosp Res Ctr, Montreal, PQ, Canada. [Hellstrom, Ann] Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden. [Chew, Emily] NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. RP Smith, LEH (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM lois.smith@childrens.harvard.edu RI Krohne, Tim/D-1497-2013; OI Krohne, Tim/0000-0003-2280-925X; Hellstrom, Ann/0000-0002-9259-1244 FU Deutsche Forschungsgemeinschaft; Canadian Institutes of Health Research; Canadian National Institute for the Blind; Juvenile Diabetes Research Foundation International; NIH [EY017017, EY017017-S1]; V. Kann Rasmussen Foundation; Roche Foundation for Anemia Research; Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center; Research to Prevent Blindness Senior Investigator Award; Alcon Research Institute Award; MacTel Foundation FX Deutsche Forschungsgemeinschaft (AS); Canadian Institutes of Health Research, Canadian National Institute for the Blind (PS); Juvenile Diabetes Research Foundation International (JC); NIH (EY017017, EY017017-S1), V. Kann Rasmussen Foundation, Roche Foundation for Anemia Research, Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center, Research to Prevent Blindness Senior Investigator Award, Alcon Research Institute Award, MacTel Foundation (LEHS). NR 91 TC 11 Z9 11 U1 0 U2 9 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD NOV PY 2011 VL 95 IS 11 BP 1496 EP 1501 DI 10.1136/bjo.2010.194241 PG 6 WC Ophthalmology SC Ophthalmology GA 837VK UT WOS:000296233900004 PM 21421650 ER PT J AU Enewold, LR Zhou, J Devesa, SS de Gonzalez, AB Anderson, WF Zahm, SH Stojadinovic, A Peoples, GE Marrogi, AJ Potter, JF McGlynn, KA Zhu, KM AF Enewold, Lindsey R. Zhou, Jing Devesa, Susan S. de Gonzalez, Amy Berrington Anderson, William F. Zahm, Shelia H. Stojadinovic, Alexander Peoples, George E. Marrogi, Aizenhawar J. Potter, John F. McGlynn, Katherine A. Zhu, Kangmin TI Thyroid Cancer Incidence among Active Duty US Military Personnel, 1990-2004 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID REPRODUCTIVE FACTORS; INCREASING INCIDENCE; UNITED-STATES; TIME TRENDS; CARCINOMA; POPULATION; EXPOSURE; RATES; PAPILLARY; DISEASE AB Background: Increases in thyroid papillary carcinoma incidence rates have largely been attributed to heightened medical surveillance and improved diagnostics. We examined papillary carcinoma incidence in an equal-access health care system by demographics that are related to incidence. Methods: Incidence rates during 1990-2004 among white and black individuals aged 20 to 49 years in the military, and the general U. S. population were compared using data from the Department of Defense's Automated Central Tumor Registry and the National Cancer Institute's Surveillance Epidemiology and End Results (SEER-9) program. Results: Incidence was significantly higher in the military than in the general population among white women [incidence rate ratio (IRR) = 1.42; 95% confidence interval (CI), 1.25-1.61], black women (IRR = 2.31; 95% CI, 1.70-2.99), and black men (IRR = 1.69, 95% CI, 1.10-2.50). Among whites, differences between the two populations were confined to rates of localized tumors (women: IRR = 1.73, 95% CI, 1.47-2.00; men: IRR = 1.51, 95% CI, 1.30-1.75), which may partially be due to variation in staging classification. Among white women, rates were significantly higher in the military regardless of tumor size and rates rose significantly over time both for tumors <= 2 cm (military: IRR = 1.64, 95% CI, 1.18-2.28; general population: IRR = 1.55, 95% CI, 1.45-1.66) and >2 cm (military: IRR = 1.74, 95% CI, 1.07-2.81; general population: IRR = 1.48, 95% CI, 1.27-1.72). Among white men, rates increased significantly only in the general population. Incidence also varied by military service branch. Conclusions: Heightened medical surveillance does not appear to fully explain the differences between the two populations or the temporal increases in either population. Impact: These findings suggest the importance of future research into thyroid cancer etiology. Cancer Epidemiol Biomarkers Prev; 20(11); 2369-76. (C) 2011 AACR. C1 [Enewold, Lindsey R.; Zhou, Jing; Stojadinovic, Alexander; Peoples, George E.; Marrogi, Aizenhawar J.; Potter, John F.; Zhu, Kangmin] Henry M Jackson Fdn, US Mil Canc Inst, Walter Reed Army Med Ctr, Rockville, MD 20852 USA. [Stojadinovic, Alexander] Walter Reed Army Med Ctr, Dept Surg, Div Surg Oncol, Washington, DC 20307 USA. [Marrogi, Aizenhawar J.] Walter Reed Army Med Ctr, Dept Pathol, Washington, DC 20307 USA. [Marrogi, Aizenhawar J.] Walter Reed Army Med Ctr, Area Lab Serv, Washington, DC 20307 USA. [Devesa, Susan S.; de Gonzalez, Amy Berrington; Anderson, William F.; Zahm, Shelia H.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Potter, John F.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. [Peoples, George E.] Brooke Army Med Ctr, Dept Surg, Ft Sam Houston, TX 78234 USA. RP Enewold, LR (reprint author), Henry M Jackson Fdn, US Mil Canc Inst, Walter Reed Army Med Ctr, 11300 Rockville Pike,Suite 1215, Rockville, MD 20852 USA. EM lenewold@hjfresearch.org RI Zahm, Shelia/B-5025-2015 FU United States Military Cancer Institute (USMCI) via Uniformed Services University of the Health Sciences under Henry M. Jackson Foundation for the Advancement of Military Medicine; Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute FX This research was supported by the United States Military Cancer Institute (USMCI) via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine and by the Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute. NR 48 TC 16 Z9 20 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2011 VL 20 IS 11 BP 2369 EP 2376 DI 10.1158/1055-9965.EPI-11-0596 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 844RO UT WOS:000296765200005 PM 21914838 ER PT J AU Fischer, SM Hawk, ET Lubet, RA AF Fischer, Susan M. Hawk, Ernest T. Lubet, Ronald A. TI Coxibs and Other Nonsteroidal Anti-Inflammatory Drugs in Animal Models of Cancer Chemoprevention SO CANCER PREVENTION RESEARCH LA English DT Review ID FAMILIAL ADENOMATOUS POLYPOSIS; MIN MOUSE MODEL; SPONTANEOUS INTESTINAL ADENOMAS; RANDOMIZED CONTROLLED-TRIAL; INDUCED SKIN CARCINOGENESIS; INDUCED COLON-CANCER; ABERRANT CRYPT FOCI; LOW-DOSE ASPIRIN; COLORECTAL-CANCER; CYCLOOXYGENASE-2 INHIBITOR AB Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds. Cancer Prev Res; 4(11); 1728-35. (C) 2011 AACR. C1 [Fischer, Susan M.] Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Smithville, TX 78957 USA. [Hawk, Ernest T.] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Smithville, TX 78957 USA. [Lubet, Ronald A.] NCI, Chemoprevent Agent Dev Grp, Bethesda, MD 20892 USA. RP Fischer, SM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Sci Pk,POB 389, Smithville, TX 78957 USA. EM smfischer@mdanderson.org FU NCI NIH HHS [N01 CN053300, R01 CA100140, R01 CA100140-01] NR 64 TC 53 Z9 54 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1728 EP 1735 DI 10.1158/1940-6207.CAPR-11-0166 PG 8 WC Oncology SC Oncology GA 844NA UT WOS:000296752800003 PM 21778329 ER PT J AU Maier, CR Hollander, MC Hobbs, EA Dogan, I Linnoila, RI Dennis, PA AF Maier, Colleen R. Hollander, M. Christine Hobbs, Evthokia A. Dogan, Irem Linnoila, R. Ilona Dennis, Phillip A. TI Nicotine Does Not Enhance Tumorigenesis in Mutant K-Ras-Driven Mouse Models of Lung Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID PROMOTES TUMOR-GROWTH; A/J MOUSE; CELL-PROLIFERATION; EPITHELIAL-CELLS; PATCH THERAPY; T-CELLS; EXPOSURE; SMOKING; MICE; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AB Smoking is the leading cause of preventable cancer deaths in the United States. Nicotine replacement therapies (NRT) have been developed to aid in smoking cessation, which decreases lung cancer incidence. However, the safety of NRT is controversial because numerous preclinical studies have shown that nicotine enhances tumor cell growth in vitro and in vivo. We modeled NRT in mice to determine the effects of physiologic levels of nicotine on lung tumor formation, tumor growth, or metastasis. Nicotine administered in drinking water did not enhance lung tumorigenesis after treatment with the tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Tumors that develop in this model have mutations in K-ras, which is commonly observed in smoking-related, human lung adenocarcinomas. In a transgenic model of mutant K-ras-driven lung cancer, nicotine did not increase tumor number or size and did not affect overall survival. Likewise, in a syngeneic model using lung cancer cell lines derived from NNK-treated mice, oral nicotine did not enhance tumor growth or metastasis. These data show that nicotine does not enhance lung tumorigenesis when given to achieve levels comparable with those of NRT, suggesting that nicotine has a dose threshold, below which it has no appreciable effect. These studies are consistent with epidemiologic data showing that NRT does not enhance lung cancer risk in former smokers. Cancer Prev Res; 4(11); 1743-51. (C) 2011 AACR. C1 [Maier, Colleen R.; Hollander, M. Christine; Hobbs, Evthokia A.; Dogan, Irem; Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Linnoila, R. Ilona] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dennis, PA (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 37,Room 1108B, Bethesda, MD 20892 USA. EM dennisp@mail.nih.gov FU Intramural NIH HHS [Z01 SC010292-10] NR 38 TC 16 Z9 16 U1 2 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1743 EP 1751 DI 10.1158/1940-6207.CAPR-11-0365 PG 9 WC Oncology SC Oncology GA 844NA UT WOS:000296752800005 PM 22027685 ER PT J AU Marshall, JR Tangen, CM Sakr, WA Wood, DP Berry, DL Klein, EA Lippman, SM Parnes, HL Alberts, DS Jarrard, DF Lee, WR Gaziano, JM Crawford, ED Ely, B Ray, M Davis, W Minasian, LM Thompson, IM AF Marshall, James R. Tangen, Catherine M. Sakr, Wael A. Wood, David P., Jr. Berry, Donna L. Klein, Eric A. Lippman, Scott M. Parnes, Howard L. Alberts, David S. Jarrard, David F. Lee, W. Robert Gaziano, J. Michael Crawford, E. David Ely, Benjamin Ray, Michael Davis, Warren Minasian, Lori M. Thompson, Ian M., Jr. TI Phase III Trial of Selenium to Prevent Prostate Cancer in Men with High-grade Prostatic Intraepithelial Neoplasia: SWOG S9917 SO CANCER PREVENTION RESEARCH LA English DT Article ID VITAMIN-E; SUBSEQUENT RISK; SERUM SELENIUM; CLINICAL-TRIAL; REPEAT BIOPSY; SELECT; SUPPLEMENTATION; CHEMOPREVENTION; ADENOCARCINOMA; ASSOCIATION AB The threat of prostate cancer and the significant and often negative impact of its treatment underscore the importance of prevention. High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a potential premalignant lesion marking an increased risk of prostate cancer and substantial evidence suggests that men with HGPIN are in need of prostate cancer prevention. In vitro, in vivo, epidemiologic, and clinical trial evidence that selenium supplementation protects against prostate cancer motivated the study we report here: a double-blind, randomized, placebo-controlled trial of selenium 200 (mu g/d) as selenomethionine in men with HGPIN. The primary endpoint was progression of HGPIN to prostate cancer over a 3-year period. This National Cancer Institute Intergroup trial was coordinated by the Southwest Oncology Group (SWOG). Of 619 enrolled patients, 423 randomized men with HGPIN (212 selenium and 211 placebo) were eligible (by central pathology review) and included in the primary analysis. Three-year cancer rates were 36.6% (placebo) versus 35.6% (selenium; P = 0.73, adjusted). The majority of patients who developed cancer on trial (70.8%, selenium and 75.5%, placebo) had a Gleason score of 6 or less than 6; there were no differences in Gleason scores between the two arms. Subset analyses included the finding of a nonsignificantly reduced prostate cancer risk (relative risk = 0.82; 95% CI: 0.40-1.69) in selenium versus placebo patients in the lowest quartile of baseline plasma selenium level (<106 ng/mL). Overall, and in all other subsets defined by baseline blood selenium levels, selenium supplementation had no effect on prostate cancer risk. The 36% prostate cancer rate in men with HGPIN indicates the association of this lesion with an elevated prostate cancer risk. Future study in this setting should focus on selenium-deficient populations and selenium pharmacogenetics. Cancer Prev Res; 4(11); 1761-9. (C) 2011 AACR. C1 [Marshall, James R.] Roswell Pk Canc Inst, Dept Canc Prevent & Populat Sci, Buffalo, NY 14263 USA. [Tangen, Catherine M.; Ely, Benjamin] SW Oncol Grp Stat Ctr, Seattle, WA USA. [Sakr, Wael A.] Wayne State Univ, Detroit, MI USA. [Wood, David P., Jr.] Univ Michigan, Ann Arbor, MI 48109 USA. [Berry, Donna L.] Dana Farber Canc Inst, Boston, MA USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Canc & Leukemia Grp B, MAVERIC Cooperat Studies Program Coordinating Ctr, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Klein, Eric A.] Cleveland Clin, Cleveland, OH 44106 USA. [Lippman, Scott M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Parnes, Howard L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Alberts, David S.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Jarrard, David F.] Univ Wisconsin, Madison, WI USA. [Lee, W. Robert] Duke Univ, Sch Med, Eastern Cooperat Oncol Grp, Durham, NC USA. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. [Thompson, Ian M., Jr.] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. RP Marshall, JR (reprint author), Roswell Pk Canc Inst, Dept Canc Prevent & Populat Sci, Elm & Carlton St, Buffalo, NY 14263 USA. EM james.marshall@roswellpark.org FU National Cancer Institute, DHHS [CA11083, CA35261, CA46282, CA35119, CA45377, CA35431, CA45450, CA27057, CA67663, CA128567, CA13612, CA74647, CA45807, CA58348, CA67575, CA63844, CA58882, CA46368, CA45560, CA63850, CA35262, CA16385, CA76132, CACA04919, CA76447, CA58416, CA46113, CA68183, CA2106, CA21115, CA59518] FX This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA14028, CA35178, CA04919, CA35192, CA105409, CA86780, CA20319, CA95860, CA42777, CA58686, CA11083, CA35261, CA46282, CA35119, CA45377, CA35431, CA45450, CA27057, CA67663, CA128567, CA13612, CA74647, CA45807, CA58348, CA67575, CA63844, CA58882, CA46368, CA45560, CA63850, CA35262, CA16385, CA76132, CA68183, CACA04919, CA76447, CA58686, CA27057, CA58416, CA46113, CA68183, CA2106, CA21115, and CA59518. NR 52 TC 49 Z9 49 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1761 EP 1769 DI 10.1158/1940-6207.CAPR-10-0343 PG 9 WC Oncology SC Oncology GA 844NA UT WOS:000296752800007 PM 21896650 ER PT J AU Kim, DJ Reddy, K Kim, MO Li, Y Nadas, J Cho, YY Kim, JE Shim, JH Song, NR Carper, A Lubet, RA Bode, AM Dong, ZG AF Kim, Dong Joon Reddy, Kanamata Kim, Myoung Ok Li, Yan Nadas, Janos Cho, Yong-Yeon Kim, Jong-Eun Shim, Jung-Hyun Song, Nu Ry Carper, Andria Lubet, Ronald A. Bode, Ann M. Dong, Zigang TI (3-Chloroacetyl)-indole, a Novel Allosteric AKT Inhibitor, Suppresses Colon Cancer Growth In Vitro and In Vivo SO CANCER PREVENTION RESEARCH LA English DT Article ID CELL-CYCLE ARREST; PLECKSTRIN-HOMOLOGY-DOMAIN; KINASE-B; DIETARY INDOLE-3-CARBINOL; 3-KINASE/AKT PATHWAY; TARGET; RESISTANCE; UBIQUITINATION; IDENTIFICATION; CHEMOTHERAPY AB Indole-3-carbinol (I3C) is produced in Brassica vegetables such as broccoli and cabbage and has been shown to inhibit proliferation and induce apoptosis in various cancer cells, including breast, prostate, colon, and leukemia. However, only high doses of I3C were shown to inhibit cell proliferation (IC(50) = 200-300 mu mol/L). Our goal here was to develop a more potent antitumor agent by modifying the structure of I3C. We created I3C derivatives and found that (3-chloroacetyl)-indole (3CAI) more strongly inhibited colon cancer cell growth than I3C. In addition, by screening 85 kinases in a competitive kinase assay, we found that 3CAI was a specific AKT inhibitor. AKT is a serine/threonine kinase that plays a pivotal role in promoting transformation and chemoresistance by inducing proliferation and inhibiting apoptosis. Therefore, AKT is regarded as a critical target for cancer therapy. 3ICA, a derivative of I3C, is a potent and specific AKT inhibitor. This compound showed significant inhibition of AKT in an in vitro kinase assay and suppressed expression of AKT direct downstream targets such as mTOR and GSK3 beta as well as induced growth inhibition and apoptosis in colon cancer cells. In addition, oral administration of this potent AKT inhibitor suppressed cancer cell growth in an in vivo xenograft mouse model. Cancer Prev Res; 4(11); 1842-51. (C) 2011 AACR. C1 [Kim, Dong Joon; Reddy, Kanamata; Kim, Myoung Ok; Li, Yan; Nadas, Janos; Cho, Yong-Yeon; Kim, Jong-Eun; Carper, Andria; Bode, Ann M.; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Cho, Yong-Yeon] Catholic Univ Korea, Dept Pharmacol, Coll Pharm, Puchon, South Korea. [Shim, Jung-Hyun] Soonchunhyang Univ, Dept Biochem, Coll Med, Cheonan, South Korea. [Song, Nu Ry] Seoul Natl Univ, Dept Agr Biotechnol, Seoul, South Korea. [Lubet, Ronald A.] NCI, Bethesda, MD 20892 USA. RP Dong, ZG (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM zgdong@hi.umn.edu RI Li, Yan/L-2129-2013; kim, jong-eun/B-3550-2017; OI kim, jong-eun/0000-0002-5030-6126; Kanamata Reddy, Srinivasa Reddy/0000-0003-3733-7531 FU Hormel Foundation; NIH [R37 CA081064, CA120388, ES016548, CA0227501]; National Cancer Institute [HHSN-261200533001C-NO1-CN-53301] FX This work was supported by The Hormel Foundation, NIH grants R37 CA081064, CA120388, ES016548, and CA0227501, and National Cancer Institute contract no. HHSN-261200533001C-NO1-CN-53301. NR 29 TC 14 Z9 14 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1842 EP 1851 DI 10.1158/1940-6207.CAPR-11-0158 PG 10 WC Oncology SC Oncology GA 844NA UT WOS:000296752800016 PM 21885813 ER PT J AU Suh, N Reddy, BS DeCastro, A Paul, S Lee, HJ Smolarek, AK So, JY Simi, B Wang, CX Janakiram, NB Steele, V Rao, CV AF Suh, Nanjoo Reddy, Bandaru S. DeCastro, Andrew Paul, Shiby Lee, Hong Jin Smolarek, Amanda K. So, Jae Young Simi, Barbara Wang, Chung Xiou Janakiram, Naveena B. Steele, Vernon Rao, Chinthalapally V. TI Combination of Atorvastatin with Sulindac or Naproxen Profoundly Inhibits Colonic Adenocarcinomas by Suppressing the p65/beta-Catenin/Cyclin D1 Signaling Pathway in Rats SO CANCER PREVENTION RESEARCH LA English DT Article ID NITRIC-OXIDE SYNTHASE; ABERRANT CRYPT FOCI; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; FAMILIAL ADENOMATOUS POLYPOSIS; DEPENDENT KINASE 4; CYCLIN D1; COLORECTAL-CANCER; BETA-CATENIN; CYCLOOXYGENASE-2 INHIBITOR; CHEMOPREVENTIVE PROPERTIES AB Evidence supports the protective role of nonsteroidal anti-inflammatory drugs (NSAID) and statins against colon cancer. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon tumor formation. F344 rats were fed AIN-76A diet, and colon tumors were induced with azoxymethane. One week after the second azoxymethane treatment, groups of rats were fed diets containing atorvastatin (200 ppm), sulindac (100 ppm), naproxen (150 ppm), or their combinations with low-dose atorvastatin (100 ppm) for 45 weeks. Administration of atorvastatin at 200 ppm significantly suppressed both adenocarcinoma incidence (52% reduction, P = 0.005) and multiplicity (58% reduction, P = 0.008). Most importantly, colon tumor multiplicities were profoundly decreased (80%-85% reduction, P < 0.0001) when given low-dose atorvastatin with either sulindac or naproxen. Also, a significant inhibition of colon tumor incidence was observed when given a low-dose atorvastatin with either sulindac (P = 0.001) or naproxen (P = 0.0005). Proliferation markers, proliferating cell nuclear antigen, cyclin D1, and beta-catenin in tumors of rats exposed to sulindac, naproxen, atorvastatin, and/or combinations showed a significant suppression. Importantly, colon adenocarcinomas from atorvastatin and NSAIDs fed animals showed reduced key inflammatory markers, inducible nitric oxide synthase and COX-2, phospho-p65, as well as inflammatory cytokines, TNF-alpha, interleukin (IL)-1 beta, and IL-4. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low-dose sulindac or naproxen, which greatly suppress the colon adenocarcinoma incidence and multiplicity. Our results suggest that low-dose atorvastatin with sulindac or naproxen might potentially be useful combinations for colon cancer prevention in humans. Cancer Prev Res; 4(11); 1895-902. (C) 2011 AACR. C1 [Janakiram, Naveena B.; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Chemoprevent & Canc Drug Dev, Dept Med,Oncol Sect, Oklahoma City, OK 73104 USA. [Suh, Nanjoo; Reddy, Bandaru S.; DeCastro, Andrew; Paul, Shiby; Lee, Hong Jin; Smolarek, Amanda K.; So, Jae Young; Simi, Barbara; Wang, Chung Xiou] Rutgers State Univ, Dept Biol Chem, Ernest Mario Sch Pharm, Piscataway, NJ USA. [Steele, Vernon] NCI, Chemoprevent Agent Dev Res Grp, NIH, Bethesda, MD 20892 USA. [Suh, Nanjoo] Canc Inst New Jersey, New Brunswick, NJ USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Chemoprevent & Canc Drug Dev, Dept Med,Oncol Sect, 975 NE 10th St,BRC 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU Rutgers, The State University of New Jersey; [NCI-N01-CN-53300]; [R01-CA94962] FX This work was supported by NCI-N01-CN-53300, R01-CA94962, and the Trustees Research Fellowship Program at Rutgers, The State University of New Jersey. NR 49 TC 27 Z9 28 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1895 EP 1902 DI 10.1158/1940-6207.CAPR-11-0222 PG 8 WC Oncology SC Oncology GA 844NA UT WOS:000296752800021 PM 21764859 ER PT J AU Daniel, CR Cross, AJ Graubard, BI Hollenbeck, AR Park, Y Sinha, R AF Daniel, Carrie R. Cross, Amanda J. Graubard, Barry I. Hollenbeck, Albert R. Park, Yikyung Sinha, Rashmi TI Prospective Investigation of Poultry and Fish Intake in Relation to Cancer Risk SO CANCER PREVENTION RESEARCH LA English DT Article ID HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; COLORECTAL-CANCER; ENDOGENOUS NITROSATION; OVARIAN-CANCER; MEAT INTAKE; RED MEAT; NATIONAL-INSTITUTES; NO ASSOCIATION; FOOD GROUPS AB Dietary guidelines advise consumers to limit intake of red meat and choose lean protein sources, such as poultry and fish. Poultry consumption has been steadily increasing in the United States, but the effect on cancer risk remains unclear. In a large U. S. cohort, we prospectively investigated poultry and fish intake and cancer risk across a range of malignancies in men and women. Diet was assessed at baseline (1995-1996) with a food frequency questionnaire in 492,186 participants of the NIH-AARP Diet and Health Study. Over a mean follow-up of 9 years, we identified 74,418 incident cancer cases. In multivariable Cox proportional hazards regression models, we estimated the substitution and addition effects of white meat (poultry and fish) intake in relation to cancer risk. In substitution models with total meat intake held constant, a 10-g (per 1,000 kcal) increase in white meat intake offset by an equal decrease in red meat intake was associated with a statistically significant reduced (3%-20%) risk of cancers of the esophagus, liver, colon, rectum, anus, lung, and pleura. In addition models with red meat intake held constant, poultry intake remained inversely associated with esophageal squamous cell carcinoma, liver cancer, and lung cancer, but we observed mixed findings for fish intake. As the dietary recommendations intend, the inverse association observed between white meat intake and cancer risk may be largely due to the substitution of red meat. Simply increasing fish or poultry intake, without reducing red meat intake, may be less beneficial for cancer prevention. Cancer Prev Res; 4(11); 1903-11. (C) 2011 AACR. C1 [Daniel, Carrie R.; Cross, Amanda J.; Park, Yikyung; Sinha, Rashmi] NCI, NIH, Dept Hlth & Human Serv, Nutr Epidemiol Branch,Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Graubard, Barry I.] NCI, Biostat Branch, Dept Hlth & Human Serv,NIH, Nutr Epidemiol Branch,Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Daniel, CR (reprint author), NCI, NIH, Dept Hlth & Human Serv, Nutr Epidemiol Branch,Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM Carrie.Daniel@nih.hhs.gov RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, NIH FX This study was funded by the Intramural Research Program of the National Cancer Institute, NIH. NR 46 TC 47 Z9 48 U1 2 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1903 EP 1911 DI 10.1158/1940-6207.CAPR-11-0241 PG 9 WC Oncology SC Oncology GA 844NA UT WOS:000296752800022 PM 21803982 ER PT J AU Lynch, SM Weinstein, SJ Virtamo, J Lan, Q Liu, CS Cheng, WL Rothman, N Albanes, D Stolzenberg-Solomon, RZ AF Lynch, Shannon M. Weinstein, Stephanie J. Virtamo, Jarmo Lan, Qing Liu, Chin-San Cheng, Wen-Ling Rothman, Nathaniel Albanes, Demetrius Stolzenberg-Solomon, Rachael Z. TI Mitochondrial DNA Copy Number and Pancreatic Cancer in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study SO CANCER PREVENTION RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; GENETIC POLYMORPHISMS; INSULIN-RESISTANCE; CIGARETTE-SMOKING; OXIDATIVE STRESS; BREAST-CANCER; COHORT; RISK; ASSOCIATION; PROGRESSION AB Diabetes, obesity, and cigarette smoke, consistent risk factors for pancreatic cancer, are sources of oxidative stress in humans that could cause mitochondrial DNA (mtDNA) damage and increase mtDNA copy number. To test whether higher mtDNA copy number is associated with increased incident pancreatic cancer, we conducted a nested case-control study in the Alpha-Tocopherol Beta Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50 to 69 years at baseline. Between 1992 and 2004, 203 incident cases of pancreatic adenocarcinoma occurred (follow-up: 12 years) among participants, with whole blood samples used for mtDNA extraction. For these cases and 656 controls, we calculated ORs and 95% CIs using unconditional logistic regression, adjusting for age, smoking, and diabetes history. All statistical tests were two sided. Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR = 1.64, 95% CI = 1.01-2.67, continuous OR = 1.14, 95% CI = 1.06-1.23), particularly for cases diagnosed during the first 7 years of follow-up (OR = 2.14, 95% CI = 1.16-3.96, P(trend) = 0.01, continuous OR = 1.21, 95% CI = 1.10-1.33), but not for cases occurring during follow-up of 7 years or greater (OR = 1.14, 95% CI = 0.53-2.45, continuous OR = 1.05, 95% CI = 0.93-1.18). Our results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and could possibly serve as a biomarker for pancreatic cancer development. Cancer Prev Res; 4(11); 1912-9. (C) 2011 AACR. C1 [Lynch, Shannon M.; Weinstein, Stephanie J.; Albanes, Demetrius; Stolzenberg-Solomon, Rachael Z.] NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Lan, Qing; Rothman, Nathaniel] NCI, Ocupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Lynch, Shannon M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Ctr Genet & Complex Traits, Philadelphia, PA 19104 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Liu, Chin-San; Cheng, Wen-Ling] Changhua Christian Hosp, Dept Neurol & Vasc, Changhua, Taiwan. [Liu, Chin-San; Cheng, Wen-Ling] Changhua Christian Hosp, Genom Res Ctr, Changhua, Taiwan. [Cheng, Wen-Ling] China Med Univ, Grad Inst Integrated Med, Taichung, Taiwan. RP Stolzenberg-Solomon, RZ (reprint author), NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 3022, Rockville, MD 20852 USA. EM rs221z@nih.gov RI Albanes, Demetrius/B-9749-2015 FU US Public Health Service from the National Cancer Institute, NIH, 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, NIH, Department of Health and Human Services. NR 39 TC 36 Z9 36 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1912 EP 1919 DI 10.1158/1940-6207.CAPR-11-0002 PG 8 WC Oncology SC Oncology GA 844NA UT WOS:000296752800023 PM 21859925 ER PT J AU Marshall, JR Ip, C Romano, K Fetterly, G Fakih, M Jovanovic, B Perloff, M Crowell, J Davis, W French-Christy, R Dew, A Coomes, M Bergan, R AF Marshall, James R. Ip, Clement Romano, Karen Fetterly, Gerald Fakih, Marwan Jovanovic, Borko Perloff, Marjorie Crowell, James Davis, Warren French-Christy, Renee Dew, Alexander Coomes, Margerie Bergan, Raymond TI Methyl Selenocysteine: Single-Dose Pharmacokinetics in Men SO CANCER PREVENTION RESEARCH LA English DT Article ID PROSTATE-CANCER CELLS; SELENIUM SUPPLEMENTATION; SE-METHYLSELENOCYSTEINE; NUTRITIONAL PREVENTION; METHYLSELENINIC ACID; MAMMARY-CANCER; BREAST-CANCER; TRIAL; RISK; CHEMOPREVENTION AB The recently published report of the SELECT evaluation of selenium and vitamin E provided strong evidence that selenium 200 mu g per day in the form of selenomethionine does not protect selenium-replete men against prostate or any other cancer. This seems to refute the result of the much smaller Nutritional Prevention of Cancer (NPC) trial of selenium. Because SELECT did not test the NPC agent, it is possible that the difference between the two trials stems partly from the use of different agents: selenomethionine in SELECT, and selenized yeast in the NPC trial. One of the organic selenium forms suspected of having strong chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine. This study characterizes the single-dose pharmacokinetics of methyl selenocysteine. Cancer Prev Res; 4(11); 1938-44. (C) 2011 AACR. C1 [Marshall, James R.; Ip, Clement; Romano, Karen; Fetterly, Gerald; Fakih, Marwan; Davis, Warren; French-Christy, Renee] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Jovanovic, Borko] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Dew, Alexander; Coomes, Margerie; Bergan, Raymond] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Dew, Alexander; Coomes, Margerie; Bergan, Raymond] Northwestern Univ, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Bergan, Raymond] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Chicago, IL 60611 USA. [Perloff, Marjorie; Crowell, James] NCI, Bethesda, MD 20892 USA. RP Marshall, JR (reprint author), Roswell Pk Canc Inst, Elm & Carlton St, Buffalo, NY 14263 USA. EM james.marshall@roswellpark.org FU National Cancer Institute (NCI) [N01-CN-35157, NWU 04-4-02, P30 CA016056] FX The work was supported by National Cancer Institute contract no. N01-CN-35157, NWU 04-4-02: "Phase I study of single oral dose of Se-methylseleno-L-cysteine (MSC) in adult men and by National Cancer Institute (NCI) grant P30 CA016056." NR 38 TC 10 Z9 11 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2011 VL 4 IS 11 BP 1938 EP 1944 DI 10.1158/1940-6207.CAPR-10-0259 PG 7 WC Oncology SC Oncology GA 844NA UT WOS:000296752800026 PM 21846796 ER PT J AU Derfoul, A Juan, AH Difilippantonio, MJ Palanisamy, N Ried, T Sartorelli, V AF Derfoul, Assia Juan, Aster H. Difilippantonio, Michael J. Palanisamy, Nallasivam Ried, Thomas Sartorelli, Vittorio TI Decreased microRNA-214 levels in breast cancer cells coincides with increased cell proliferation, invasion and accumulation of the Polycomb Ezh2 methyltransferase SO CARCINOGENESIS LA English DT Article ID GROUP PROTEIN EZH2; GENE-EXPRESSION; SKELETAL-MUSCLE; PROSTATE-CANCER; STEM-CELLS; DIFFERENTIATION; PROGRESSION; REPRESSION; TARGETS; MARKER AB MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression by inhibiting translation or promoting degradation of specific target messenger RNAs (mRNAs). Alteration of the levels of a number of miRNAs is common in solid and hematological tumors. We have shown previously that miR-214 regulates Ezh2 in skeletal muscle and embryonic stem cells. The current study was aimed at examining the role of miR-214 in breast cancer where miR-214 levels are reduced but whether this phenomenon bears a functional relevance is unknown. MiR-214 expression was inversely correlated with Ezh2 mRNA and protein levels in breast cancer cell lines and at least one copy of the miR-214 alleles was found to be deleted in 24% (6/25) of primary breast tumors. Experimental increase of miR-214 in breast cancer cell lines correlated with reduction of Ezh2 protein levels, a known marker of invasion and aggressive breast cancer behavior. Supporting a direct targeting mechanism, miR-214 decreased luciferase activity from a construct containing the Ezh2 3' untranslated region. Expression of miR-214 specifically reduced cell proliferation of breast cancer cells and inhibited the invasive potential of a highly metastatic breast cancer cell line. These findings indicate that reduced miR-214 levels may contribute to breast tumorigenesis by allowing abnormally elevated Ezh2 accumulation and subsequent unchecked cell proliferation and invasion. C1 [Derfoul, Assia; Juan, Aster H.; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Difilippantonio, Michael J.; Ried, Thomas] NCI, Sect Canc Genom, Genet Branch, CCR,NIH, Bethesda, MD 20892 USA. [Palanisamy, Nallasivam] Natl Genome Ctr, Singapore, Singapore. [Palanisamy, Nallasivam] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA. [Palanisamy, Nallasivam] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. RP Sartorelli, V (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr,Room 1351, Bethesda, MD 20892 USA. EM sartorev@mail.nih.gov OI Palanisamy, Nallasivam/0000-0002-0633-9772 FU National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health FX Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 35 TC 58 Z9 66 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2011 VL 32 IS 11 BP 1607 EP 1614 DI 10.1093/carcin/bgr184 PG 8 WC Oncology SC Oncology GA 842VD UT WOS:000296628400005 PM 21828058 ER PT J AU Liu, XX Piao, YS Arnold, JT AF Liu, Xunxian Piao, Yun-Shang Arnold, Julia T. TI Transforming growth factor beta 1 increase of hydroxysteroid dehydrogenase proteins is partly suppressed by red clover isoflavones in human primary prostate cancer-derived stromal cells SO CARCINOGENESIS LA English DT Article ID EPITHELIAL-CELLS; TGF-BETA; IGF-I; REACTIVE STROMA; DHEA; DEHYDROEPIANDROSTERONE; TESTOSTERONE; PROGRESSION; METABOLISM; INDUCTION AB Transforming growth factor beta 1 (TGF-beta 1) increases dehydro-epiandrosterone (DHEA) metabolism to androgens and prostate-specific antigen (PSA) in a prostate tissue model where stromal (6S) cells and epithelial (LAPC-4) cells are cocultured. Red clover (RC) isoflavones inhibits transforming growth factor (TGF)-beta-induced androgenicity. Mechanisms controlling those activities were explored. Three hydroxysteroid dehydrogenases (HSDs), 3 beta-HSD, HSD-17 beta 1 and HSD-17 beta 5 involved in metabolizing DHEA to testosterone (TESTO) were investigated. Individual depletion of HSDs in 6S cells significantly reduced TGF-beta 1/DHEA-induced PSA in LAPC-4 cells in cocultures. Monomer amounts of 3 beta-HSD were similar without or with TGF-beta 1 in both cell types but aggregates of 3 beta-HSD in 6S cells were much higher than those in LAPC-4 cells and were upregulated by TGF beta in 6S cells. Basal and TGF-beta 1-treated levels of HSD-17 beta 1 and HSD-17 beta 5 in LAPC-4 cells were significantly lower than in 6S cells, whereas levels of HSD-17 beta 1 but not HSD-17 beta 5 were TGF beta inducible. 6S cell HSD genes expression induced by TGF beta or androgen signaling was insignificant to contribute TGF-beta 1/DHEA-upregulated protein levels of HSDs. RC decreased TGF-beta 1- upregulation of aggregates of 3 beta-HSD but not HSD-17 beta 1. Depletion of TGF beta receptors (TGF beta Rs) reduced TGF-beta 1/DHEA-upregulated HSDs and TESTO. Immunoprecipitation studies demonstrated that TGF-beta 1 disrupted associations of TGF beta Rs/HSDs aggregates, whereas RC suppressed the dissociations of aggregates of 3 beta-HSD but not HSD-17 beta 1 from the receptors. Given that TGF beta Rs are recycled with or without ligand, TGF-beta 1-induced disassociation of the HSDs from TGF beta Rs may increase stability and activity of the HSDs. These data suggest a pathway connecting overproduction of TGF beta with increased PSA in prostate cancer. C1 [Liu, Xunxian; Piao, Yun-Shang; Arnold, Julia T.] Natl Ctr Complementary & Alternat Med, Endocrine Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Liu, XX (reprint author), Natl Ctr Complementary & Alternat Med NCCAM, Endocrine Sect, Intramural Res Program, NIH Bldg 10,Room 2B47,MSC 1547,9000 Rockville Pik, Bethesda, MD 20892 USA. EM xunxian1@mail.nih.gov FU National Center for Complementary and Alternative, National Institutes of Health, Bethesda, MD FX Intramural Research Program of the National Center for Complementary and Alternative, National Institutes of Health, Bethesda, MD 20892. NR 27 TC 4 Z9 4 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2011 VL 32 IS 11 BP 1648 EP 1654 DI 10.1093/carcin/bgr206 PG 7 WC Oncology SC Oncology GA 842VD UT WOS:000296628400010 PM 21914638 ER PT J AU Kumar, NP Anuradha, R Suresh, R Ganesh, R Shankar, J Kumaraswami, V Nutman, TB Babu, S AF Kumar, N. Pavan Anuradha, R. Suresh, R. Ganesh, R. Shankar, Janani Kumaraswami, V. Nutman, Thomas B. Babu, Subash TI Suppressed Type 1, Type 2, and Type 17 Cytokine Responses in Active Tuberculosis in Children SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; MYCOBACTERIUM-TUBERCULOSIS; INTERFERON-GAMMA; CHILDHOOD TUBERCULOSIS; PEDIATRIC TUBERCULOSIS; GLOBAL EPIDEMIOLOGY; IMMUNE-RESPONSES; DISEASE; INFECTION; BLOOD AB Type 1 cytokine responses are known to play an important role in immunity to tuberculosis (TB) in children, although little is known about other factors that might be important. In addition, children are more prone to developing extrapulmonary manifestations of TB than adults. To identify the immune responses important both in control of infection and in extrapulmonary dissemination, we examined mycobacterium-specific cytokine responses of children with pulmonary TB (PTB) and extrapulmonary TB (ETB) and compared them with those of healthy control children (HC). No significant differences were found in the cytokine responses either with no stimulation or following mycobacterial-antigen (Ag) stimulation between children with PTB and ETB. On the other hand, children with active TB compared with HC showed markedly diminished production of type 1 (gamma interferon [IFN-gamma] and tumor necrosis factor alpha [TNF-alpha]), 2 (interleukin 4 [IL-4] and IL-13), and 17 (IL-17A, IL-21, and IL-23)-associated cytokines with no stimulation and in response to mycobacterial antigens. This was not associated with significantly altered production of IL-10 or transforming growth factor beta (TGF-beta). Among children with ETB, those with neurologic involvement exhibited more significantly diminished Ag-driven IFN-gamma and IL-17 production. Pediatric TB is characterized by diminished type 1, 2, and 17 cytokine responses, with the most profound diminution favoring development of neurologic TB, suggesting a crucial role for these cytokines in protection against pediatric tuberculosis. C1 [Kumar, N. Pavan; Anuradha, R.; Babu, Subash] Natl Inst Hlth, Int Ctr Excellence Res, Madras 600031, Tamil Nadu, India. [Suresh, R.; Ganesh, R.; Shankar, Janani] Kanchi Kamakoti CHILDS Trust Hosp, Madras, Tamil Nadu, India. [Kumaraswami, V.] TB Res Ctr, Madras, Tamil Nadu, India. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Babu, Subash] NCI Frederick, SAIC Frederick Inc, Frederick, MD USA. RP Babu, S (reprint author), Natl Inst Hlth, Int Ctr Excellence Res, Madras 600031, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study received financial support from the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 43 TC 14 Z9 16 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD NOV PY 2011 VL 18 IS 11 BP 1856 EP 1864 DI 10.1128/CVI.05366-11 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 842QJ UT WOS:000296613800010 PM 21955625 ER PT J AU Gorres, JP Lager, KM Kong, WP Royals, M Todd, JP Vincent, AL Wei, CJ Loving, CL Zanella, EL Janke, B Kehrli, ME Nabel, GJ Rao, SS AF Gorres, J. Patrick Lager, Kelly M. Kong, Wing-Pui Royals, Michael Todd, John-Paul Vincent, Amy L. Wei, Chih-Jen Loving, Crystal L. Zanella, Eraldo L. Janke, Bruce Kehrli, Marcus E., Jr. Nabel, Gary J. Rao, Srinivas S. TI DNA Vaccination Elicits Protective Immune Responses against Pandemic and Classic Swine Influenza Viruses in Pigs SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID H1N1 2009 VIRUS; TIME RT-PCR; A VIRUS; EUROPEAN PIGS; IMMUNIZATION; CHALLENGE; INFECTION; VACCINES; HEMAGGLUTININ; MICE AB Swine influenza is a highly contagious viral infection in pigs that significantly impacts the pork industry due to weight loss and secondary infections. There is also the potential of a significant threat to public health, as was seen in 2009 when the pandemic H1N1 influenza virus strain emerged from reassortment events among avian, swine, and human influenza viruses within pigs. As classic and pandemic H1N1 strains now circulate in swine, an effective vaccine may be the best strategy to protect the pork industry and public health. Current inactivated-virus vaccines available for swine influenza protect only against viral strains closely related to the vaccine strain, and egg-based production of these vaccines is insufficient to respond to large outbreaks. DNA vaccines are a promising alternative since they can potentially induce broad-based protection with more efficient production methods. In this study we evaluated the potentials of monovalent and trivalent DNA vaccine constructs to (i) elicit both humoral and gamma interferon (IFN-gamma) responses and (ii) protect pigs against viral shedding and lung disease after challenge with pandemic H1N1 or classic swine H1N1 influenza virus. We also compared the efficiency of a needle-free vaccine delivery method to that of a conventional needle/syringe injection. We report that DNA vaccination elicits robust serum antibody and cellular responses after three immunizations and confers significant protection against influenza virus challenge. Needle-free delivery elicited improved antibody responses with the same efficiency as conventional injection and should be considered for development as a practical alternative for vaccine administration. C1 [Gorres, J. Patrick; Todd, John-Paul; Rao, Srinivas S.] NIH, Lab Anim Med, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Lager, Kelly M.; Vincent, Amy L.; Loving, Crystal L.; Kehrli, Marcus E., Jr.] ARS, Virus & Prion Dis Res Unit, Natl Anim Dis Ctr, USDA, Ames, IA 50010 USA. [Royals, Michael] PharmaJet Inc, Golden, CO 80401 USA. [Zanella, Eraldo L.] Univ Passo Fundo, Curso Med Vet, BR-99001970 Passo Fundo, RS, Brazil. [Janke, Bruce] Iowa State Univ, Coll Vet Med Vet Diagnost & Prod Anim Med, Ames, IA 50011 USA. RP Rao, SS (reprint author), 40 Convent Dr, Bethesda, MD 20895 USA. EM srao1@mail.nih.gov OI Royals, Michael/0000-0003-3639-3101 FU NIH Vaccine Research Center FX This research was supported by the Intramural Research Program of the NIH Vaccine Research Center. NR 54 TC 24 Z9 25 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD NOV PY 2011 VL 18 IS 11 BP 1987 EP 1995 DI 10.1128/CVI.05171-11 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 842QJ UT WOS:000296613800028 PM 21918118 ER PT J AU Shomaker, LB Tanoesky-Kraff, M Stern, EA Miller, R Zocca, JM Field, SE Yanovski, SZ Hubbard, V Yanovski, JA AF Shomaker, Lauren B. Tanoesky-Kraff, Marian Stern, Elizabeth A. Miller, Rachel Zocca, Jaclyn M. Field, Sara E. Yanovski, Susan Z. Hubbard, Van S. Yanovski, Jack A. TI Longitudinal Study of Depressive Symptoms and Progression of Insulin Resistance in Youth at Risk for Adult Obesity SO DIABETES CARE LA English DT Article ID TYPE-2 DIABETES-MELLITUS; METABOLIC SYNDROME; CHILDREN; PUBERTY; SENSITIVITY; ADOLESCENTS; STRESS; ONSET; WOMEN AB OBJECTIVE-The purpose of this study was to determine whether having childhood depressive symptoms is a risk factor that prospectively predicts impairment in glucose homeostasis. RESEARCH DESIGN AND METHODS-A non treatment-seeking sample of 115 children (aged 5-13 years), oversampled for being at risk for adult obesity, was assessed at baseline and again similar to 6 years later. Children self-reported depressive symptoms using the Children's Depression Inventory at baseline. Insulin resistance was assessed at baseline and follow-up with the homeostasis model assessment of insulin resistance index (HOMA-IR). RESULTS-Children's depressive symptoms were a significant predictor of follow-up HOMA-IR, fasting insulin, and fasting glucose in models accounting for baseline HOMA-IR, insulin, or glucose values; sex; race; baseline age; baseline BMI; change in BMI at follow-up; family history of type 2 diabetes; and time in the study (P < 0.01). CONCLUSIONS-In this study, depressive symptomatology at baseline predicted the progression of insulin resistance during child and adolescent development independent of changes in BMI. Research is needed to determine whether early intervention to decrease elevated depressive symptoms in youth ameliorates later development of insulin resistance and lessens the risk of type 2 diabetes. C1 [Shomaker, Lauren B.; Tanoesky-Kraff, Marian; Stern, Elizabeth A.; Zocca, Jaclyn M.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Shomaker, Lauren B.; Tanoesky-Kraff, Marian; Miller, Rachel; Field, Sara E.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Yanovski, Susan Z.] NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. [Hubbard, Van S.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [1F32HD056762]; NICHD [1ZIAHD000641]; Division of Nutrition Research Coordination; National Institute of Minority Health and Health Disparities; Office of Behavioral and Social Sciences Research FX This research was supported by National Research Service Award 1F32HD056762 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (to L.B.S.) and Intramural Research Program Grant 1ZIAHD000641 from the NICHD, with supplemental funding from the Division of Nutrition Research Coordination, the National Institute of Minority Health and Health Disparities, and the Office of Behavioral and Social Sciences Research (to J.A.Y.). J.A.Y. is a Commissioned Officer in the U.S. Public Health Service, Department of Health and Human Services. The funding organizations played no role in the design and conduct of the study; the collection, management, analysis, and interpretation of data; or the preparation or review of the manuscript. NR 25 TC 22 Z9 23 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2011 VL 34 IS 11 BP 2458 EP 2463 DI 10.2337/dc11-1131 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 847EQ UT WOS:000296955100027 PM 21911779 ER PT J AU Bhasin, S Jasjua, GK Pencina, M D'Agostino, R Coviello, AD Vasan, RS Travison, TG AF Bhasin, Shalender Jasjua, Guneet K. Pencina, Michael D'Agostino, Ralph, Sr. Coviello, Andrea D. Vasan, Ramachandran S. Travison, Thomas G. TI Sex Hormone-Binding Globulin, but Not Testosterone, Is Associated Prospectively and Independently With Incident Metabolic Syndrome in Men The Framingham Heart Study SO DIABETES CARE LA English DT Article ID SERUM TESTOSTERONE; NATIONAL-HEART; RISK; INSULIN; HYPOGONADISM; METAANALYSIS; PREDICTION; WOMEN; LUNG AB OBJECTIVE-The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We determined whether testosterone or sex hormone binding globulin (SHBG) is independently associated with the risk of metabolic syndrome. RESEARCH DESIGN AND METHODS-Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography-tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS-Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components. CONCLUSIONS-SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men. C1 [Bhasin, Shalender; Coviello, Andrea D.; Travison, Thomas G.] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Jasjua, Guneet K.; Pencina, Michael; D'Agostino, Ralph, Sr.] Boston Univ, Sch Med, Dept Math, Stat & Consulting Unit, Boston, MA 02118 USA. [D'Agostino, Ralph, Sr.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Coviello, Andrea D.; Vasan, Ramachandran S.] Boston Univ, Sect Prevent Med, Boston, MA 02215 USA. [Coviello, Andrea D.; Vasan, Ramachandran S.] Boston Univ, Epidemiol Sect, Boston, MA 02215 USA. [Travison, Thomas G.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. RP Bhasin, S (reprint author), Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. EM bhasin@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health [1RO1-AG-31206]; National Institute on Aging [5P30AG031679]; Centers for Disease Control and Prevention Foundation; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This project was supported primarily by National Institutes of Health Grant 1RO1-AG-31206 (to S.B. and R.S.V.). Additional support was provided by the Boston Claude D. Pepper Older Americans Independence Center Grant 5P30AG031679 from the National Institute on Aging and by a grant from the Centers for Disease Control and Prevention Foundation. The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study Contract (N01-HC-25195). NR 25 TC 45 Z9 50 U1 0 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2011 VL 34 IS 11 BP 2464 EP 2470 DI 10.2337/dc11-0888 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 847EQ UT WOS:000296955100028 PM 21926281 ER PT J AU Morahan, BJ Strobel, C Hasan, U Czesny, B Mantel, PY Marti, M Eksi, S Williamson, KC AF Morahan, Belinda J. Strobel, Carolyn Hasan, Uzma Czesny, Beata Mantel, Pierre-Yves Marti, Matthias Eksi, Saliha Williamson, Kim C. TI Functional Analysis of the Exported Type IV HSP40 Protein PfGECO in Plasmodium falciparum Gametocytes SO EUKARYOTIC CELL LA English DT Article ID ERYTHROCYTE SURFACE-ANTIGEN; RED-BLOOD-CELLS; INTERCELLULAR-ADHESION MOLECULE-1; DIGESTIVE VACUOLE PLASMEPSINS; TARGETED GENE DISRUPTION; HEAT-SHOCK PROTEINS; DNAJ-LIKE PROTEINS; INFECTED ERYTHROCYTES; MALARIA PARASITES; HOST ERYTHROCYTE AB During Plasmodium falciparum infection, host red blood cell (RBC) remodeling is required for the parasite's survival. Such modifications are mediated by the export of parasite proteins into the RBC that alter the architecture of the RBC membrane and enable cytoadherence. It is probable that some exported proteins also play a protective role against the host defense response. This may be of particular importance for the gametocyte stage of the life cycle that is responsible for malaria transmission, since the gametocyte remains in contact with blood as it proceeds through five morphological stages (I to V) during its 12-day maturation. Using microarray analysis, we identified several genes with encoded secretory or export sequences that were differentially expressed during early gametocytogenesis. One of these, PfGECO, encodes a predicted type IV heat shock protein 40 (HSP40) that we show is expressed in gametocyte stages I to IV and is exported to the RBC cytoplasm. HSPs are traditionally induced under stressful conditions to maintain homeostasis, but PfGECO expression was not increased upon heat shock, suggesting an alternate function. Targeted disruption of PfGECO indicated that the gene is not essential for gametocytogenesis in vitro, and quantitative reverse transcriptase PCR (RT-PCR) showed that there was no compensatory expression of the other type IV HSP40 genes. Although P. falciparum HSP40 members are implicated in the trafficking of proteins to the RBC surface, removal of PfGECO did not affect the targeting of other exported gametocyte proteins. This work has expanded the repertoire of known gametocyte-exported proteins to include a type IV HSP40, PfGECO. C1 [Morahan, Belinda J.; Williamson, Kim C.] NIAID, LMVR, NIH, Bethesda, MD 20892 USA. [Strobel, Carolyn; Hasan, Uzma; Czesny, Beata; Eksi, Saliha; Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. [Mantel, Pierre-Yves; Marti, Matthias] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Morahan, BJ (reprint author), NIAID, LMVR, NIH, TBIII Rm3E28,12735 Twinbrook Pkwy, Bethesda, MD 20892 USA. EM belinda.morahan@nih.gov FU Public Health Service [AI069314, AI48826]; National Institute of Allergy and Infectious Disease; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This investigation received financial support from Public Health Service grants AI069314 and AI48826 from the National Institute of Allergy and Infectious Disease and from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 94 TC 12 Z9 12 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD NOV PY 2011 VL 10 IS 11 BP 1492 EP 1503 DI 10.1128/EC.05155-11 PG 12 WC Microbiology; Mycology SC Microbiology; Mycology GA 844BX UT WOS:000296723600014 PM 21965515 ER PT J AU Root, TL Szatkiewicz, JP Jonassaint, CR Thornton, LM Pinheiro, AP Strober, M Bloss, C Berrettini, W Schork, NJ Kaye, WH Bergen, AW Magistretti, P Brandt, H Crawford, S Crow, S Fichter, MM Goldman, D Halmi, KA Johnson, C Kaplan, AS Keel, PK Klump, KL La Via, M Mitchell, JE Rotondo, A Treasure, J Woodside, DB Bulik, CM AF Root, Tammy L. Szatkiewicz, Jin P. Jonassaint, Charles R. Thornton, Laura M. Pinheiro, Andrea Poyastro Strober, Michael Bloss, Cinnamon Berrettini, Wade Schork, Nicholas J. Kaye, Walter H. Bergen, Andrew W. Magistretti, Pierre Brandt, Harry Crawford, Steve Crow, Scott Fichter, Manfred M. Goldman, David Halmi, Katherine A. Johnson, Craig Kaplan, Allan S. Keel, Pamela K. Klump, Kelly L. La Via, Maria Mitchell, James E. Rotondo, Alessandro Treasure, Janet Woodside, D. Blake Bulik, Cynthia M. TI Association of Candidate Genes with Phenotypic Traits Relevant to Anorexia Nervosa SO EUROPEAN EATING DISORDERS REVIEW LA English DT Article DE covariates; eating disorders; association studies; personality; genetic ID GENOME-WIDE ASSOCIATION; POPULATION-BASED TWIN; BULIMIA-NERVOSA; EATING-DISORDERS; LINKAGE ANALYSIS; RISK-FACTORS; SAMPLE DESCRIPTION; CONTROLLED FAMILY; SUSCEPTIBILITY; SET AB This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein, we investigate alternative phenotypes associated with AN. In 1762 females, using regression analyses, we examined the following: (i) lowest illness-related attained body mass index; (ii) age at menarche; (iii) drive for thinness; (iv) body dissatisfaction; (v) trait anxiety; (vi) concern over mistakes; and (vii) the anticipatory worry and pessimism versus uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes. Copyright (C) 2011 John Wiley & Sons, Ltd and Eating Disorders Association. C1 [Szatkiewicz, Jin P.; Thornton, Laura M.; Pinheiro, Andrea Poyastro; La Via, Maria; Bulik, Cynthia M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Root, Tammy L.; Jonassaint, Charles R.] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Strober, Michael] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Bloss, Cinnamon; Schork, Nicholas J.] Scripps Res Inst, Scripps Genom Med, La Jolla, CA 92037 USA. [Berrettini, Wade] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Kaye, Walter H.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Magistretti, Pierre] Ecole Polytech Fed Lausanne, Brain Mind Inst, CH-1015 Lausanne, Switzerland. [Magistretti, Pierre] Univ Lausanne, Sch Med, Dept Psychiat, Ctr Psychiat Neurosci, Lausanne, Switzerland. [Brandt, Harry; Crawford, Steve] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Crow, Scott] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Fichter, Manfred M.] Roseneck Hosp Behav Med, Prien Am Chiemsee, Germany. [Fichter, Manfred M.] Univ Munich LMU, Dept Psychiat, Munich, Germany. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Halmi, Katherine A.] Cornell Univ, New York Presbyterian Hosp, Westchester Div, Weill Med Coll, White Plains, NY USA. [Johnson, Craig] Eating Recovery Ctr, Denver, CO USA. [Kaplan, Allan S.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Kaplan, Allan S.] Toronto Gen Hosp, Res Inst, Toronto, ON, Canada. [Kaplan, Allan S.] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada. [Keel, Pamela K.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Klump, Kelly L.] Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. [Mitchell, James E.] Neuropsychiat Res Inst, Fargo, ND USA. [Mitchell, James E.] Univ N Dakota, Dept Clin Neurosci, Sch Med & Hlth Sci, Fargo, ND USA. [Rotondo, Alessandro] Univ Pisa, Pisa, Italy. [Treasure, Janet] Univ London, Kings Coll, Eating Disorders Sect, Inst Psychiat, London WC1E 7HU, England. [Woodside, D. Blake] Toronto Gen Hosp, Program Eating Disorders, Toronto, ON, Canada. [Woodside, D. Blake] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Bulik, Cynthia M.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. RP Bulik, CM (reprint author), Univ N Carolina, Dept Psychiat, 101 Manning Dr,CB 7160, Chapel Hill, NC 27599 USA. EM cbulik@med.unc.edu RI Goldman, David/F-9772-2010; Jonassaint, Charles/I-2772-2014; OI Goldman, David/0000-0002-1724-5405; Jonassaint, Charles/0000-0002-5662-5806; Bergen, Andrew/0000-0002-1237-7644; Treasure, Janet/0000-0003-0871-4596 FU Intramural NIH HHS [Z01 AA000301-09]; NHLBI NIH HHS [5T32HL007180‐35, T32 HL007180]; NIAAA NIH HHS [K01 AA018719, K01AA18719‐01A1]; NIMH NIH HHS [T32 MH076694, MH‐66117, R01 MH066117, T32 MH076694-01A1, T32MH076694] NR 52 TC 13 Z9 13 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1072-4133 J9 EUR EAT DISORD REV JI Eur. Eat. Disord. Rev. PD NOV-DEC PY 2011 VL 19 IS 6 BP 487 EP 493 DI 10.1002/erv.1138 PG 7 WC Psychology, Clinical SC Psychology GA 847KS UT WOS:000296972400004 PM 21780254 ER PT J AU Mideo, N Nelson, WA Reece, SE Bell, AS Read, AF Day, T AF Mideo, Nicole Nelson, William A. Reece, Sarah E. Bell, Andrew S. Read, Andrew F. Day, Troy TI BRIDGING SCALES IN THE EVOLUTION OF INFECTIOUS DISEASE LIFE HISTORIES: APPLICATION SO EVOLUTION LA English DT Article ID MALARIA PLASMODIUM-CHABAUDI; FUNCTION-VALUED TRAITS; WITHIN-HOST DYNAMICS; PARASITE VIRULENCE; TRADE-OFF; POPULATION BIOLOGY; MOSQUITO INFECTION; GENETIC-ANALYSIS; SEX-RATIO; TRANSMISSION AB Within- and between-host disease processes occur on the same timescales, therefore changes in the within-host dynamics of parasites, resources, and immunity can interact with changes in the epidemiological dynamics to affect evolutionary outcomes. Consequently, studies of the evolution of disease life histories, that is, infection-age-specific patterns of transmission and virulence, have been constrained by the need for a mechanistic understanding of within-host disease dynamics. In a companion paper (Day et al. 2011), we develop a novel approach that quantifies the relevant within-host aspects of disease through genetic covariance functions. Here, we demonstrate how to apply this theory to data. Using two previously published datasets from rodent malaria infections, we show how to translate experimental measures into disease life-history traits, and how to quantify the covariance in these traits. Our results show how patterns of covariance can interact with epidemiological dynamics to affect evolutionary predictions for disease life history. We also find that the selective constraints on disease life-history evolution can vary qualitatively, and that "simple" virulence-transmission trade-offs that are often the subject of experimental investigation can be obscured by trade-offs within one trait alone. Finally, we highlight the type and quality of data required for future applications. C1 [Mideo, Nicole; Reece, Sarah E.] Univ Edinburgh, Ctr Immun Infect & Evolut, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland. [Nelson, William A.; Day, Troy] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Reece, Sarah E.] Univ Edinburgh, Inst Evolut, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland. [Reece, Sarah E.] Univ Edinburgh, Inst Immunol, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland. [Reece, Sarah E.] Univ Edinburgh, Inst Infect Res, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland. [Bell, Andrew S.; Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16827 USA. [Bell, Andrew S.; Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, Dept Entomol, University Pk, PA 16827 USA. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Day, Troy] Queens Univ, Dept Math & Stat, Kingston, ON K7L 3N6, Canada. RP Mideo, N (reprint author), Univ Edinburgh, Ctr Immun Infect & Evolut, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland. EM N.Mideo@ed.ac.uk; tday@mast.queensu.ca RI Mideo, Nicole/F-4520-2010; Reece, Sarah/C-9447-2009; Nelson, William/D-1405-2013 FU Wellcome Trust; NSERC; Canada Research Chairs Program FX We thank M. Morrissey, D. Nussey and A. Wilson for discussion; two anonymous reviewers for helpful suggestions on the manuscript; and the Wellcome Trust (NM, SR, AB, AR), an NSERC Discovery Grant (WN), an NSERC Steacie Fellowship and the Canada Research Chairs Program (TD) for funding. NR 53 TC 17 Z9 17 U1 0 U2 26 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-3820 J9 EVOLUTION JI Evolution PD NOV PY 2011 VL 65 IS 11 BP 3298 EP 3310 DI 10.1111/j.1558-5646.2011.01382.x PG 13 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 843VK UT WOS:000296702800022 PM 22023593 ER PT J AU Rudrabhatla, P Jaffe, H Pant, HC AF Rudrabhatla, Parvathi Jaffe, Howard Pant, Harish C. TI Direct evidence of phosphorylated neuronal intermediate filament proteins in neurofibrillary tangles (NFTs): phosphoproteomics of Alzheimer's NFTs SO FASEB JOURNAL LA English DT Article DE Tau; sarkosyl; AD brain ID PAIRED HELICAL FILAMENTS; MILD COGNITIVE IMPAIRMENT; PREFRONTAL CORTEX AREA-9; NEUROFILAMENT PROTEIN; PYRAMIDAL NEURONS; TAU-PROTEIN; HYPERPHOSPHORYLATED-TAU; ANTIGENIC DETERMINANTS; QUANTITATIVE-ANALYSIS; STEREOLOGIC ANALYSIS AB Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain pathology of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. NFTs contain aberrantly hyperphosphorylated Tau as paired helical filaments (PHFs). Although NFs have been shown immunohistologically to be part of NFTs, there has been debate that the identity of NF proteins in NFTs is due to the cross-reactivity of phosphorylated NF antibodies with phospho-Tau. Here, we provide direct evidence on the identity of NFs in NFTs by immunochemical and mass spectrometric analysis. We have purified sarkosyl-insoluble NFTs and performed liquid chromatography/tandem mass spectrometry of NFT tryptic digests. The phosphoproteomics of NFTs clearly identified NF-M phosphopeptides SPVPKS*PVEEAK, corresponding to Ser685, and KAES*PVKEEAVAEVVTITK, corresponding to Ser736, and an NF-H phosphopeptide, EPDDAKAKEPS*KP, corresponding to Ser942. Western blotting of purified tangles with SMI31 showed a 150-kDa band corresponding to phospho-NF-M, while RT97 antibodies detected phospho-NF-H. The proteomics analysis also identified an NF-L peptide (ALYEQEIR, EAEEEKKVEGAGEEQAAAK) and another intermediate filament protein, vimentin (FADLSEAANR). Mass spectrometry revealed Tau phosphopeptides corresponding to Thr231, Ser235, Thr181, Ser184, Ser185, Thr212, Thr217, Ser396, and Ser403. And finally, phosphopeptides corresponding to MAP1B (corresponding to Ser1270, Ser1274, and Ser1779) and MAP2 (corresponding to Thr350, Ser1702, and Ser1706) were identified. In corresponding matched control preparations of PHF/NFTs, none of these phosphorylated neuronal cytoskeletal proteins were found. These studies independently demonstrate that NF proteins are an integral part of NFTs in AD brains.-Rudrabhatla, P., Jaffe, H., Pant, H. C. Direct evidence of phosphorylated neuronal intermediate filament proteins in neurofibrillary tangles (NFTs): phosphoproteomics of Alzheimer's NFTs. FASEB J. 25, 3896-3905 (2011). www.fasebj.org C1 [Pant, Harish C.] NINDS, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Jaffe, Howard] NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bldg 49,Rm 2A28, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov FU U.S. National Institute of Neurological Disorders and Stroke, National Institutes of Health; Dr. Philip Grant FX This work is supported by the grants from the U.S. National Institute of Neurological Disorders and Stroke, National Institutes of Health. The authors acknowledge the Harvard Brain Resource Center (Boston, MA, USA) and the National Institute of Child Health and Human Development Brain and Tissue Bank (Bethesda, MD, USA) for providing human brain tissue. The authors thank Dr. Philip Grant for extensive editing and reviewing the manuscript. NR 54 TC 36 Z9 38 U1 1 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD NOV PY 2011 VL 25 IS 11 BP 3896 EP 3905 DI 10.1096/fj.11-181297 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 844BT UT WOS:000296723100014 PM 21828286 ER PT J AU Wang, Q Levay, K Chanturiya, T Dvoriantchikova, G Anderson, KL Bianco, SDC Ueta, CB Molano, RD Pileggi, A Gurevich, EV Gavrilova, O Slepak, VZ AF Wang, Qiang Levay, Konstantin Chanturiya, Tatyana Dvoriantchikova, Galina Anderson, Karen L. Bianco, Suzy D. C. Ueta, Cintia B. Molano, R. Damaris Pileggi, Antonello Gurevich, Eugenia V. Gavrilova, Oksana Slepak, Vladlen Z. TI Targeted deletion of one or two copies of the G protein beta subunit G beta 5 gene has distinct effects on body weight and behavior in mice SO FASEB JOURNAL LA English DT Article DE RGS protein; obesity; insulin; pancreas; RGS7 ID RGS PROTEINS; REGULATORS; RECEPTOR; FAMILY; COMPLEX; DOMAIN; SELECTIVITY; ACTIVATION; MODULATOR; SURVIVAL AB We investigated the physiological role of G beta 5, a unique G protein beta subunit that dimerizes with regulators of G protein signaling (RGS) proteins of the R7 family instead of G gamma. G beta 5 is essential for stability of these complexes, so that its knockout (KO) causes degradation of the entire G beta 5-R7 family. We report that the G beta 5-KO mice remain leaner than the wild type (WT) throughout their lifetime and are resistant to a high-fat diet. They have a 5-fold increase in locomotor activity, increased thermogenesis, and lower serum insulin, all of which correlate with a higher level of secreted epinephrine. Heterozygous (HET) mice are 2-fold more active than WT mice. Surprisingly, with respect to body weight, the HET mice display a phenotype opposite to that of the KO mice: by the age of 6 mo, they are >= 15% heavier than the WT and have increased adiposity, insulin resistance, and liver steatosis. These changes occur in HET mice fed a normal diet and without apparent hyperphagia, mimicking basic characteristics of human metabolic syndrome. We conclude that even a partial reduction in G beta 5-R7 level can perturb normal animal metabolism and behavior. Our data on G beta 5 haploinsufficient mice may explain earlier observations of genetic linkage between R7 family mutations and obesity in humans.-Wang, Q., Levay, K., Chanturiya, T., Dvoriantchikova, G., Anderson, K. L., Bianco, S. D. C., Ueta, C. B., Molano, R. D., Pileggi, A., Gurevich, E. V., Gavrilova, O., and Slepak, V. Z. Targeted deletion of one or two copies of the G protein beta subunit G beta 5 gene has distinct effects on body weight and behavior in mice. FASEB J. 25, 3949-3957 (2011). www.fasebj.org C1 [Wang, Qiang; Levay, Konstantin; Bianco, Suzy D. C.; Slepak, Vladlen Z.] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Dvoriantchikova, Galina] Univ Miami, Miller Sch Med, Dept Ophthalmol, Miami, FL 33136 USA. [Anderson, Karen L.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Bianco, Suzy D. C.; Ueta, Cintia B.] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA. [Molano, R. Damaris; Pileggi, Antonello] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Pileggi, Antonello] Univ Miami, Miller Sch Med, Dept Surg, Div Cellular Transplantat, Miami, FL 33136 USA. [Chanturiya, Tatyana; Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD USA. [Gurevich, Eugenia V.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. RP Slepak, VZ (reprint author), Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, 1600 NW 10th Ave, Miami, FL 33136 USA. EM v.slepak@miami.edu RI Ueta, Cintia/D-6832-2013; Molano, Ruth Damaris/B-8633-2015; Pileggi, Antonello/A-2394-2008; Bianco, Suzy/E-8892-2010 OI Molano, Ruth Damaris/0000-0002-6132-8750; Pileggi, Antonello/0000-0001-7819-2813; Bianco, Suzy/0000-0003-3794-9853 FU U.S. National Institutes of Health (NIH) [GM 060019, 1R01 EB008009, NS065868]; Juvenile Diabetes Research Foundation; NIH [DK70460, NIHU42 RR016603]; City of Hope (Duarte, CA, USA) FX The authors thank Dr. Ching-Kang Chen (Virginia Commonwealth University, Richmond, VA, USA) for G beta 5-KO mice and Drs. Yossef Itzhak, Ronald Goldberg, Alessia Fornoni, and Valery Shestopalov for providing necessary equipment and invaluable critical discussions. The authors are also grateful to Darla Karpinsky, Elsie Zahr-Akrawi, Maite Lopez, Yelena Gadea, and Susana Villate for technical assistance. This study was supported by U.S. National Institutes of Health (NIH) grants GM 060019 (V.Z.S), 1R01 EB008009, and NS065868 (E.V.G) and by the Juvenile Diabetes Research Foundation (A.P.). Pancreatic islets were obtained through the support of NIH grants DK70460 and NIHU42 RR016603 and the City of Hope (Duarte, CA, USA). NR 42 TC 12 Z9 12 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD NOV PY 2011 VL 25 IS 11 BP 3949 EP 3957 DI 10.1096/fj.11-190157 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 844BT UT WOS:000296723100019 PM 21804131 ER PT J AU Uchida, N Hsieh, MM Hayakawa, J Madison, C Washington, KN Tisdale, JF AF Uchida, N. Hsieh, M. M. Hayakawa, J. Madison, C. Washington, K. N. Tisdale, J. F. TI Optimal conditions for lentiviral transduction of engrafting human CD34(+) cells SO GENE THERAPY LA English DT Article DE hematopoietic stem cell; human CD34(+) cell; humanized xenograft mouse; lentiviral vector; transduction efficiency ID HEMATOPOIETIC STEM-CELLS; EX-VIVO EXPANSION; SEVERE COMBINED IMMUNODEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; MOBILIZED PERIPHERAL-BLOOD; MURINE BETA-THALASSEMIA; GENE-TRANSFER; MOUSE MODEL; LENTIVECTOR CORRECTS; REPOPULATING CELLS AB Cytokines are required for gamma-retroviral transduction of human CD34(+) cells. However, cytokines may reduce engraftment of CD34(+) cells and may not be necessary for their lentiviral transduction. We sought to optimize transduction and engraftment of human CD34(+) cells using lentiviral vectors. Single 24 h transduction of human CD34(+) cells with human immunodeficiency virus type 1 (HIV1)-based lentiviral vectors in media containing stem cell factor (SCF), FMS-like tyrosine kinase 3 (FLT3) ligand, thrombopoietin (each 100 ng ml(-1)) and 10% fetal bovine serum was compared with various cytokine conditions during ex vivo culture and assayed using humanized xenograft mice for 6 months after transplantation. Serum-free media improved transduction efficiency of human CD34(+) cells. Interleukin-3 (20 ng ml(-1)) had little effect on transduction efficiency or engraftment. Threefold higher cytokine mixture (each 300 ng ml(-1)) reduced engraftment of CD34(+) cells. SCF alone (100 ng ml(-1)) proved insufficient for maintaining engraftment ability and reduced transduction efficiency. Short-term prestimulation had little effect on transduction efficiency or engraftment, yet 24 h prestimulation showed higher transduction efficiency, higher gene expression levels and lower engraftment. In summary, 24 h prestimulation followed by single 24-h lentiviral transduction in serum-free media with SCF, FLT3 ligand and thrombopoietin yields high transduction efficiency to engrafting human CD34(+) cells, and is applicable in human clinical gene therapy trials. Gene Therapy (2011) 18, 1078-1086; doi:10.1038/gt.2011.63; published online 5 May 2011 C1 [Uchida, N.; Hsieh, M. M.; Hayakawa, J.; Madison, C.; Washington, K. N.; Tisdale, J. F.] NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU National Heart, Lung and Blood Institute (NHLBI); National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) FX This work was supported by the intramural research program of the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). NR 48 TC 18 Z9 19 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD NOV PY 2011 VL 18 IS 11 BP 1078 EP 1086 DI 10.1038/gt.2011.63 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 846ID UT WOS:000296889500007 PM 21544097 ER PT J AU Zhou, BY Shi, JX Whittemore, AS AF Zhou, Baiyu Shi, Jianxin Whittemore, Alice S. TI Optimal Methods for Meta-Analysis of Genome-Wide Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE combining GWAS; effect-size heterogeneity; meta-analysis; non centrality parameter; score statistics; Wald statistics ID COMMON VARIANTS; IMPUTATION; PHASE; SCHIZOPHRENIA; REPLICATION; EFFICIENCY; GENOTYPES; RISK AB Meta-analysis of genome-wide association studies involves testing single nucleotide polymorphisms (SNPs) using summary statistics that are weighted sums of site-specific score or Wald statistics. This approach avoids having to pool individual-level data. We describe the weights that maximize the power of the summary statistics. For small effect-sizes, any choice of weights yields summary Wald and score statistics with the same power, and the optimal weights are proportional to the square roots of the sites' Fisher information for the SNP's regression coefficient. When SNP effect size is constant across sites, the optimal summary Wald statistic is the well-known inverse-variance-weighted combination of estimated regression coefficients, divided by its standard deviation. We give simple approximations to the optimal weights for various phenotypes, and show that weights proportional to the square roots of study sizes are suboptimal for data from case-control studies with varying case-control ratios, for quantitative trait data when the trait variance differs across sites, for count data when the site-specific mean counts differ, and for survival data with different proportions of failing subjects. Simulations suggest that weights that accommodate intersite variation in imputation error give little power gain compared to those obtained ignoring imputation uncertainties. We note advantages to combining site-specific score statistics, and we show how they can be used to assess effect-size heterogeneity across sites. The utility of the summary score statistic is illustrated by application to a meta-analysis of schizophrenia data in which only site-specific P-values and directions of association are available. Genet. Epidemiol. 35:581-591, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Shi, Jianxin] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Whittemore, AS (reprint author), Stanford Univ, Sch Med, Dept Hlth Res & Policy, 259 Campus Dr, Stanford, CA 94305 USA. EM alicesw@stanford.edu RI Zhou, Baiyu/H-3506-2012 FU NIH [R01 CA094069, U01 CA122171, N01-CP-95671] FX Contract grant sponsor: NIH; Contract grant numbers: R01 CA094069; U01 CA122171; N01-CP-95671. NR 33 TC 12 Z9 12 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2011 VL 35 IS 7 BP 581 EP 591 DI 10.1002/gepi.20603 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 845TT UT WOS:000296846900001 PM 21922536 ER PT J AU Shriner, D AF Shriner, Daniel TI Approximate and Exact Tests of Hardy-Weinberg Equilibrium Using Uncertain Genotypes SO GENETIC EPIDEMIOLOGY LA English DT Article DE quality control; measurement error; genotype probabilities ID GENOME-WIDE ASSOCIATION; MULTIPLE ALLELES; POPULATION; LAW; IMPUTATION; ERRORS; POWER AB Testing for Hardy-Weinberg equilibrium (HWE) is commonly used as a quality control filter in genome-wide scans for markers with experimentally determined genotypes. In contrast, for markers with imputed genotypes, there are post-imputation metrics of quality that can be used as screens but there are no formal tests of deviation from HWE. Similarly, there are no formal tests of deviation from HWE for probabilistic genotypes that are generated by sequencing projects. Here, I describe generalizations of the approximate chi(2) and exact tests of HWE for use with uncertain genotypes. The tests fully account for the probabilities of all possible genotypes at a marker for each individual. By computer simulation, the approximate and exact tests are shown to maintain valid control of the type I error rate. Calculations of the loss of power as the uncertainty in genotypes increases are illustrated. The tests are compatible with chip-based genotypes for single-nucleotide polymorphisms and copy number polymorphisms, imputed genotypes, and probabilistic assignments of genotype from variable-coverage sequence data. Genet. Epidemiol. 35:632-637, 2011. (C) 2011 Wiley Periodicals, Inc. C1 NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Shriner, D (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047,12 South Dr,MSC 5635, Bethesda, MD 20892 USA. EM shrinerda@mail.nih.gov FU Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362] FX The contents of this publication are solely the responsibility of the author and do not necessarily represent the official view of the National Institutes of Health. This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). NR 35 TC 3 Z9 3 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2011 VL 35 IS 7 BP 632 EP 637 DI 10.1002/gepi.20612 PG 6 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 845TT UT WOS:000296846900006 PM 21922537 ER PT J AU Fan, R Zhong, M Wang, S Zhang, Y Andrew, A Karagas, M Chen, H Amos, CI Xiong, M Moore, JH AF Fan, R. Zhong, M. Wang, S. Zhang, Y. Andrew, A. Karagas, M. Chen, H. Amos, C. I. Xiong, M. Moore, J. H. TI Entropy-Based Information Gain Approaches to Detect and to Characterize Gene-Gene and Gene-Environment Interactions/Correlations of Complex Diseases SO GENETIC EPIDEMIOLOGY LA English DT Article DE gene-gene and gene-environment interactions; entropy; mutual information; interaction information; total correlation information ID MULTIFACTOR-DIMENSIONALITY REDUCTION; COMBINATORIAL APPROACH; RHEUMATOID-ARTHRITIS; MATHEMATICAL-THEORY; EPISTASIS; SUSCEPTIBILITY; COMMUNICATION; SMOKING; CANCER AB For complex diseases, the relationship between genotypes, environment factors, and phenotype is usually complex and nonlinear. Our understanding of the genetic architecture of diseases has considerably increased over the last years. However, both conceptually and methodologically, detecting gene-gene and gene-environment interactions remains a challenge, despite the existence of a number of efficient methods. One method that offers great promises but has not yet been widely applied to genomic data is the entropy-based approach of information theory. In this article, we first develop entropy-based test statistics to identify two-way and higher order gene-gene and gene-environment interactions. We then apply these methods to a bladder cancer data set and thereby test their power and identify strengths and weaknesses. For two-way interactions, we propose an information gain (IG) approach based on mutual information. For three-ways and higher order interactions, an interaction IG approach is used. In both cases, we develop one-dimensional test statistics to analyze sparse data. Compared to the naive chi-square test, the test statistics we develop have similar or higher power and is robust. Applying it to the bladder cancer data set allowed to investigate the complex interactions between DNA repair gene single nucleotide polymorphisms, smoking status, and bladder cancer susceptibility. Although not yet widely applied, entropy-based approaches appear as a useful tool for detecting gene-gene and gene-environment interactions. The test statistics we develop add to a growing body methodologies that will gradually shed light on the complex architecture of common diseases. Genet. Epidemiol. 35:706-721, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Fan, R.; Wang, S.; Zhang, Y.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Zhong, M.] Abbott Labs, Abbott Pk, IL 60064 USA. [Wang, S.] Yunnan Univ, Sch Informat Sci & Engn, Kunming 650091, Peoples R China. [Andrew, A.; Karagas, M.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Chen, H.] NCI, Surveillance Res Program, Rockville, MD USA. [Amos, C. I.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Xiong, M.] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. [Moore, J. H.] Dartmouth Med Sch, Dept Genet, Lebanon, NH USA. RP Fan, R (reprint author), Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. EM rfan@stat.tamu.edu RI yu, yan/C-2322-2012; Chen, Huann-Sheng/D-6328-2013 OI Chen, Huann-Sheng/0000-0002-5905-8050 FU National Cancer Institute [R01-CA133996]; NIH [LM009012]; Intergovernmental Personnel Act (IPA); National Natural Science Foundation [10901135]; Natural Science Foundation of Yunnan Province [2008CD081, 2010CC003]; Natural Science Foundation of Yunnan Province, P. R. China [2008CD081, 2010CC003] FX Contract grant sponsor: National Cancer Institute; Contract grant number: R01-CA133996; Contract grant sponsor: NIH; Contract grant number: LM009012; Contract grant sponsors: Intergovernmental Personnel Act (IPA); National Natural Science Foundation; Contract grant number: 10901135; Contract grant sponsor: Natural Science Foundation of Yunnan Province; Contract grant numbers: 2008CD081, 2010CC003.; The research was supported by a Research and Travel Support from the Intergovernmental Personnel Act (IPA), National Cancer Institute, NIH for Fan R., the National Cancer Institute grant R01-CA133996 for Amos C., NIH grant LM009012 for Moore J.H., and National Natural Science Foundation (10901135) & Natural Science Foundation of Yunnan Province (2008CD081, 2010CC003), P. R. China, for Wang S. We thank Ms. Davnah R. Urbach a lot for helping us in the writings of the article to remove numerous typographical, grammatical, and bibliographical errors. NR 38 TC 22 Z9 24 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2011 VL 35 IS 7 BP 706 EP 721 DI 10.1002/gepi.20621 PG 16 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 845TT UT WOS:000296846900015 PM 22009792 ER PT J AU Martin, MM Ryan, M Kim, R Zakas, AL Fu, HQ Lin, CM Reinhold, WC Davis, SR Bilke, S Liu, HF Doroshow, JH Reimers, MA Valenzuela, MS Pommier, Y Meltzer, PS Aladjem, MI AF Martin, Melvenia M. Ryan, Michael Kim, RyangGuk Zakas, Anna L. Fu, Haiqing Lin, Chii Mei Reinhold, William C. Davis, Sean R. Bilke, Sven Liu, Hongfang Doroshow, James H. Reimers, Mark A. Valenzuela, Manuel S. Pommier, Yves Meltzer, Paul S. Aladjem, Mirit I. TI Genome-wide depletion of replication initiation events in highly transcribed regions SO GENOME RESEARCH LA English DT Article ID EUKARYOTIC DNA-REPLICATION; RNA-SEQ; ORIGIN; GENE; EXPRESSION; PROMOTER; REPLICON; LOCUS; MODEL; SPECIFICATION AB This report investigates the mechanisms by which mammalian cells coordinate DNA replication with transcription and chromatin assembly. In yeast, DNA replication initiates within nucleosome-free regions, but studies in mammalian cells have not revealed a similar relationship. Here, we have used genome-wide massively parallel sequencing to map replication initiation events, thereby creating a database of all replication initiation sites within nonrepetitive DNA in two human cell lines. Mining this database revealed that genomic regions transcribed at moderate levels were generally associated with high replication initiation frequency. In genomic regions with high rates of transcription, very few replication initiation events were detected. High-resolution mapping of replication initiation sites showed that replication initiation events were absent from transcription start sites but were highly enriched in adjacent, downstream sequences. Methylation of CpG sequences strongly affected the location of replication initiation events, whereas histone modifications had minimal effects. These observations suggest that high levels of transcription interfere with formation of pre-replication protein complexes. Data presented here identify replication initiation sites throughout the genome, providing a foundation for further analyses of DNA-replication dynamics and cell-cycle progression. C1 [Martin, Melvenia M.; Zakas, Anna L.; Fu, Haiqing; Lin, Chii Mei; Reinhold, William C.; Doroshow, James H.; Pommier, Yves; Aladjem, Mirit I.] NCI, Mol Pharmacol Lab, CCR, Bethesda, MD 20892 USA. [Ryan, Michael; Kim, RyangGuk] InSilico Solut, Fairfax, VA 22033 USA. [Davis, Sean R.; Bilke, Sven; Meltzer, Paul S.] NCI, Genet Branch, CCR, Bethesda, MD 20892 USA. [Liu, Hongfang] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Reimers, Mark A.] Virginia Commonwealth Univ, Sch Med, Dept Biostat, Richmond, VA 23298 USA. [Valenzuela, Manuel S.] Meharry Med Coll, Sch Med, Dept Biochem & Canc Biol, Nashville, TN 37208 USA. RP Aladjem, MI (reprint author), NCI, Mol Pharmacol Lab, CCR, Bethesda, MD 20892 USA. EM aladjem@mail.nih.gov RI Aladjem, Mirit/G-2169-2010; OI Aladjem, Mirit/0000-0002-1875-3110; Davis, Sean/0000-0002-8991-6458 FU NIH, Center for Cancer Research, National Cancer Institute; NIH [CA138180]; Howard Hughes Medical Institute FX We thank Bao Tran and Michelle Mehaffey for expert technical assistance in sequencing of nascent strands and Dr. Tobi Guennel for high quality CGH data. This study was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute; by NIH grant CA138180 to M. S. V.; and by a scholarship from the Howard Hughes Medical Institute. NR 52 TC 58 Z9 58 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD NOV PY 2011 VL 21 IS 11 BP 1822 EP 1832 DI 10.1101/gr.124644.111 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 843TW UT WOS:000296696600006 PM 21813623 ER PT J AU Ghany, MG Kim, HY Stoddard, A Wright, EC Seeff, LB Lok, ASF AF Ghany, Marc G. Kim, Hae-Young Stoddard, Anne Wright, Elizabeth C. Seeff, Leonard B. Lok, Anna S. F. CA HALT-C Trial Grp TI Predicting Clinical Outcomes Using Baseline and Follow-Up Laboratory Data from the Hepatitis C Long-Term Treatment Against Cirrhosis Trial SO HEPATOLOGY LA English DT Article ID VIRUS-INFECTION; LIVER FIBROSIS; SCORE; MODEL; PROGRESSION; MORTALITY; THERAPY; TESTS; RISK AB Predicting clinical outcomes in patients with chronic hepatitis C is challenging. We used the hepatitis C long-term treatment against cirrhosis (HALT-C) trial database to develop two models, using baseline values of routinely available laboratory tests together with changes in these values during follow-up to predict clinical decompensation and liver-related death/liver transplant in patients with advanced hepatitis C. Patients randomized to no treatment and who had >= 2-year follow-up without a clinical outcome were included in the analysis. Four variables (platelet count, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ratio, total bilirubin, and albumin) with three categories of change (stable, mild, or severe) over 2 years were analyzed. Cumulative incidence of clinical outcome was determined by Kaplan-Meier analysis and Cox regression was used to evaluate predictors of clinical outcome. In all, 470 patients with 60 events were used to develop models to predict clinical decompensation. Baseline values of all four variables were predictive of decompensation. There was a general trend of increasing outcomes with more marked worsening of laboratory values over 2 years, particularly for patients with abnormal baseline values. A model that included baseline platelet count, AST/ALT ratio, bilirubin, and severe worsening of platelet count, bilirubin, and albumin was the best predictor of clinical decompensation. A total of 483 patients with 79 events were used to evaluate predictors of liver-related death or liver transplant. A model that included baseline platelet count and albumin as well as severe worsening of AST/ALT ratio and albumin was the best predictor of liver-related outcomes. Conclusion: Both the baseline value and the rapidity in change of the value of routine laboratory variables were shown to be important in predicting clinical outcomes in patients with advanced chronic hepatitis C. (HEPATOLOGY 2011;54:1527-1537) C1 [Ghany, Marc G.; Seeff, Leonard B.] NIDDK, Liver Dis Branch, NIH, US Dept HHS, Bethesda, MD USA. [Kim, Hae-Young; Stoddard, Anne] New England Res Inst, Watertown, MA 02172 USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, US Dept HHS, Bethesda, MD USA. [Seeff, Leonard B.] NIDDK, Div Digest Dis & Nutr, NIH, US Dept HHS, Bethesda, MD USA. [Lok, Anna S. F.] Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI USA. RP Ghany, MG (reprint author), Bldg 10,Room 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov OI Yang, Shuman/0000-0002-9638-0890 FU University of Massachusetts Medical Center, Worcester, MA [N01-DK-9-2326]; University of Connecticut Health Center, Farmington, CT [M01RR-06192]; St. Louis University School of Medicine, St. Louis, MO [N01-DK-9-2324]; Massachusetts General Hospital, Boston, MA [N01-DK-9-2319, M01RR-01066, 1 UL1 RR025758-01]; Harvard Clinical and Translational Science Center; University of Colorado Denver, School of Medicine, Aurora, CO [N01-DK-9-2327, M01RR-00051, 1 UL1 RR 025780-01]; University of California Irvine, Irvine, CA [N01-DK-9-2320, M01RR-00827]; University of Texas Southwestern Medical Center, Dallas, TX [N01-DK-9-2321, M01RR-00633, 1 UL1 RR024982-01]; North and Central Texas Clinical and Translational Science Initiative; University of Southern California, Los Angeles, CA [N01-DK-9-2325, M01RR-00043]; University of Michigan Medical Center, Ann Arbor, MI [N01-DK-9-2323, M01RR-00042, 1 UL1 RR024986]; Michigan Center for Clinical and Health Research; Virginia Commonwealth University Health System, Richmond, VA [N01-DK-9-2322, M01RR-00065]; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD; University of Washington, Seattle, WA [N01-DK-9-2318]; New England Research Institutes, Water-town, MA [N01-DK-9-2328]; National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute; National Center for Minority Health and Health Disparities; National Center for Research Resources, National Institutes of Health (NIH); NIH, NIDDK; Hoffmann-La Roche, Inc. (now Genentech) with the National Institutes of Health FX In addition to the authors of this article the following individuals were instrumental in the planning, conduct, and/or care of patients enrolled in this study at each of the participating institutions as follows: University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN; University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Herbert L. Bonkovsky, MD, Gloria Borders, RN, Michelle Kelley, RN, ANP; St. Louis University School of Medicine, St. Louis, MO: (Contract N01-DK-9-2324) Adrian M. Di Bisceglie, MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN; Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center) Jules L. Dienstag, MD, Raymond T. Chung, MD, Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark; University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01) Gregory T. Everson, MD, Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN; University of California Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Timothy R. Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, Choon Park, RN; University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) William M. Lee, MD, Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH; University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) Karen L. Lindsay, MD, MMM, Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN; University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research) Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS; Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065) Mitchell L. Shiffman, MD, Richard K. Sterling, MD, MSc, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, Paula Smith, RN; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD: T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN, Vanessa Haynes-Williams, RN; National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: James E. Everhart, MD, MPH, Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD; University of Washington, Seattle, WA: (Contract N01-DK-9-2318) Chihiro Morishima, MD, David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, M.Ed.; New England Research Institutes, Water-town, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD, Teresa M. Curto, MSW, MPH; Inova Fairfax Hospital, Falls Church, VA: Zachary D. Goodman, MD, PhD, Fanny Monge, Michelle Parks; Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD.; Supported by the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases (NIAID); the National Cancer Institute; the National Center for Minority Health and Health Disparities; by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (NIH grant numbers are listed below); and by the Intramural Research Program of the NIH, NIDDK (M. G. Ghany). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc. (now Genentech), through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. NR 17 TC 14 Z9 15 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 NOV PY 2011 VL 54 IS 5 BP 1527 EP 1537 DI 10.1002/hep.24550 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 840LX UT WOS:000296443100007 PM 22045670 ER PT J AU Allen, VC Lachance, C Rios-Ellis, B Kaphingst, KA AF Allen, Vincent C., Jr. Lachance, Christina Rios-Ellis, Britt Kaphingst, Kimberly A. TI Issues in the Assessment of "Race" Among Latinos: Implications for Research and Policy SO HISPANIC JOURNAL OF BEHAVIORAL SCIENCES LA English DT Article DE racial identity; racial measurement; health disparities; Latino ID RACIAL IDENTITY; UNITED-STATES; HEALTH-CARE; ETHNICITY; IDENTIFICATION; CLASSIFICATION; RACE/ETHNICITY; ORGANIZATIONS; DOMINICANS; RECORDS AB Measurement of race and ethnicity is integral to assessing and addressing health disparities experienced by minorities. However, the unique experiences of Latinos related to race and the discordance between understandings of race among Latinos and the predominant U.S. conceptualizations of this construct impact how Latinos respond to measurement approaches. As a result, data collection methodologies often yield ambiguous responses that reveal little about this population. This article examines Latinos' racial responding, and how this relates to their experiences and understanding of their racial identity. We recommend the use of a combined race and ethnicity question and open-ended race and ethnicity questions, when feasible, which will likely yield more meaningful data that can be used to address this populations' health needs. C1 [Allen, Vincent C., Jr.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Lachance, Christina] NHGRI, Hlth Commun Grp, Social & Behav Res Branch, NIH, Montgomery Village, AL USA. [Rios-Ellis, Britt] Natl Council La Raza, CSULB, Ctr Community Hlth Evaluat & Leadership Training, Long Beach, CA USA. [Kaphingst, Kimberly A.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. RP Allen, VC (reprint author), Univ Calif Los Angeles, Box 951563,1193B Franz Hall, Los Angeles, CA 90095 USA. EM vcallenjr@gmail.com FU Intramural NIH HHS [Z01 HG200321-04] NR 40 TC 6 Z9 6 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0739-9863 J9 HISPANIC J BEHAV SCI JI Hisp. J. Behav. Sci. PD NOV PY 2011 VL 33 IS 4 BP 411 EP 424 DI 10.1177/0739986311422880 PG 14 WC Psychology, Multidisciplinary SC Psychology GA 846PL UT WOS:000296915600001 PM 23239903 ER PT J AU Velayati, A DePaolo, J Gupta, N Choi, JH Moaven, N Westbroek, W Goker-Alpan, O Goldin, E Stubblefield, BK Kolodny, E Tayebi, N Sidransky, E AF Velayati, Arash DePaolo, John Gupta, Nidhi Choi, Jae H. Moaven, Nima Westbroek, Wendy Goker-Alpan, Ozlem Goldin, Ehud Stubblefield, Barbara K. Kolodny, Edwin Tayebi, Nahid Sidransky, Ellen TI A Mutation in SCARB2 is a Modifier in Gaucher Disease SO HUMAN MUTATION LA English DT Article DE Gaucher disease; myoclonic epilepsy; LIMP-2; SCARB2; glucocerebrosidase ID BETA-GLUCOCEREBROSIDASE; MEMBRANE-PROTEIN; LIMP-2; EPILEPSY AB Lysosomal integral membrane protein type 2 (LIMP-2) is responsible for proper sorting and lysosomal targeting of glucocerebrosidase, the enzyme deficient in Gaucher disease (GD). Mutations in the gene for LIMP-2, SCARB2, are implicated in inherited forms of myoclonic epilepsy, and myoclonic epilepsy is part of the phenotypic spectrum associated with GD. We investigated whether SCARB2 mutations impact the Gaucher phenotype focusing on patients with myoclonic epilepsy, including a pair of siblings with GD who were discordant for myoclonic seizures. Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy, absent from his sibling and controls. Glucocerebrosidase activity, Western blots, real-time PCR, and immunofluorescence studies demonstrated markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2, and diminished glucocerebrosidase in lysosomes. The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase. Sequencing of SCARB2 in 13 other subjects with GD and myoclonic epilepsy and 40 controls failed to identify additional mutations. The study provides further evidence for the association of LIMP-2 and myoclonic epilepsy, explains the drastically different phenotypes encountered in the siblings, and demonstrates that LIMP-2 can serve as a modifier in GD. Hum Mutat 32: 1232-1238, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Velayati, Arash; DePaolo, John; Gupta, Nidhi; Choi, Jae H.; Moaven, Nima; Westbroek, Wendy; Goker-Alpan, Ozlem; Goldin, Ehud; Stubblefield, Barbara K.; Tayebi, Nahid; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Kolodny, Edwin] NYU, Dept Neurol, Sch Med, New York, NY 10016 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health FX Contract grant sponsors: Intramural Research Programs of the National Human Genome Research Institute; National Institutes of Health. NR 16 TC 27 Z9 31 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2011 VL 32 IS 11 BP 1232 EP 1238 DI 10.1002/humu.21566 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 840HJ UT WOS:000296429800006 PM 21796727 ER PT J AU Franklin, SS Levy, D AF Franklin, Stanley S. Levy, Daniel TI Aging, Blood Pressure, and Heart Failure What are the Connections? SO HYPERTENSION LA English DT Editorial Material ID ISOLATED SYSTOLIC HYPERTENSION; CARDIOVASCULAR-DISEASE; NATURAL-HISTORY; RISK; COMMUNITY; DYSFUNCTION; MORTALITY; ADULTS; OLDER C1 [Franklin, Stanley S.] Univ Calif Irvine, Heart Dis Prevent Program, Sch Med, Irvine, CA 92697 USA. [Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Franklin, SS (reprint author), Univ Calif Irvine, Heart Dis Prevent Program, Sch Med, Sprague Hall 112, Irvine, CA 92697 USA. EM ssfranklinmd@earthlink.net FU Intramural NIH HHS [Z01 HL006001-01, Z01 HL006001-02, Z99 HL999999] NR 19 TC 5 Z9 6 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 NOV PY 2011 VL 58 IS 5 BP 760 EP 762 DI 10.1161/HYPERTENSIONAHA.111.179119 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HQ UT WOS:000296588100636 PM 21947472 ER PT J AU Foster, MC Hwang, SJ Porter, SA Massaro, JM Hoffmann, U Fox, CS AF Foster, Meredith C. Hwang, Shih-Jen Porter, Stacy A. Massaro, Joseph M. Hoffmann, Udo Fox, Caroline S. TI Fatty Kidney, Hypertension, and Chronic Kidney Disease The Framingham Heart Study SO HYPERTENSION LA English DT Article DE renal sinus fat; hypertension; chronic kidney disease; blood pressure; computed tomography; epidemiology ID GLOMERULAR-FILTRATION-RATE; SERUM CYSTATIN-C; OBESITY-INDUCED HYPERTENSION; RENAL-VEIN CONSTRICTION; METABOLIC SYNDROME; ADIPOSE-TISSUE; BLOOD-PRESSURE; RISK-FACTORS; ASSOCIATION; CREATININE AB Ectopic fat depots may mediate local and systemic disease. Animal models of diet-induced obesity demonstrate increased fat accumulation in the renal sinus. The association of renal sinus fat with hypertension, chronic kidney disease, and other metabolic disorders has not been studied in a large, community-based sample. Participants from the Framingham Heart Study (n = 2923; mean age: 54 years; 51% women) underwent quantification of renal sinus fat area using computed tomography. High renal sinus fat ("fatty kidney") was defined using sex-specific 90th percentiles in a healthy referent subsample. Multivariable linear and logistic regression was used to model metabolic risk factors as a function of fatty kidney and log-transformed renal sinus fat. Multivariable models were adjusted for age, sex, and outcome-specific covariates and then additionally adjusted for body mass index or abdominal visceral adipose tissue. The prevalence of fatty kidney was 30.1% (n = 879). Individuals with fatty kidney had a higher odds ratio (OR) of hypertension (OR: 2.12; P < 0.0001), which persisted after adjustment for body mass index (OR: 1.49; P < 0.0001) or visceral adipose tissue (OR: 1.24; P = 0.049). Fatty kidney was also associated with an increased OR for chronic kidney disease (OR: 2.30; P = 0.005), even after additionally adjusting for body mass index (OR: 1.86; P = 0.04) or visceral adipose tissue (OR: 1.86; P = 0.05). We observed no association between fatty kidney and diabetes mellitus after adjusting for visceral adipose tissue. In conclusion, fatty kidney is a common condition that is associated with an increased risk of hypertension and chronic kidney disease. Renal sinus fat may play a role in blood pressure regulation and chronic kidney disease. (Hypertension. 2011;58:784-790.). Online Data Supplement C1 [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Foster, Meredith C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Porter, Stacy A.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute [N01-HC-25195] FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195). NR 42 TC 74 Z9 77 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2011 VL 58 IS 5 BP 784 EP U266 DI 10.1161/HYPERTENSIONAHA.111.175315 PG 15 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HQ UT WOS:000296588100644 PM 21931075 ER PT J AU Tu, WZ Eckert, GJ DiMeglio, LA Yu, ZS Jung, J Pratt, JH AF Tu, Wanzhu Eckert, George J. DiMeglio, Linda A. Yu, Zhangsheng Jung, Jeesun Pratt, J. Howard TI Intensified Effect of Adiposity on Blood Pressure in Overweight and Obese Children SO HYPERTENSION LA English DT Article DE hypertension; obesity; leptin; heart rate; sympathetic nervous system ID BODY-MASS INDEX; HYPERTENSION; ADOLESCENTS; CHILDHOOD; DISEASE; WEIGHT; LEPTIN; RISK; ALDOSTERONE; ASSOCIATION AB In children, blood pressure (BP) and risk for hypertension are proportional to degree of adiposity. Whether the relationship to BP is similar over the full range of adiposity is less clear. Subjects from a cohort study (n = 1111; 50% male and 42% black) contributed 9102 semiannual BP and height/weight assessments. The mean enrollment age was 10.2 years, and mean follow-up was 4.5 years. Adiposity was expressed as body mass index percentile, which accounted for effects of age and sex. The following observations were made. The effect of relative adiposity on BP was minimal until the body mass index percentile reached 85, beginning of the overweight category, at which point the effect of adiposity on BP increased by 4-fold. Similarly intensified adiposity effects on BP were observed in children aged <= 10, 11 to 14 years, and >= 15 years. Serum levels of the adipose tissue-derived hormone, leptin, together with heart rate, showed an almost identically patterned relation to BP to that of body mass index percentile and BP, thus implicating a possible mediating role for leptin. In conclusion, there is a marked intensification of the influence of adiposity on BP when children reach the categories of overweight and obese. Among the possible pathways, leptin may be a potentially important mediator acting through the sympathetic nervous system (reflected in heart rate). The findings have relevance to interventions designed to prevent or treat adiposity-related increases in BP and to the analytic approaches used in epidemiological studies. (Hypertension. 2011;58:818-824.) C1 [Tu, Wanzhu; Eckert, George J.; Yu, Zhangsheng; Pratt, J. Howard] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46204 USA. [DiMeglio, Linda A.] Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Pratt, J. Howard] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. [Tu, Wanzhu] Regenstrief Inst Inc, Indianapolis, IN USA. [Jung, Jeesun] NIAAA, Washington, DC USA. RP Tu, WZ (reprint author), Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46204 USA. EM wtu1@iupui.edu OI DiMeglio, Linda/0000-0002-8033-6078 FU National Heart, Lung, and Blood Institute [RO1-HL095086]; Veterans Health Administration FX This work was supported by National Heart, Lung, and Blood Institute grant RO1-HL095086 and a Veterans Health Administration merit review grant. NR 33 TC 47 Z9 50 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2011 VL 58 IS 5 BP 818 EP 824 DI 10.1161/HYPERTENSIONAHA.111.175695 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HQ UT WOS:000296588100649 PM 21968752 ER PT J AU Guichard, JL Desai, RV Ahmed, MI Mujib, M Fonarow, GC Feller, MA Ekundayo, OJ Bittner, V Aban, IB White, M Aronow, WS Love, TE Bakris, GL Zieman, SJ Ahmed, A AF Guichard, Jason L. Desai, Ravi V. Ahmed, Mustafa I. Mujib, Marjan Fonarow, Gregg C. Feller, Margaret A. Ekundayo, O. James Bittner, Vera Aban, Inmaculada B. White, Michel Aronow, Wilbert S. Love, Thomas E. Bakris, George L. Zieman, Susan J. Ahmed, Ali TI Isolated Diastolic Hypotension and Incident Heart Failure in Older Adults SO HYPERTENSION LA English DT Article DE aging; blood pressure; diastolic; heart failure; pulse pressure ID ISOLATED SYSTOLIC HYPERTENSION; CHRONIC KIDNEY-DISEASE; BLOOD-PRESSURE; CARDIOVASCULAR HEALTH; PULSE PRESSURE; ARTERIAL STIFFNESS; PROPENSITY SCORE; FOLLOW-UP; MORTALITY; RISK AB Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure >= 100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age >= 65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively, who were balanced on 58 baseline characteristics. During >12 years of median follow-up, centrally adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension, respectively (hazard ratio associated with isolated diastolic hypotension: 1.33 [95% CI: 1.10-1.61]; P = 0.004). Among the 5376 prematch individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% CI: 1.09-1.53; P = 0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure. (Hypertension. 2011; 58: 895-901.) C1 [Ahmed, Ali] Univ Alabama, Ctr Aging, Birmingham, AL 35294 USA. [Desai, Ravi V.] Lehigh Valley Hosp, Allentown, PA USA. [Fonarow, Gregg C.; Ekundayo, O. James] Univ Calif Los Angeles, Los Angeles, CA USA. [Ekundayo, O. James] Meharry Med Coll, Nashville, TN 37208 USA. [White, Michel] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Aronow, Wilbert S.] New York Med Coll, Valhalla, NY 10595 USA. [Love, Thomas E.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Bakris, George L.] Univ Chicago, Chicago, IL 60637 USA. [Zieman, Susan J.] NIA, NIH, Bethesda, MD 20892 USA. [Ahmed, Ali] Vet Affairs Med Ctr, Birmingham, AL USA. RP Ahmed, A (reprint author), Univ Alabama, Ctr Aging, 1530 3rd Ave S,CH 19,Suite 219, Birmingham, AL 35294 USA. EM aahmed@uab.edu RI Mujib, Marjan/J-2709-2013; OI Mujib, Marjan/0000-0002-3261-8599; Bittner, Vera/0000-0001-9456-850X FU National Heart, Lung, and Blood Institute; National Institutes of Health from the National Heart, Lung, and Blood Institute [R01-HL085561, R01-HL085561-S, R01-HL097047]; CHS FX The CHS was conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the CHS investigators.; A.A. is supported by the National Institutes of Health through grants (R01-HL085561, R01-HL085561-S, and R01-HL097047) from the National Heart, Lung, and Blood Institute and a generous gift from Jean B. Morris of Birmingham, Ala. NR 35 TC 14 Z9 14 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2011 VL 58 IS 5 BP 895 EP 901 DI 10.1161/HYPERTENSIONAHA.111.178178 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HQ UT WOS:000296588100660 PM 21947466 ER PT J AU Ding, Y Cheng, J Wu, CC Joshi, K Zhang, F Falck, JR Schwartzman, ML AF Ding, Yan Cheng, Jennifer Wu, Cheng-Chia Joshi, Krutanjuli Zhang, Frank Falck, John R. Schwartzman, Michal L. TI Role of The Renin-angiotensin System in 20-HETE-Mediated Endothelial Cell Dysfunction SO HYPERTENSION LA English DT Meeting Abstract CT High Blood Pressure Research Scientific Sessions CY SEP 20-24, 2011 CL Orlando, FL SP Amer Heart Assoc (AHA), Council High Blood Pressure Res, Council Kidney Cardiovasc Dis, Inter-Amer Soc Hypertens (IASH) DE 20-HETE angiotensin-converting enzyme Angiotensin II receptor type 1 C1 [Ding, Yan; Wu, Cheng-Chia; Joshi, Krutanjuli; Zhang, Frank; Schwartzman, Michal L.] New York Med Coll, Valhalla, NY 10595 USA. [Cheng, Jennifer] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Falck, John R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 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 NOV PY 2011 VL 58 IS 5 BP E129 EP E129 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HQ UT WOS:000296588100392 ER PT J AU Ke, L Graubard, BI Albanes, D Fraser, DR Weinstein, JS Virtamo, J Brock, KE AF Ke, Liang Graubard, Barry I. Albanes, Demetrius Fraser, David R. Weinstein, J. Stephanie Virtamo, Jarmo Brock, Kaye E. TI Hypertension and Other Cardiovascular Risk Factors and Vitamin D Status in Middle-Aged Healthy Finnish Men SO HYPERTENSION LA English DT Meeting Abstract CT Scientific Sessions of High Blood Pressure Research CY SEP 20-24, 2011 CL Orlando, FL SP Council High Blood Pressure Res, Council Kidney Cardiovasc Dis & Inter-Amer Soc Hypertens (IASH) DE Hypertension Vitamin D Pulse C1 [Ke, Liang; Fraser, David R.; Brock, Kaye E.] Univ Sydney, Sydney, NSW 2006, Australia. [Graubard, Barry I.; Albanes, Demetrius; Weinstein, J. Stephanie] NCI, Bethesda, MD 20892 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015 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 NOV PY 2011 VL 58 IS 5 BP E130 EP E130 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HQ UT WOS:000296588100399 ER PT J AU Reiter, CE Miller, JL Alayash, AI AF Reiter, Chad E. Miller, Jeffery L. Alayash, Abdu I. TI Effects of Carbon Monoxide on Vascular Endothelial Cells Under Hypoxia and in the Presence of Cell-Free Hemoglobin and Sickle Red Blood Cells SO HYPERTENSION LA English DT Meeting Abstract CT Scientific Sessions of High Blood Pressure Research CY SEP 20-24, 2011 CL Orlando, FL SP Council High Blood Pressure Res, Council Kidney Cardiovasc Dis & Inter-Amer Soc Hypertens (IASH) DE vascular mitochondria oxygen uptake C1 [Reiter, Chad E.; Alayash, Abdu I.] CBER, FDA, Bethesda, MD USA. [Miller, Jeffery L.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD NOV PY 2011 VL 58 IS 5 BP E161 EP E161 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842HQ UT WOS:000296588100532 ER PT J AU Celi, FS Zemskova, M Linderman, JD Smith, S Drinkard, B Sachdev, V Skarulis, MC Kozlosky, M Csako, G Costello, R Pucino, F AF Celi, Francesco S. Zemskova, Marina Linderman, Joyce D. Smith, Sheila Drinkard, Bart Sachdev, Vandana Skarulis, Monica C. Kozlosky, Merel Csako, Gyorgy Costello, Rene Pucino, Frank TI Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind, Crossover Trial of Liothyronine Versus Levothyroxine SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID THYROXINE PLUS TRIIODOTHYRONINE; THYROID-HORMONE REPLACEMENT; COMBINATION REGIMEN; 3,5,3'-TRIIODOTHYRONINE; DISEASE; T-4; SELENODEIODINASE; HYPERTHYROIDISM; BIOAVAILABILITY; EUTHYROIDISM AB Context: Levothyroxine (L-T(4)) therapy is based on the assumption that the conversion of T(4) into T(3) provides adequate amounts of active hormone at target tissues. However, in rodents, L-T(4) alone does not restore a euthyroid state in all tissues. Previous combination L-T(4)/liothyronine (L-T(3)) therapy trials focused on quality-of-life endpoints, and limited information is available on the effects on other measures of thyroid hormone action. Objective: Our objective was to evaluate the efficacy of thyroid hormone replacement with L-T(4) or L-T(3) at doses producing equivalent normalization of TSH. Participants, Design, and Setting: Fourteen hypothyroid patients participated in this randomized, double-blind, crossover intervention at the National Institutes of Health Clinical Center. Interventions: L-T(3) or L-T(4) were administered thrice daily to achieve a target TSH from 0.5-1.5 mU/liter. Volunteers were studied as inpatients after 6 wk on a stable dose and at the target TSH. Main Outcome Measures: Serum thyroid hormones, lipid parameters, and indices of glucose metabolism were evaluated. Results: No difference was observed in TSH between L-T(3) and L-T(4) treatments. L-T(3) resulted in significant weight loss [ L-T(4), 70.6 +/- 12.5, vs. L-T(3), 68.5 +/- 11.9 kg (P = 0.009)] and in a 10.9 +/- 10.0% decrease in total cholesterol (P = 0.002), 13.3 +/- 12.1% decrease in low-density lipoprotein-cholesterol (P = 0.002), and an 18.3 +/- 28.6% decrease in apolipoprotein B (P = 0.018). No significant differences were observed in high-density lipoprotein-cholesterol, heart rate, blood pressure, exercise tolerance, or insulin sensitivity. Conclusions: The substitution of L-T(3) for L-T(4) at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity. (J Clin Endocrinol Metab 96: 3466-3474, 2011) C1 [Celi, Francesco S.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, CRC, Bethesda, MD 20892 USA. [Drinkard, Bart] Ctr Clin, Dept Rehabil Med, Bethesda, MD 20892 USA. [Sachdev, Vandana] NHLBI, Translat Med Branch, Bethesda, MD 20892 USA. [Kozlosky, Merel] NIH, Dept Nutr, Bethesda, MD 20892 USA. [Csako, Gyorgy; Costello, Rene] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Celi, FS (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, CRC, Bldg 10,Room 6-3940,10 Ctr Dr,MSC 1613, Bethesda, MD 20892 USA. EM fc93a@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [Z01-DK047057-02]; Clinical Center, NIH FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases program Z01-DK047057-02, and the Clinical Center, NIH. NR 41 TC 34 Z9 35 U1 4 U2 17 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 NOV PY 2011 VL 96 IS 11 BP 3466 EP 3474 DI 10.1210/jc.2011-1329 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 844MF UT WOS:000296750600052 PM 21865366 ER PT J AU Farrell, WE Azevedo, MF Batista, DL Smith, A Bourdeau, I Horvath, A Boguszewski, M Quezado, M Stratakis, CA AF Farrell, William E. Azevedo, Monalisa F. Batista, Dalia L. Smith, Alastair Bourdeau, Isabelle Horvath, Anelia Boguszewski, Margaret Quezado, Martha Stratakis, Constantine A. TI Unique Gene Expression Profile Associated with an Early-Onset Multiple Endocrine Neoplasia (MEN1)-Associated Pituitary Adenoma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID COMPLEMENTARY DEOXYRIBONUCLEIC-ACID; MEN1 GENE; TRANSGENIC MICE; CANDIDATE GENES; ARRAY ANALYSIS; TYPE-1 MEN1; TUMORS; CANCER; FEATURES; CLONING AB Context: Multiple endocrine neoplasia type 1(MEN1) is caused by mutations in the menin(MEN1) gene. The mechanism(s) by which MEN1 mutations lead to pituitary tumor formation remain(s) unknown. Objective: The aim of the study was to identify the pediatric MEN1-associated pituitary tumor transcriptome. Patients and Methods: A patient harboring a MEN1 mutation (c.525C>G; p.H139D) who presented with an early-onset mammosomatotroph pituitary adenoma was studied. Microarray analysis was performed in the tumor sample and compared with the profile observed in normal pituitaries and in a sporadic mammosomatotropinoma. Validation of the microarray results was performed using quantitative real-time PCR and immunohistochemical analysis for selected genes. Results: In theMEN1-associated pituitary adenoma, 59 and 24 genes were found to be significantly up-and down-regulated, respectively. The up-regulated genes included those involved in cell growth and maintenance, apoptosis, growth arrest, and tumorigenesis. Moreover, we observed decreased expression in genes neuroendocrine in nature and related to growth or apoptosis. Only 21 of the 59 genes differentially expressed in the MEN1-associated adenoma showed a similar expression profile to that seen in the sporadic mammosomatotropinoma; for some genes an opposite expression profile was observed. Conclusions: We identified changes in the transcriptome that occur in pituitary GH- and PRL-producing cells after the loss of menin expression; some of the gene changes are necessary for tumor evolution, and others may be tertiary. Nevertheless, the rare overlap between the expression profiles of the MEN1 tumor vs. that of its sporadic counterpart suggests that these tumors evolve along different molecular pathways. (J Clin Endocrinol Metab 96: E1905-E1914, 2011) C1 [Farrell, William E.; Azevedo, Monalisa F.; Batista, Dalia L.; Smith, Alastair; Bourdeau, Isabelle; Horvath, Anelia; Boguszewski, Margaret; Quezado, Martha; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Farrell, William E.] Univ Keele, Inst Sci & Technol Med, Keele ST5 5BG, N Staffordshire, England. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Levesque, Isabelle/A-1899-2012 FU National Institutes of Health of the Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Cancer Institute; University of Keele; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; University of Brasilia, Brazil FX This work was supported by the National Institutes of Health Intramural Programs of the Eunice Kennedy Shriver National Institute of Child Health & Human Development and the National Cancer Institute; and also, in part, by a grant from the University of Keele (to W.E.F.) and by a grant from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico and the University of Brasilia, Brazil (to M.F.A.). NR 50 TC 10 Z9 10 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 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2011 VL 96 IS 11 BP E1905 EP E1914 DI 10.1210/jc.2011-1127 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 844MF UT WOS:000296750600027 PM 21917868 ER PT J AU Gaujoux, S Tissier, F Ragazzon, B Rebours, V Saloustros, E Perlemoine, K Vincent-Dejean, C Meurette, G Cassagnau, E Dousset, B Bertagna, X Horvath, A Terris, B Carney, JA Stratakis, CA Bertherat, J AF Gaujoux, Sebastien Tissier, Frederique Ragazzon, Bruno Rebours, Vinciane Saloustros, Emmanouil Perlemoine, Karine Vincent-Dejean, Caroline Meurette, Guillaume Cassagnau, Elisabeth Dousset, Bertrand Bertagna, Xavier Horvath, Anelia Terris, Benoit Carney, J. Aidan Stratakis, Constantine A. Bertherat, Jerome TI Pancreatic Ductal and Acinar Cell Neoplasms in Carney Complex: A Possible New Association SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NODULAR ADRENOCORTICAL DISEASE; REGULATORY SUBUNIT; PRKAR1A GENE; SIGNALING PATHWAYS; WNT/BETA-CATENIN; MUTATIONS; KINASE; CARCINOMA; TUMORS; BETA AB Context: Carney complex (CNC) is a rare disease inherited as an autosomal dominant trait, associated with various tumors, and caused most frequently by inactivation of the PRKAR1A gene. Objectives: In our recent investigation of a large cohort of CNC patients, we identified several cases of pancreatic neoplasms. This possible association and PRKAR1A's possible involvement in pancreatic tumor have not been reported previously. Patients and Methods: Nine patients (2.5%) with CNC and pancreatic neoplasms in an international cohort of 354 CNC patients were identified; we studied six of them. Immunohistochemistry and PRKAR1A sequencing were obtained. Results: Three men and three women with a mean age of 49 yr (range 34-75 yr) had acinar cell carcinoma (n = 2), adenocarcinoma (n = 1), and intraductal pancreatic mucinous neoplasm(n = 3). Five patients had a germline PRKAR1A mutation, including two patients with acinar cell carcinoma, for whom mutations were found in a hemizygous state in the tumor, suggesting loss of heterozygosity. PRKAR1A expression was not detected in five of the six pancreatic neoplasms from CNC patients, whereas the protein was amply expressed on other sporadic pancreatic tumors and normal tissue. Conclusion: An unexpectedly high prevalence of rare pancreatic tumors was found among CNC patients. Immunohistochemistry and loss-of-heterozygosity studies suggest that PRKAR1A could function as a tumor suppressor gene in pancreatic tissue, at least in the context of CNC. Clinicians taking care of CNC patients should be aware of the possible association of CNC with a potentially aggressive pancreatic neoplasm. (J Clin Endocrinol Metab 96: E1888-E1895, 2011) C1 [Gaujoux, Sebastien; Tissier, Frederique; Dousset, Bertrand; Bertagna, Xavier; Terris, Benoit; Bertherat, Jerome] Univ Paris 05, F-75005 Paris, France. [Rebours, Vinciane] Hop Beaujon, AP HP, Dept Gastroenterol, F-92110 Clichy, France. [Saloustros, Emmanouil; Horvath, Anelia; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Endocrinol Sect, NIH, Bethesda, MD 20892 USA. [Saloustros, Emmanouil; Horvath, Anelia; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Genet Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Cassagnau, Elisabeth] Ctr Hosp Univ Hotel Dieu, Dept Pathol, F-44000 Nantes, France. [Vincent-Dejean, Caroline] Ctr Hosp Univ Hotel Dieu, Clin Endocrinol, F-44000 Nantes, France. [Meurette, Guillaume] Ctr Hosp Univ Hotel Dieu, Clin Chirurg Digest & Endocrinienne, Clin Chirurg 2, F-44000 Nantes, France. [Carney, J. Aidan] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Bertherat, J (reprint author), Hop Cochin, Serv Malad Endocriniennes & Metab, 27 Rue Faubourg St Jacques, F-75014 Paris, France. EM jerome.bertherat@cch.aphp.fr RI Meurette, Guillaume/M-1419-2015; Ragazzon, Bruno/E-6541-2017; OI Ragazzon, Bruno/0000-0001-9476-4973; Saloustros, Emmanouil /0000-0002-0485-0120 FU Agence Nationale pour la Recherche [ANR06-MRAR-007, ANR08-GENOPAT-002]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; AP-HP; European Society of Surgical Oncology (ESSO) FX This work was supported by grants from the Agence Nationale pour la Recherche (ANR06-MRAR-007 and ANR08-GENOPAT-002) and the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. S. G. was the recipient of a grant from the AP-HP and from the European Society of Surgical Oncology (ESSO). NR 48 TC 18 Z9 19 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 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2011 VL 96 IS 11 BP E1888 EP E1895 DI 10.1210/jc.2011-1433 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 844MF UT WOS:000296750600025 PM 21900385 ER PT J AU Rader, F Costantini, O Jarrett, C Gorodeski, EZ Lauer, MS Blackstone, EH AF Rader, Florian Costantini, Otto Jarrett, Craig Gorodeski, Eiran Z. Lauer, Michael S. Blackstone, Eugene H. TI Quantitative electrocardiography for predicting postoperative atrial fibrillation after cardiac surgery SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; ISCHEMIC-STROKE; HEART-DISEASE; RISK; IMPACT; ARRHYTHMIAS; AMIODARONE; PREVENTION; TRIAL AB Background: Atrial fibrillation (AF) after cardiac surgery is a common marker of poor outcomes. Quantitative electrocardiographic (ECG) measurements may be valuable predictors of postoperative AF. Methods: We evaluated clinical and ECG predictors of postoperative AF in 13 356 patients who underwent cardiac surgery in sinus rhythm. Results: A total of 4724 patients (35%) developed postoperative AF. P-wave amplitude in leads aVR and VI were the strongest ECG predictors. A less negative P-wave amplitude in lead aVR was associated with increased risk for postoperative AF (odds ratio, 1.46; 95% confidence interval, 1.32-1.61), as was a more positive or a more negative P-wave amplitude in lead Vi (odds ratio, 1.25; 95% confidence interval, 1.16-1.36) after adjusting for clinical and procedural predictors of postoperative AF. Reclassification analysis showed a 7% discrimination improvement (P <.0001). Conclusions: P-wave amplitude in lead aVR and lead V, are powerful predictors of postoperative AF and, in combination with other clinical predictors, can guide application of prophylactic interventions. (C) 2011 Elsevier Inc. All rights reserved. C1 [Rader, Florian; Costantini, Otto] Case Western Reserve Univ, Heart & Vasc Ctr, Cleveland, OH 44118 USA. [Jarrett, Craig] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44118 USA. [Lauer, Michael S.] NHLBI, Div Prevent & Populat Sci, Washington, DC USA. [Blackstone, Eugene H.] Cleveland Clin, Dept Thorac & Cardiovasc Surg, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Blackstone, Eugene H.] Cleveland Clin, Res Inst, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. RP Rader, F (reprint author), Case Western Reserve Univ, Heart & Vasc Ctr, Metrohlth Campus,2500 Metrohlth Dr, Cleveland, OH 44118 USA. EM frader@metrohealth.org RI Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Gorodeski, Eiran/0000-0003-3756-8831 FU National Center for Research Resources, National Institutes of Health [RR024990] FX Research support: grant number RR024990 from the National Center for Research Resources, National Institutes of Health. No industry support was received. NR 25 TC 8 Z9 10 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2011 VL 44 IS 6 BP 761 EP 767 DI 10.1016/j.jelectrocard.2010.12.005 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843GO UT WOS:000296660500027 PM 21276589 ER PT J AU Rastinehad, AR Turkbey, B Mani, H Shah, V Bernardo, M Pohida, T Pang, YX Daar, D Benjamin, CJ McKinney, YL Shih, J Merino, MJ Pinto, PA Choyke, PL AF Rastinehad, Ardeshir R. Turkbey, Baris Mani, Haresh Shah, Vijay Bernardo, Marcelino Pohida, Thomas Pang, Yuxi Daar, Dagane Benjamin, Compton J. McKinney, Yolanda L. Shih, Joanna Merino, Maria J. Pinto, Peter A. Choyke, Peter L. TI HISTOPATHOLOGIC CORRELATION USING MRI-BASED SPECIMEN MOLDS TO DETERMINE THE POSITIVE/NEGATIVE PREDICTIVE VALUE OF MULTIPARAMETRIC 3T MRI OF PROSTATE CANCER SO JOURNAL OF ENDOUROLOGY LA English DT Meeting Abstract C1 [Rastinehad, Ardeshir R.; Turkbey, Baris; Mani, Haresh; Shah, Vijay; Bernardo, Marcelino; Pohida, Thomas; Pang, Yuxi; Daar, Dagane; Benjamin, Compton J.; McKinney, Yolanda L.; Shih, Joanna; Merino, Maria J.; Pinto, Peter A.; Choyke, Peter L.] NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD NOV PY 2011 VL 25 SU 1 BP A287 EP A287 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 844ZI UT WOS:000296792201242 ER PT J AU Rastinehad, AR Chokshi, S Benjamin, CJ Turkbey, B Chung, PH Krueker, J Xu, S Locklin, JK Gates, SP Linehan, WM Choyke, PL Wood, BJ Pinto, PA AF Rastinehad, Ardeshir R. Chokshi, Saurin Benjamin, Compton J. Turkbey, Baris Chung, Paul H. Krueker, Jochen Xu, Sheng Locklin, Julia K. Gates, Stacey P. Linehan, W. Marston Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI PROSTATE CANCER DETECTION RATES USING A MR/TRUS FUSION SYSTEM: IN PATIENTS WITH A PREVIOUS NEGATIVE PROSTATE BIOPSY SO JOURNAL OF ENDOUROLOGY LA English DT Meeting Abstract C1 [Rastinehad, Ardeshir R.; Chokshi, Saurin; Benjamin, Compton J.; Turkbey, Baris; Chung, Paul H.; Krueker, Jochen; Xu, Sheng; Locklin, Julia K.; Gates, Stacey P.; Linehan, W. Marston; Choyke, Peter L.; Wood, Bradford J.; Pinto, Peter A.] NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. 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 0892-7790 J9 J ENDOUROL JI J. Endourol. PD NOV PY 2011 VL 25 SU 1 BP A190 EP A190 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 844ZI UT WOS:000296792200581 ER PT J AU Vora, A Williams, H Chinn, D Khadoury, S Kreuker, J Choyke, P Wood, B Bratslavsky, G Turkbey, B Pinto, P AF Vora, Anup Williams, Heinric Chinn, Douglass Khadoury, Sam Kreuker, Jochen Choyke, Peter Wood, Bradford Bratslavsky, Gennady Turkbey, Baris Pinto, Peter TI ROLE OF ENDORECTAL MRI-FUSION PROSTATE BIOPSY IN TREATMENT OF LOCALIZED PROSTATE CANCER BEFORE AND AFTER HIGH-INTENSITY FOCUSED ULTRASOUND (HIFU) THERAPY SO JOURNAL OF ENDOUROLOGY LA English DT Meeting Abstract C1 [Vora, Anup] Georgetown Univ Hosp, Washington, DC USA. [Williams, Heinric; Choyke, Peter; Wood, Bradford; Bratslavsky, Gennady; Turkbey, Baris; Pinto, Peter] NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. [Khadoury, Sam; Kreuker, Jochen] Phillips Engn, Briarcliff Manor, NY USA. [Chinn, Douglass] Chinn & Chinn Associates, Arcadia, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD NOV PY 2011 VL 25 SU 1 BP A268 EP A268 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 844ZI UT WOS:000296792201187 ER PT J AU Vora, A Williams, H Khadoury, S Kreuker, J Buckner, C Turkbey, B Bratslavsky, G Wood, B Choyke, P Pinto, P AF Vora, Anup Williams, Heinric Khadoury, Sam Kreuker, Jochen Buckner, Carey Turkbey, Baris Bratslavsky, Gennady Wood, Bradford Choyke, Peter Pinto, Peter TI APICAL UNDERSAMPLING OF THE PROSTATE ON TWELVE CORE TRANSRECTAL ULTRASOUND (TRUS) BIOPSY DETECTED BY MRI-GUIDED ELECTROMAGNETIC MAPPED FUSION BIOPSY SO JOURNAL OF ENDOUROLOGY LA English DT Meeting Abstract C1 [Vora, Anup] Georgetown Univ Hosp, Dept Urol, Washington, DC 20007 USA. [Williams, Heinric; Buckner, Carey; Turkbey, Baris; Bratslavsky, Gennady; Wood, Bradford; Choyke, Peter; Pinto, Peter] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Khadoury, Sam; Kreuker, Jochen] Phillips Engn, Briarcliff Manor, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD NOV PY 2011 VL 25 SU 1 BP A268 EP A268 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 844ZI UT WOS:000296792201186 ER PT J AU Friedman, KM DeVillier, LE Feldman, SA Rosenberg, SA Dudley, ME AF Friedman, Kevin M. DeVillier, Laura E. Feldman, Steven A. Rosenberg, Steven A. Dudley, Mark E. TI Augmented Lymphocyte Expansion from Solid Tumors With Engineered Cells for Costimulatory Enhancement SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE costimulation; tumor-infiltrating lymphocytes; adoptive immunotherapy ID CD8 T-CELLS; ANTIGEN-PRESENTING CELLS; NATURAL-KILLER-CELLS; EX-VIVO EXPANSION; METASTATIC MELANOMA; INFILTRATING LYMPHOCYTES; ADOPTIVE IMMUNOTHERAPY; MONOCLONAL-ANTIBODIES; IN-VIVO; EFFECTOR FUNCTION AB Treatment of patients with adoptive T-cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single-cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Previous studies have evaluated artificial antigen presenting cells for their antigen-specific and costimulatory properties. We investigated engineered cells for costimulatory enhancement (ECCE) consisting of K562 cells that express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (P = 0.001) from single-cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8(+) CD62L(+) and CD8(+) CD27(+) T cells then comparable interleukin-2-expanded TIL and maintained antitumor reactivity. Moreover, ECCE improved TIL expansion from nonmelanoma-cell suspensions similar to that seen with melanoma tumors. These data demonstrate that the addition of ECCE to TIL production will enable the treatment of patients that are ineligible using current methods. C1 [Friedman, Kevin M.; DeVillier, Laura E.; Feldman, Steven A.; Rosenberg, Steven A.; Dudley, Mark E.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Dudley, ME (reprint author), NCI, Surg Branch, NIH, CRC 3W-5752,10 Ctr Dr, Bethesda, MD 20892 USA. EM Dudleym@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 52 TC 8 Z9 8 U1 0 U2 3 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 NOV-DEC PY 2011 VL 34 IS 9 BP 651 EP 661 DI 10.1097/CJI.0b013e31823284c3 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 837VO UT WOS:000296234800004 PM 21989413 ER PT J AU Ujhazy, P Carbone, D AF Ujhazy, Peter Carbone, David TI Summary of Presentations from the 11th Targeted Therapies for Lung Cancer Meeting Immunotherapy and Vaccines for Treatment of Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article ID PHASE-II; TUMORS C1 [Ujhazy, Peter] NCI, Translat Res Pogram, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Carbone, David] Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN USA. RP Ujhazy, P (reprint author), NCI, Translat Res Pogram, Div Canc Treatment & Diag, 6116 Execut Blvd,Room 7013, Rockville, MD 20852 USA. EM pu5s@nih.gov NR 8 TC 1 Z9 1 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 NOV PY 2011 VL 6 IS 11 SU 4 BP S1815 EP S1817 DI 10.1097/01.JTO.0000407570.29900.a5 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 843WA UT WOS:000296705500015 PM 22005542 ER PT J AU Domino, SE Bodurtha, J Nagel, JD AF Domino, Steven E. Bodurtha, Joann Nagel, Joan D. CA BIRCWH Program Leadership TI Interdisciplinary Research Career Development: Building Interdisciplinary Research Careers in Women's Health Program Best Practices SO JOURNAL OF WOMENS HEALTH LA English DT Article AB Background: The Office of Research on Women's Health (ORWH) and the National Institutes of Health (NIH) Institutes and Centers and the Agency for Health Care Research and Quality (AHRQ) have sponsored an interdisciplinary research career development program in five funding cycles since 2000 through a K12 mechanism titled "Building Interdisciplinary Research Careers in Women's Health (BIRCWH)." As of 2010, 407 scholars have been supported in interdisciplinary women's health research and a total of 63 BIRCWH program awards have been made to 41 institutions across the U. S. Methods: In an effort to share practical approaches to interdisciplinary research training, currently funded BIRCWH sites were invited to submit 300-word bullet-point style summaries describing their best practices in interdisciplinary research training following a common format with an emphasis on practices that are innovative, can be reproduced in other places, and advance women's health research. Results and Conclusions: Twenty-six program narratives provide unique perspectives along with common elements and themes in interdisciplinary research training best practices. C1 [Domino, Steven E.] Univ Michigan, Von Voigtlander Womens Hosp L4100, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Bodurtha, Joann] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA. [Bodurtha, Joann] Virginia Commonwealth Univ, Dept Pediat, Richmond, VA USA. [Bodurtha, Joann] Virginia Commonwealth Univ, Dept Obstet Gynecol, Richmond, VA USA. [Bodurtha, Joann] Virginia Commonwealth Univ, Dept Epidemiol, Richmond, VA USA. [Bodurtha, Joann] Virginia Commonwealth Univ, Dept Community Hlth, Richmond, VA USA. [Nagel, Joan D.] NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Domino, SE (reprint author), Univ Michigan, Von Voigtlander Womens Hosp L4100, Dept Obstet & Gynecol, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM sedomino@med.umich.edu OI Sherman, Bonnie/0000-0002-6322-8366 FU NICHD NIH HHS [K12 HD051953, K12 HD055884, P50 HD044405] NR 7 TC 4 Z9 5 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 NOV PY 2011 VL 20 IS 11 BP 1587 EP 1601 DI 10.1089/jwh.2011.3165 PG 15 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 846SV UT WOS:000296924400002 PM 21923414 ER PT J AU Yamazaki, Y Moore, R Negishi, M AF Yamazaki, Yuichi Moore, Rick Negishi, Masahiko TI Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver SO LABORATORY INVESTIGATION LA English DT Article DE CAR; hepatic progenitor; laser capture microdissection; nuclear receptor; oval cell proliferation ID CONSTITUTIVE ACTIVE/ANDROSTANE RECEPTOR; STEM-CELLS; REGENERATION; GENES; PXR; TRANSLOCATION; METABOLISM; INDUCTION; SUBFAMILY; ROLES AB The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma. Laboratory Investigation (2011) 91, 1624-1633; doi:10.1038/labinvest.2011.115; published online 8 August 2011 C1 [Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU NIH, National Institute of Environmental Health [Z01ES71005-01] FX We extend our sincerest appreciations towards Drs Gordon Flake, Jim Squires and Mark Hoenerhoff at NIEHS for their critical reading of this manuscript and comments. We thank Ms Patricia Stockton for excellent technical assistance of LCM. We also thank DNA sequence and histology cores at NIEHS for their excellent assistances. This study was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health: Z01ES71005-01. NR 23 TC 14 Z9 15 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD NOV PY 2011 VL 91 IS 11 BP 1624 EP 1633 DI 10.1038/labinvest.2011.115 PG 10 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 842MK UT WOS:000296603400008 PM 21826054 ER PT J AU Loi, S Symmans, WF Bartlett, JMS Fumagalli, D Van't Veer, L Forbes, JF Bedard, P Denkert, C Zujewski, J Viale, G Pusztai, L Esserman, LJ Leyland-Jones, BR AF Loi, Sherene Symmans, W. Fraser Bartlett, John M. S. Fumagalli, Debora Van't Veer, Laura Forbes, John F. Bedard, Philippe Denkert, Carsten Zujewski, JoAnne Viale, Giuseppe Pusztai, Lajos Esserman, Laura J. Leyland-Jones, Brian R. TI Proposals for uniform collection of biospecimens from neoadjuvant breast cancer clinical trials: timing and specimen types SO LANCET ONCOLOGY LA English DT Article ID FINE-NEEDLE-ASPIRATION; GENE-EXPRESSION PROFILES; ENDOCRINE THERAPY; PROGNOSTIC VALUE; CHEMOTHERAPY; HETEROGENEITY; PREDICTION; CARCINOMA; APOPTOSIS; MARKERS AB In this Personal View, we outline proposals for uniform collection of biospecimens obtained in neoadjuvant breast cancer trials undertaken by the Breast International Group (BIG) and the National Cancer Institute-sponsored North American Breast Cancer Group (NABCG). These proposals aim to standardise collection of high-quality specimens, with respect to both type and timing, to enhance and allow integration of results obtained from neoadjuvant trials done by several groups. They should be considered in parallel with recommendations for tissue-specimen collection and handling previously developed by BIG and NABCG. We propose that tumour tissue (formalin-fixed, paraffin-embedded and samples dedicated for molecular studies) should be taken at baseline, 1-3 weeks after the start of treatment, and at definitive surgery, with clear prioritisation in the study protocol of number, order, and preservation of samples to be gathered. This step should be accompanied by blood collection (plasma, serum, and whole blood) whenever possible. We advocate strongly a move towards one diagnostic and research biopsy procedure in all women with breast cancers potentially suitable for neoadjuvant treatment. If possible, patients should be referred at the outset to specialised centres to give them the opportunity to participate in neoadjuvant clinical trials, thereby avoiding several biopsy procedures. C1 [Leyland-Jones, Brian R.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Loi, Sherene; Fumagalli, Debora] Inst Jules Bordet, Breast Canc Translat Res Lab, B-1000 Brussels, Belgium. [Loi, Sherene; Fumagalli, Debora] Inst Jules Bordet, Breast Int Grp, B-1000 Brussels, Belgium. [Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Pusztai, Lajos] Univ Texas MD Anderson Canc Ctr, Dept Breast Oncol, Houston, TX 77030 USA. [Bartlett, John M. S.] Univ Edinburgh, Edinburgh Canc Res Ctr, Endocrine Canc Grp, Edinburgh, Midlothian, Scotland. [Van't Veer, Laura] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, Breast Oncol Program, San Francisco, CA 94143 USA. [Esserman, Laura J.] Univ Calif San Francisco, Carol Franc Buck Breast Care Ctr, San Francisco, CA 94143 USA. [Forbes, John F.] Univ Newcastle, Australian & New Zealand Breast Canc Trials Grp, Newcastle, NSW 2300, Australia. [Bedard, Philippe] Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Denkert, Carsten] Charite Hosp, Inst Pathol, Berlin, Germany. [Zujewski, JoAnne] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Viale, Giuseppe] European Inst Oncol, Dept Pathol & Lab Med, Milan, Italy. RP Leyland-Jones, BR (reprint author), Emory Univ, Sch Med, 1365-B Clifton Rd NE,B Bldg,Room B5115, Atlanta, GA 30322 USA. EM leyland@emory.edu RI Loi, Sherene/H-1979-2016; OI Denkert, Carsten/0000-0002-2249-0982; Loi, Sherene/0000-0001-6137-9171 FU Breast Cancer Research Foundation (BCRF) FX The BIG and NABCG collaboration is supported by a Breast Cancer Research Foundation (BCRF) grant. We thank Martine J Piccart, William C Wood, and Larry Norton for their support. BIG-NABCG Neoadjuvant Working Group biosampling subteam members: Sherene Loi, Debora Fumagalli, Jose Baselga, Laura Van't Veer, Carsten Denkert, John F Forbes, Philippe Bedard, Mark Basik, John M S Bartlett, Giuseppe Viale, and Brian R Leyland-Jones (for BIG); JoAnne Zujewski, Laura Esserman, Lajos Pusztai, and W Fraser Symmans (for NABCG); and Phuong Dinh, Amal Arahmani, and Carolyn Straehle (BIG headquarters coordinating office, Brussels, Belgium). NR 24 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2011 VL 12 IS 12 BP 1162 EP 1168 DI 10.1016/S1470-2045(11)70117-6 PG 7 WC Oncology SC Oncology GA 842GC UT WOS:000296581400026 PM 21684810 ER PT J AU de Beer, R van Ormondt, D van der Veen, JW Graveron-Demilly, D AF de Beer, R. van Ormondt, D. van der Veen, J. W. Graveron-Demilly, D. TI Creating the Semipar custom plug-in for the jMRUI platform SO MEASUREMENT SCIENCE AND TECHNOLOGY LA English DT Article DE jMRUI; plug-in; Java core code; Fortran algorithm code; JNI; MRS; quantitation; unknown common lineshape (decay); two-NLLS criterion; QUEST; NMR scope AB This work is related to the FAST jMRUI signal-analysis package. Recently this package has been refactored as a plug-in platform, allowing end-users to add their own features. Here we describe the creation of a jMRUI custom plug-in named Semipar. This plug-in integrates into jMRUI a two-NLLS criterion that we have recently developed for handling the quantitation of in vivo MRS signals with an unknown common lineshape. The Semipar plug-in was tested by applying it to a simulated MRS signal. This signal was generated by using the various methods and tools of the jMRUI platform. It was found that-depending on the SNR of the signal-the Semipar approach can improve the MRS quantitation results. C1 [de Beer, R.; van Ormondt, D.] Delft Univ Technol, Dept Appl Phys, Delft, Netherlands. [van der Veen, J. W.] NIH, MRS Core Facil, Bethesda, MD 20892 USA. [Graveron-Demilly, D.] Univ Lyon 1, CNRS, UMR 5220, INSERM,U630, F-69622 Villeurbanne, France. RP de Beer, R (reprint author), Delft Univ Technol, Dept Appl Phys, Delft, Netherlands. EM r.debeer@tudelft.nl FU Marie-Curie Research Training Network FAST [MRTNCT-2006-035801] FX This work is supported by Marie-Curie Research Training Network FAST (MRTNCT-2006-035801). NR 13 TC 2 Z9 2 U1 0 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-0233 EI 1361-6501 J9 MEAS SCI TECHNOL JI Meas. Sci. Technol. PD NOV PY 2011 VL 22 IS 11 AR 114022 DI 10.1088/0957-0233/22/11/114022 PG 9 WC Engineering, Multidisciplinary; Instruments & Instrumentation SC Engineering; Instruments & Instrumentation GA 842CB UT WOS:000296563500023 ER PT J AU Tranah, GJ Manini, TM Lohman, KK Nalls, MA Kritchevsky, S Newman, AB Harris, TB Miljkovic, I Biffi, A Cummings, SR Liu, YM AF Tranah, Gregory J. Manini, Todd M. Lohman, Kurt K. Nalls, Michael A. Kritchevsky, Stephen Newman, Anne B. Harris, Tamara B. Miljkovic, Iva Biffi, Alessandro Cummings, Steven R. Liu, Yongmei TI Mitochondrial DNA variation in human metabolic rate and energy expenditure SO MITOCHONDRION LA English DT Article DE Metabolic rate; Energetics; Mitochondria; Mitochondrial haplogroups; mtDNA; Oxidative phosphorylation ID DOUBLY-LABELED WATER; CYTOCHROME-C-OXIDASE; PHYSICAL-ACTIVITY; DROSOPHILA-MELANOGASTER; ADAPTIVE SELECTION; HUMAN MTDNA; SPERM MOTILITY; LONGEVITY; EPISTASIS; EVOLUTION AB The role of climate in driving selection of mtDNA as Homo sapiens migrated out of Africa into Eurasia remains controversial. We evaluated the role of mtDNA variation in resting metabolic rate (RMR) and total energy expenditure (TEE) among 294 older, community-dwelling African and European American adults from the Health, Aging and Body Composition Study. Common African haplogroups L0, L2 and L3 had significantly lower RMRs than European haplogroups H, JT and UK with haplogroup L1 RMR being intermediate to these groups. This study links mitochondrial haplogroups with ancestry-associated differences in metabolic rate and energy expenditure. (C) 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 [Tranah, Gregory J.] UCSF, Calif Pacific Med Ctr Res Inst, San Francisco Coordinating Ctr, San Francisco, CA 94107 USA. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL 32601 USA. [Lohman, Kurt K.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Kritchevsky, Stephen; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. [Newman, Anne B.; Miljkovic, Iva] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Biffi, Alessandro] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Biffi, Alessandro] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Biffi, Alessandro] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. RP Tranah, GJ (reprint author), UCSF, Calif Pacific Med Ctr Res Inst, San Francisco Coordinating Ctr, 185 Berry St,Lobby 4,Suite 5700, San Francisco, CA 94107 USA. EM gtranah@sfcc-cpmc.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Miljkovic, Iva/0000-0002-3155-9777; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIH, National Institute on Aging; NIA [N01AG62101, N01AG62103, N01AG62106, 1R03AG032498-01, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C] FX This research is supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, N01AG62106 and NIA grant 1R03AG032498-01. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. NR 66 TC 13 Z9 13 U1 1 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2011 VL 11 IS 6 BP 855 EP 861 DI 10.1016/j.mito.2011.04.005 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 846ZI UT WOS:000296941300003 PM 21586348 ER PT J AU Kasiviswanathan, R Copeland, WC AF Kasiviswanathan, Rajesh Copeland, William C. TI Biochemical analysis of the G517V POLG variant reveals wild-type like activity SO MITOCHONDRION LA English DT Article DE POLG; DNA polymerase; Mitochondrial disease ID DNA-POLYMERASE-GAMMA; PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; ACCESSORY SUBUNIT; DISEASE MUTATIONS; REPLICATION; NEUROPATHY; DEPLETION; DEFECTS AB The c.1550g --> t mutation in the POW gene causing the G517V substitution has been reported by many groups to be associated with a variety of mitochondrial diseases, including autosomal dominant and recessive forms of ataxia neuropathy, myopathy and microcephaly, progressive external ophthalmoplegia, diabetes, strokes, hypotonia, and epilepsy. However, the variable disease presentation and age of onset raises suspicion of its pathogenicity. Because of the varied reported associated symptoms and request from physicians to address the consequence of this mutation, we have carried out the biochemical analysis of the purified recombinant human DNA polymerase gamma protein harboring the G517V substitution. These analyses revealed that the G517V mutant enzyme retained 80-90% of wild-type DNA polymerase activity, in addition to its functional interaction with the p55 accessory subunit. DNA binding by the mutant was also only slightly lower than the wild-type enzyme. Our data suggest that the G517V mutation by itself in pol gamma most likely does not have a role in mitochondrial disorders. (C) 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 [Kasiviswanathan, Rajesh; Copeland, William C.] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov RI Kasiviswanathan, Rajesh/D-2744-2012 FU NIH, National Institute of Environmental Health Sciences [ES 065078, ES 065080] FX We thank Dr. Tammy Collins and Maggie Humble for critically reading this manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES 065078 and ES 065080). NR 29 TC 14 Z9 14 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2011 VL 11 IS 6 BP 929 EP 934 DI 10.1016/j.mito.2011.08.003 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 846ZI UT WOS:000296941300014 PM 21856450 ER PT J AU West, KA Dennis, PA AF West, Kip A. Dennis, Phillip A. TI Starting with the ABCs: Akt in Breast Cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Editorial Material C1 [Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20889 USA. [West, Kip A.] Infin Pharmaceut, Cambridge, MA USA. RP Dennis, PA (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 37 Convent Dr,Rm 1118B, Bethesda, MD 20889 USA. EM pdennis@nih.gov NR 0 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2011 VL 10 IS 11 BP 2031 EP 2031 DI 10.1158/1535-7163.MCT-11-0712 PG 1 WC Oncology SC Oncology GA 844ZA UT WOS:000296791300016 PM 22072813 ER PT J AU Bialkowska, AB Crisp, M Bannister, T He, YJ Chowdhury, S Schurer, S Chase, P Spicer, T Madoux, F Tian, CL Hodder, P Zaharevitz, D Yang, VW AF Bialkowska, Agnieszka B. Crisp, Melissa Bannister, Thomas He, Yuanjun Chowdhury, Sarwat Schuerer, Stephan Chase, Peter Spicer, Timothy Madoux, Franck Tian, Chenlu Hodder, Peter Zaharevitz, Daniel Yang, Vincent W. TI Identification of Small-Molecule Inhibitors of the Colorectal Cancer Oncogene Kruppel-like Factor 5 Expression by Ultrahigh-Throughput Screening SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; TRANSCRIPTION FACTOR KLF5; EMBRYONIC STEM-CELLS; CARDIAC-GLYCOSIDES; CELLULAR PROLIFERATION; SELF-RENEWAL; GENE; P38; KRUPPEL-LIKE-FACTOR-5; TUMORIGENESIS AB The transcription factor Kruppel-like factor 5 (KLF5) is primarily expressed in the proliferative zone of the mammalian intestinal epithelium, where it regulates cell proliferation. Studies showed that inhibition of KLF5 expression reduces proliferation rates in human colorectal cancer cells and intestinal tumor formation in mice. To identify chemical probes that decrease levels of KLF5, we used cell-based ultrahigh-throughput screening (uHTS) to test compounds in the public domain of NIH, the Molecular Libraries Probe Production Centers Network library. The primary screen involved luciferase assays in the DLD-1/pGL4.18hKLF5p cell line, which stably expressed a luciferase reporter driven by the human KLF5 promoter. A cytotoxicity counter-screen was done in the rat intestinal epithelial cell line, IEC-6. We identified 97 KLF5-selective compounds with EC(50) < 10 mu mol/L for KLF5 inhibition and EC(50) > 10 mu mol/L for IEC-6 cytotoxicity. The two most potent compounds, CIDs (PubChem Compound IDs) 439501 and 5951923, were further characterized on the basis of computational, Western blot, and cell viability analyses. Both of these compounds, and two newly synthesized structural analogs of CID 5951923, significantly reduced endogenous KLF5 protein levels and decreased viability of several colorectal cancer cell lines without any apparent impact on IEC-6 cells. Finally, when tested in the NCI-60 panel of human cancer cell lines, compound CID 5951923 was selectively active against colon cancer cells. Our results show the feasibility of uHTS in identifying novel compounds that inhibit colorectal cancer cell proliferation by targeting KLF5. Mol Cancer Ther; 10(11); 2043-51. (C) 2011 AACR. C1 [Bialkowska, Agnieszka B.; Tian, Chenlu; Yang, Vincent W.] Emory Univ, Sch Med, Dept Med, Div Digest Dis, Atlanta, GA USA. [Yang, Vincent W.] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Div Digest Dis, Atlanta, GA USA. [Crisp, Melissa; Bannister, Thomas; He, Yuanjun; Chowdhury, Sarwat; Chase, Peter; Spicer, Timothy; Madoux, Franck; Hodder, Peter] Scripps Res Inst, Mol Screening Ctr, Jupiter, FL USA. [Schuerer, Stephan] Univ Miami, Dept Pharmacol, Miami, FL USA. [Schuerer, Stephan] Univ Miami, Ctr Computat Sci, Miami, FL USA. [Zaharevitz, Daniel] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Bialkowska, AB (reprint author), SUNY Stony Brook, Dept Med, Sch Med, HSC T-16, Stony Brook, NY 11794 USA. EM oberzyna@gmail.com; vincent.yang@stonybrook.edu FU NIH Molecular Library Screening Center Network (MLPCN) [MH084512]; NIH [DA26215, DK052230, DK64399, CA084179] FX The NIH Molecular Library Screening Center Network (MLPCN, Grant# MH084512) supported the research efforts of T. Bannister, P. Chase, S. Chowdhury, M. Crisp, Y. He, P. Hodder, F. Madoux, S. Schurer, and T. Spicer. The work was supported by NIH DA26215, DK052230, DK64399, and CA084179. NR 41 TC 18 Z9 18 U1 0 U2 9 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 NOV PY 2011 VL 10 IS 11 BP 2043 EP 2051 DI 10.1158/1535-7163.MCT-11-0550 PG 9 WC Oncology SC Oncology GA 844ZA UT WOS:000296791300019 PM 21885866 ER PT J AU Sengupta, P Jovanovic-Talisman, T Skoko, D Renz, M Veatch, SL Lippincott-Schwartz, J AF Sengupta, Prabuddha Jovanovic-Talisman, Tijana Skoko, Dunja Renz, Malte Veatch, Sarah L. Lippincott-Schwartz, Jennifer TI Probing protein heterogeneity in the plasma membrane using PALM and pair correlation analysis SO NATURE METHODS LA English DT Article ID GPI-ANCHORED PROTEINS; CELL-SURFACE; LOCALIZATION MICROSCOPY; RAFTS; SUPERRESOLUTION; NANOCLUSTERS; MICRODOMAINS; CYTOSKELETON; ACTIVATION; MOLECULES AB Photoactivated localization microscopy (PALM) is a powerful approach for investigating protein organization, yet tools for quantitative, spatial analysis of PALM datasets are largely missing. Combining pair-correlation analysis with PALM (PC-PALM), we provide a method to analyze complex patterns of protein organization across the plasma membrane without determination of absolute protein numbers. The approach uses an algorithm to distinguish a single protein with multiple appearances from clusters of proteins. This enables quantification of different parameters of spatial organization, including the presence of protein clusters, their size, density and abundance in I:he plasma membrane. Using this method, we demonstrate distinct nanoscale organization of plasma-membrane proteins with different membrane anchoring and Lipid partitioning characteristics in COS-7 cells, and show dramatic changes in glycosylphosphatidylinositol (GPI)-anchored protein arrangement under varying perturbations. PC-PALM is thus an effective tool with broad applicability for analysis of protein heterogeneity and function, adaptable to other single-molecule strategies. C1 [Sengupta, Prabuddha; Jovanovic-Talisman, Tijana; Skoko, Dunja; Renz, Malte; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriyer Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20817 USA. [Veatch, Sarah L.] Univ Michigan, Dept Biophys, Ann Arbor, MI 48109 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriyer Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20817 USA. EM jlippin@helix.nih.gov RI Veatch, Sarah/G-9512-2016; OI Veatch, Sarah/0000-0002-9317-2308; Sengupta, Prabuddha/0000-0001-7094-6967; Jovanovic-Talisman, Tijana/0000-0003-1928-4763 FU US National Institutes of Health [R00GM87810] FX We thank G. Patterson (US National Institute of Biomedical Imaging and Bioengineering) for providing plasmid constructs; E. Ambroggio (US National Institute of Child Health and Development) for providing purified PAGFP protein; H. Hess and G. Stengel for providing the Peak Selector software and valuable discussion; S. Manley for help in setting up the PALM microscope; B. Baird and D. Holowka for valuable discussions. S.L.V. was supported by US National Institutes of Health grant R00GM87810. NR 30 TC 195 Z9 196 U1 8 U2 62 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 NOV PY 2011 VL 8 IS 11 BP 969 EP 975 DI 10.1038/NMETH.1704 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 846IY UT WOS:000296891800022 PM 21926998 ER PT J AU Hastings, C AF Hastings, Clare TI Reader Poses Questions Regarding Article's Methodology Authors' Response SO ONCOLOGY NURSING FORUM LA English DT Letter C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Hastings, C (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2011 VL 38 IS 6 BP 617 EP 617 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 846WE UT WOS:000296933100003 ER PT J AU Williams, KJ Boshoff, HI Krishnan, N Gonzales, J Schnappinger, D Robertson, BD AF Williams, Kerstin J. Boshoff, Helena I. Krishnan, Nitya Gonzales, Jacqueline Schnappinger, Dirk Robertson, Brian D. TI The Mycobacterium tuberculosis beta-oxidation genes echA5 and fadB3 are dispensable for growth in vitro and in vivo SO TUBERCULOSIS LA English DT Article DE Mycobacterium tuberculosis; beta-Oxidation; Essential; Fatty acids; echA5; fadB3 ID EXPRESSION; PERSISTENCE; INFECTION; MICE; CHOLESTEROL; MACROPHAGES; MUTAGENESIS; SURVIVAL; INSIGHTS; REQUIRES AB There are several lines of evidence pointing towards the importance of beta-oxidation in host survival of Mycobacterium tuberculosis including enormous gene redundancy for this process; approximately 100 genes are annotated as beta-oxidation genes for the five biochemical reactions that break down fatty acids into acetyl-CoA. Although most of these genes are predicted to be non-essential, two of the genes (echA5 and fadB3) are annotated as essential for growth in vitro, and therefore could be considered as putative drug targets. However, here we report the construction of echA5 and fadB3 null mutants confirming they are non-essential. No significant difference in growth between the mutant and parent strains was observed in either standard Middlebrook medium or in minimal medium supplemented with various carbon sources. Macrophage survival and mouse infection studies also showed no significant difference between the mutant and parent strains. Therefore, we conclude that these genes are dispensable for growth in vitro and in vivo. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Williams, Kerstin J.; Krishnan, Nitya; Robertson, Brian D.] Univ London Imperial Coll Sci Technol & Med, Ctr Mol Med & Infect, Dept Med, London SW7 2AZ, England. [Boshoff, Helena I.; Gonzales, Jacqueline] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Schnappinger, Dirk] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY USA. RP Robertson, BD (reprint author), Univ London Imperial Coll Sci Technol & Med, Ctr Mol Med & Infect, Dept Med, Flowers Bldg, London SW7 2AZ, England. EM b.robertson@imperial.ac.uk OI Robertson, Brian D./0000-0001-5785-5307 FU Bill & Melinda Gates Foundation; Wellcome Trust through the Grand Challenges in Global Health Initiative [077381]; US National Institutes of Health, the US National Institute of Allergy and Infectious Disease FX KW, HB, DS and BR are funded by the Bill & Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative (Grant 077381). This study was also supported (in part) by the Intramural Research Program of the US National Institutes of Health, the US National Institute of Allergy and Infectious Disease. NR 25 TC 11 Z9 11 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 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD NOV PY 2011 VL 91 IS 6 BP 549 EP 555 DI 10.1016/j.tube.2011.06.006 PG 7 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 844MN UT WOS:000296751400006 PM 21764638 ER PT J AU Cook, MB AF Cook, Michael Blaise TI Non-Acid Reflux: The Missing Link Between Gastric Atrophy and Esophageal Squamous Cell Carcinoma? SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Editorial Material ID INCREASED RISK-FACTOR; GASTROESOPHAGEAL-REFLUX; HELICOBACTER-PYLORI; SERUM PEPSINOGENS; ALKALINE REFLUX; CANCER; ACID; CARCINOGENESIS; ADENOCARCINOMA; ASSOCIATION AB Esophageal cancer is the eighth most common incident cancer in the world and, due to the poor survival rate it confers, ranks sixth among all cancers in mortality. In developed countries of the western world, the incidence of esophageal squamous cell carcinoma (ESCC) has undergone a decline and adenocarcinoma now constitutes approximately half of all esophageal cancers. In these relatively low-risk areas, tobacco smoking and alcohol consumption account for similar to 90% of ESCC cases. Eastern countries have much higher incidences of ESCC and epidemiologic evidence would suggest that there are additional unknown causal mechanisms. Gastric atrophy has consistently been associated with ESCC, but its causal relevance has been questioned. In this issue of the American Journal of Gastroenterology, Uno et al. offer evidence that a causal link between these two entities is non-acid reflux. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS Suite 550,Room 5014, Rockville, MD 20852 USA. EM michael.cook@nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX This study was supported by Intramural Program of the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. NR 38 TC 8 Z9 8 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD NOV PY 2011 VL 106 IS 11 BP 1930 EP 1932 DI 10.1038/ajg.2011.288 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 844ZD UT WOS:000296791700006 PM 22056574 ER PT J AU Brubaker, L Norton, PA Albo, ME Chai, TC Dandreo, KJ Lloyd, KL Lowder, JL Sirls, LT Lemack, GE Arisco, AM Xu, Y Kusek, JW AF Brubaker, Linda Norton, Peggy A. Albo, Michael E. Chai, Toby C. Dandreo, Kimberly J. Lloyd, Keith L. Lowder, Jerry L. Sirls, Larry T. Lemack, Gary E. Arisco, Amy M. Xu, Yan Kusek, John W. CA Urinary Incontinence Treatment TI Adverse events over two years after retropubic or transobturator midurethral sling surgery: findings from the Trial of Midurethral Slings (TOMUS) study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 37th Annual Scientific Meeting of the Society-of-Gynecologic-Surgeons CY APR 11-13, 2011 CL San Antonio, TX SP Soc Gynecol Surg DE adverse events; midurethral slings; surgical complications ID STRESS URINARY-INCONTINENCE; FREE VAGINAL TAPE; COMPLICATIONS; METAANALYSIS AB OBJECTIVE: To describe surgical complications in 597 women over a 24-month period after randomization to retropubic or transobturator midurethral slings. STUDY DESIGN: During the Trial of Midurethral Slings study, the Data Safety Monitoring Board regularly reviewed summary reports of all adverse events using the Dindo Surgical Complication Scale. Logistic regression models were created to explore associations between clinicodemographic factors and surgical complications. RESULTS: A total of 383 adverse events were observed among 253 of the 597 women (42%). Seventy-five adverse events (20%) were classified as serious (serious adverse events); occurring in 70 women. Intraoperative bladder perforation (15 events) occurred exclusively in the retropubic group. Neurologic adverse events were more common in the transobturator group than in retropubic (32 events vs 20 events, respectively). Twenty-three (4%) women experienced mesh complications, including delayed presentations, in both groups. CONCLUSION: Adverse events vary by procedure, but are common after midurethral sling. Most events resolve without significant sequelae. C1 [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60626 USA. [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Dept Urol, Chicago, IL USA. [Norton, Peggy A.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Albo, Michael E.] Univ Calif San Diego, Sch Med, Dept Surg, Div Urol, San Diego, CA 92103 USA. [Chai, Toby C.] Univ Maryland, Sch Med, Dept Urol, Baltimore, MD 21201 USA. [Dandreo, Kimberly J.; Xu, Yan] New England Res Inst, Watertown, MA 02172 USA. [Lloyd, Keith L.] Univ Alabama, Med Sch Birmingham, Dept Urol, Birmingham, AL USA. [Lowder, Jerry L.] Univ Pittsburgh, Sch Med, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Sirls, Larry T.] William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. [Lemack, Gary E.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Arisco, Amy M.] Univ Texas San Antonio, Dept Urol, San Antonio, TX USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD USA. RP Brubaker, L (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60626 USA. FU NIDDK NIH HHS [U01 DK060380, U01 DK058231, U01 DK060379, U01 DK058234, U01 DK058225, U01 DK060379-08, U01 DK058229, U01 DK060397, U01 DK060393, U01 DK060395] NR 10 TC 22 Z9 22 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2011 VL 205 IS 5 AR 498.e1 DI 10.1016/j.ajog.2011.07.011 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 842EB UT WOS:000296572300042 PM 21925636 ER PT J AU Greer, LG Casey, BM Halvorson, LM Spong, CY McIntire, DD Cunningham, FG AF Greer, Laura G. Casey, Brian M. Halvorson, Lisa M. Spong, Catherine Y. McIntire, Donald D. Cunningham, F. Gary TI Antithyroid antibodies and parity: further evidence for microchimerism in autoimmune thyroid disease SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE autoimmune thyroid disease; microchimerism; thyroid peroxidase antibody ID HASHIMOTOS-THYROIDITIS; PEROXIDASE AUTOANTIBODIES; FETAL MICROCHIMERISM; PREGNANCY OUTCOMES; HUMAN HEALTH; POPULATION; WOMEN; LONG; ASSOCIATION; PREVALENCE AB OBJECTIVE: Fetal microchimerism may have a role in development of autoimmune thyroid disorders. Using parity as a surrogate for increasing fetal cell exposure, we analyzed its association with thyroid peroxidase antibody levels. STUDY DESIGN: Secondary analysis of serum thyroid analytes determined in 17,298 women from a population-based prospective study between 2001 and 2003. Sera were assayed for thyrotropin, free thyroxine, and antithyroid peroxidase antibodies. We analyzed the relationship between thyroid peroxidase antibodies and increasing parity. RESULTS: The incidence of abnormally elevated thyroid peroxidase antibody levels (>50 IU/mL) increased with advancing parity, but was not significant after adjustment for maternal characteristics. However, at higher thyroid peroxidase antibody levels (>500 IU/mL), a significant relationship with advancing parity persisted after adjustments (P = .002). CONCLUSION: Advancing parity is associated with an increased risk for high serum concentrations of antithyroid peroxidase antibodies. This suggests fetal microchimerism may play a role in development of autoimmune thyroid disorders. C1 [Greer, Laura G.; Casey, Brian M.; Halvorson, Lisa M.; McIntire, Donald D.; Cunningham, F. Gary] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Greer, LG (reprint author), Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. FU National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network [HD-04-023] FX Supported by a grant from the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network (HD-04-023). NR 29 TC 4 Z9 4 U1 1 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2011 VL 205 IS 5 AR 471.e1 DI 10.1016/j.ajog.2011.06.060 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 842EB UT WOS:000296572300027 PM 21944225 ER PT J AU Blair, KS Geraci, M Korelitz, K Otero, M Towbin, K Ernst, M Leibenluft, E Blair, RJR Pine, DS AF Blair, Karina S. Geraci, Marilla Korelitz, Katherine Otero, Marcela Towbin, Ken Ernst, Monique Leibenluft, Ellen Blair, R. J. R. Pine, Daniel S. TI The Pathology of Social Phobia Is Independent of Developmental Changes in Face Processing SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID GENERALIZED ANXIETY DISORDER; PREFRONTAL CORTEX ACTIVATION; AMYGDALA ACTIVATION; FACIAL EXPRESSIONS; CHILDHOOD ANXIETY; FUNCTIONAL MRI; ANGRY FACES; ADOLESCENTS; CHILDREN; MODULATION AB Objective: While social phobia in adolescence predicts the illness in adulthood, no study has directly compared the neural responses in social phobia in adults and adolescents. The authors examined neural responses to facial expressions in adults and adolescents with social phobia to determine whether the neural correlates of adult social phobia during face processing also manifest in adolescent social phobia. Method: Blood-oxygen-level-dependent (BOLD) responses were compared in 39 medication-free participants with social phobia (25 adults and 14 adolescents) and 39 healthy comparison subjects (23 adults and 16 adolescents) matched on age, IQ, and gender. During fMRI scans, participants saw angry, fearful, and neutral expression stimuli while making a gender judgment. Results: Significant diagnosis-by-emotion interactions were observed within the amygdala and the rostral anterior cingulate cortex, as has previously been hypothesized. In these regions, both the adolescent and adult social phobia patients showed significantly increased BOLD responses relative to their respective age-matched comparison subjects, and there was no evidence of age-related modulation of between-group differences. These enhanced responses occurred specifically when viewing angry (rostral anterior cingulate cortex) and fearful (amygdala and rostral anterior cingulate cortex) expressions but not when viewing neutral expressions. In addition, the severity of social phobia was significantly correlated with the enhanced rostral anterior cingulate cortex response in the adults. Conclusions: The neural correlates of adult social phobia during face processing also manifest in adolescents. Neural correlates that are observed in adult social phobia may represent the persistence of profiles established earlier in life rather than adaptive responses to such earlier perturbations or maturational changes. These cross-sectional observations might encourage longitudinal fMRI studies of adolescent social phobia. C1 [Blair, Karina S.; Geraci, Marilla; Korelitz, Katherine; Otero, Marcela; Towbin, Ken; Ernst, Monique; Leibenluft, Ellen; Blair, R. J. R.; Pine, Daniel S.] NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. RP Blair, KS (reprint author), NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. EM peschark@mail.nih.gov FU NIMH FX Supported by the NIMH Intramural Research Program. NR 40 TC 24 Z9 24 U1 14 U2 21 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2011 VL 168 IS 11 BP 1202 EP 1209 DI 10.1176/appi.ajp.2011.10121740 PG 8 WC Psychiatry SC Psychiatry GA 843FS UT WOS:000296658300015 PM 21632650 ER PT J AU Sohani, AR Jaffe, ES Harris, NL Ferry, JA Pittaluga, S Hasserjian, RP AF Sohani, Aliyah R. Jaffe, Elaine S. Harris, Nancy Lee Ferry, Judith A. Pittaluga, Stefania Hasserjian, Robert P. TI Nodular Lymphocyte-Predominant Hodgkin Lymphoma With Atypical T Cells: A Morphologic Variant Mimicking Peripheral T-Cell Lymphoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE nodular lymphocyte-predominant Hodgkin lymphoma; LP cells; atypical T cells; peripheral T-cell lymphoma; IgD ID LARGE B-CELLS; DIFFERENTIAL-DIAGNOSIS; H-CELLS; DISEASE; EXPRESSION; IMMUNOGLOBULIN; CLASSIFICATION; TRANSFORMATION; PROLIFERATION; TRANSCRIPTION AB Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct Hodgkin lymphoma subtype composed of few neoplastic lymphocyte-predominant (LP) cells in a background of reactive small B and T cells. We have seen occasional NLPHL cases that contain background T cells with prominent cytologic atypia, raising the differential diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) or a composite lymphoma. We sought to characterize the clinicopathologic features of such cases. Eleven NLPHL cases with atypical T cells diagnosed from 1977 to 2010 were identified at 2 institutions and compared with 24 control NLPHL cases lacking atypical T cells. All 9 male patients and 2 female patients presented with localized peripheral lymphadenopathy. In comparison with control patients, they were younger (median age, 13.8 vs. 36.1 y; P = 0.015), with more frequent cervical lymph node involvement (54.5% vs. 8.3%, P = 0.015). In all 11 cases, areas of NLPHL with typical B-cell-rich nodules containing LP cells were present. Nine cases contained sheets of atypical T cells surrounding primary and secondary follicles in a pattern mimicking the T-zone pattern of PTCL-NOS; the remaining 2 cases contained atypical T cells presented as large clusters at the periphery of B-cell-rich nodules. In all cases, the atypical T-cell-rich areas contained rare scattered LP cells, which were IgD(+) in 5 of 7 cases (71.4%). The atypical T cells showed no pan-T-cell antigen loss or aberrant T-cell antigen expression in any case, and polymerase chain reaction or Southern blot analysis showed no evidence of T-cell clonality in 6 cases tested. The atypical T cells exhibited a variable immunophenotype with respect to germinal center, follicular T-helper, T-regulatory, and cytotoxic T-cell markers. Among 8 patients with clinical follow-up (median follow-up: 6.4 y), 5 patients had recurrent NLPHL at 6 months to 12 years after diagnosis and 6 patients are alive without disease at 9 months to 18 years after diagnosis. In comparison with control patients, NLPHL patients with atypical T cells were more likely to develop recurrent NLPHL (71.4% vs. 13.6%, P = 0.008) and to have a shorter time to relapse (P = 0.04). Our findings suggest that some cases of NLPHL, occurring predominantly in younger patients, contain prominent populations of morphologically atypical T cells that may raise the possibility of concurrent nodal involvement by PTCL-NOS, a rare diagnosis in children. The clinical behavior of these cases appears similar to that of NLPHL with T-cell-rich diffuse areas, with a higher risk of disease recurrence and no difference in overall survival; however, this finding warrants confirmation in studies of larger numbers of patients. C1 [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Sohani, Aliyah R.; Harris, Nancy Lee; Ferry, Judith A.; Hasserjian, Robert P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Jaffe, Elaine S.; Pittaluga, Stefania] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Sohani, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St,WRN 219, Boston, MA 02114 USA. EM arsohani@partners.org OI Jaffe, Elaine/0000-0003-4632-0301 NR 48 TC 17 Z9 19 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2011 VL 35 IS 11 BP 1666 EP 1678 DI 10.1097/PAS.0b013e31822832de PG 13 WC Pathology; Surgery SC Pathology; Surgery GA 842DJ UT WOS:000296569500007 PM 21997687 ER PT J AU Miettinen, M Wang, ZF Sarlomo-Rikala, M Osuch, C Rutkowski, P Lasota, J AF Miettinen, Markku Wang, Zeng-Feng Sarlomo-Rikala, Maarit Osuch, Czeslaw Rutkowski, Piotr Lasota, Jerzy TI Succinate Dehydrogenase-Deficient GISTs: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 66 Gastric GISTs With Predilection to Young Age SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE succinate dehydrogenase subunit B; SDHB; succinate dehydrogenase; gastrointestinal stromal tumor; prognosis ID GASTROINTESTINAL STROMAL TUMORS; CARNEY-STRATAKIS-SYNDROME; OF-THE-LITERATURE; TERM-FOLLOW-UP; GERMLINE MUTATIONS; PDGFRA MUTATIONS; SDH MUTATIONS; C-KIT; PARAGANGLIOMA; TRIAD AB Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients < 20 years, and a substantial percentage of those in patients < 40 years, but only rare GISTs in older adults were SDH deficient. There was a female predominance of over 2:1. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT-positive and DOG1/Ano 1-positive and almost always smooth muscle actin negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients, and peritoneal and liver metastases occurred in 8 and 10 patients, respectively. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in > 50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up. C1 [Miettinen, Markku; Wang, Zeng-Feng; Lasota, Jerzy] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Miettinen, Markku] Joint Pathol Ctr, Silver Spring, MD USA. [Sarlomo-Rikala, Maarit] Helsinki Univ Hosp, Dept Pathol, Haartman Inst, Helsinki, Finland. [Sarlomo-Rikala, Maarit] Helsinki Univ Hosp, HusLab, Helsinki, Finland. [Osuch, Czeslaw] Jagellonian Univ, Dept Gen & Gastrointestinal Surg, Krakow, Poland. [Rutkowski, Piotr] M Sklodowska Curie Mem Canc Ctr, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland. [Rutkowski, Piotr] Inst Oncol, Warsaw, Poland. RP Miettinen, M (reprint author), NCI, Lab Surg Pathol, 9000 Rockville Pike,Bldg 10,Rm 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov OI Rutkowski, Piotr/0000-0002-8920-5429 FU NIH/NCI; Ministry of Science and Higher Education, Republic of Poland [NN402 2092 35] FX Supported by the NIH/NCI intramural research program and in part by grant NN402 2092 35 from the Ministry of Science and Higher Education, Republic of Poland. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 38 TC 114 Z9 124 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2011 VL 35 IS 11 BP 1712 EP 1721 DI 10.1097/PAS.0b013e3182260752 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 842DJ UT WOS:000296569500013 PM 21997692 ER PT J AU Stewart, CA Fisher, SJ Wang, Y Stewart, MD Hewitt, SC Rodriguez, KF Korach, KS Behringer, RR AF Stewart, C. Allison Fisher, Sara J. Wang, Ying Stewart, M. David Hewitt, Sylvia C. Rodriguez, Karina F. Korach, Kenneth S. Behringer, Richard R. TI Uterine Gland Formation in Mice Is a Continuous Process, Requiring the Ovary after Puberty, But Not after Parturition SO BIOLOGY OF REPRODUCTION LA English DT Article DE endometrium; female reproductive tract; uterine gland; uterus ID FEMALE REPRODUCTIVE-TRACT; DEOXYRIBONUCLEIC-ACID SYNTHESIS; BETA-CATENIN; ESTROGEN-RECEPTOR; GENE-EXPRESSION; NEONATAL MOUSE; ENDOMETRIAL DEVELOPMENT; PROGESTERONE-RECEPTORS; RAT UTERUS; MORPHOGENESIS AB Uterine gland formation occurs postnatally in an ovary- and steroid-independent manner in many species, including humans. Uterine glands secrete substances that are essential for embryo survival. Disruption of gland development during the postnatal period prevents gland formation, resulting in infertility. Interestingly, stabilization of beta-catenin (CTNNB1) in the uterine stroma causes a delay in gland formation rather than a complete absence of uterine glands. Thus, to determine if a critical postnatal window for gland development exists in mice, we tested the effects of extending the endocrine environment of pregnancy on uterine gland formation by treating neonatal mice with estradiol, progesterone, or oil for 5 days. One uterine horn was removed before puberty, and the other was collected at maturity. Some mice were also ovariectomized before puberty. The hormone-treated mice exhibited a delay in uterine gland formation. Hormone-treatment increased the abundance of uterine CTNNB1 and estrogen receptor alpha (ESR1) before puberty, indicating possible mechanisms for delayed gland formation. Despite having fewer glands, progesterone-treated mice were fertile, suggesting that a threshold number of glands is required for pregnancy. Mice that were ovariectomized before puberty did not undergo further uterine growth or gland development. Finally, to establish the role of the ovary in postpartum uterine gland regeneration, mice were either ovariectomized or given a sham surgery after parturition, and uteri were evaluated 1 wk later. We found that the ovary is not required for uterine growth or gland development following parturition. Thus, uterine gland development occurs continuously in mice and requires the ovary after puberty, but not after parturition. C1 [Stewart, C. Allison; Fisher, Sara J.; Wang, Ying; Stewart, M. David; Behringer, Richard R.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Stewart, M. David] Univ Houston, Dept Biol & Biochem, Houston, TX USA. [Hewitt, Sylvia C.; Rodriguez, Karina F.; Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC USA. RP Behringer, RR (reprint author), 1515 Holcombe Blvd,Unit 1010, Houston, TX 77030 USA. EM rrb@mdanderson.org OI Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health (NIH) [HD30284]; Ben F. Love endowment; NIH Cancer Center [CA16672]; National Institute of Environmental Health Sciences/NIH Division of Intramural Research [Z01ES70065] FX Research supported by National Institutes of Health (NIH) grant HD30284 and the Ben F. Love endowment to R. R. B. Veterinary resources supported by NIH Cancer Center Support grant CA16672 and National Institute of Environmental Health Sciences/NIH Division of Intramural Research grant Z01ES70065 to K.S.K. NR 62 TC 19 Z9 19 U1 0 U2 5 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD NOV PY 2011 VL 85 IS 5 BP 954 EP 964 DI 10.1095/biolreprod.111.091470 PG 11 WC Reproductive Biology SC Reproductive Biology GA 842FU UT WOS:000296580000009 PM 21734259 ER PT J AU Gamaleddin, I Guranda, M Goldberg, SR Le Foll, B AF Gamaleddin, Islam Guranda, Mihail Goldberg, Steven R. Le Foll, Bernard TI The selective anandamide transport inhibitor VDM11 attenuates reinstatement of nicotine seeking behaviour, but does not affect nicotine intake SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE nicotine; anandamide; cannabinoid; self-administration; VDM11 ID CANNABINOID-RECEPTOR LIGANDS; CB1 RECEPTOR; ENDOCANNABINOID SYSTEM; ESTER URB597; IN-VIVO; ANTAGONIST; HYDROLYSIS; BRAIN; AM404; DRUG AB BACKGROUND AND PURPOSE The endocannabinoid system appears to play a pivotal role in mediating the rewarding and reinforcing effects of nicotine. Recent studies have shown that the inhibition of fatty acid amide hydrolase (FAAH) attenuates reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues. FAAH hydrolyses the endogenous endocannabinoid anandamide, as well as other non-cannabinoid ligands such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). As OEA and PEA can attenuate both nicotine-taking and nicotine-seeking behaviour, the specific role of anandamide remains unclear. In this study, we have tested the selective anadamide uptake inhibitor, VDM11, which elevates anandamide levels without affecting levels of OEA/PEA, on nicotine-taking and nicotine-seeking behaviour. EXPERIMENTAL APPROACH We used a nicotine intravenous self-administration model in rats to assess the effect of VDM11, given i.p., on nicotine taking using fixed and progressive ratio schedules of reinforcement as well as on reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues. KEY RESULTS VDM11 did not affect levels of responding for nicotine under fixed-ratio and progressive-ratio schedules of reinforcement. In contrast, VDM11 dose-dependently attenuated reinstatement of nicotine-seeking behaviour induced by nicotine-associated cues and nicotine priming. CONCLUSIONS AND IMPLICATIONS These results indicate that ligands elevating anandamide levels could have therapeutic value for preventing relapse into nicotine-seeking behaviour and should be tested in humans trying to quit smoking. C1 [Gamaleddin, Islam; Guranda, Mihail; Le Foll, Bernard] Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. [Le Foll, Bernard] Univ Toronto, Dept Family & Community Med, Dept Psychiat, Dept Pharmacol & Toxicol,Inst Med Sci, Toronto, ON M5S 2S1, Canada. [Gamaleddin, Islam; Le Foll, Bernard] Ctr Addict & Mental Hlth, Addict Program, Toronto, ON, Canada. [Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD USA. RP Le Foll, B (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM bernard_lefoll@camh.net RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Heart & Stroke Foundation [NA 6901]; Egyptian Ministry of Higher Education - Ain Shams University; National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA FX This research was supported by a grant from the Heart & Stroke Foundation, grant # NA 6901 and Egyptian Ministry of Higher Education - Ain Shams University and by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA. NR 50 TC 25 Z9 26 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD NOV PY 2011 VL 164 IS 6 BP 1652 EP 1660 DI 10.1111/j.1476-5381.2011.01440.x PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 846MR UT WOS:000296908300009 PM 21501143 ER PT J AU Hsiao, CP Moore, IM Insel, KC Merkle, CJ AF Hsiao, Chao-Pin Moore, Ida M. Insel, Kathleen C. Merkle, Carrie J. TI High Perceived Stress Is Linked to Afternoon Cortisol Levels and Greater Symptom Distress in Patients With Localized Prostate Cancer SO CANCER NURSING LA English DT Article DE Perceived stress; Prostate cancer; Radiation therapy; Radical prostatectomy; Salivary cortisol; Stress; Symptoms; Symptom distress ID QUALITY-OF-LIFE; UNDER-THE-CURVE; SALIVARY CORTISOL; INDIVIDUAL-DIFFERENCES; PSYCHOSOCIAL FACTORS; PATIENTS PERCEPTIONS; BREAST-CANCER; DIURNAL CYCLE; THERAPY; OUTCOMES AB Background: Patients treated with radical prostatectomy (RP) or radiation therapy (RT) for prostate cancer can experience stress and symptoms that impact quality of life. Objective: The objectives of this study were to describe cortisol levels, perceived stress, symptoms, and symptom distress; compare differences in variables measured between RP and RT; and identify associations among cortisol levels, perceived stress, symptoms, and symptom distress in patients treated for localized prostate cancer. Methods: A descriptive, cross-sectional study was conducted with 53 patients (RP n = 24, RT n = 29). Data from saliva, questionnaires, and interviews were collected within 3 months of treatment. Saliva samples were collected at 4 times over 2 consecutive days. Data were analyzed using descriptive statistics, correlations, and regressions. Results: A robust diurnal rhythm of cortisol secretion with heightened levels in the early morning and lowered levels late in the day was found. On average, the entire sample had moderate symptoms and symptom distress for urinary, bowel, and sexual dysfunction. The RP group reported significantly more urinary and sexual dysfunction symptoms and fewer bowel symptoms than did the RT group. Perceived stress was positively correlated with higher afternoon cortisol levels and greater symptom distress. Conclusion: Moderate symptoms and symptom distress found in our sample indicate the need for interventions to address these outcomes in men treated for prostate cancer. Self-reported perceived stress can be used to assess the stress level and symptom distress in clinic setting. Implications for Practice: Patients treated for prostate cancer with RP or RT should be assessed for symptoms and symptom distress and targeted for early symptom management interventions. C1 [Hsiao, Chao-Pin] NINR, NIH, Bethesda, MD 20892 USA. [Moore, Ida M.; Insel, Kathleen C.; Merkle, Carrie J.] Univ Arizona, Coll Nursing, Tucson, AZ 85721 USA. RP Hsiao, CP (reprint author), NINR, NIH, 10 Ctr Dr,CRC-2-1339, Bethesda, MD 20892 USA. EM hsiaoc@mail.nih.gov FU Beta Mu Chapter of Sigma Theta Tau International Honor Society of Nursing; Yuma Friends of Arizona Health Sciences Center FX This study was supported by the Beta Mu Chapter of Sigma Theta Tau International Honor Society of Nursing and the Young Investigator Award funds from Yuma Friends of Arizona Health Sciences Center. NR 48 TC 6 Z9 6 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD NOV-DEC PY 2011 VL 34 IS 6 BP 470 EP 478 DI 10.1097/NCC.0b013e31820a5943 PG 9 WC Oncology; Nursing SC Oncology; Nursing GA 842RA UT WOS:000296615800010 PM 21372704 ER PT J AU Patterson, AD Maurhofer, O Beyoglu, D Lanz, C Krausz, KW Pabst, T Gonzalez, FJ Dufour, JF Idle, JR AF Patterson, Andrew D. Maurhofer, Olivier Beyoglu, Diren Lanz, Christian Krausz, Kristopher W. Pabst, Thomas Gonzalez, Frank J. Dufour, Jean-Francois Idle, Jeffrey R. TI Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Plasma Metabolomics and Lipid Profiling SO CANCER RESEARCH LA English DT Article ID ACID BETA-OXIDATION; SPECTROMETRY-BASED METABOLOMICS; GENE-EXPRESSION PROFILES; ACTIVATED-RECEPTOR-ALPHA; GAMMA-IRRADIATED RATS; MASS-SPECTROMETRY; PEROXISOME-PROLIFERATOR; BIOMARKER DISCOVERY; LIVER-CIRRHOSIS; HEPATITIS AB There has been limited analysis of the effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating endogenous metabolites. Here, we report the findings of a plasma metabolomic investigation of HCC patients by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), random forests machine learning algorithm, and multivariate data analysis. Control subjects included healthy individuals as well as patients with liver cirrhosis or acute myeloid leukemia. We found that HCC was associated with increased plasma levels of glycodeoxycholate, deoxycholate 3-sulfate, and bilirubin. Accurate mass measurement also indicated upregulation of biliverdin and the fetal bile acids 7 alpha-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochol-4,6-dien-24-oic acid in HCC patients. A quantitative lipid profiling of patient plasma was also conducted by ultraperformance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UPLC-ESI-TQMS). By this method, we found that HCC was also associated with reduced levels of lysophosphocholines and in 4 of 20 patients with increased levels of lysophosphatidic acid [LPA(16:0)], where it correlated with plasma a-fetoprotein levels. Interestingly, when fatty acids were quantitatively profiled by gas chromatography-mass spectrometry (GC-MS), we found that lignoceric acid (24: 0) and nervonic acid (24: 1) were virtually absent from HCC plasma. Overall, this investigation illustrates the power of the new discovery technologies represented in the UPLC-ESI-QTOFMS platform combined with the targeted, quantitative platforms of UPLC-ESI-TQMS and GC-MS for conducting metabolomic investigations that can engender new insights into cancer pathobiology. Cancer Res; 71(21); 6590-600. (C)2011 AACR. C1 [Maurhofer, Olivier; Beyoglu, Diren; Lanz, Christian; Dufour, Jean-Francois; Idle, Jeffrey R.] Univ Bern, Hepatol Res Grp, Dept Clin Res, CH-3010 Bern, Switzerland. [Patterson, Andrew D.; Krausz, Kristopher W.; Gonzalez, Frank J.; Idle, Jeffrey R.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pabst, Thomas] Univ Bern, Inselspital, Univ Clin Med Oncol, CH-3010 Bern, Switzerland. [Dufour, Jean-Francois; Idle, Jeffrey R.] Univ Bern, Inselspital, Univ Clin Visceral Surg & Med, CH-3010 Bern, Switzerland. RP Idle, JR (reprint author), Univ Bern, Hepatol Res Grp, Dept Clin Res, Murtenstr 35, CH-3010 Bern, Switzerland. EM jeff.idle@ikp.unibe.ch RI Patterson, Andrew/G-3852-2012; OI Patterson, Andrew/0000-0003-2073-0070; Idle, Jeff/0000-0002-6143-1520 FU NIH, National Cancer Institute; NIH, (NIAID) [U19 AI067773-05/-06]; NIH, (NIEHS) [U01 ES016013]; Bernerische und Schweizerische Krebsliga, Sasella Foundation; Hassan Badawi Foundation Against Liver Cancer FX This work was supported by NIH, National Cancer Institute Intramural Research Program (A.D. Patterson, K.W. Krausz, and F.J. Gonzalez), NIH grants U19 AI067773-05/-06 (NIAID; C. Lanz and J.R. Idle) and U01 ES016013 (NIEHS; A.D. Patterson, K.W. Krausz, and F.J. Gonzalez), and Bernerische und Schweizerische Krebsliga, Sasella Foundation, and the Hassan Badawi Foundation Against Liver Cancer (O. Maurhofer, J.R. Idle, and J-F. Dufour). NR 48 TC 98 Z9 105 U1 7 U2 76 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD NOV 1 PY 2011 VL 71 IS 21 BP 6590 EP 6600 DI 10.1158/0008-5472.CAN-11-0885 PG 11 WC Oncology SC Oncology GA 842ML UT WOS:000296603500006 PM 21900402 ER PT J AU Lu, H Yang, XP Duggal, P Allen, CT Yan, B Cohen, J Nottingham, L Romano, RA Sinha, S King, KE Weinberg, WC Chen, Z Van Waes, C AF Lu, Hai Yang, Xinping Duggal, Praveen Allen, Clint T. Yan, Bin Cohen, Jonah Nottingham, Liesl Romano, Rose-Anne Sinha, Satrajit King, Kathryn E. Weinberg, Wendy C. Chen, Zhong Van Waes, Carter TI TNF-alpha Promotes c-REL/Delta Np63 alpha Interaction and TAp73 Dissociation from Key Genes That Mediate Growth Arrest and Apoptosis in Head and Neck Cancer SO CANCER RESEARCH LA English DT Article ID FACTOR-KAPPA-B; SQUAMOUS-CELL CARCINOMA; TUMOR-NECROSIS-FACTOR; TRANSCRIPTION FACTOR; BINDING MOTIFS; DELTA-NP63-ALPHA; P53; EXPRESSION; CISPLATIN; SURVIVAL AB Inflammation-induced activation of proto-oncogenic NF-kappa B/REL and dysfunction of tumor suppressor TP53/p63/p73 family transcription factors are key events in cancer progression. How inflammatory signaling coordinates dysregulation of these two transcription factor families during oncogenesis remains incompletely understood. Here, we observed that oncoprotein c-REL and tumor suppressor TAp73 are coexpressed and complex with Delta Np63 alpha in the nucleus of a subset of head and neck squamous cell carcinoma (HNSCC) cell lines with mutant (mt)TP53. TNF-alpha, a proinflammatory cytokine, promoted c-REL nuclear translocation, c-REL/Delta Np63 alpha interaction, and dissociation of TAp73 from Delta Np63 alpha and the nucleus to the cytoplasm, whereas c-REL siRNA knockdown attenuated this effect. Overexpression of c-REL or a c-REL kappa B-site DNA-binding mutant enhanced protein interaction with Delta Np63 alpha and TAp73 dissociation, implicating c-REL/Delta Np63 alpha-specific interactions in these effects. We discovered that TNF-alpha or genetic alteration of c-REL expression inversely modulates Delta Np63 alpha/TAp73 interactions on distinct p63 DNA-binding sites, including those for key growth arrest and apoptotic genes p21WAF1, NOXA, and PUMA. Functionally, c-REL repressed these genes and the antiproliferative effects of TNF-alpha or TAp73. Conversely, c-REL siRNA depletion enhanced TAp73 promoter interaction and expression of genes mediating growth arrest and apoptosis. Similar to TNF-alpha-treated HNSCC lines, human HNSCC tumors and hyperplastic squamous epithelia of transgenic mice overexpressing Delta Np63 alpha that exhibit inflammation also show increased nuclear c-REL/Delta Np63 alpha and cytoplasmic TAp73 localization. These findings unveil a novel and reversible dynamic mechanism whereby proinflammatory cytokine TNF-alpha-induced c-REL/Delta Np63 alpha interactions inactivate tumor suppressor TAp73 function, promoting TNF-alpha resistance and cell survival in cancers with mtTP53. Cancer Res; 71(21); 6867-77. (C) 2011 AACR. C1 [Lu, Hai; Yang, Xinping; Duggal, Praveen; Allen, Clint T.; Yan, Bin; Cohen, Jonah; Nottingham, Liesl; Chen, Zhong; Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [King, Kathryn E.; Weinberg, Wendy C.] FDA Ctr Drug Evaluat & Res, Bethesda, MD USA. [Romano, Rose-Anne; Sinha, Satrajit] SUNY Buffalo, Dept Biochem, Ctr Excellence Bioinformat & Life Sci, Buffalo, NY 14214 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, CRC Rm 4-2732,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov; vanwaesc@nidcd.nih.gov FU NIDCD [Z01-DC-000016, DC-000073]; NIH-Pfizer; HHMI-NIH FX The work received support from NIDCD Intramural Research Projects Z01-DC-000016 and DC-000073. C.T. Allen was supported by the NIH-Pfizer Clinical Research Training Program; J. Cohen was supported by the HHMI-NIH Scholars Program. NR 37 TC 37 Z9 37 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD NOV 1 PY 2011 VL 71 IS 21 BP 6867 EP 6877 DI 10.1158/0008-5472.CAN-11-2460 PG 11 WC Oncology SC Oncology GA 842ML UT WOS:000296603500033 PM 21933882 ER PT J AU Balenga, NAB Aflaki, E Kargl, J Platzer, W Schroder, R Blattermann, S Kostenis, E Brown, AJ Heinemann, A Waldhoer, M AF Balenga, Nariman A. B. Aflaki, Elma Kargl, Julia Platzer, Wolfgang Schroeder, Ralf Blaettermann, Stefanie Kostenis, Evi Brown, Andrew J. Heinemann, Akos Waldhoer, Maria TI GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils (vol 21, pg 1452, 2011) SO CELL RESEARCH LA English DT Correction C1 [Balenga, Nariman A. B.; Kargl, Julia; Platzer, Wolfgang; Heinemann, Akos; Waldhoer, Maria] Med Univ Graz, Inst Expt & Clin Pharmacol, A-8010 Graz, Austria. [Aflaki, Elma] Med Univ Graz, Inst Mol Biol & Biochem, A-8010 Graz, Austria. [Schroeder, Ralf; Blaettermann, Stefanie; Kostenis, Evi] Univ Bonn, Inst Pharmaceut Biol, Sect Mol Cellular & Pharmacobiol, D-5300 Bonn, Germany. [Brown, Andrew J.] GlaxoSmithKline Inc, Med Res Ctr, Dept Screening & Compound Profiling, Stevenage, Herts, England. RP Balenga, NAB (reprint author), NIAID, Mol & Signal Transduct Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM nariman.balenga@nih.gov; mriw@hagedorn.dk RI Aghaei Balenga, Nariman/A-5895-2011 OI Aghaei Balenga, Nariman/0000-0002-2741-9595 NR 1 TC 0 Z9 0 U1 0 U2 2 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYAND ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD NOV PY 2011 VL 21 IS 11 BP 1641 EP 1641 DI 10.1038/cr.2011.169 PG 1 WC Cell Biology SC Cell Biology GA 843WJ UT WOS:000296706700015 ER PT J AU Magnani, JW Rienstra, M Lin, H Sinner, MF Lubitz, SA McManus, DD Dupuis, J Ellinor, PT Benjamin, EJ AF Magnani, Jared W. Rienstra, Michiel Lin, Honghuang Sinner, Moritz F. Lubitz, Steven A. McManus, David D. Dupuis, Josee Ellinor, Patrick T. Benjamin, Emelia J. TI Atrial Fibrillation Current Knowledge and Future Directions in Epidemiology and Genomics SO CIRCULATION LA English DT Article DE atrial fibrillation; arrhythmias, cardiac; epidemiology; genetics; genomics; review; risk factors ID OF-FUNCTION MUTATION; CA2+-ACTIVATED K+ CHANNEL; CONGESTIVE-HEART-FAILURE; COMMUNITY-BASED COHORT; RISK-FACTORS; ATHEROSCLEROSIS RISK; FUNCTIONAL MODULES; AFRICAN-AMERICANS; SMALL-CONDUCTANCE; ISCHEMIC-STROKE C1 [Magnani, Jared W.] Boston Univ, Sch Med, Sect Cardiovasc Med, Dept Med, Boston, MA 02118 USA. [Magnani, Jared W.; Sinner, Moritz F.; Dupuis, Josee; Benjamin, Emelia J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Rienstra, Michiel] Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands. [Sinner, Moritz F.; Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Sinner, Moritz F.] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. RP Magnani, JW (reprint author), Boston Univ, Sch Med, Sect Cardiovasc Med, Dept Med, 88 E Newton St, Boston, MA 02118 USA. EM jmagnani@bu.edu OI Lin, Honghuang/0000-0003-3043-3942; Dupuis, Josee/0000-0003-2871-3603; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU American Heart Association [09FTF 2190028]; Netherlands Organization for Scientific Research [825.09.020]; German Heart Foundation; National Institutes of Health (NIH) [R37HL69874-08, U01HL105268, HL092577, RO1AG028321, RC1-HL01056, 1R01HL102214, 5R21DA027021, 1RO1HL104156, 1K24HL105780]; [6R01-NS17950]; [N01-HC25195] FX Dr Magnani is supported by American Heart Association Award 09FTF 2190028. Dr Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Rubicon grant 825.09.020). Dr Sinner is supported by the German Heart Foundation. Dr McManus is supported by grants from the National Institutes of Health (NIH; R37HL69874-08, U01HL105268). This work was supported by grants from the NIH to Drs Benjamin and Ellinor (HL092577), Dr Benjamin (RO1AG028321, RC1-HL01056, 1R01HL102214), and Dr Ellinor (5R21DA027021, 1RO1HL104156, 1K24HL105780) and by 6R01-NS17950 and N01-HC25195. NR 147 TC 102 Z9 106 U1 1 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD NOV 1 PY 2011 VL 124 IS 18 BP 1982 EP U170 DI 10.1161/CIRCULATIONAHA.111.039677 PG 16 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842JB UT WOS:000296593800021 PM 22042927 ER PT J AU Milman, G Schwope, DM Schwilke, EW Darwin, WD Kelly, DL Goodwin, RS Gorelick, DA Huestis, MA AF Milman, Garry Schwope, David M. Schwilke, Eugene W. Darwin, William D. Kelly, Deanna L. Goodwin, Robert S. Gorelick, David A. Huestis, Marilyn A. TI Oral Fluid and Plasma Cannabinoid Ratios after Around-the-Clock Controlled Oral Delta(9)-Tetrahydrocannabinol Administration SO CLINICAL CHEMISTRY LA English DT Article ID 2-DIMENSIONAL GAS-CHROMATOGRAPHY; METABOLITE 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; SIMULTANEOUS QUANTIFICATION; MASS-SPECTROMETRY; GC-MS; PHARMACOKINETIC PROPERTIES; DELTA-9-TETRAHYDROCANNABINOL; MARIJUANA; 11-NOR-9-CARBOXY-THC; 11-HYDROXY-THC AB BACKGROUND: Oral fluid (OF) testing is increasingly important for drug treatment, workplace, and drugged-driving programs. There is interest in predicting plasma or whole-blood concentrations from OF concentrations; however, the relationship between these matrices is incompletely characterized because of few controlled drug-administration studies. METHODS: Ten male daily cannabis smokers received around-the-clock escalating 20-mg oral Delta(9)-tetrahydrocannabinol (THC, dronabinol) doses (40-120 mg/day) for 8 days. Plasma and OF samples were simultaneously collected before, during, and after dosing. OF THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCCOOH) were quantified by GC-MS at 0.5-mu g/L, 0.5-mu g/L, and 7.5-ng/L limits of quantification (LOQs), respectively. In plasma, the LOQs were 0.25 mu g/L for THC and THCCOOH, and 0.5 mu g/L for 11-hydroxy-THC. RESULTS: Despite multiple oral THC administrations each day and increasing plasma THC concentrations, OF THC concentrations generally decreased over time, reflecting primarily previously self-administered smoked cannabis. The logarithms of the THC concentrations in oral fluid and plasma were not significantly correlated (r = -0.10; P = 0.065). The OF and plasma THCCOOH concentrations, albeit with 1000-fold higher concentrations in plasma, increased throughout dosing. The logarithms of OF and plasma THCCOOH concentrations were significantly correlated (r = 0.63; P < 0.001), although there was high interindividual variation. A high OF/plasma THC ratio and a high OF THC/THCCOOH ratio indicated recent cannabis smoking. CONCLUSIONS: OF monitoring does not reliably detect oral dronabinol intake. The time courses of THC and THCCOOH concentrations in plasma and OF were different after repeated oral THC doses, and high interindividual variation was observed. For these reasons, OF cannabinoid concentrations cannot predict concurrent plasma concentrations. (C) 2011 American Association for Clinical Chemistry C1 [Huestis, Marilyn A.] NIDA, IRP, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. [Gorelick, David A.] NIDA, Off Sci Director, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, IRP, NIH, Biomed Res Ctr, 251 Bayview Blvd,Rm 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse at the NIH; National Institute on Drug Abuse; Residential Research Support Services Contract [HHSN271200599091, N01Da-5-9909] FX Intramural Research Program, National Institute on Drug Abuse at the NIH and National Institute on Drug Abuse, Residential Research Support Services Contract (grant no. HHSN271200599091 CADB, contract no. N01Da-5-9909). NR 40 TC 19 Z9 20 U1 2 U2 18 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD NOV PY 2011 VL 57 IS 11 BP 1597 EP 1606 DI 10.1373/clinchem.2011.169490 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 842NL UT WOS:000296606100019 PM 21875944 ER PT J AU Frolov, VA Shnyrova, AV Zimmerberg, J AF Frolov, Vadim A. Shnyrova, Anna V. Zimmerberg, Joshua TI Lipid Polymorphisms and Membrane Shape SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID BIOLOGICAL-MEMBRANES; PHOSPHOLIPID-MEMBRANES; SPONTANEOUS CURVATURE; UNILAMELLAR VESICLES; LYOTROPIC PHASES; FORCE GENERATION; GIANT LIPOSOMES; CELL-MEMBRANE; PROTEINS; BILAYERS AB Morphological plasticity of biological membrane is critical for cellular life, as cells need to quickly rearrange their membranes. Yet, these rearrangements are constrained in two ways. First, membrane transformations may not lead to undesirable mixing of, or leakage from, the participating cellular compartments. Second, membrane systems should be metastable at large length scales, ensuring the correct function of the particular organelle and its turnover during cellular division. Lipids, through their ability to exist with many shapes (polymorphism), provide an adequate construction material for cellular membranes. They can self-assemble into shells that are very flexible, albeit hardly stretchable, which allows for their far-reaching morphological and topological behaviors. In this article, we will discuss the importance of lipid polymorphisms in the shaping of membranes and its role in controlling cellular membrane morphology. C1 [Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Frolov, Vadim A.; Shnyrova, Anna V.] Ctr Mixto CSIC UPV EHU, Unidad Biofis, Leioa 48940, Spain. [Frolov, Vadim A.; Shnyrova, Anna V.] Univ Basque Country, Dept Biochim & Biol Mol, Leioa 48940, Spain. [Frolov, Vadim A.] Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Spain. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov OI Frolov, Vadim/0000-0002-0653-5669 NR 79 TC 37 Z9 37 U1 2 U2 25 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD NOV PY 2011 VL 3 IS 11 AR a004747 DI 10.1101/cshperspect.a004747 PG 14 WC Cell Biology SC Cell Biology GA 843TM UT WOS:000296695500006 PM 21646378 ER PT J AU Fredericks, WJ McGarvey, T Wang, HY Lal, P Puthiyaveettil, R Tomaszewski, J Sepulveda, J Labelle, E Weiss, JS Nickerson, ML Kruth, HS Brandt, W Wessjohann, LA Malkowicz, SB AF Fredericks, William J. McGarvey, Terry Wang, Huiyi Lal, Priti Puthiyaveettil, Raghunath Tomaszewski, John Sepulveda, Jorge Labelle, Ed Weiss, Jayne S. Nickerson, Michael L. Kruth, Howard S. Brandt, Wolfgang Wessjohann, Ludger A. Malkowicz, S. Bruce TI The Bladder Tumor Suppressor Protein TERE1 (UBIAD1) Modulates Cell Cholesterol: Implications for Tumor Progression SO DNA AND CELL BIOLOGY LA English DT Article ID PROSTATE-CANCER CELLS; VITAMIN-K; APOLIPOPROTEIN-E; CARCINOMA-CELLS; CORNEAL-DYSTROPHY; OXIDATIVE STRESS; MITOCHONDRIAL CHOLESTEROL; HEPATOCELLULAR-CARCINOMA; XENOBIOTIC RECEPTOR; MACROPHAGE ABCA1 AB Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression. C1 [Fredericks, William J.] Univ Penn, Dept Surg, Div Urol, VAMC Philadelphia, Philadelphia, PA 19104 USA. [McGarvey, Terry] Kirksville Osteopath Med Sch, Dept Anat, Kirksville, MO USA. [Lal, Priti; Puthiyaveettil, Raghunath; Tomaszewski, John; Sepulveda, Jorge] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Malkowicz, S. Bruce] Vet Affairs Med Ctr, Dept Surg Urol & Pathol, Philadelphia, PA USA. [Sepulveda, Jorge] Vet Affairs Med Ctr, Pathol Serv, Philadelphia, PA USA. [Labelle, Ed] Gloucester Cty Coll, Sewell, NJ USA. [Weiss, Jayne S.] Louisiana State Univ, Dept Ophthalmol, New Orleans, LA USA. [Weiss, Jayne S.] Louisiana State Univ, Ctr Eye, New Orleans, LA 70112 USA. [Nickerson, Michael L.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Kruth, Howard S.] NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. [Brandt, Wolfgang; Wessjohann, Ludger A.] Leibniz Inst Plant Biochem, Halle, Germany. RP Fredericks, WJ (reprint author), Univ Penn, Dept Surg, Div Urol, VAMC Philadelphia, Univ & Woodland Ave,Room A418, Philadelphia, PA 19104 USA. EM william.fredericks@uphs.upenn.edu FU Veterans Affairs Merit Review; Veterans Affairs Medical Center Philadelphia FX We thank the Veterans Affairs Merit Review and the Veterans Affairs Medical Center Philadelphia for the grant support to S.B. Malkowicz. We thank the Innisfree Foundation of Bryn Mawr, PA, and The Castleman Family Fund for their generous support to S.B. Malkowicz and W.J. Fredericks. NR 92 TC 21 Z9 21 U1 1 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5498 J9 DNA CELL BIOL JI DNA Cell Biol. PD NOV PY 2011 VL 30 IS 11 BP 851 EP 864 DI 10.1089/dna.2011.1315 PG 14 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 843GW UT WOS:000296661300001 PM 21740188 ER PT J AU Archambeault, DR Tomaszewski, J Childs, AJ Anderson, RA Yao, HHC AF Archambeault, Denise R. Tomaszewski, Jessica Childs, Andrew J. Anderson, Richard A. Yao, Humphrey Hung-Chang TI Testicular Somatic Cells, not Gonocytes, Are the Major Source of Functional Activin A during Testis Morphogenesis SO ENDOCRINOLOGY LA English DT Article ID RAT SERTOLI CELLS; SERUM FSH-LEVELS; GERM-CELL; SEMEN QUALITY; SEMINIFEROUS EPITHELIUM; POSTNATAL-DEVELOPMENT; DYSGENESIS SYNDROME; CRE RECOMBINASE; TRANSGENIC MICE; INHIBIN-ALPHA AB Proper development of the seminiferous tubules (or testis cords in embryos) is critical for male fertility. Sertoli cells, somatic components of the seminiferous tubules, serve as nurse cells to the male germline, and thus their numbers decide the quantity of sperm output in adulthood. We previously identified activin A, the protein product of the activin beta A(Inhba) gene, as a key regulator of murine Sertoli cell proliferation and testis cord expansion during embryogenesis. Although our genetic studies implicated fetal Leydig cells as the primary producers of testicular activin A, gonocytes are another potential source. To investigate the relative contribution of gonocyte-derived activin A to testis morphogenesis, we compared testis development in the Inhba global knockout mouse, which lacks activin A production in all cells (including the gonocytes), and a steroidogenic factor 1 (Sf1)-specific conditional knockout model in which activin A expression in testicular somatic cells is disrupted but gonocyte expression of activin A remains intact. Surprisingly, testis development was comparable in these two models of activin A insufficiency, with similar reductions in Sertoli cell proliferation and minor differences in testis histology. Thus, our findings suggest activin A from male gonocytes is insufficient to promote Sertoli cell proliferation and testis cord expansion in the absence of somatic cell-derived activin A. Evaluation of adult male mice with fetal disruption of activin A revealed reduced testis size, lowered sperm production, altered testicular histology, and elevated plasma FSH levels, defects reminiscent of human cases of androgen-sufficient idiopathic oligozoospermia. (Endocrinology 152: 4358-4367, 2011) C1 [Archambeault, Denise R.; Tomaszewski, Jessica; Yao, Humphrey Hung-Chang] Univ Illinois, Dept Comparat Biosci, Urbana, IL 61802 USA. [Childs, Andrew J.; Anderson, Richard A.] Univ Edinburgh, MRC, Ctr Reprod Hlth, Edinburgh EH16 4TJ, Midlothian, Scotland. [Yao, Humphrey Hung-Chang] NIEHS, Reprod Dev Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Yao, HHC (reprint author), NIEHS, Reprod Dev Biol Grp, Lab Reprod & Dev Toxicol, NIH, 111 TWAlexander Dr,C4-10, Res Triangle Pk, NC 27709 USA. EM yaoh3@niehs.nih.gov RI Yao, Humphrey Hung-Chang/B-4795-2010; OI Yao, Humphrey Hung-Chang/0000-0003-2944-8469; Childs, Andrew/0000-0003-3937-4037 FU National Institutes of Health [HD046861, T32 ES07326]; United Kingdom MRC [WBS U. 1276.00.002.00001]; Medical Research Scotland [354] FX This study was funded by the National Institutes of Health (HD046861 and Intramural Research Fund to H.H.-C.Y; Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant Predoctoral Traineeships in Endocrine, Developmental, and Reproductive Toxicology or T32 ES07326 to D. R. A.), the United Kingdom MRC (WBS U. 1276.00.002.00001 to R. A. A.), and Medical Research Scotland (354 Germany to A.J.C.). NR 64 TC 5 Z9 5 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2011 VL 152 IS 11 BP 4358 EP 4367 DI 10.1210/en.2011-1288 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 842GR UT WOS:000296583900038 PM 21952240 ER PT J AU Schirren, J Eberlein, M Fischer, A Bolukbas, S AF Schirren, Joachim Eberlein, Michael Fischer, Andreas Boeluekbas, Servet TI The role of sleeve resections in advanced nodal disease SO EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY LA English DT Article DE NSCLC; Sleeve resection; Stage IIIA; Stage IIIB ID CELL LUNG-CANCER; PULMONARY-ARTERY; SURVIVAL; CHEMOTHERAPY; DISSECTION; LOBECTOMY; THERAPY; PNEUMONECTOMY AB Objective: The aim of this study was to compare the short-term and long-term results of sleeve resections depending on limited nodal disease (N0/N1, LND) and advanced nodal disease (N2/N3, AND) for non-small cell lung cancer (NSCLC) at a single institution. Methods: We retrospectively reviewed our prospective database of all NSCLC patients undergoing sleeve resections between January 1999 and December 2008. Patients' characteristics, morbidity, mortality, locoregional recurrence, distant recurrence, and survival were analyzed corresponding to LND and AND. Results: The indication was NSCLC for 170 sleeve resections (LND: n = 120; AND: n = 50) out of 213 consecutive sleeve resections. Both groups were statistically equal with regard to age (LND 61.8 +/- 12.4 vs AND 60.8 +/- 9.6 years), gender, co-morbidities, type of sleeve resection (bronchial vs bronchovascular), number of dissected lymph nodes (LND 40.0 +/- 12.4 vs AND 36.7 +/- 14.0), histology and completeness of resection (LND 96.7% vs AND 98.0%), respectively. More patients had induction chemotherapy in AND group (p = 0.049). The short-term results were equal on the subject of morbidity rate (LND: 34.2%, AND: 44.0%), secondary pneumonectomy (LND: 1.7%, AND: 4.0%), and mortality rate (LND: 5.0%, AND: 6.0%), respectively. LND was associated with a better 5-year-survival rate (LND: 67%; AND: 42%) and mean survival (LND: 80.8 months; AND: 37.7 months; p = 0.014). In the long-term follow-up, more distant metastases were detected in AND group (26.0% vs 14.2%, p = 0.079) in contrast to identical locoregional recurrence (LND: 1.7%; AND: 0%). In the event of metastazing, the mean time to the development of distant metastases was similar (LND: 19.1 months; AND: 12.4 months; p = 0.2). Conclusions: Lymph node involvement is a negative prognostic factor concerning long-term survival. Sleeve resections in AND do not result in higher morbidity and mortality. But even in AND, sleeve resections are associated with promising long-term survival and extraordinary local control of the disease as a result of high complete resection rates. High rate of distant failure warrants further investigation for the systemic control of the disease. (C) 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. C1 [Schirren, Joachim; Boeluekbas, Servet] Dr Horst Schmidt Klin, Dept Thorac Surg, D-65199 Wiesbaden, Germany. [Eberlein, Michael] Johns Hopkins Univ, Div Pulm & Crit Care Med, Sch Med, Baltimore, MD USA. [Eberlein, Michael] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Fischer, Andreas] Dr Horst Schmidt Klin, Dept Anesthesiol, D-65199 Wiesbaden, Germany. [Fischer, Andreas] Dr Horst Schmidt Klin, Dept Intens Care Med, D-65199 Wiesbaden, Germany. RP Bolukbas, S (reprint author), Dr Horst Schmidt Klin, Dept Thorac Surg, Ludwig Erhard Str 100, D-65199 Wiesbaden, Germany. EM Dr.Bolukbas@gmx.de NR 25 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1010-7940 J9 EUR J CARDIO-THORAC JI Eur. J. Cardio-Thorac. Surg. PD NOV PY 2011 VL 40 IS 5 BP 1157 EP 1163 DI 10.1016/j.ejcts.2011.02.037 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 841SV UT WOS:000296534300026 PM 21454086 ER PT J AU Kadiiska, MB Hatch, GE Nyska, A Jones, DP Hensley, K Stocker, R George, MM Van Thiel, DH Stadler, K Barrett, JC Mason, RP AF Kadiiska, Maria B. Hatch, Gary E. Nyska, Abraham Jones, Dean P. Hensley, Kenneth Stocker, Roland George, Magdalene M. Van Thiel, David H. Stadler, Krisztian Barrett, J. Carl Mason, Ronald P. TI Biomarkers of Oxidative Stress Study IV: Ozone exposure of rats and its effect on antioxidants in plasma and bronchoalveolar lavage fluid SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Ozone; Rat; Plasma; Tocopherols; Ascorbic acid; Glutathione; Uric acid; Free radicals ID INDUCED LUNG INFLAMMATION; LOW-DENSITY-LIPOPROTEIN; SRR-ALPHA-TOCOPHEROL; AIRWAY HYPERRESPONSIVENESS; ASCORBIC-ACID; MURINE LUNG; VITAMIN-C; URIC-ACID; TOXICITY; CELLS AB The objective of this study was to determine whether acutely exposing rats to ozone would result in the loss of antioxidants from plasma and bronchoalveolar lavage fluid (BALF). Additional goals were to compare analyses of the same antioxidant concentration between different laboratories, to investigate which methods have the sensitivity to detect decreased levels of antioxidants, and to identify a reliable measure of oxidative stress in ozone-exposed rats. Male Fisher rats were exposed to either 2.0 or 5.0 ppm ozone inhalation for 2 h. Blood plasma and BALE samples were collected 2, 7, and 16 h after the exposure. It was found that ascorbic acid in plasma collected from rats after the higher dose of ozone was lower at 2 h, but not later. BALF concentrations of ascorbic acid were decreased at both 2 and 7 h postexposure. Tocopherols (alpha, delta, gamma), 5-nitro-gamma-tocopherol, tocol, glutathione (GSH/GSSG), and cysteine (Cys/CySS) were not decreased, regardless of the dose or postexposure time point used for sample collection. Uric acid was significantly increased by the low dose at 2 h and the high dose at the 7 h point, probably because of the accumulation of blood plasma in the lung from ozone-increased alveolar capillary permeability. We conclude that measurements of antioxidants in plasma are not sensitive biomarkers for oxidative damage induced by ozone and are not a useful choice for the assessment of oxidative damage by ozone in vivo. Published by Elsevier Inc. C1 [Kadiiska, Maria B.; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Hatch, Gary E.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Nyska, Abraham] Tel Aviv Univ, Sackler Sch Med, IL-36576 Tel Aviv, Israel. [Jones, Dean P.] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Hensley, Kenneth] Univ Toledo, Med Ctr, Dept Pathol, Toledo, OH 43614 USA. [Stocker, Roland] Univ Sydney, Ctr Vasc Res, Sydney, NSW 2006, Australia. [George, Magdalene M.; Van Thiel, David H.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Stadler, Krisztian] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Barrett, J. Carl] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. RP Kadiiska, MB (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM Kadiiska@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH FX This research was supported by the National Institute of Environmental Health Sciences Intramural Research Program, NIH. The authors thank Jean Corbett, Ralph Wilson, John Seely, Ralph Slade, Joel Norwood, John McKee, Robert McConnaughey, Kay Crissman, Judy Richards, Linda K. Wong, and Qu Feng for excellent technical support. The authors also thank Dr. Ann Motten and Ms. Mary J. Mason for editorial assistance. The research described in this article does not necessarily reflect the views and policies of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. NR 52 TC 15 Z9 15 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 IS 9 BP 1636 EP 1642 DI 10.1016/j.freeradbiomed.2011.07.013 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 834JC UT WOS:000295954600002 PM 21824516 ER PT J AU Mukhopadhyay, P Horvath, B Kechrid, M Tanchian, G Rajesh, M Naura, AS Boulares, AH Pacher, P AF Mukhopadhyay, Partha Horvath, Bela Kechrid, Malek Tanchian, Galin Rajesh, Mohanraj Naura, Amarjit S. Boulares, A. Hamid Pacher, Pal TI Poly(ADP-ribose) polymerase-1 is a key mediator of cisplatin-induced kidney inflammation and injury SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Nephropathy; Cisplatin; Poly(ADP-ribose) polymerase; Free radicals ID ADP-RIBOSE SYNTHETASE; INDUCED HEART-FAILURE; INDUCED RENAL INJURY; INDUCED CELL-DEATH; FACTOR-KAPPA-B; NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; PHARMACOLOGICAL INHIBITION; REPERFUSION INJURY; CARDIAC DYSFUNCTION AB Cisplatin is a commonly used chemotherapeutic drug, the clinical use of which is limited by the development of dose-dependent nephrotoxicity. Enhanced inflammatory response, oxidative stress, and cell death have been implicated in the development of cisplatin-induced nephropathy; however, the precise mechanisms are elusive. Overactivation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) by oxidative DNA damage under various pathological conditions promotes cell death and up-regulation of key proinflammatory pathways. In this study, using a well-established model of nephropathy, we have explored the role of PARP-1 in cisplatin-induced kidney injury. Genetic deletion or pharmacological inhibition of PARP-1 markedly attenuated the cisplatin-induced histopathological damage, impaired renal function (elevated serum BUN and creatinine levels), and enhanced inflammatory response (leukocyte infiltration; TNF-alpha, IL-1 beta, F4/80, adhesion molecules ICAM-1/VCAM-1 expression) and consequent oxidative/nitrative stress (4-HNE, 8-OHdG, and nitrotyrosine content; NOX2/NOX4 expression). PARP inhibition also facilitated the cisplatin-induced death of cancer cells. Thus, PARP activation plays an important role in cisplatin-induced kidney injury, and its pharmacological inhibition may represent a promising approach to preventing the cisplatin-induced nephropathy. This is particularly exciting because several PARP inhibitors alone or in combination with DNA-damaging anticancer agents show considerable promise in clinical trials for treatment of various malignancies (e.g., triple-negative breast cancer). Published by Elsevier Inc. C1 [Mukhopadhyay, Partha; Horvath, Bela; Kechrid, Malek; Tanchian, Galin; Rajesh, Mohanraj; Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Naura, Amarjit S.; Boulares, A. Hamid] Louisiana State Univ, Hlth Sci Ctr, Stanley Scott Canc Ctr, New Orleans, LA 70112 USA. [Naura, Amarjit S.; Boulares, A. Hamid] Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol, New Orleans, LA 70112 USA. [Horvath, Bela] Semmelweis Univ, Inst Human Physiol & Clin Expt Res, Budapest, Hungary. RP Pacher, P (reprint author), NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Horvath, Bela/A-7368-2009; Pacher, Pal/B-6378-2008; MUKHOPADHYAY, PARTHA/G-3890-2010 OI Pacher, Pal/0000-0001-7036-8108; MUKHOPADHYAY, PARTHA/0000-0002-1178-1274 FU NIH/NIAAA; Hungarian Scientific Research Fund fellowship [OTKA-NKTH-EU MB08 80238]; [HL072889] FX This study was supported by the Intramural Research Program of the NIH/NIAAA (to P.P.) and by HL072889 (to A.H.B). Authors are indebted to Dr. George Kunos, the scientific director of NIAAA, for continuous support. Dr. Horvath is the recipient of a Hungarian Scientific Research Fund fellowship (OTKA-NKTH-EU MB08 80238). Dr. Pacher dedicates this study to his beloved mother Iren Bolfert, who died from complications of chemotherapy. NR 106 TC 36 Z9 36 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2011 VL 51 IS 9 BP 1774 EP 1788 DI 10.1016/j.freeradbiomed.2011.08.006 PG 15 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 834JC UT WOS:000295954600016 PM 21884784 ER PT J AU Turriff, A Levy, HP Biesecker, B AF Turriff, Amy Levy, Howard P. Biesecker, Barbara TI Prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome SO GENETICS IN MEDICINE LA English DT Article DE Klinefelter syndrome; 47; XXY; depression; illness perceptions; stigma ID SEX-CHROMOSOME ABNORMALITIES; COMORBIDITY SURVEY REPLICATION; QUALITY-OF-LIFE; COMMUNITY SAMPLE; CONFOUNDER-SELECTION; MULTIPLE-SCLEROSIS; BODY-COMPOSITION; HYPOGONADAL MEN; OLDER MEN; CES-D AB Purpose: To determine the prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome. Methods: Individuals (n = 310) aged 14-75 years with self-reported Klinefelter syndrome were recruited from regional and national support networks to complete a web-based survey. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Perceived consequences (Illness Perceptions Questionnaire), perceived stigma (Perceived Social Stigmatization Scale), and coping (Ways of Coping Checklist-Revised) were also measured and evaluated as correlates of depressive symptoms. Results: Overall, 68.8% of the study participants reported clinically significant levels of depressive symptoms as indicated by a Center for Epidemiologic Studies Depression Scale score >16. The use of emotion-focused coping strategies (P < 0.01), perceptions of stigmatization (P < 0.01), perceived negative consequences of Klinefelter syndrome (P < 0.01), and the importance of having children in the future (P < 0.05) were all significantly associated with depressive symptoms. Conclusions: Individuals with Klinefelter syndrome may be at increased risk for depression. Routine screening for depressive symptoms and appropriate referral and evaluation may be warranted. Genet Med 2011:13(11):966-972. C1 [Turriff, Amy; Biesecker, Barbara] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Turriff, Amy] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Levy, Howard P.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Levy, Howard P.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Turriff, A (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, 10 Ctr Dr,MSC 1860,Bldg 10,Room 10N226, Bethesda, MD 20892 USA. EM turriffa@mail.nih.gov FU National Human Genome Research Institute FX The research was supported by the Intramural Research Program of the National Human Genome Research Institute. We thank the adolescents and adults with XXY who participated in this study and the XXY support networks for assisting us with study recruitment. We also thank Carolyn Bondy, MD, and Donald Rosenstein, MD, for their feedback on this article and Cristofer Price, PhD, at Abt Associates for his statistical input. NR 54 TC 16 Z9 16 U1 5 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD NOV PY 2011 VL 13 IS 11 BP 966 EP 972 DI 10.1097/GIM.0b013e3182227576 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 843IU UT WOS:000296666300008 PM 21799429 ER PT J AU Wilson, TM Maric, I Shukla, J Brown, M Santos, C Simakova, O Khoury, P Fay, MP Kozhich, A Kolbeck, R Metcalfe, DD Klion, AD AF Wilson, Todd M. Maric, Irina Shukla, Juhi Brown, Margaret Santos, Carlo Simakova, Olga Khoury, Paneez Fay, Michael P. Kozhich, Alexander Kolbeck, Roland Metcalfe, Dean D. Klion, Amy D. TI IL-5 receptor alpha levels in patients with marked eosinophilia or mastocytosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Hypereosinophilic syndrome; IL-5; mast cell; eosinophil; mastocytosis ID HUMAN MAST-CELLS; GM-CSF; DECREASED EXPRESSION; SOLUBLE ISOFORMS; IN-VITRO; INTERLEUKIN-5; MEPOLIZUMAB; CYTOKINES; ASTHMA; CHAIN AB Background: IL-5 plays a central role in the development and maintenance of eosinophilia (EO) and eosinophil activation in a wide variety of eosinophilic disorders. Although IL-5, IL-3, and GM-CSF can modulate the expression of IL-5 receptor alpha (IL-5R alpha) on eosinophils in vitro, little is known about soluble and surface IL-5R alpha levels in vivo. Objective: To assess soluble and surface IL-5R alpha levels in patients with EO and/or mastocytosis. Methods: Surface IL-5R alpha expression was assessed by flow cytometry in blood and/or bone marrow from subjects with EO (n = 39) and systemic mastocytosis (n = 8) and from normal volunteers (n = 28). Soluble IL-5R alpha (sIL-5R alpha) level was measured in a cohort of 177 untreated subjects and correlated with EO, eosinophil activation, and serum tryptase and cytokine levels. Results: IL-5R alpha expression on eosinophils inversely correlated with EO (r = 20.48; P < .0001), whereas serum levels of sIL-5R alpha increased with the eosinophil count (r = 0.56; P < .0001) and serum IL-5 (r = 0.40; P < .0001) and IL-13 (r = 0.29; P = .004) levels. Of interest, sIL-5R alpha level was significantly elevated in patients with systemic mastocytosis without EO. Although sIL-5R alpha levels correlated with serum tryptase levels in these patients, eosinophil activation, assessed by CD69 expression on eosinophils and serum eosinophil-derived neurotoxin levels, was increased compared with that in normal subjects. Conclusions: These data are consistent with an in vivo IL-5R alpha regulatory pathway in human eosinophils similar to that described in vitro and involving a balance between soluble and surface receptor levels. This may have implications with respect to the use of novel therapeutic agents targeting IL-5 and its receptor in patients with EO and/or mastocytosis. (J Allergy Clin Immunol 2011;128:1086-92.) C1 [Shukla, Juhi; Brown, Margaret; Santos, Carlo; Simakova, Olga; Khoury, Paneez; Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Shukla, Juhi; Brown, Margaret; Santos, Carlo; Simakova, Olga; Khoury, Paneez; Klion, Amy D.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Kozhich, Alexander; Kolbeck, Roland] MedImmune LLC, Dept Resp Inflammat & Autoimmun, Gaithersburg, MD USA. [Maric, Irina] NIAID, Dept Lab Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Wilson, Todd M.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 50,Room 6351, Bethesda, MD 20892 USA. EM aklion@nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; MedImmune FX This study was supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. MedImmune LLC provided the protocol and reagents for the sIL-5R alpha ELISA.; Disclosure of potential conflict of interest: A. D. Klion has received research support from MedImmune. The rest of the authors have declared that they have no conflict of interest. NR 32 TC 13 Z9 14 U1 0 U2 4 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 NOV PY 2011 VL 128 IS 5 BP 1086 EP U263 DI 10.1016/j.jaci.2011.05.032 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA 842FJ UT WOS:000296578200023 PM 21762978 ER PT J AU Freeman, AF Ding, L Holland, SM Uzel, G AF Freeman, Alexandra F. Ding, Li Holland, Steven M. Uzel, Gulbu TI Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID MATRIX METALLOPROTEINASES; STAT3; MUTATIONS C1 [Freeman, Alexandra F.; Ding, Li; Holland, Steven M.; Uzel, Gulbu] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NIAID, Biostat Res Branch, Div Clin Res, NIH, Bethesda, MD USA. RP Freeman, AF (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM guzel@niaid.nih.gov NR 10 TC 0 Z9 0 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 NOV PY 2011 VL 128 IS 5 BP 1124 EP 1127 DI 10.1016/j.jaci.2011.07.046 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 842FJ UT WOS:000296578200035 ER PT J AU Varadarajan, N Julg, B Yamanaka, YJ Chen, HB Ogunniyi, AO McAndrew, E Porter, LC Piechocka-Trocha, A Hill, BJ Douek, DC Pereyra, F Walker, BD Love, JC AF Varadarajan, Navin Julg, Boris Yamanaka, Yvonne J. Chen, Huabiao Ogunniyi, Adebola O. McAndrew, Elizabeth Porter, Lindsay C. Piechocka-Trocha, Alicja Hill, Brenna J. Douek, Daniel C. Pereyra, Florencia Walker, Bruce D. Love, J. Christopher TI A high-throughput single-cell analysis of human CD8(+) T cell functions reveals discordance for cytokine secretion and cytolysis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IMMUNE CONTROL; HIV; ANTIGEN; PROLIFERATION; REPLICATION; LYMPHOCYTE; MEMORY; INFECTION; PERFORIN AB CD8(+) T cells are a key component of the adaptive immune response to viral infection. An inadequate CD8(+) T cell response is thought to be partly responsible for the persistent chronic infection that arises following infection with HIV. It is therefore critical to identify ways to define what constitutes an adequate or inadequate response. IFN-gamma production has been used as a measure of T cell function, but the relationship between cytokine production and the ability of a cell to lyse virus-infected cells is not clear. Moreover, the ability to assess multiple CD8(+) T cell functions with single-cell resolution using freshly isolated blood samples, and subsequently to recover these cells for further functional analyses, has not been achieved. As described here, to address this need, we have developed a high-throughput, automated assay in 125-p1 microwells to simultaneously evaluate the ability of thousands of individual CD8(+) T cells from HIV-infected patients to mediate lysis and to produce cytokines. This concurrent, direct analysis enabled us to investigate the correlation between immediate cytotoxic activity and short-term cytokine secretion. The majority of in vivo primed, circulating HIV-specific CD8(+) T cells were discordant for cytolysis and cytokine secretion, notably IFN-gamma, when encountering cognate antigen presented on defined numbers of cells. Our approach should facilitate determination of signatures of functional variance among individual effector CD8(+) T cells, including those from mucosal samples and those induced by vaccines. C1 [Varadarajan, Navin; Ogunniyi, Adebola O.; Love, J. Christopher] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Julg, Boris; Chen, Huabiao; McAndrew, Elizabeth; Porter, Lindsay C.; Piechocka-Trocha, Alicja; Pereyra, Florencia; Walker, Bruce D.; Love, J. Christopher] Ragan Inst MGH MIT & Harvard, Boston, MA USA. [Yamanaka, Yvonne J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Chen, Huabiao; Piechocka-Trocha, Alicja; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Hill, Brenna J.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Love, J. Christopher] Eli & Edythe L Broad Inst, Cambridge, MA USA. RP Love, JC (reprint author), MIT, Dept Chem Engn, 77 Massachusetts Ave,Bldg 76-253, Cambridge, MA 02139 USA. EM clove@mit.edu OI Varadarajan, Navin/0000-0001-7524-8228 FU Susan and Phillip T. Ragon Foundation; W.M. Keck Foundation; Charles A. Dana Foundation; Ragon Institute of MGH; Ragon Institute of MIT; Ragon Institute of Harvard; Mark and Lisa Schwartz Foundation; Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation; National Science Foundation; NIH [NIGMS 5T32GM008334] FX The authors thank T.M. Gierahn and M.H. Foley for helpful discussions and J. Choi and M.H. Foley for technical assistance. This research was supported by grants from the Susan and Phillip T. Ragon Foundation, the W.M. Keck Foundation, the Charles A. Dana Foundation, the Ragon Institute of MGH, MIT, and Harvard, the Mark and Lisa Schwartz Foundation, and the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation. Y.J. Yamanaka was supported in part by a fellowship from the National Science Foundation. A.O. Ogunniyi was supported in part by the NIH (NIGMS 5T32GM008334). J.C. Love is a Latham Family Career Development Professor. NR 48 TC 70 Z9 70 U1 3 U2 28 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 NOV PY 2011 VL 121 IS 11 BP 4322 EP 4331 DI 10.1172/JCI58653 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 840ZY UT WOS:000296482700016 PM 21965332 ER PT J AU Faul, C Amaral, AP Oskouei, B Hu, MC Sloan, A Isakova, T Gutierrez, OM Aguillon-Prada, R Lincoln, J Hare, JM Mundel, P Morales, A Scialla, J Fischer, M Soliman, EZ Chen, J Go, AS Rosas, SE Nessel, L Townsend, RR Feldman, HI Sutton, MS Ojo, A Gadegbeku, C Di Marco, GS Reuter, S Kentrup, D Tiemann, K Brand, M Hill, JA Moe, OW Kuro-o, M Kusek, JW Keane, MG Wolf, M AF Faul, Christian Amaral, Ansel P. Oskouei, Behzad Hu, Ming-Chang Sloan, Alexis Isakova, Tamara Gutierrez, Orlando M. Aguillon-Prada, Robier Lincoln, Joy Hare, Joshua M. Mundel, Peter Morales, Azorides Scialla, Julia Fischer, Michael Soliman, Elsayed Z. Chen, Jing Go, Alan S. Rosas, Sylvia E. Nessel, Lisa Townsend, Raymond R. Feldman, Harold I. Sutton, Martin St. John Ojo, Akinlolu Gadegbeku, Crystal Di Marco, Giovana Seno Reuter, Stefan Kentrup, Dominik Tiemann, Klaus Brand, Marcus Hill, Joseph A. Moe, Orson W. Kuro-o, Makoto Kusek, John W. Keane, Martin G. Wolf, Myles TI FGF23 induces left ventricular hypertrophy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CHRONIC KIDNEY-DISEASE; GROWTH-FACTOR 23; MYOSIN HEAVY-CHAIN; STAGE RENAL-DISEASE; X-LINKED HYPOPHOSPHATEMIA; RECEPTOR TYROSINE KINASES; RAT CARDIAC MYOCYTES; GENE-EXPRESSION; MYOCARDIAL PERFORMANCE; SIGNALING PATHWAYS AB Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intrarnyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD. C1 [Faul, Christian; Amaral, Ansel P.; Sloan, Alexis; Isakova, Tamara; Aguillon-Prada, Robier; Scialla, Julia; Wolf, Myles] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Faul, Christian; Amaral, Ansel P.; Sloan, Alexis] Univ Miami, Miller Sch Med, Dept Cell Biol & Anat, Miami, FL 33136 USA. [Oskouei, Behzad; Hare, Joshua M.] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA. [Hu, Ming-Chang; Hill, Joseph A.; Moe, Orson W.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Hu, Ming-Chang] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Hu, Ming-Chang; Kuro-o, Makoto] Univ Texas SW Med Ctr Dallas, Charles & Jane Pak Ctr Mineral Metab & Clin Res, Dallas, TX 75390 USA. [Gutierrez, Orlando M.] Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Gutierrez, Orlando M.] Univ Alabama, Sch Med, Dept Med, Div Nephrol, Birmingham, AL USA. [Lincoln, Joy] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Lincoln, Joy] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Mundel, Peter] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Renal Unit, Boston, MA USA. [Morales, Azorides] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Fischer, Michael] Jesse Brown VA Med Ctr, Dept Med, Chicago, IL USA. [Fischer, Michael] Univ Illinois, Med Ctr, Chicago, IL USA. [Fischer, Michael] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr, Winston Salem, NC USA. [Chen, Jing] Tulane Sch Med, Dept Med, New Orleans, LA USA. [Go, Alan S.] Kaiser Permanente No Calif, Div Res, San Francisco, CA USA. [Go, Alan S.] UCSF, Dept Epidemiol, San Francisco, CA USA. [Go, Alan S.] UCSF, Dept Biostat, San Francisco, CA USA. [Go, Alan S.] UCSF, Dept Med, San Francisco, CA USA. [Rosas, Sylvia E.; Townsend, Raymond R.; Feldman, Harold I.] Univ Penn, Sch Med, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Nessel, Lisa; Feldman, Harold I.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Sutton, Martin St. John; Keane, Martin G.] Univ Penn, Sch Med, Dept Med, Div Cardiol, Philadelphia, PA 19104 USA. [Gadegbeku, Crystal] Temple Univ, Schostl Med, Dept Internal Med, Sect Nephrol & Kidney Transplantat, Philadelphia, PA 19122 USA. [Ojo, Akinlolu] Univ Michigan Hlth Syst, Dept Internal Med, Ann Arbor, MI USA. [Di Marco, Giovana Seno; Reuter, Stefan; Kentrup, Dominik; Brand, Marcus] Univ Munster, Dept Internal Med D, D-4400 Munster, Germany. [Tiemann, Klaus] Univ Munster, Dept Cardiol & Angiol, Munster, Germany. [Hill, Joseph A.] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Moe, Orson W.] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. [Kuro-o, Makoto] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. RP Wolf, M (reprint author), 1120 NW 14th St,Suite 819, Miami, FL 33136 USA. EM cfaul@med.miami.edu; mwolf2@med.miami.edu RI Rosas, Sylvia/D-1106-2009; OI Seno Di Marco, Giovana/0000-0002-1877-638X FU NephCure Foundation; American Heart Association; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center; George M. O'Brien Kidney Research Core Center/UT Southwestern Medical Center at Dallas [NIH P30DK-07938]; Stifterverband fur die Deutsche Wissenschaft and Simon-Claussen-Stiftung [H 1405409999915626]; Inter-disciplinary Research Initiative of the University of Miami Miller School of Medicine; Department of Veterans Affairs; National Institutes of Health [F30DK091057, K23DK087858, K23DK081673, R01DK091392, R01AG019712, R01DK076116, R01DK081374]; National Institute of Diabetes and Digestive and Kidney Diseases [5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, 5U01DK060902]; institutional Clinical Translational Science Awards; NIH; University of Pennsylvania [UL1 RR024134]; Johns Hopkins University [UL1 RR025005]; University of Maryland [GCRC M01 RR16500]; Case Western Reserve University Clinical and Translational Science Collaborative (University Hospitals of Cleveland, Cleveland Clinic Foundation, and MetroHealth) [UL1 RR024989]; University of Michigan [GCRC M01 RR-000042, UL1 RR024986]; University of Illinois at Chicago [UL1 RR029879]; Tulane/LSU/Charity Hospital General Clinical Research Center [RR05096]; Kaiser-UCSF-CTSI [RR024131]; Abbott Laboratories; Ardelyx; Genzyme FX This study was supported by grants from the NephCure Foundation (to C. Faul), the American Heart Association (to C. Faul and M.C. Hu), the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center (to M.C. Hu), the George M. O'Brien Kidney Research Core Center/UT Southwestern Medical Center at Dallas (NIH P30DK-07938 to O.W. Moe), the Stifterverband fur die Deutsche Wissenschaft and Simon-Claussen-Stiftung (H 1405409999915626 to M. Brand), the Inter-disciplinary Research Initiative of the University of Miami Miller School of Medicine (to C. Faul, J.M. Hare, and M. Wolf), a Health Services Research and Development Service Career Development Award from the Department of Veterans Affairs (to M.J. Fischer), and grants F30DK091057 (to A.P. Amaral), K23DK087858 (to T. Isakova), K23DK081673 (to O.M. Gutierrez), R01DK091392 (to M.C. Hu, M. Kuro-o, and O.W. Moe), R01AG019712 (to M. Kuro-o), R01DK076116 (to M. Wolf), and R01DK081374 (to M. Wolf) from the National Institutes of Health. Funding for the CRIC study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (grant no. 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902). In addition, this work was supported in part by the following institutional Clinical Translational Science Awards and other NIH grants: University of Pennsylvania, UL1 RR024134; Johns Hopkins University, UL1 RR025005; University of Maryland, GCRC M01 RR16500; Case Western Reserve University Clinical and Translational Science Collaborative (University Hospitals of Cleveland, Cleveland Clinic Foundation, and MetroHealth), UL1 RR024989; University of Michigan, GCRC M01 RR-000042 and UL1 RR024986; University of Illinois at Chicago, UL1 RR029879; Tulane/LSU/Charity Hospital General Clinical Research Center, RR05096; and Kaiser-UCSF-CTSI, RR024131.; Tamara Isakova has served as a consultant and received honoraria from Shire. Orlando M. Gutierrez has received honoraria from Genzyme. Sylvia E. Rosas has received research support from Abbott Laboratories. Makoto Kuro-o has received research support from Ardelyx and Genzyme and honoraria from Amgen and Genzyme. Myles Wolf has served as a consultant or received honoraria from Abbott Laboratories, Amgen, Ardelyx, Baxter, Cytochroma, Genzyme, Luitpold Pharmaceuticals Inc., Novartis, Mitsubishi, and Shire. NR 89 TC 615 Z9 645 U1 5 U2 31 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 NOV PY 2011 VL 121 IS 11 BP 4393 EP 4408 DI 10.1172/JCI46122 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 840ZY UT WOS:000296482700022 PM 21985788 ER PT J AU Ortiz, AM Klatt, NR Li, B Yi, Y Tabb, B Hao, XP Sternberg, L Lawson, B Carnathan, PM Cramer, EM Engram, JC Little, DM Ryzhova, E Gonzalez-Scarano, F Paiardini, M Ansari, AA Ratcliffe, S Else, JG Brenchley, JM Collman, RG Estes, JD Derdeyn, CA Silvestri, G AF Ortiz, Alexandra M. Klatt, Nichole R. Li, Bing Yi, Yanjie Tabb, Brian Hao, Xing Pei Sternberg, Lawrence Lawson, Benton Carnathan, Paul M. Cramer, Elizabeth M. Engram, Jessica C. Little, Dawn M. Ryzhova, Elena Gonzalez-Scarano, Francisco Paiardini, Mirko Ansari, Aftab A. Ratcliffe, Sarah Else, James G. Brenchley, Jason M. Collman, Ronald G. Estes, Jacob D. Derdeyn, Cynthia A. Silvestri, Guido TI Depletion of CD4(+) T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; SOOTY MANGABEYS; VAGINAL TRANSMISSION; EFFECTOR FUNCTIONS; AIDS PATHOGENESIS; NONHUMAN-PRIMATES; VIRAL REPLICATION; CD8-T-CELL MEMORY; HIV-1 INFECTION; CD4-T-CELL HELP AB CD4(+) T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4(+) T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SW-infected rhesus macaques (RMs) that suggest that CD4(+) T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4(+) T cells during primary SW infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4(+) lymphocyte-depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8(+) T cell- and B cell-mediated SW-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SW-envelopes. Our results suggest that the antiviral CD4(+) T cell response may play an important role in limiting SW replication, which has implications for the design of HIV vaccines. C1 [Ortiz, Alexandra M.; Li, Bing; Lawson, Benton; Carnathan, Paul M.; Paiardini, Mirko; Else, James G.; Derdeyn, Cynthia A.; Silvestri, Guido] Yerkes Natl Primate Res Ctr, Atlanta, GA 30033 USA. [Ortiz, Alexandra M.; Li, Bing; Lawson, Benton; Carnathan, Paul M.; Paiardini, Mirko; Else, James G.; Derdeyn, Cynthia A.; Silvestri, Guido] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Ortiz, Alexandra M.; Yi, Yanjie; Cramer, Elizabeth M.; Collman, Ronald G.] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Ortiz, Alexandra M.; Carnathan, Paul M.; Cramer, Elizabeth M.; Engram, Jessica C.; Paiardini, Mirko; Silvestri, Guido] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Klatt, Nichole R.; Brenchley, Jason M.] NIH, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Yi, Yanjie; Collman, Ronald G.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Tabb, Brian; Hao, Xing Pei; Sternberg, Lawrence; Estes, Jacob D.] NCI, AIDS & Canc Virus Program, SAIC Frederick, NIH, Frederick, MD USA. [Little, Dawn M.; Ansari, Aftab A.] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Ryzhova, Elena; Gonzalez-Scarano, Francisco] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Ratcliffe, Sarah] Univ Penn, Sch Med, Dept Biostat, Philadelphia, PA 19104 USA. RP Silvestri, G (reprint author), Yerkes Natl Primate Res Ctr, 3014 EVC Bldg,954 Gatewood Rd NE, Atlanta, GA 30033 USA. EM gsilves@emory.edu OI Ratcliffe, Sarah/0000-0002-6644-8284 FU NIH [AI-66998, RR-00165]; National Cancer Institute, NIH [HHSN261200800001E] FX We acknowledge Stephanie Ehnert, Chris Souder, and all the animal care and veterinary staff at the Yerkes National Primate Research Center; the Virology Core of the Emory Center for AIDS Research (CFAR); the University of Pennsylvania CFAR; the University of Pennsylvania Flow Cytometry Core; and the NIH nonhuman primate reagent resource. We also thank Ann Chahroudi for critical reading of this manuscript. The Cdr-OKT4A-huIgG1 depleting mAb used in this study was provided by Keith Reimann. The SIVmac251 used to infect the RMs was provided by Chris Miller. This work was supported by NIH grants AI-66998 (to G. Silvestri) and RR-00165 (to Yerkes National Primate Research Center). This project has been funded in part with federal funds from the National Cancer Institute, 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, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 56 TC 64 Z9 65 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 NOV PY 2011 VL 121 IS 11 BP 4433 EP 4445 DI 10.1172/JCI46023 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 840ZY UT WOS:000296482700025 PM 22005304 ER PT J AU Wang, RH Kim, HS Xiao, CY Xu, XL Gavrilova, O Deng, CX AF Wang, Rui-Hong Kim, Hyun-Seok Xiao, Cuiying Xu, Xiaoling Gavrilova, Oksana Deng, Chu-Xia TI Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TRANSCRIPTION FACTOR FKHR; NONALCOHOLIC FATTY LIVER; PROTEIN-KINASE B; RICTOR-MTOR COMPLEX; GENE-EXPRESSION; PHOSPHATIDYLINOSITOL 3-KINASE; MITOCHONDRIAL-FUNCTION; TUMOR-SUPPRESSOR; METABOLISM; SIRTUINS AB Insulin resistance is a major risk factor for type 2 diabetes mellitus. The protein encoded by the sirtuin 1 (Sirt1) gene, which is a mouse homolog of yeast Sir2, is implicated in the regulation of glucose metabolism and insulin sensitivity; however, the underlying mechanism remains elusive. Here, using mice with a liver-specific null mutation of Sirt1, we have identified a signaling pathway involving Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and Foxo1 that regulates gluconeogenesis. We found that Sirt1 positively regulates transcription of the gene encoding Rictor, triggering a cascade of phosphorylation of Akt at S473 and Foxol at S253 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (Pepck). Liver-specific Sirt1 deficiency caused hepatic glucose overproduction, chronic hyperglycemia, and increased ROS production. This oxidative stress disrupted mTorc2 and impaired mTorc2/Akt signaling in other insulin-sensitive organs, leading to insulin resistance that could be largely reversed with antioxidant treatment. These data delineate a pathway through which Sirt1 maintains insulin sensitivity and suggest that treatment with antioxidants might provide protection against progressive insulin resistance in older human populations. C1 [Wang, Rui-Hong; Kim, Hyun-Seok; Xiao, Cuiying; Xu, Xiaoling; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU National Institute of Diabetes, and Digestive and Kidney Diseases, NIH, USA FX We gratefully acknowledge William Jou and Tatyana Chanturiya for technical assistance with clamps and serum analysis and members of the Deng laboratory for helpful discussion. This work was supported by the Intramural Research Program of the National Institute of Diabetes, and Digestive and Kidney Diseases, NIH, USA. NR 63 TC 115 Z9 118 U1 1 U2 19 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 NOV PY 2011 VL 121 IS 11 BP 4477 EP 4490 DI 10.1172/JCI46243 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 840ZY UT WOS:000296482700028 PM 21965330 ER PT J AU Wohlfert, EA Grainger, JR Bouladoux, N Konkel, JE Oldenhove, G Ribeiro, CH Hall, JA Yagi, R Naik, S Bhairavabhotla, R Paul, WE Bosselut, R Wei, G Zhao, KJ Oukka, M Zhu, JF Belkaid, Y AF Wohlfert, Elizabeth A. Grainger, John R. Bouladoux, Nicolas Konkel, Joanne E. Oldenhove, Guillaume Ribeiro, Carolina Hager Hall, Jason A. Yagi, Ryoji Naik, Shruti Bhairavabhotla, Ravikiran Paul, William E. Bosselut, Remy Wei, Gang Zhao, Keji Oukka, Mohamed Zhu, Jinfang Belkaid, Yasmine TI GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TRANSCRIPTION FACTOR GATA-3; CONTROL INTESTINAL INFLAMMATION; IN-VIVO; CYTOKINE PRODUCTION; TH2 CELLS; TGF-BETA; THYMOCYTE DEVELOPMENT; SUPPRESSIVE FUNCTION; RETINOIC-ACID; HELPER-CELLS AB Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on their capacity to accumulate at inflamed sites and appropriately adapt to their local environment. To date, the factors involved in the control of these aspects of Treg physiology remain poorly understood. Here, we show that the canonical Th2 transcription factor GATA3 is selectively expressed in Tregs residing in barrier sites including the gastrointestinal tract and the skin. GATA3 expression in both murine and human Tregs was induced upon TCR and IL-2 stimulation. Although GATA3 was not required to sustain Treg homeostasis and function at steady state, GATA3 played a cardinal role in Treg physiology during inflammation. Indeed, the intrinsic expression of GATA3 by Tregs was required for their ability to accumulate at inflamed sites and to maintain high levels of Foxp3 expression in various polarized or inflammatory settings. Furthermore, our data indicate that GATA3 limits Treg polarization toward an effector T cell phenotype and acquisition of effector cytokines in inflamed tissues. Overall, our work reveals what we believe to be a new facet in the complex role of GATA3 in T cells and highlights what may be a fundamental role in controlling Treg physiology during inflammation. C1 [Wohlfert, Elizabeth A.; Grainger, John R.; Bouladoux, Nicolas; Oldenhove, Guillaume; Ribeiro, Carolina Hager; Hall, Jason A.; Naik, Shruti; Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Konkel, Joanne E.] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. [Hall, Jason A.; Naik, Shruti] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Yagi, Ryoji; Bhairavabhotla, Ravikiran; Paul, William E.; Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wei, Gang; Zhao, Keji] NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. [Oukka, Mohamed] Univ Washington, Dept Pediat, Ctr Immun & Immunotherapies, Seattle Childrens Res Inst, Seattle, WA 98195 USA. RP Belkaid, Y (reprint author), 4 Ctr Dr,B1-28, Bethesda, MD 20892 USA. EM JFZHU@niaid.nih.gov; YBelkaid@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012; Ribeiro, Carolina/H-9772-2013 OI Ribeiro, Carolina/0000-0002-6912-5536 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; NCI, Center for Cancer Research; NIH, National Institute of Dental and Craniofacial Research; The Crohn's and Colitis Foundation of America [2387] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (to Y. Belkaid and W.E. Paul), and NCI, Center for Cancer Research (to R. Bhairavabhotla), NIH, National Institute of Dental and Craniofacial Research, and The Crohn's and Colitis Foundation of America (ref #2387 to E.A. Wohlfert). We thank Rajat Varma for his assistance with the confocal microscopy. We thank Kevin Holmes and the NIAID sorting facility and Kim Beacht for technical assistance. We thank WanJun Chen, Annie Kilby, Sean Spencer, and Mike Molloy for their critical reading of the manuscript. NR 86 TC 145 Z9 149 U1 1 U2 17 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 NOV PY 2011 VL 121 IS 11 BP 4503 EP 4515 DI 10.1172/JCI57456 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 840ZY UT WOS:000296482700030 PM 21965331 ER PT J AU Choi, BY Kim, HM Ito, T Lee, KY Li, XM Monahan, K Wen, YQ Wilson, E Kurima, K Saunders, TL Petralia, RS Wangemann, P Friedman, TB Griffith, AJ AF Choi, Byung Yoon Kim, Hyoung-Mi Ito, Taku Lee, Kyu-Yup Li, Xiangming Monahan, Kelly Wen, Yaqing Wilson, Elizabeth Kurima, Kiyoto Saunders, Thomas L. Petralia, Ronald S. Wangemann, Philine Friedman, Thomas B. Griffith, Andrew J. TI Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GENOTYPE-PHENOTYPE CORRELATION; PENDRED-SYNDROME; INNER-EAR; DEAFNESS; PDS; GENE; MUTATIONS; INSIGHT; PROTEIN; CELLS AB Mutations in human SLC26A4 are a common cause of hearing loss associated with enlarged vestibular aqueducts (EVA). SLC26A4 encodes pendrin, an anion-base exchanger expressed in inner ear epithelial cells that secretes HCO3- into endolymph. Studies of Slc26a4-null mice indicate that pendrin is essential for inner ear development, but have not revealed whether pendrin is specifically necessary for homeostasis. Slc26a4-null mice are profoundly deaf, with severe inner ear malformations and degenerative changes that do not model the less severe human phenotype. Here, we describe studies in which we generated a binary transgenic mouse line in which Slc26a4 expression could be induced with doxycycline. The transgenes were crossed onto the Slc26a4-null background so that all functional pendrin was derived from the transgenes. Varying the temporal expression of Slc26a4 revealed that E16.5 to P2 was the critical interval in which pendrin was required for acquisition of normal hearing. Lack of pendrin during this period led to endolymphatic acidification, loss of the endocochlear potential, and failure to acquire normal hearing. Doxycycline initiation at E18.5 or discontinuation at E17.5 resulted in partial hearing loss approximating the human EVA auditory phenotype. These data collectively provide mechanistic insight into hearing loss caused by SLC26A4 mutations and establish a model for further studies of EVA-associated heating loss. C1 [Ito, Taku; Lee, Kyu-Yup; Monahan, Kelly; Wen, Yaqing; Kurima, Kiyoto; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. [Choi, Byung Yoon; Wilson, Elizabeth; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Kim, Hyoung-Mi; Li, Xiangming; Wangemann, Philine] Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. [Saunders, Thomas L.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, 5 Res Court,Room 2B-29, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov RI Wangemann, Philine/N-2826-2013; OI Saunders, Thom/0000-0003-2015-101X FU NIH [DC-000060-10, DC-000039-14, DC-000003-23, P20-RR017686]; CVM-SMILE from Kansas State University FX We thank Yoshiyuki Kawashima, Shin-ichiro Kitajiri, and Harold Neely for technical advice; Parna Chattaraj, Ya-Xian Wang, and NIDCD animal care staff for technical support; Doris Wu and Matthew Kelley for comments on the manuscript; and NIDCD colleagues for helpful discussions. This work was supported by NIH intramural research funds DC-000060-10 (to A.J. Griffith), DC-000039-14 (to T.B. Friedman) and DC-000003-23 (R.S. Petralia), CVM-SMILE from Kansas State University (to P. Wangemann), and NIH extramural fund P20-RR017686. Y. Wen was a Howard Hughes Medical Institute/NIH Research Scholar. NR 37 TC 19 Z9 20 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 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2011 VL 121 IS 11 BP 4516 EP 4525 DI 10.1172/JCI59353 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 840ZY UT WOS:000296482700031 PM 21965328 ER PT J AU King, KS Prodanov, T Kantorovich, V Fojo, T Hewitt, JK Zacharin, M Wesley, R Lodish, M Raygada, M Gimenez-Roqueplo, AP McCormack, S Eisenhofer, G Milosevic, D Kebebew, E Stratakis, CA Pacak, K AF King, Kathryn S. Prodanov, Tamara Kantorovich, Vitaly Fojo, Tito Hewitt, Jacqueline K. Zacharin, Margaret Wesley, Robert Lodish, Maya Raygada, Margarita Gimenez-Roqueplo, Anne-Paule McCormack, Shana Eisenhofer, Graeme Milosevic, Dragana Kebebew, Electron Stratakis, Constantine A. Pacak, Karel TI Metastatic Pheochromocytoma/Paraganglioma Related to Primary Tumor Development in Childhood or Adolescence: Significant Link to SDHB Mutations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SUCCINATE-DEHYDROGENASE; PLASMA METHOXYTYRAMINE; GERMLINE MUTATIONS; PARAGANGLIOMA; GENE; DOPAMINE; CHILDREN; SUSCEPTIBILITY; MANAGEMENT AB Purpose To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence. Patients and Methods From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. Results Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. Conclusion The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/ paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation. J Clin Oncol 29: 4137-4142. (C) 2011 by American Society of Clinical Oncology C1 [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. [Fojo, Tito; Kebebew, Electron] NCI, NIH, Bethesda, MD 20892 USA. [Wesley, Robert] NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Kantorovich, Vitaly] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Hewitt, Jacqueline K.; Zacharin, Margaret] Royal Childrens Hosp Melbourne, Parkville, Vic, Australia. [Gimenez-Roqueplo, Anne-Paule] Hop Europe Georges Pompidou, AP HP, Paris, France. [Gimenez-Roqueplo, Anne-Paule] Hop Europe Georges Pompidou, INSERM, UMR 970, Paris Cardiovasc Res Ctr, Paris, France. [Gimenez-Roqueplo, Anne-Paule] Univ Paris 05, Paris, France. [McCormack, Shana] Childrens Hosp Boston, Boston, MA USA. [Eisenhofer, Graeme] Univ Dresden, Dresden, Germany. [Milosevic, Dragana] Mayo Clin, Rochester, MN USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH,Clin Res Ctr, Bldg 10,1-E,Rm 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Hewitt, Jacqueline/F-6082-2012; OI Hewitt, Jacqueline/0000-0002-3809-8475 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 28 TC 55 Z9 56 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2011 VL 29 IS 31 BP 4137 EP 4142 DI 10.1200/JCO.2011.34.6353 PG 6 WC Oncology SC Oncology GA 842NB UT WOS:000296605100017 PM 21969497 ER PT J AU Kim, C Tang, G Pogue-Geile, KL Costantino, JP Baehner, FL Baker, J Cronin, MT Watson, D Shak, S Bohn, OL Fumagalli, D Taniyama, Y Lee, A Reilly, ML Vogel, VG McCaskill-Stevens, W Ford, LG Geyer, CE Wickerham, DL Wolmark, N Paik, S AF Kim, Chungyeul Tang, Gong Pogue-Geile, Katherine L. Costantino, Joseph P. Baehner, Frederick L. Baker, Joffre Cronin, Maureen T. Watson, Drew Shak, Steven Bohn, Olga L. Fumagalli, Debora Taniyama, Yusuke Lee, Ahwon Reilly, Megan L. Vogel, Victor G. McCaskill-Stevens, Worta Ford, Leslie G. Geyer, Charles E., Jr. Wickerham, D. Lawrence Wolmark, Norman Paik, Soonmyung TI Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor-Positive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT BREAST; PROGESTERONE-RECEPTOR; ENDOCRINE THERAPY; CHEMOTHERAPY; RECURRENCE; TRIAL; SURVIVAL; ASSAY AB Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors. J Clin Oncol 29:4160-4167. (C) 2011 by American Society of Clinical Oncology C1 [Paik, Soonmyung] Natl Surg Adjuvant Breast & Bowel Project, Div Pathol, Pittsburgh, PA 15212 USA. [Tang, Gong; Costantino, Joseph P.] Univ Pittsburgh, Sch Publ Hlth, Pittsburgh, PA 15260 USA. [Geyer, Charles E., Jr.; Wickerham, D. Lawrence; Wolmark, Norman] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Vogel, Victor G.] Geisinger Hlth Syst, Danville, PA USA. [Baehner, Frederick L.; Baker, Joffre; Cronin, Maureen T.; Watson, Drew; Shak, Steven] Genom Hlth, Redwood City, CA USA. [Baehner, Frederick L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [McCaskill-Stevens, Worta; Ford, Leslie G.] NCI, Bethesda, MD 20892 USA. RP Paik, S (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Div Pathol, 1307 Fed St,Ste 303, Pittsburgh, PA 15212 USA. EM soon.paik@nsabp.org OI kim, chungyeul/0000-0002-9636-5228 FU Public Health Service [U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651]; National Cancer Institute, Department of Health and Human Services [U24-CA-114732]; Pennsylvania Department of Health; Genomic Health FX Supported by Public Health Service Grants No. U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U24-CA-114732 from the National Cancer Institute, Department of Health and Human Services; in part by a grant with the Pennsylvania Department of Health; and by Genomic Health. NR 20 TC 46 Z9 47 U1 0 U2 5 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 NOV 1 PY 2011 VL 29 IS 31 BP 4160 EP 4167 DI 10.1200/JCO.2010.32.9615 PG 8 WC Oncology SC Oncology GA 842NB UT WOS:000296605100020 PM 21947828 ER PT J AU Polley, MYC Lamborn, KR Chang, SM Butowski, N Clarke, JL Prados, M AF Polley, Mei-Yin C. Lamborn, Kathleen R. Chang, Susan M. Butowski, Nicholas Clarke, Jennifer L. Prados, Michael TI Conditional Probability of Survival in Patients With Newly Diagnosed Glioblastoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-II; RADIATION-THERAPY; TUMOR RESPONSE; TEMOZOLOMIDE; MULTIFORME AB Purpose The disease outcome for patients with cancer is typically described in terms of estimated survival from diagnosis. Conditional probability offers more relevant information regarding survival for patients once they have survived for some time. We report conditional survival probabilities on the basis of 498 patients with glioblastoma multiforme receiving radiation and chemotherapy. For 1-year survivors, we evaluated variables that may inform subsequent survival. Motivated by the trend in data, we also evaluated the assumption of constant hazard. Patients and Methods Patients enrolled onto seven phase II protocols between 1975 and 2007 were included. Conditional survival probabilities and 95% CIs were calculated. The Cox proportional hazards model was used to evaluate prognostic values of age, Karnofsky performance score (KPS), and prior progression 1-year post diagnosis. To assess the constant hazard assumption, we used a likelihood-ratio test to compare the Weibull and exponential distributions. Results The probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years were 35%, 49%, 69%, and 93%, respectively. For patients who survived for 1 year, lower KPS and progression were significantly predictive of shorter survival (both P < .001), but age was not (hazard ratio, 1.22 for a 10-year increase; P = .25). The Weibull distribution fits the data significantly better than exponential (P = .02), suggesting nonconstant hazard. Conclusion Conditional probabilities provide encouraging information regarding life expectancy to survivors of glioblastoma multiforme. Our data also showed that the constant hazard assumption may be violated in modern brain tumor trials. For single-arm trials, we advise using individual patient data from historical data sets for efficacy comparisons. J Clin Oncol 29:4175-4180. (C) 2011 by American Society of Clinical Oncology C1 [Polley, Mei-Yin C.] NCI, Biometr Res Branch, NIH, Rockville, MD 20892 USA. [Lamborn, Kathleen R.; Chang, Susan M.; Butowski, Nicholas; Clarke, Jennifer L.; Prados, Michael] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Polley, MYC (reprint author), NCI, Biometr Res Branch, NIH, Room 8124,Execut Plaza N,6130 Execut Blvd, Rockville, MD 20892 USA. EM polleymc@mail.nih.gov FU National Institutes of Health [P50 CA097257]; Schering-Plough; Novartis FX Supported by National Institutes of Health Brain Tumor Specialized Program of Research Excellence Grant No. P50 CA097257.; Funding: Susan M. Chang, Schering-Plough, Novartis NR 11 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2011 VL 29 IS 31 BP 4175 EP 4180 DI 10.1200/JCO.2010.32.4343 PG 6 WC Oncology SC Oncology GA 842NB UT WOS:000296605100022 PM 21969507 ER PT J AU Condon, TV Sawyer, RT Fenton, MJ Riches, DWH AF Condon, Tracy Voss Sawyer, Richard T. Fenton, Matthew J. Riches, David W. H. TI Lung dendritic cells at the innate-adaptive immune interface SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE asthma; alveolar macrophage; antigen processing ID THYMIC STROMAL LYMPHOPOIETIN; ANTIGEN-PRESENTING CELLS; TOLL-LIKE RECEPTORS; CD4(+) T-CELLS; BRONCHOALVEOLAR LAVAGE FLUID; ALLERGIC AIRWAY INFLAMMATION; TRANSCRIPTION FACTOR E2-2; LYMPHOID-TISSUE IBALT; RESPIRATORY-TRACT; IN-VIVO AB This review updates the basic biology of lung DCs and their functions. Lung DCs have taken center stage as cellular therapeutic targets in new vaccine strategies for the treatment of diverse human disorders, including asthma, allergic lung inflammation, lung cancer, and infectious lung disease. The anatomical distribution of lung DCs, as well as the division of labor between their subsets, aids their ability to recognize and endocytose foreign substances and to process antigens. DCs can induce tolerance in or activate naive T cells, making lung DCs well-suited to their role as lung sentinels. Lung DCs serve as a functional signaling/sensing unit to maintain lung homeostasis and orchestrate host responses to benign and harmful foreign substances. J. Leukoc. Biol. 90: 883-895; 2011. C1 [Condon, Tracy Voss; Riches, David W. H.] Natl Jewish Hlth, Dept Pediat, Cell Biol Program, Denver, CO 80206 USA. [Condon, Tracy Voss; Riches, David W. H.] Univ Colorado, Sch Med, Dept Immunol, Aurora, CO USA. [Riches, David W. H.] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO USA. [Riches, David W. H.] Univ Colorado, Sch Med, Div Pulm Sci & Crit Care Med, Dept Med, Aurora, CO USA. [Sawyer, Richard T.; Fenton, Matthew J.] NIAID, Asthma Allergy & Inflammat Branch, Div Allergy Immunol & Transplantat, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Riches, DWH (reprint author), Natl Jewish Hlth, Dept Pediat, Cell Biol Program, Iris & Michael Smith Bldg,Rm A549,1400 Jackson St, Denver, CO 80206 USA. EM richesd@njhealth.org FU National Heart, Lung and Blood Institute of the National Institutes of Health [HL68628]; U.S. Department of Defense [DOD W81XWH-07-1-0550-Mason] FX This work was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health (grant HL68628) and by the U.S. Department of Defense (grant DOD W81XWH-07-1-0550-Mason). The authors also wish to thank Dr. Elizabeth Redente for critical review of the manuscript and help in the preparation of the figures. NR 160 TC 37 Z9 39 U1 0 U2 8 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 NOV PY 2011 VL 90 IS 5 BP 883 EP 895 DI 10.1189/jlb.0311134 PG 13 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 843ZF UT WOS:000296716000007 PM 21807741 ER PT J AU Liu, J Sirenko, S Juhaszova, M Ziman, B Shetty, V Rain, S Shukla, S Spurgeon, HA Vinogradova, TM Maltsev, VA Lakatta, EG AF Liu, Jie Sirenko, Syevda Juhaszova, Magdalena Ziman, Bruce Shetty, Veena Rain, Silvia Shukla, Shweta Spurgeon, Harold A. Vinogradova, Tatiana M. Maltsev, Victor A. Lakatta, Edward G. TI A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Sinoatrial node; Automaticity; Adenylyl cyclase-cyclic amp-protein kinase a-Ca2+ Signaling Cascade; Ca2+ cycling proteins; Phospholamban phosphorylation; Local Ca2+ releases ID SPONTANEOUS BEATING RATE; CARDIAC-PACEMAKER CELLS; RYANODINE RECEPTOR; CA2+ RELEASE; DIASTOLIC DEPOLARIZATION; HEART-RATE; CHANNELS; LOCALIZATION; MYOCYTES; BASAL AB Recent perspectives on sinoatrial nodal cell (SANC)* function indicate that spontaneous sarcoplasmic reticulum (SR) Ca2+ cycling, i.e. an intracellular "Ca2+ clock," driven by cAMP-mediated, PICA-dependent phosphorylation, interacts with an ensemble of surface membrane electrogenic molecules ("surface membrane clock") to drive SANC normal automaticity. The role of AC-cAMP-PKA-Ca2+ signaling cascade in mouse, the species most often utilized for genetic manipulations, however, has not been systematically tested. Here we show that Ca2+ cycling proteins (e.g. RyR2, NCX1, and SERCA2) are abundantly expressed in mouse SAN and that spontaneous, rhythmic SR generated local Ca2+ releases (LCRs) occur in skinned mouse SANC, clamped at constant physiologic [Ca2+]. Mouse SANG also exhibits a high basal level of phospholamban (PLB) phosphorylation at the PICA-dependent site, Serine16. Inhibition of intrinsic PICA activity or inhibition of PDE in SANG, respectively: reduces or increases PLB phosphorylation, and markedly prolongs or reduces the LCR period: and markedly reduces or accelerates SAN spontaneous firing rate. Additionally, the increase in AP firing rate by PICA-dependent phosphorylation by beta-adrenergic receptor (beta-AR) stimulation requires normal intracellular Ca2+ cycling, because the beta-AR chronotropic effect is markedly blunted when SR Ca2+ cycling is disrupted. Thus, AC-cAMP-PKA-Ca2+ signaling cascade is a major mechanism of normal automaticity in mouse SANG. Published by Elsevier Ltd. C1 [Liu, Jie; Sirenko, Syevda; Juhaszova, Magdalena; Ziman, Bruce; Rain, Silvia; Shukla, Shweta; Spurgeon, Harold A.; Vinogradova, Tatiana M.; Maltsev, Victor A.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. [Liu, Jie] Univ Sydney, Muscle Cell Funct Lab, Sch Med Sci, Sydney, NSW 2006, Australia. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov RI Liu, Jie/D-8063-2012 FU NIH, National Institute on Aging; MedStar Research Institute FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. NR 47 TC 10 Z9 11 U1 0 U2 3 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 NOV PY 2011 VL 51 IS 5 BP 730 EP 739 DI 10.1016/j.yjmcc.2011.07.028 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 829SL UT WOS:000295604500012 PM 21840316 ER PT J AU Yaniv, Y Juhaszova, M Lyashkov, AE Spurgeon, HA Sollott, SJ Lakatta, EG AF Yaniv, Yael Juhaszova, Magdalena Lyashkov, Alexey E. Spurgeon, Harold A. Sollott, Steven J. Lakatta, Edward G. TI Ca2+-regulated-cAMP/PKA signaling in cardiac pacemaker cells links ATP supply to demand SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Calcium-activated adenylyl cyclase; Constitutive basal PKA-dependent phosphorylation; Bioenergetics; Pacemaker automaticity; Respiration ID DEPENDENT PROTEIN-KINASE; SINOATRIAL NODE CELLS; HEART IN-VIVO; INTRACELLULAR CA2+; CYCLIC-AMP; MAMMALIAN MITOCHONDRIA; CYTOCHROME-C; RABBIT HEART; SINUS NODE; PHOSPHORYLATION AB Rationale: In sinoatrial node cells (SANC), Ca2+ activates adenylate cyclase (AC) to generate a high basal level of cAMP-mediated/protein kinase A (PKA)-dependent phosphorylation of Ca2+ cycling proteins. These result in spontaneous sarcoplasmic-reticulum (SR) generated rhythmic Ca2+ oscillations during diastolic depolarization, that not only trigger the surface membrane to generate rhythmic action potentials (APs), but, in a feed-forward manner, also activate AC/PKA signaling. ATP is consumed to pump Ca2+ to the SR, to produce cAMP, to support contraction and to maintain cell ionic homeostasis. Objective: Since feedback mechanisms link ATP-demand to ATP production, we hypothesized that (1) both basal ATP supply and demand in SANC would be Ca2+-cAMP/PKA dependent; and (2) due to its feed-forward nature, a decrease in flux through the Ca2+-cAMP/PKA signaling axis will reduce the basal ATP production rate. Methods and results: O-2 consumption in spontaneous beating SANC was comparable to ventricular myocytes (VM) stimulated at 3 Hz. Graded reduction of basal Ca2+-cAMP/PKA signaling to reduce ATP demand in rabbit SANC produced graded ATP depletion (r(2)=0.96), and reduced O-2 consumption and flavoprotein fluorescence. Neither inhibition of glycolysis, selectively blocking contraction nor specific inhibition of mitochondrial Ca2+ flux reduced the ATP level. Conclusions: Feed-forward basal Ca2+-cAMP/PKA signaling both consumes ATP to drive spontaneous APs in SANC and is tightly linked to mitochondria! ATP production. Interfering with Ca2+-cAMP/PKA signaling not only slows the firing rate and reduces ATP consumption, but also appears to reduce ATP production so that ATP levels fall. This distinctly differs from VM, which lack this feed-forward basal cAMP/PKA signaling, and in which ATP level remains constant when the demand changes. Published by Elsevier Ltd. C1 [Yaniv, Yael; Juhaszova, Magdalena; Lyashkov, Alexey E.; Spurgeon, Harold A.; Sollott, Steven J.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@mail.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU National Institute on Aging, National Institutes of Health FX The work was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 33 TC 21 Z9 21 U1 0 U2 6 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 NOV PY 2011 VL 51 IS 5 BP 740 EP 748 DI 10.1016/j.yjmcc.2011.07.018 PG 9 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 829SL UT WOS:000295604500013 PM 21835182 ER PT J AU Higgins, RD Raju, T Edwards, AD Azzopardi, DV Bose, CL Clark, RH Ferriero, DM Guillet, R Gunn, AJ Hagberg, H Hirtz, D Inder, TE Jacobs, SE Jenkins, D Juul, S Laptook, AR Lucey, JF Maze, M Palmer, C Papile, L Pfister, RH Robertson, NJ Rutherford, M Shankaran, S Silverstein, FS Soll, RF Thoresen, M Walsh, WF AF Higgins, Rosemary D. Raju, Tonse Edwards, A. David Azzopardi, Denis V. Bose, Carl L. Clark, Reese H. Ferriero, Donna M. Guillet, Ronnie Gunn, Alistair J. Hagberg, Henrik Hirtz, Deborah Inder, Terrie E. Jacobs, Susan E. Jenkins, Dorothea Juul, Sandra Laptook, Abbot R. Lucey, Jerold F. Maze, Mervyn Palmer, Charles Papile, LuAnn Pfister, Robert H. Robertson, Nicola J. Rutherford, Mary Shankaran, Seetha Silverstein, Faye S. Soll, Roger F. Thoresen, Marianne Walsh, William F. CA Eunice Kennedy Shriver Natl Inst TI Hypothermia and Other Treatment Options for Neonatal Encephalopathy: An Executive Summary of the Eunice Kennedy Shriver NICHD Workshop SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; WHOLE-BODY HYPOTHERMIA; AMPLITUDE-INTEGRATED ELECTROENCEPHALOGRAM; RANDOMIZED-CONTROLLED-TRIAL; MODERATE HYPOTHERMIA; THERAPEUTIC HYPOTHERMIA; SYSTEMIC HYPOTHERMIA; MILD HYPOTHERMIA; NEUROPROTECTIVE THERAPY; CEREBRAL HYPOTHERMIA C1 [Higgins, Rosemary D.; Raju, Tonse; Edwards, A. David; Azzopardi, Denis V.; Bose, Carl L.; Clark, Reese H.; Ferriero, Donna M.; Guillet, Ronnie; Gunn, Alistair J.; Hagberg, Henrik; Hirtz, Deborah; Inder, Terrie E.; Jacobs, Susan E.; Jenkins, Dorothea; Juul, Sandra; Laptook, Abbot R.; Lucey, Jerold F.; Maze, Mervyn; Palmer, Charles; Papile, LuAnn; Pfister, Robert H.; Robertson, Nicola J.; Rutherford, Mary; Shankaran, Seetha; Silverstein, Faye S.; Soll, Roger F.; Thoresen, Marianne; Walsh, William F.; Eunice Kennedy Shriver Natl Inst] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. RP Higgins, RD (reprint author), NICHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Execut Blvd,Room 4B03B,MSC 7510, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov OI Hagberg, Henrik/0000-0003-3962-1448; Gunn, Alistair/0000-0003-0656-7035 FU Intramural NIH HHS [Z99 HD999999]; Medical Research Council [G0802853] NR 85 TC 66 Z9 69 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD NOV PY 2011 VL 159 IS 5 BP 851 EP U200 DI 10.1016/j.jpeds.2011.08.004 PG 9 WC Pediatrics SC Pediatrics GA 842GA UT WOS:000296581100032 PM 21875719 ER PT J AU Ogge, G Chaiworapongsa, T Romero, R Hussein, Y Kusanovic, JP Yeo, L Kim, CJ Hassan, SS AF Ogge, Giovanna Chaiworapongsa, Tinnakorn Romero, Roberto Hussein, Youssef Pedro Kusanovic, Juan Yeo, Lami Kim, Chong Jai Hassan, Sonia S. TI Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia SO JOURNAL OF PERINATAL MEDICINE LA English DT Article; Proceedings Paper CT 58th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 16-26, 2011 CL Miami Beach, FL SP Soc Gynecol Invest DE Classification; gestational age; maternal underperfusion; placental infarction; villous changes ID UTERINE ARTERY DOPPLER; FOR-GESTATIONAL-AGE; INTRAUTERINE GROWTH RESTRICTION; UTEROPLACENTAL BLOOD-FLOW; PREGNANCY-INDUCED HYPERTENSION; CIRCULATING ANGIOGENIC FACTORS; LONG-TERM MORTALITY; LINKED GAMMA-CAMERA; BED SPIRAL ARTERIES; FETAL-GROWTH AB Objective: Preeclampsia (PE) has been classified into early- and late-onset disease. These two phenotypic variants of PE have been proposed to have a different pathophysiology. However, the gestational age cut-off to define "early" vs. "late" PE has varied among studies. The objective of this investigation was to determine the prevalence of lesions consistent with maternal underperfusion of the placenta in patients with PE as a function of gestational age. Study design: A nested case-control study of 8307 singleton pregnant women who deliver after 20 weeks of gestation was constructed based on a cohort. Cases were defined as those with PE (n=910); controls were pregnant women who did not have a hypertensive disorder in pregnancy (n=7397). The frequency of maternal underperfusion of the placenta (according to the criteria of the Society for Pediatric Pathology) was compared between the two groups. Logistic regression was used for analysis. Estimated relative risks (RRs) were calculated from odds ratios. Results: 1) The prevalence of lesions consistent with maternal underperfusion was higher in patients with PE than in the control group [43.3% vs. 15.9%, unadjusted odds ratio 4.0 (95% CI 3.5-4.7); P<0.001]; 2) the estimated RR of maternal underperfusion lesions in PE was higher than in the control group [RR=2.8 (95% CI 2.5-3.0)]; 3) the lower the gestational age at delivery, the higher the RR for these lesions; 4) early-onset PE, regardless of the gestational age used to define it (<32, 33, 34, 35 or 37 weeks) had a significantly higher frequency of placental lesions consistent with maternal underperfusion than late-onset PE (P<0.001 for all). Conclusions: 1) The earlier the gestational age of preeclampsia at delivery, the higher the frequency of placental lesions consistent with maternal underperfusion; 2) our data suggest that demonstrable placental involvement as determined by pathologic examination differs in early-and late-onset preeclampsia; and 3) this phenomenon appears to be a continuum, and we could not identify a clear and unambiguous gestational age at which lesions consistent with underperfusion would not be present. C1 [Chaiworapongsa, Tinnakorn; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Pedro Kusanovic, Juan] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Pedro Kusanovic, Juan] Hosp Dr Sotero del Rio, Ctr Perinatal Res, Santiago, Chile. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. [Chaiworapongsa, Tinnakorn] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Ogge, Giovanna; Chaiworapongsa, Tinnakorn; Romero, Roberto; Hussein, Youssef; Yeo, Lami; Kim, Chong Jai; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. RP Chaiworapongsa, T (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu FU Intramural NIH HHS [ZIA HD002400-20] NR 160 TC 84 Z9 88 U1 0 U2 11 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD NOV PY 2011 VL 39 IS 6 BP 641 EP 652 DI 10.1515/JPM.2011.098 PG 12 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 844RM UT WOS:000296765000003 PM 21848483 ER PT J AU Chaiworapongsa, T Romero, R Berry, SM Hassan, SS Yoon, BH Edwin, S Mazor, M AF Chaiworapongsa, Tinnakorn Romero, Roberto Berry, Stanley M. Hassan, Sonia S. Yoon, Bo Hyun Edwin, Samuel Mazor, Moshe TI The role of granulocyte colony-stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Chorioamnionitis; cordocentesis; fetal infection; fetal plasma; FIRS; G-CSF; interleukin-6; pregnancy; prematurity; preterm labor ID TUMOR-NECROSIS-FACTOR; PRETERM PREMATURE RUPTURE; FACTOR G-CSF; AMNIOTIC-FLUID INTERLEUKIN-6; HEMATOPOIETIC GROWTH-FACTORS; UMBILICAL-CORD PLASMA; WHITE-MATTER LESIONS; ARACHIDONATE LIPOXYGENASE METABOLITES; MONOCYTE CHEMOTACTIC PROTEIN-1; INTRAUTERINE INFECTION AB Objectives: Fetal neutrophilia is present in two-thirds of cases with the fetal inflammatory response syndrome (FIRS). The mechanisms responsible for this finding have not been elucidated. Granulocyte colony-stimulating factor (G-CSF) is the primary physiologic regulator of neutrophil production and plays a key role in the rapid generation and release of neutrophils in stressful conditions (i.e., infection). The objective of this study was to determine: 1) whether FIRS was associated with changes in fetal plasma G-CSF concentrations; and 2) if fetal plasma G-CSF concentrations correlated with fetal neutrophil counts, chorioamnionitis, neonatal morbidity/mortality and cordocentesis-to-delivery interval. Study design: Percutaneous umbilical cord blood sampling was performed in a population of patients with preterm labor (n=107). A fetal plasma interleukin-6 (IL-6) concentration >11 pg/mL was used to define FIRS. Cord blood G-CSF was measured by a sensitive and specific immunoassay. An absolute neutrophil count was determined and corrected for gestational age. Receiver operating characteristic (ROC) curve, survival analysis and Cox proportional hazard model Results: 1) G-CSF was detected in all fetal blood samples; 2) fetuses with FIRS had a higher median fetal plasma G-CSF concentration than those without FIRS (P<0.001); 3) a fetal plasma G-CSF concentration >= 134 pg/mL (derived from an ROC curve) was associated with a shorter cordocentesis-to-delivery interval, a higher frequency of chorioamnionitis (clinical and histological), intra-amniotic infection, and composite neonatal morbidity/mortality than a fetal plasma concentration below this cut-off; and 4) a fetal plasma G-CSF concentration >= 134 pg/mL was associated with a shorter cordocentesis-to-delivery interval (hazard ratio 3.2; 95% confidence interval 1.8-5.8) after adjusting for confounders. Conclusions: 1) G-CSF concentrations are higher in the peripheral blood of fetuses with FIRS than in fetuses without FIRS; and 2) a subset of fetuses with FIRS with elevated fetal plasma G-CSF concentrations are associated with neutrophilia, a shorter procedure-to-delivery interval, chorioamnionitis and increased perinatal morbidity and mortality. C1 [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Hutzel Womens Hosp, Detroit, MI 48201 USA. [Berry, Stanley M.] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Edwin, Samuel] Biosurety Div USARIID, Frederick, MD USA. [Mazor, Moshe] Ben Gurion Univ Negev, Soroka Med Ctr, IL-84105 Beer Sheva, Israel. 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 RI Yoon, Bo Hyun/H-6344-2011 FU Perinatology Research Branch; Division of Intramural Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH; DHHS 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, NIH, DHHS. NR 162 TC 19 Z9 19 U1 0 U2 5 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD NOV PY 2011 VL 39 IS 6 BP 653 EP 666 DI 10.1515/JPM.2011.072 PG 14 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 844RM UT WOS:000296765000004 PM 21801092 ER PT J AU Shankaran, S Bann, C Das, A Lester, B Bada, H Bauer, CR La Gasse, L Higgins, RD AF Shankaran, S. Bann, C. Das, A. Lester, B. Bada, H. Bauer, C. R. La Gasse, L. Higgins, R. D. CA Eunice Kennedy Shriver Natl Inst TI Risk for obesity in adolescence starts in early childhood SO JOURNAL OF PERINATOLOGY LA English DT Article DE overweight; obesity; preschool; early elementary; late elementary ID BODY-MASS INDEX; METABOLIC SYNDROME; OVERWEIGHT; CHILDREN; PREGNANCY; ASSOCIATION; ADULTHOOD; EXPOSURE; PREVALENCE; ALCOHOL AB Objective: The objective of this study was to assess the predictive value of body mass index (BMI) at earlier ages on risk of overweight/obesity at age of 11 years. Study Design: This is a longitudinal study of 907 children from birth to age of 11 years. Predictors include BMI at earlier ages and outcome is overweight/obesity status at age of 11 years. Analyses were adjusted for covariates known to affect BMI. Result: At 11 years, 17% were overweight and 25% were obese. Children whose BMI was measured as >= 85th percentile once at preschool age had a twofold risk for overweight/obesity at 11 years of age. Risk increased by 11-fold if a child's BMI measured was noted more than once during this age. During early elementary years, if a child's BMI was>85th percentile once, risk for overweight/obesity at 11 years was fivefold and increased by 72-fold if noted more than two times. During late elementary years, if a child's BMI was>85th percentile once, risk for overweight/obesity was 26-fold and increased by 351-fold if noted more than two times. Risk of overweight/obesity at 11 years was noted with higher maternal prepregnancy weight, higher birth weight, female gender and increased television viewing. Conclusion: Children in higher BMI categories at young ages have a higher risk of overweight/obesity at 11 years of age. Effect size was greater for measurements taken closer to 11 years of age. Pediatricians need to identify children at-risk for adolescent obesity and initiate counseling and intervention at earlier ages. Journal of Perinatology (2011) 31, 711-716; doi:10.1038/jp.2011.14; published online 17 March 2011 C1 [Shankaran, S.] Wayne State Univ Sch Med, Dept Pediat, Detroit, MI USA. [Bann, C.; Das, A.] RTI Int, Dept Stat & Epidemiol, Res Triangle Pk, NC USA. [La Gasse, L.] Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI 02908 USA. [Bada, H.] Univ Kentucky, Dept Neonatol, Lexington, KY USA. [Bauer, C. R.] Univ Miami, Dept Pediat, Miami, FL 33152 USA. [Higgins, R. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Pediat, Bethesda, MD USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM sshankar@med.wayne.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute on Drug Abuse (NIDA); Administration on Children, Youth, and Families; Center for Substance Abuse and Treatment; Eunice Kennedy Shriver; National Institute of Child Health and Human Development [U10HD21385, 10HD36790, U10HD27904, U10HD42638, U10HD21397] FX The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute on Drug Abuse (NIDA), the Administration on Children, Youth, and Families and the Center for Substance Abuse and Treatment provided grant support for recruiting subjects into the Maternal Lifestyle Study from 1993 to 1995. NIDA and NICHD provided funding to conduct follow-up examinations in three phases: at 1, 4, 8, 10, 12, 18, 24 and 36 months corrected age (Phase I); at 31/2, 4, 41/2, 5, 51/2, 6, and 7 years of age (Phase II); and at 8, 9, 10 and 11 years of age (Phase III). The funding agencies provided overall oversight of study conduct, but all data analyses and interpretation were completed independent of the funding agencies. We are indebted to our medical and nursing colleagues, the infants and their parents who agreed to take part in this study. Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, Dr Abhik Das (DCC Principal Investigator) and Dr Sylvia Tan (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. The following investigators, in addition to those listed as authors, participated in this study: Steering Committee Chair: Barry M Lester, PhD, Brown University. Brown University Warren Alpert Medical School Women & Infants Hospital of Rhode Island (U10 HD27904, N01 HD23159): Barry M Lester, PhD, Cynthia Miller-Loncar, PhD; Linda L. LaGasse, PhD; Jean Twomey, PhD. Eunice Kennedy Shriver National Institute of Child Health and Human Development: Rosemary D Higgins, MD. National Institute on Drug Abuse: Vincent L Smeriglio, PhD; Nicolette Borek, PhD. RTI International (U10 HD36790): W Kenneth Poole, PhD; Abhik Das, PhD; Jane Hammond, PhD; Debra Fleischmann, BS. University of Miami Holtz Children's Hospital (GCRC M01 RR16587, U10 HD21397): Charles R Bauer, MD; Ann L Graziotti, MSN, ARNP; Rafael Guzman, MSW; Carmel Azemar, MSW. University of Tennessee (U10 HD42638): Henrietta S Bada, MD; Toni Whitaker, MD; Charlotte Bursi, MSSW; Pamela Lenoue, RN Wayne State University Hutzel Women's Hospital and Children's Hospital of Michigan (U10 HD21385)-Seetha Shankaran, MD; Eunice Woldt, RN MSN; Jay Ann Nelson, BSN. Supported by the Eunice Kennedy Shriver. The National Institute of Child Health and Human Development. Grant Numbers: U10HD21385 (S Shankaran) 10HD36790(C Bann) U10HD27904 (B Lester), U10HD42638 (H Bada) and U10HD21397 (CR Bauer). NR 33 TC 12 Z9 12 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD NOV PY 2011 VL 31 IS 11 BP 711 EP 716 DI 10.1038/jp.2011.14 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 842IH UT WOS:000296590600004 PM 21415836 ER PT J AU Saksena, S Slee, A Waldo, AL Freemantle, N Reynolds, M Rosenberg, Y Rathod, S Grant, S Thomas, E Wyse, DG AF Saksena, Sanjeev Slee, April Waldo, Albert L. Freemantle, Nick Reynolds, Mathew Rosenberg, Yves Rathod, Snehal Grant, Shannon Thomas, Elizabeth Wyse, D. George TI Cardiovascular Outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) An Assessment of Individual Antiarrhythmic Drug Therapies Compared With Rate Control With Propensity Score-Matched Analyses SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE antiarrhythmic drugs; atrial fibrillation; cardiovascular hospitalizations; cardiovascular outcomes; clinical trials; outcomes research ID SINUS RHYTHM; CATHETER ABLATION; UNITED-STATES; MORTALITY; EVENTS; IMPACT AB Objectives The impact of individual antiarrhythmic drugs (AADs) on mortality and hospital stay in atrial fibrillation (AF) was evaluated. Background Cardiovascular (CV) outcomes in AF patients receiving pharmacologic rhythm control therapy have not been compared with rate control therapy on the basis of AAD selection. Methods We compared CV outcomes in the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial in subgroups defined by the initial AAD selected with propensity score matched subgroups from the rate arm (Rate). Results Seven hundred twenty-nine amiodarone patients, 606 sotalol patients, and 268 Class 1C patients were matched. The composite outcome of mortality or cardiovascular hospital stays (CVH) showed better outcomes with Rate compared with amiodarone (hazard ratio [HR]: 1.18, 95% confidence interval [CI]: 1.03 to 1.36, p = 0.02), sotalol (HR: 1.32, 95% CI: 1.13 to 1.54, p < 0.001), and Class 1C (HR: 1.22, 95% CI: 0.97 to 1.56, p = 0.10). There was a nonsignificant increase in mortality with amiodarone (HR: 1.20, 95% CI: 0.94 to 1.53, p = 0.15) with the risk of non-CV death being significantly higher with amiodarone versus Rate (HR: 1.11, 95% CI: 1.01 to 1.24, p = 0.04). First CVH event rates at 3 years were 47% for amiodarone, 50% for sotalol, and 44% for Class 1C versus 40%, 40%, and 36%, respectively, for Rate (amiodarone HR: 1.20, 95% CI: 1.03 to 1.40, p = 0.02, sotalol HR: 1.364, 95% CI: 1.16 to 1.611, p < 0.001, Class 1C HR: 1.24, 95% CI: 0.96 to 1.60, p = 0.09). Time to CVH with intensive care unit stay or death was shorter with amiodarone (HR: 1.22, 95% CI: 1.02 to 1.46, p = 0.03). Conclusions In AFFIRM, composite mortality and CVH outcomes differed for Rate and AADs due to differences in CVH; CVH event rates during follow-up were high for all cohorts, but they were higher for all groups on AADs. Death, intensive care unit hospital stay, and non-CV death were more frequent with amiodarone. (Atrial Fibrillation Follow-Up Investigation of Rhythm Management; NCT00000556) (J Am Coll Cardiol 2011; 58: 1975-85) (C) 2011 by the American College of Cardiology Foundation C1 [Saksena, Sanjeev; Slee, April; Waldo, Albert L.; Freemantle, Nick; Reynolds, Mathew; Rathod, Snehal; Grant, Shannon; Thomas, Elizabeth; Wyse, D. George] Electrophysiol Res Fdn, Warren, NJ USA. [Rosenberg, Yves] NHLBI, Bethesda, MD 20892 USA. RP Saksena, S (reprint author), RWJ Med Sch, Dept Med, 161 Washington Valley Rd,Suite 201, Warren, NJ 07059 USA. EM cmenj@aol.com OI Freemantle, Nick/0000-0001-5807-5740 FU National Heart Lung and Blood Institute; Medtronic Inc.; St. Jude Medical Inc.; Sanofi-Aventis; Sorin Group; Aryx Pharmaceuticals FX Dr. Saksena is or has been a consultant, investigator, and research grant recipient for the National Heart Lung and Blood Institute, Medtronic Inc., St. Jude Medical Inc., Sanofi-Aventis, Sorin Group, and Aryx Pharmaceuticals; and has been a Speakers' Bureau member for Sanofi-Aventis. Dr. Waldo is a consultant to Sanofi-Aventis, Ortho-McNeil-Janssen, Biotronik, St. Jude Medical, Daiichi, Sankyo Pharmaceuticals, Medtronic Inc., Astellas Pharma, Biosense Webster Inc., Bristol-Myers Squibb, Portola, Boehringer Ingelheim, CardioInsight Technologies, Merck, AtriCure Inc., and Sanofi-Aventis; and is a speaker for Sanofi-Aventis. Dr. Freemantle is a consultant for Sanofi-Aventis, Merck, Pfizer, Eli Lilly, Novo Nordisk, and Medtronic. Dr. Reynolds has received a research grant and is a consultant/advisory board member for Sanofi-Aventis. Dr. Wyse is a consultant to Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Sanofi-Aventis, Biotronik, Boston Scientific/Guidant, National Heart, Lung and Blood Institute, Duke Clinical Research Institute, European Commission, Merck, Medtronic, and Bayer, and Speakers' Bureau member for Sanofi-Aventis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. For list of investigators and affiliated institutions, please see the Online Appendix. NR 22 TC 47 Z9 50 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD NOV 1 PY 2011 VL 58 IS 19 BP 1975 EP 1985 DI 10.1016/j.jacc.2011.07.036 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 841VC UT WOS:000296542300008 PM 22032709 ER PT J AU Sorlie, P Wei, GS AF Sorlie, Paul Wei, Gina S. TI Population-Based Cohort Studies: Still Relevant? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT News Item DE cohort studies; epidemiology; NHLBI ID ASSOCIATION; CONSORTIUM; HEALTH; HEART; RISK AB This commentary discusses the question whether observational epidemiology studies using a population-based cohort design continue to make an impact on the prevention and treatment of cardiovascular disease. Although these studies are large and comprehensive, have they advanced from the early recognition of traditional risk factors to become relevant in the current complex research environment? Five themes are discussed: 1) their role in scientific discovery, including in the context of clinical trials' role in interventional research; 2) their value in encompassing diverse ethnic and age groups to remain relevant to the changing diversity of the United States; 3) the research potential of combining these datasets into large consortia; 4) the ability to use advances in biomedical research technologies; and 5) the recognition that these are national resources that allow outside research community to analyze the collected data and to originate novel ancillary studies. The National Heart, Lung, and Blood Institute longitudinal cohort studies offer opportunities that hold great promise in improving evaluation of personal risk, identifying mechanisms of disease, and directing potential targets for behavior and medical interventions. (J Am Coll Cardiol 2011; 58: 2010-3) (C) 2011 by the American College of Cardiology Foundation C1 [Sorlie, Paul; Wei, Gina S.] NHLBI, Epidemiol Branch, Prevent & Populat Sci Program, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Sorlie, P (reprint author), NHLBI, Epidemiol Branch, Prevent & Populat Sci Program, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10210, Bethesda, MD 20892 USA. EM sorliep@nhlbi.nih.gov NR 19 TC 10 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD NOV 1 PY 2011 VL 58 IS 19 BP 2010 EP 2013 DI 10.1016/j.jacc.2011.08.020 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 841VC UT WOS:000296542300014 PM 22032715 ER PT J AU Loeb, S Metter, EJ Carter, HB AF Loeb, Stacy Metter, E. Jeffrey Carter, H. Ballentine TI Re: An Empirical Evaluation of Guidelines on Prostate-Specific Antigen Velocity in Prostate Cancer Detection SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Loeb, Stacy] NYU, Dept Urol, Sch Med, New York, NY 10016 USA. [Carter, H. Ballentine] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Metter, E. Jeffrey] NIA, NIH, Clin Res Branch, Baltimore, MD 21224 USA. RP Loeb, S (reprint author), NYU, Dept Urol, Sch Med, 550 1st Ave,VZ30 6th Floor 612, New York, NY 10016 USA. EM stacyloeb@gmail.com OI Loeb, Stacy/0000-0003-3933-9207 NR 6 TC 2 Z9 2 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 NOV PY 2011 VL 103 IS 21 BP 1636 EP U78 DI 10.1093/jnci/djr352 PG 2 WC Oncology SC Oncology GA 843HK UT WOS:000296662700012 PM 21926375 ER PT J AU Gipson, C Brown, P AF Gipson, Chester Brown, Patricia TI A word from USDA and OLAW SO LAB ANIMAL LA English DT Editorial Material C1 [Gipson, Chester] USDA, APHIS, AC, Washington, DC 20250 USA. [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. RP Gipson, C (reprint author), USDA, APHIS, AC, Washington, DC 20250 USA. NR 1 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 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD NOV PY 2011 VL 40 IS 11 BP 338 EP 338 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 843GM UT WOS:000296660300015 PM 22012191 ER PT J AU Launer, LJ Miller, ME Williamson, JD Lazar, RM Gerstein, HC Murray, AM Sullivan, M Horowitz, KR Ding, JZ Marcovina, S Lovato, LC Lovato, J Margolis, KL O'Connor, P Lipkin, EW Hirsch, J Coker, L Maldjian, J Sunshine, JL Truwit, C Davatzikos, C Bryan, RN AF Launer, Lenore J. Miller, Michael E. Williamson, Jeff D. Lazar, Ron M. Gerstein, Hertzel C. Murray, Anne M. Sullivan, Mark Horowitz, Karen R. Ding, Jingzhong Marcovina, Santica Lovato, Laura C. Lovato, James Margolis, Karen L. O'Connor, Patrick Lipkin, Edward W. Hirsch, Joy Coker, Laura Maldjian, Joseph Sunshine, Jeffrey L. Truwit, Charles Davatzikos, Christos Bryan, R. Nick CA ACCORD MIND Investigators TI Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy SO LANCET NEUROLOGY LA English DT Article ID COGNITIVE FUNCTION; ALZHEIMER-DISEASE; WHITE-MATTER; ATROPHY; MRI; PROGRESSION; IMPAIRMENT; DEMENTIA; METAANALYSIS; MELLITUS AB Background People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control. Methods The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7.5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6.0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7.0-7.9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSSI) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910. Findings We consecutively enrolled 2977 patients (mean age 62.5 years; SD 5.8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0.32, 95% CI -0.28 to 0.91; p=0.2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4.62, 2.0 to 7.3; p=0.0007). Interpretation Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants. C1 [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Miller, Michael E.; Lovato, Laura C.; Lovato, James] Wake Forest Univ, Dept Biostat Sci, Sch Med, Winston Salem, NC 27109 USA. [Lazar, Ron M.] Columbia Univ Coll Phys & Surg, Dept Neurol Surg, New York, NY 10032 USA. [Lazar, Ron M.] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Murray, Anne M.; Truwit, Charles] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Murray, Anne M.] Chron Dis Res Grp, Minneapolis, MN USA. [Horowitz, Karen R.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. [Marcovina, Santica] Univ Washington, NW Lipid Metab & Diabet Res Labs, Seattle, WA 98195 USA. [Gerstein, Hertzel C.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Sullivan, Mark] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Margolis, Karen L.; O'Connor, Patrick] Hlth Partners Res Fdn, Minneapolis, MN USA. [Lipkin, Edward W.] Univ Washington, Med Ctr, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Hirsch, Joy] Columbia Univ, Dept Radiol, New York, NY USA. [Hirsch, Joy] Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA. [Maldjian, Joseph] Wake Forest Univ, Baptist Med Ctr, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Maldjian, Joseph] Wake Forest Univ, Ctr Diabet Res, Baptist Med Ctr, Winston Salem, NC 27109 USA. [Sunshine, Jeffrey L.] Case Western Reserve Univ, Univ Hosp, Case Ctr Imaging Res, Cleveland, OH 44106 USA. [Truwit, Charles] Hennepin Fac Associates Facil, Minneapolis, MN USA. [Davatzikos, Christos; Bryan, R. Nick] Univ Penn Hlth Syst, Dept Radiol, Philadelphia, PA USA. [Williamson, Jeff D.; Ding, Jingzhong; Coker, Laura] Wake Forest Univ, Dept Internal Med, Roena B Kulynych Ctr Memory, Winston Salem, NC 27109 USA. [Coker, Laura] Wake Forest Univ, Dept Social Sci & Hlth Policy, Winston Salem, NC 27109 USA. [Gerstein, Hertzel C.] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. RP Launer, LJ (reprint author), NIA, Intramural Res Program, NIH, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov RI Gerstein, Hertzel/B-1235-2013; Melhem, Elias/E-5205-2013; Bryan, R. Nick/P-1661-2014; OI Gerstein, Hertzel/0000-0001-8072-2836; Hirsch, Joy/0000-0002-1418-6489 FU US National Institute on Aging; US National Heart, Lung, and Blood Institute; Sanofi-Aventis; GlaxoSmithKline; Eli Lilly; Novo Nordisk; AstraZeneca; Bristol-Myers Squibb; Roche; Merck; Bayer; Janssen-Ortho; Pronova; Boehringer Ingelheim; NIA; NHLBI [AG-0002, N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184] FX Funding US National Institute on Aging and US National Heart, Lung, and Blood Institute.; HCG has received consulting fees from Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Roche, Merck, Bayer, and Janssen-Ortho; institutional grant support to McMaster University from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, Merck, Pronova, Roche, Eli Lilly, and Boehringer Ingelheim; and lecture fees from Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, and Novo Nordisk. All other authors declare that they have no conflicts of interest.; ACCORD MIND was funded through an intra-agency agreement between NIA and NHLBI (AG-0002) and the NIA Intramural Research Program. ACCORD was funded by NHLBI (N01-HC-95178; N01-HC-95179; N01-HC-95180; N01-HC-95181; N01-HC-95182; N01-HC-95183; N01-HC-95184). The following companies provided study drugs, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough. NR 38 TC 159 Z9 161 U1 4 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2011 VL 10 IS 11 BP 969 EP 977 DI 10.1016/S1474-4422(11)70188-0 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 839WJ UT WOS:000296399900006 PM 21958949 ER PT J AU Thomalla, G Cheng, B Ebinger, M Hao, Q Tourdias, T Wu, O Kim, JS Breuer, L Singer, OC Warach, S Christensen, S Treszl, A Forkert, ND Galinovic, I Rosenkranz, M Engelhorn, T Kohrmann, M Endres, M Kang, DW Dousset, V Sorensen, AG Liebeskind, DS Fiebach, JB Fiehler, J Gerloff, C AF Thomalla, Goetz Cheng, Bastian Ebinger, Martin Hao, Qing Tourdias, Thomas Wu, Ona Kim, Jong S. Breuer, Lorenz Singer, Oliver C. Warach, Steven Christensen, Soren Treszl, Andras Forkert, Nils D. Galinovic, Ivana Rosenkranz, Michael Engelhorn, Tobias Koehrmann, Martin Endres, Matthias Kang, Dong-Wha Dousset, Vincent Sorensen, A. Gregory Liebeskind, David S. Fiebach, Jochen B. Fiehler, Jens Gerloff, Christian CA STIR Imaging Investigator VISTA Imaging Investigator TI DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4-5 h if symptom onset (PRE-FLAIR): a multicentre observational study SO LANCET NEUROLOGY LA English DT Article ID INVERSION-RECOVERY FLAIR; UNKNOWN-ONSET; CEREBRAL INFARCTION; CIRCADIAN VARIATION; PREDICT TIME; DIFFUSION; THROMBOLYSIS; MRI; MANAGEMENT; ALTEPLASE AB Background Many patients with stroke are precluded from thrombolysis treatment because the time from onset of their symptoms is unknown. We aimed to test whether a mismatch in visibility of an acute ischaemic lesion between diffusion-weighted MRI (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI (DWI-FLAIR mismatch) can be used to detect patients within the recommended time window for thrombolysis. Methods In this multicentre observational study, we analysed clinical and MRI data from patients presenting between Jan 1,2001, and May 31,2009, with acute stroke for whom DWI and FLAIR were done within 12 h of observed symptom onset. Two neurologists masked to clinical data judged the visibility of acute ischaemic lesions on DWI and FLAIR imaging, and DWI-FLAIR mismatch was diagnosed by consensus. We calculated predictive values of DWI-FLAIR mismatch for the identification of patients with symptom onset within 4.5 h and within 6 h and did multivariate regression analysis to identify potential confounding covariates. This study is registered with ClinicalTrials.gov, number NCT01021319. Findings The final analysis included 543 patients. Mean age was 66.0 years (95% CI 64.7-67.3) and median National Institutes of Health Stroke Scale score was 8 (IQR 4-15). Acute ischaemic lesions were identified on DWI in 516 patients (95%) and on FLAIR in 271 patients (50%). Interobserver agreement for acute ischaemic lesion visibility on FLAIR imaging was moderate (kappa=0.569,95% CI 0.504-0.634). DWI-FLAIR mismatch identified patients within 4.5 h of symptom onset with 62% (95% CI 57-67) sensitivity, 78% (72-84) specificity, 83% (79-88) positive predictive value, and 54% (48-60) negative predictive value. Multivariate regression analysis identified a longer time to MRI (p<0.0001), a lower age (p=0-0009), and a larger DWI lesion volume (p=0.0226) as independent predictors of lesion visibility on FLAIR imaging. Interpretation Patients with an acute ischaemic lesion detected with DWI but not with FLAIR imaging are likely to be within a time window for which thrombolysis is safe and effective. These findings lend support to the use of DWI-FLAIR mismatch for selection of patients in a future randomised trial of thrombolysis in patients with unknown time of symptom onset. C1 [Thomalla, Goetz; Cheng, Bastian; Rosenkranz, Michael; Gerloff, Christian] Univ Klinikum Hamburg Eppendorf, Neurol Klin & Poliklin, Kopf & Neurozentrum, D-20246 Hamburg, Germany. [Treszl, Andras] Univ Klinikum Hamburg Eppendorf, Inst Med Biometrie & Epidemiol, D-20246 Hamburg, Germany. [Forkert, Nils D.] Univ Klinikum Hamburg Eppendorf, Inst Computat Neurosci, D-20246 Hamburg, Germany. [Fiehler, Jens] Univ Klinikum Hamburg Eppendorf, Klin & Poliklin Neuroradiol Diagnost & Intervent, Diagnost Zentrum, D-20246 Hamburg, Germany. [Ebinger, Martin; Galinovic, Ivana; Fiebach, Jochen B.] Charite Univ Med Berlin, Ctr Schlaganfallforsch, Berlin, Germany. [Endres, Matthias] Charite Univ Med Berlin, Dept Neurol, Berlin, Germany. [Hao, Qing; Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Tourdias, Thomas; Dousset, Vincent] Univ Bordeaux, Inst Bioimagerie Bordeaux, Serv NeuroImagerie Diagnost & Therapeut, CHU Bordeaux,CNRS UMS 3428, Bordeaux, France. [Wu, Ona; Sorensen, A. Gregory] Harvard Univ, Sch Med, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging,Massachus, Boston, MA 02115 USA. [Kim, Jong S.; Kang, Dong-Wha] Univ Ulsan, Asan Med Ctr, Dept Neurol, Coll Med, Seoul, South Korea. [Breuer, Lorenz; Koehrmann, Martin] Univ Erlangen Nurnberg, Dept Neurol, D-8520 Erlangen, Germany. [Engelhorn, Tobias] Univ Erlangen Nurnberg, Dept Neuroradiol, Erlangen, Germany. [Singer, Oliver C.] Goethe Univ Frankfurt, Neurol Klin, Univ Klinikum, Frankfurt, Germany. [Warach, Steven] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Christensen, Soren] Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Melbourne, Vic 3050, Australia. RP Thomalla, G (reprint author), Univ Klinikum Hamburg Eppendorf, Neurol Klin & Poliklin, Kopf & Neurozentrum, Martinistr 52, D-20246 Hamburg, Germany. EM thomalla@uke.uni-hamburg.de RI Forkert, Nils Daniel/K-6273-2012 OI Forkert, Nils Daniel/0000-0003-2556-3224 FU French Government; Astra Zeneca; Sanofi-Aventis; Boehringer Ingelheim; Lundbeck; Siemens; Syngis; Synard; Bayer Vital; EBS Technologies; GlaxoSmithKline; Pfizer; Silk Road Medical; Union Chimique Beige; National Institutes of Health; American College of Radiology Imaging Network; Biogen; Genzyme; Mitsubishi; General Electrics; Olea; Else Kroner-Fresenius-Stiftung; French Government (PHRC); Else Knoner-Fresenius-Stiftung [2009_A36]; EPITHET (Echoplanar Imaging Thrombolysis Evaluation Trial) investigators; University of California; Los Angeles Stroke investigators; VIRAGE; Departments of Neurology and Neuroradiology; Federal Ministry of Education and Research via the grant Center for Stroke Research Berlin [01 EO 0801]; European Union [202213, 223153]; Volkswagen Foundation; National Health and Medical Research Council (Australia); National Stroke Foundation (Australia); Heart Foundation of Australia; French national grant FX VD has received a national grant from the French Government. MEn has received grant support from Astra Zeneca and Sanofi-Aventis, has participated in advisory board meetings of Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Sanofi-Aventis, and has received honoraria from Novartis, Pfizer, Bayer, Astra Zeneca, Boehringer Ingelheim, Sanofi-Aventis, Trommsdorff, Berlin-Chemie, GlaxoSmithKline, and Bristol-Myers Squibb. JBF has received fees as a board member, consultant, or lecturer from Boehringer Ingelheim, Lundbeck, Siemens, Syngis, and Synard. CG has received fees as a consultant or lecture fees from Bayer Vital, Boehringer Ingelheim, EBS Technologies, GlaxoSmithKline, Lundbeck, Pfizer, Sanofi-Aventis, Silk Road Medical, and Union Chimique Beige. DSL has received fees as a consultant for CoAxia and Concentric Medical. AGS was supported by grants from the National Institutes of Health, has received fees as a board member, consultant, or lecturer from the American College of Radiology Imaging Network, Biogen, Genzyme, Mitsubishi, and has received royalties from General Electrics and Olea. GT has received a research grant from the Else Kroner-Fresenius-Stiftung. TT has received a national grant from the French Government (PHRC). OW was supported in part by grants from the National Institutes of Health. LB, BC, SC, MEb, TE, JF, NDF, IG, QH, D-WK, JSK, MK, MR, OCS, AT, and SW declare that they have no conflicts of interest.; PRE-FLAIR received funding from the Else Knoner-Fresenius-Stiftung (2009_A36). Funding was provided for central data collection and analysis; there was no funding for inclusion of patients. We thank the EPITHET (Echoplanar Imaging Thrombolysis Evaluation Trial) investigators, the University of California, Los Angeles Stroke investigators, all co-investigators of VIRAGE. and all our colleagues from the Departments of Neurology and Neuroradiology, and medical and technical staff in the participating centres for their support. In Berlin, data were collected within the 1000+ study, which has received funding from the Federal Ministry of Education and Research via the grant Center for Stroke Research Berlin (01 EO 0801). This work was further supported by the European Union Seventh Framework Programme grant agreement No 202213 and No 223153 (European Stroke Network), the Volkswagen Foundation, and the Deutsche Forschungsgemeinschaft. EPITHET was funded by the National Health and Medical Research Council (Australia), the National Stroke Foundation (Australia), and the Heart Foundation of Australia. VIRAGE is supported by French national grant PHRC. NR 37 TC 128 Z9 134 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2011 VL 10 IS 11 BP 978 EP 986 DI 10.1016/S1474-4422(11)70192-2 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 839WJ UT WOS:000296399900007 PM 21978972 ER PT J AU Mathews, MS Chighvinadze, D Gach, HM Uzal, FA Madsen, SJ Hirschberg, H AF Mathews, Marlon S. Chighvinadze, David Gach, H. Michael Uzal, Francisco A. Madsen, Steen J. Hirschberg, Henry TI Cerebral Edema Following Photodynamic Therapy Using Endogenous and Exogenous Photosensitizers in Normal Brain SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE photodynamic therapy; PDT; cerebral edema; ALA; AlPcS2a; vasogenic edema; endogenous photosensitizer; exogenous photosensitizer; amino levulenic acid; aluminum phthalocyanine disulfonate ID SULFONATED ALUMINUM PHTHALOCYANINES; 5-AMINOLEVULINIC ACID; GLIOBLASTOMA-MULTIFORME; INTRACRANIAL-PRESSURE; MALIGNANT GLIOMA; DRUG-DELIVERY; HEAD-INJURY; BARRIER; PHOTOFRIN; RESECTION AB Background and Objective: Failure of treatment for high-grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy such as photodynamic therapy (PDT) could be of benefit. The increase in brain edema following PDT using endogenous and exogenous photosensitizers was compared in terms of animal survival, MR imaging, and histopathological changes in normal brain. Materials and Methods: Fischer rats were exposed to increasing laser light treatment following intraperitoneal injection of either the photosensitizers 5-aminolevulinic acid (ALA) or aluminum phthalocyanine disulfonate (AlPcS2a). Light treatment was applied either via an optical fiber inserted directly into the brain parenchyma or through a fiber applied to the surface of the intact skull. Edema development was followed by T2-weighted MR imaging. Results: ALA and AlPcS2a PDT resulted in a fluence dependent increase in cerebral edema and mortality. AlPcS2a PDT showed significant edema and mortality even at low fluences following interstitial light delivery, which was reduced with surface illumination. The mechanism of edema was determined to be vasogenic by response to steroid therapy and confirmed on histological images. Conclusions: T2 and contrast enhanced T1 MRI scanning proved to be a highly effective and noninvasive modality in following the development of the edema reaction and the degree and time course of blood-brain barrier dysfunction thus allowing the use of fewer animals. ALA mediated PDT induced a lower edema reaction than that observed with the photosensitizer AlPcS2a. Lasers Surg. Med. 43: 892-900, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Mathews, Marlon S.] Univ Calif Irvine, Dept Neurosurg, Orange, CA 92668 USA. [Mathews, Marlon S.; Hirschberg, Henry] Univ Calif Irvine, Beckman Laser Inst, Irvine, CA USA. [Chighvinadze, David; Gach, H. Michael; Madsen, Steen J.; Hirschberg, Henry] Univ Nevada, Dept Hlth Phys & Diagnost Sci, Las Vegas, NV 89154 USA. [Uzal, Francisco A.] Univ Calif Davis, Sch Vet Med, San Bernardino, CA USA. [Gach, H. Michael] NCI, Las Vegas, NV USA. RP Mathews, MS (reprint author), 101 City Dr S,Bldg 56,Suite 400, Orange, CA 92868 USA. EM marlonmathews@yahoo.com FU Nevada Cancer Institute; NVCI; Norwegian Radium Hospital Research Foundation FX The authors are grateful for the support of the Nevada Cancer Institute which sponsored this research through the NVCI Collaborative Grant Program. Henry Hirschberg is grateful for the support of the Norwegian Radium Hospital Research Foundation. Portions of this work were made possible through access to the Laser-Microbeam and Medical Program (LAMMP) and the Chao Cancer Center Optical Biology Shared Resource at the University of California, Irvine. NR 41 TC 10 Z9 12 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD NOV PY 2011 VL 43 IS 9 BP 892 EP 900 DI 10.1002/lsm.21135 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 840RZ UT WOS:000296460000005 PM 22006731 ER PT J AU Kreitman, RJ AF Kreitman, Robert J. TI Synergistic targeting of leukemia with leukotoxin and chemotherapy SO LEUKEMIA RESEARCH LA English DT Editorial Material ID ANTI-MESOTHELIN IMMUNOTOXIN; PHASE-I; SS1P; INFUSION; TOXIN C1 [Kreitman, Robert J.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NIH, Bldg 37,Room 5124B,9000 Rockville Pike, Bethesda, MD 20854 USA. EM kreitmar@mail.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD NOV PY 2011 VL 35 IS 11 BP 1438 EP 1439 DI 10.1016/j.leukres.2011.06.028 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 841YU UT WOS:000296551900018 PM 21764132 ER PT J AU Han, PKJ Klein, WMP Arora, NK AF Han, Paul K. J. Klein, William M. P. Arora, Neeraj K. TI Varieties of Uncertainty in Health Care: A Conceptual Taxonomy SO MEDICAL DECISION MAKING LA English DT Article DE uncertainty; risk; taxonomy; framework ID SHARED DECISION-MAKING; RISK-ASSESSMENT; AMBIGUITY; PHYSICIANS; PROBABILITY; PREFERENCES; INFORMATION; INTOLERANCE; TOLERANCE; SCIENCE AB Uncertainty is a pervasive and important problem that has attracted increasing attention in health care, given the growing emphasis on evidence-based medicine, shared decision making, and patient-centered care. However, our understanding of this problem is limited, in part because of the absence of a unified, coherent concept of uncertainty. There are multiple meanings and varieties of uncertainty in health care that are not often distinguished or acknowledged although each may have unique effects or warrant different courses of action. The literature on uncertainty in health care is thus fragmented, and existing insights have been incompletely translated to clinical practice. This article addresses this problem by synthesizing diverse theoretical and empirical literature from the fields of communication, decision science, engineering, health services research, and psychology and developing a new integrative conceptual taxonomy of uncertainty. A 3-dimensional taxonomy is proposed that characterizes uncertainty in health care according to its fundamental sources, issues, and locus. It is shown how this new taxonomy facilitates an organized approach to the problem of uncertainty in health care by clarifying its nature and prognosis and suggesting appropriate strategies for its analysis and management. C1 [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04105 USA. [Klein, William M. P.; Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Han, PKJ (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 39 Forest Ave, Portland, ME 04105 USA. EM hanp@mmc.org OI Han, Paul/0000-0003-0165-1940 FU National Cancer Institute, National Institutes of Health [HHSN261200900524P] FX Received 29 June 2010 from the Center for Outcomes Research and Evaluation, Maine Medical Center, Portland, Maine (PKJH) and the Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland (WMPK, NKA). This work was supported by contract HHSN261200900524P from the National Cancer Institute, National Institutes of Health. Portions of this work were presented at the 2009 International Conference on Communication in Healthcare, Miami, Florida, October 4, 2009. Revision accepted for publication 17 November 2010. NR 66 TC 101 Z9 101 U1 4 U2 35 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD NOV-DEC PY 2011 VL 31 IS 6 BP 828 EP 838 DI 10.1177/0272989X11393976 PG 11 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 843UA UT WOS:000296697100010 PM 22067431 ER PT J AU Shao, HP Xi, LQ Raffeld, M Feldman, AL Ketterling, RP Knudson, R Rodriguez-Canales, J Hanson, J Pittaluga, S Jaffe, ES AF Shao, Haipeng Xi, Liqiang Raffeld, Mark Feldman, Andrew L. Ketterling, Rhett P. Knudson, Ryan Rodriguez-Canales, Jaime Hanson, Jeffrey Pittaluga, Stefania Jaffe, Elaine S. TI Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases SO MODERN PATHOLOGY LA English DT Article DE CLL; dendritic cells; histiocytic sarcoma; laser capture microdissection; p53; transdifferentiation ID FOLLICULAR LYMPHOMA; TRANSCRIPTION FACTORS; B-LYMPHOCYTES; TRANSFORMATION; TRANSDIFFERENTIATION; DIFFERENTIATION; MICRODISSECTION; PLURIPOTENCY; MACROPHAGES; COMMITMENT AB Histiocytic and interdigitating dendritic cell sarcomas are rare tumors originating from bone marrow-derived myeloid stem cells. Recent studies have shown evidence of cross-lineage transdifferentiation of B cells in follicular lymphoma to histiocytic and dendritic cell sarcomas. In this study, we report the morphologic, molecular and cytogenetic analysis of seven cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with histiocytic and dendritic cell sarcomas. All seven patients were elderly males (median age 71 years). The B-cell neoplasms preceded the development of the histiocytic and dendritic cell sarcomas in six of seven patients, and one patient had both tumors diagnosed at the same time. The tumors included four interdigitating dendritic cell sarcomas: one Langerhans cell sarcoma, one histiocytic sarcoma and one immature neoplasm with evidence of histiocytic origin. Laser-capture microdissection and PCR analysis showed identical clonal immunoglobulin gene rearrangements in the two phenotypically distinct components in all cases. There was a preferential usage of IGHV4-39 by the V-D-J gene rearrangement. By fluorescence in situ hybridization (FISH) analysis, two cases showed deletion 17p in both components, whereas four cases had normal cytogenetic findings by FISH in the CLL/SLL cells, but acquired cytogenetic abnormalities in the corresponding histiocytic and dendritic tumors. Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in five of six cases studied. Compared with the CLL/SLL cells, the histiocytic/dendritic cells were largely negative for PAX5, but showed strong expression of PU.1 and variable and weak expression of CEBP beta. Our study provides evidence for transdifferentiation of CLL/SLL B cells to tumors of dendritic and less often histiocytic lineage, and suggests that secondary genetic events may play a role in this phenomenon. Modern Pathology (2011) 24, 1421-1432; doi:10.1038/modpathol.2011.102; published online 10 June 2011 C1 [Shao, Haipeng; Xi, Liqiang; Raffeld, Mark; Rodriguez-Canales, Jaime; Hanson, Jeffrey; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Feldman, Andrew L.; Ketterling, Rhett P.; Knudson, Ryan] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. EM ejaffe@mail.nih.gov RI Feldman, Andrew/D-5028-2012; OI Rodriguez-Canales, Jaime/0000-0002-0885-2377; Jaffe, Elaine/0000-0003-4632-0301 FU Center for Cancer Research, National Cancer Institute FX This study was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute. We thank Dr Anne Vandersteenhoven of Palmetto Richland Memorial Hospital (Columbia, SC), Dr Fan Zhou of Southwest Washington Medical Center (Vancouver, WA), Dr Stephen C Groo of Western Regional Medical Command and Madigan Army Medical Center (Tacoma, WA), Dr Wayne Tam of New York Presbyterian Hospital (New York, NY), Dr Yu Wang of St Luke's Cornwall Hospital (Newburgh, NY) and Dr Nathan A Dunsmore of Greater Baltimore Medical Center (Baltimore, MD) for their contribution of cases in this study. We also thank Thu Anh Pham and Trinh Pham in our molecular laboratory for their assistance with the molecular studies and Cynthia Harris and Hong Jin in our immunohistology lab for their help with the immunostains. NR 46 TC 42 Z9 45 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD NOV PY 2011 VL 24 IS 11 BP 1421 EP 1432 DI 10.1038/modpathol.2011.102 PG 12 WC Pathology SC Pathology GA 844HT UT WOS:000296739000002 PM 21666687 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, Jennifer TI An evolving paradigm for the secretory pathway? SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GOLGI-APPARATUS; BREFELDIN-A; LIVING CELLS; MEMBRANE-TRANSPORT; RECYCLING PATHWAY; PLASMA-MEMBRANE; PROTEIN; YEAST; MICROSCOPY; DYNAMICS AB The paradigm that the secretory pathway consists of a stable endoplasmic reticulum and Golgi apparatus, using discrete transport vesicles to exchange their contents, gained important support from groundbreaking biochemical and genetic studies during the 1980s. However, the subsequent development of new imaging technologies with green fluorescent protein introduced data on dynamic processes not fully accounted for by the paradigm. As a result, we may be seeing an example of how a paradigm is evolving to account for the results of new technologies and their new ways of describing cellular processes. C1 Eunice Shriver Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Shriver Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov NR 47 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 1 PY 2011 VL 22 IS 21 BP 3929 EP 3932 DI 10.1091/mbc.E11-05-0452 PG 4 WC Cell Biology SC Cell Biology GA 842MJ UT WOS:000296603300006 PM 22039065 ER PT J AU Salmon, ED Waterman, CM AF Salmon, E. D. Waterman, Clare M. TI How we discovered fluorescent speckle microscopy SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MICROTUBULES; DYNAMICS; TURNOVER; CELLS; ACTIN AB Fluorescent speckle microscopy (FSM) is a method for measuring the movements and dynamic assembly of macromolecular assemblies such as cytoskeletal filaments (e.g., microtubules and actin) or focal adhesions within large arrays in living cells or in preparations in vitro. The discovery of the method depended on recognizing the importance of unexpected fluorescence images of microtubules obtained by time-lapse recording of vertebrate epithelial cells in culture. In cells that were injected with fluorescent tubulin at similar to 10% of the cytosol pool, microtubules typically appeared as smooth threads with a nearly constant fluorescence intensity. One day, when an unusually low concentration of fluorescent tubulin was injected into cells, the images from a sensitive cooled charge-coupled detector camera showed microtubules with an unusual "speckled" appearance-there were fluorescent dots with variable intensity and spacing along the microtubules. A first thought was that the speckles were an artifact. With further thought, we surmised that the speckles could be telling us something about stochastic association of tubulin dimers with the growing end of a microtubule. Numerous experiments confirmed the latter hypothesis. Subsequently the method we call FSM has proven to be very valuable. The speckles turned out not to be a meaningless artifact, but rather a serendipitous find. C1 [Salmon, E. D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Salmon, ED (reprint author), Univ N Carolina, Dept Biol, CB 3280, Chapel Hill, NC 27599 USA. EM tsalmon@email.unc.edu OI Waterman, Clare/0000-0001-6142-6775 NR 10 TC 2 Z9 2 U1 0 U2 2 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 NOV 1 PY 2011 VL 22 IS 21 BP 3940 EP 3942 DI 10.1091/mbc.E11-07-0646 PG 3 WC Cell Biology SC Cell Biology GA 842MJ UT WOS:000296603300009 PM 22039068 ER PT J AU Federhen, S AF Federhen, Scott TI Comment on 'Birdstrikes and barcoding: can DNA methods help make the airways safer?' SO MOLECULAR ECOLOGY RESOURCES LA English DT Editorial Material DE birdstrike; BoLD; COI; DNA barcode; GenBank; species identification AB GenBank is the database of record for public sequence data. Results reported in the scientific literature that are based on sequence data cannot be evaluated if the underlying data is not in the public record. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Federhen, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A, Bethesda, MD 20894 USA. EM federhen@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 1 TC 5 Z9 5 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-098X J9 MOL ECOL RESOUR JI Mol. Ecol. Resour. PD NOV PY 2011 VL 11 IS 6 BP 937 EP 938 DI 10.1111/j.1755-0998.2011.03054.x PG 2 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 840EN UT WOS:000296421200001 PM 21899722 ER PT J AU Prust, MJ Gropman, AL Hauser, N AF Prust, Morgan J. Gropman, Andrea L. Hauser, Natalie TI New frontiers in neuroimaging applications to inborn errors of metabolism SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Brain injury; Diffusion tensor imaging (DTI); Functional MRI (fMRI); Inborn error of metabolism (IEM); Magnetic resonance imaging neuroimaging; Magnetic resonance spectroscopy (MRS) ID SYRUP-URINE-DISEASE; MAGNETIC-RESONANCE-SPECTROSCOPY; ORNITHINE TRANSCARBAMYLASE DEFICIENCY; UREA CYCLE DISORDERS; WHITE-MATTER ABNORMALITIES; DIFFUSION-WEIGHTED MRI; ORGANIC-ACID DISORDERS; METHYLMALONIC ACIDEMIA; FABRY-DISEASE; BRAIN-TISSUE AB Most inborn inborn errors of metabolism (IEMs) are associated with potential for injury to the developing central nervous system resulting in chronic encephalopathy, though the etiopathophysiology of neurological injury have not been fully established in many disorders. Shared mechanisms can be envisioned such as oxidative injury due to over-activation of N-Methyl-D-Aspartate (NMDA) receptors with subsequent glutamatergic damage, but other causes such as energy depletion or inflammation are possible. Neuroimaging has emerged as a powerful clinical and research tool for studying the brain in a noninvasive manner. Several platforms exist to study neural networks underlying cognitive processes, white matter/myelin microstructure, and cerebral metabolism in vivo. The scope and limitations of these methods will be discussed in the context of valuable information they provide in the study and management of selected inborn errors of metabolism. This review is not meant to be an exhaustive coverage of diagnostic findings on MRI in multiple IEMs, but rather to illustrate how neuroimaging modalities beyond Ti and 12 images, can add depth to an understanding of the underlying brain changes evoked by the selected IEMs. Emphasis will be placed on techniques that are available in the clinical setting. Though technically complex, many of these modalities have moved - or soon will - to the clinical arena. (C) 2011 Elsevier Inc. All rights reserved. C1 [Prust, Morgan J.; Gropman, Andrea L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Gropman, Andrea L.; Hauser, Natalie] NHGRI, Med Genet Branch, Bethesda, MD USA. RP Gropman, AL (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM agropman@childrensnational.org FU NCRR NIH HHS [U54 RR019453]; NICHD NIH HHS [U54 HD061221] NR 84 TC 5 Z9 8 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2011 VL 104 IS 3 BP 195 EP 205 DI 10.1016/j.ymgme.2011.06.020 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800001 PM 21778100 ER PT J AU Wakabayashi, K Gustafson, AM Sidransky, E Goldin, E AF Wakabayashi, Kazuyo Gustafson, Ann Marie Sidransky, Ellen Goldin, Ehud TI Mucolipidosis type IV: An update SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Mucolipidiosis; Lysosomal storage disorder; Mucolipin; Gastrin; Corpus collosum; Cation channel ID CORPUS-CALLOSUM; CATION CHANNEL; LYSOSOMAL-STORAGE; NATURAL-HISTORY; PROTEIN TRPML1; INBORN-ERRORS; TRAFFICKING; METABOLISM; AGENESIS; VARIANT AB Mucolipidosis type IV (MLIV) is a neurodevelopmental as well as neurodegenerative disorder with severe psychomotor developmental delay, progressive visual impairment, and achlorydria. It is characterized by the presence of lysosomal inclusions in many cell types in patients. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1, a member of the transient receptor potential (TRP) cation channel family. Although approximately 70-80% of patients identified are Ashkenazi Jewish, MLIV is a pan-ethnic disorder. Importantly, while MLIV is thought to be a rare disease, its frequency may be greater than currently appreciated, for its common presentation as a cerebral palsy-like encephalopathy can lead to misdiagnosis. Moreover, patients with milder variants are often not recognized as having MLIV. This review provides an update on the ethnic distribution, clinical manifestations, laboratory findings, methods of diagnosis, molecular genetics, differential diagnosis, and treatment of patients with MLIV. An enhanced awareness of the manifestations of this disorder may help to elucidate the true frequency and range of symptoms associated with MLIV, providing insight into the pathogenesis of this multi-system disease. Published by Elsevier Inc. C1 [Wakabayashi, Kazuyo; Gustafson, Ann Marie; Sidransky, Ellen; Goldin, Ehud] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Division of Intramural Research of the National Human Genome Research Institute; National Institutes of Health FX This research was supported by the Division of Intramural Research of the National Human Genome Research Institute, and the National Institutes of Health. NR 66 TC 25 Z9 27 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2011 VL 104 IS 3 BP 206 EP 213 DI 10.1016/j.ymgme.2011.06.006 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800002 PM 21763169 ER PT J AU Sarkar, C Zhang, ZJ Mukherjee, AB AF Sarkar, Chinmoy Zhang, Zhongjian Mukherjee, Anil B. TI Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from INCL patients SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Lysosomal storage disease; Neurodegeneration; Infantile neuronal ceroid lipofuscinosis; Batten disease; PTC124; Nonsense mutation ID NEURONAL CEROID-LIPOFUSCINOSIS; NONSENSE MUTATIONS; MOUSE MODEL; DISEASE; DEFICIENCY; ACTIVATION; DISORDERS; NEURODEGENERATION; DISRUPTION; STRATEGIES AB Infantile neuronal ceroid lipofuscinosis (INCL), a lethal hereditary neurodegenerative lysosomal storage disorder, affects mostly children. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. Nonsense mutations in a gene generate premature termination codons producing truncated, nonfunctional or deleterious proteins. PPT1 nonsense-mutations account for approximately 31% of INCL patients in the US. Currently, there is no effective treatment for this disease. While aminoglycosides such as gentamycin suppress nonsense mutations, inherent toxicity of aminoglycosides prohibits chronic use in patients. PTC124 is a non-toxic compound that induces ribosomal read-through of premature termination codons. We sought to determine whether PTC124-treatment of cultured cells from INCL patients carrying nonsense mutations in the PPT1 gene would correct PPT1 enzyme-deficiency with beneficial effects. Our results showed that PTC124-treatment of cultured cells from INCL patients carrying PPT1 nonsense-mutations induced PPT1 enzymatic activity in a dose- and time-dependent manner. This low level of PPT1 enzyme activity induced by PTC124 is virtually identical to that induced by gentamycin-treatment. Even though only a modest increase in PPT1 activity was achieved by PTC124-treatment of INCL cells, this treatment reduced the levels of thioester (constituent of ceroid) load. Our results suggest that PTC124-treatment induces PPT1 enzymatic activity in cultured cells from INCL patients carrying PPT1 nonsense-mutations, and this modest enzymatic activity has demonstrable beneficial effects on these cells. The clinical relevance of these effects may be tested in animal models of INCL carrying nonsense mutations in the PPT1 gene. Published by Elsevier Inc. C1 [Sarkar, Chinmoy; Zhang, Zhongjian; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bldg 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Batten Disease Support and Research Association (BDSRA) FX We thank S.W. Levin, J.Y. Chou and I. Owens for critical review of the manuscript and helpful suggestions. We also thank H.-S. Jun for his help and suggestions for conducting the FACS analyses. This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health and by a grant from the Batten Disease Support and Research Association (BDSRA). NR 34 TC 28 Z9 28 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2011 VL 104 IS 3 BP 338 EP 345 DI 10.1016/j.ymgme.2011.05.021 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800021 PM 21704547 ER PT J AU Roberts-Pilgrim, AM Makareeva, E Myles, MH Besch-Williford, CL Brodeur, AC Walker, AL Leikin, S Franklin, CL Phillips, CL AF Roberts-Pilgrim, Anna M. Makareeva, Elena Myles, Matthew H. Besch-Williford, Cynthia L. Brodeur, Amanda C. Walker, Andrew L. Leikin, Sergey Franklin, Craig L. Phillips, Charlotte L. TI Deficient degradation of homotrimeric type I collagen, alpha 1 (I)(3) glomerulopathy in oim mice SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Collagen; Extracellular matrix; Glomerular sclerosis; Fibrosis; Matrix metalloproteinase ID EPITHELIAL-MESENCHYMAL TRANSITION; MATRIX-METALLOPROTEINASE ACTIVITY; OSTEOGENESIS IMPERFECTA MURINE; WOLCOTT-RALLISON-SYNDROME; GROWTH-FACTOR-BETA; MESANGIAL CELLS; GELATINASE-A; MOUSE MODEL; ENDOPLASMIC-RETICULUM; MOLECULAR-MECHANISM AB Col1a2-deficient (oim) mice synthesize homotrimeric type I collagen due to nonfunctional pro alpha 2(1) collagen chains. Our previous studies revealed a postnatal, progressive type I collagen glomerulopathy in this mouse model, but the mechanism of the sclerotic collagen accumulation within the renal mesangium remains unclear. The recent demonstration of the resistance of homotrimeric type I collagen to cleavage by matrix metalloproteinases (MMPs), led us to investigate the role of MMP-resistance in the glomerulosclerosis of Col1a2-deficient mice. We measured the pre- and post-translational expression of type I collagen and MMPs in glomeruli from heterozygous and homozygous animals. Both the heterotrimeric and homotrimeric isotypes of type I collagen were equally present in whole kidneys of heterozygous mice by immunohistochemistry and biochemical analysis, but the sclerotic glomerular collagen was at least 95-98% homotrimeric, suggesting homotrimeric type I collagen is the pathogenic isotype of type I collagen in glomerular disease. Although steady-state MMP and Col1a1 mRNA levels increased with the disease progression, we found these changes to be a secondary response to the deficient clearance of MMP-resistant homotrimers. Increased renal MMP expression was not sufficient to prevent homotrimeric type I collagen accumulation. (C) 2011 Elsevier Inc. All rights reserved. C1 [Roberts-Pilgrim, Anna M.; Brodeur, Amanda C.; Walker, Andrew L.; Phillips, Charlotte L.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Makareeva, Elena; Leikin, Sergey] NICHD, NIH, Bethesda, MD 20892 USA. [Myles, Matthew H.; Besch-Williford, Cynthia L.; Franklin, Craig L.] Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA. [Brodeur, Amanda C.; Phillips, Charlotte L.] Univ Missouri, Dept Child Hlth, Columbia, MO 65212 USA. RP Phillips, CL (reprint author), Univ Missouri, Dept Biochem, 117 Schweitzer Hall, Columbia, MO 65211 USA. EM arpilgrim@path.wustl.edu; makareee@mail.nih.gov; MylesM@missouri.edu; BeschWillifordC@missouri.edu; BrodeurA@health.missouri.edu; andrewwalker707@gmail.com; leikins@mail.nih.gov; FranklinC@missouri.edu; PhillipsCL@missouri.edu RI Makareeva, Elena/F-5183-2011; Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU Leda J. Sears Trust Foundation; NIH/NIDDK [DK069522]; NIH/Clinical Biodetectives Training Grant [R90-DK071510-03]; NICHD FX This work was supported in part by the Leda J. Sears Trust Foundation Grant, NIH/NIDDK Grant, DK069522, NIH/Clinical Biodetectives Training Grant, R90-DK071510-03 and the Intramural Research Program of NICHD. The funding sources had no involvement in the study design, collection, analysis or interpretation of data, writing of the report or in the decision to submit the paper for publication. NR 96 TC 5 Z9 5 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2011 VL 104 IS 3 BP 373 EP 382 DI 10.1016/j.ymgme.2011.07.025 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800026 PM 21855382 ER PT J AU Chan, K Davis, J Pai, SY Bonilla, FA Puck, JM Apkon, M AF Chan, Kee Davis, Joie Pai, Sung-Yun Bonilla, Francisco A. Puck, Jennifer M. Apkon, Michael TI A Markov model to analyze cost-effectiveness of screening for severe combined immunodeficiency (SCID) SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Severe combined immunodeficiency (SCID); Newborn screening; Cost-effectiveness; Markov models; T-cell receptor excision circle (TREC); Hematopoietic cell transplant ID STEM-CELL TRANSPLANTATION; MEDICAL DECISION-MAKING; QUALITY-OF-LIFE; THYMIC OUTPUT; HEALTH; CHILDREN; DISEASE; DEFICIENCY; UNIVERSAL; BENEFITS AB Objective: To evaluate the cost-effectiveness of universal neonatal screening for T cell lymphocytopenia in enhancing quality of life and life expectancy for children with severe combined immunodeficiency (SCID). Methods: Decision trees were created and analyzed to estimate the cost, life years, and quality adjusted life years (QALYs) across a population when universal screening for lack of T cells is used to detect SCID, as implemented in five states, compared to detection based on recognizing symptoms and signs of disease. Terminal values of each tree limb were derived through Markov models simulating the natural history of three cohorts: unaffected subjects; those diagnosed with SCID as neonates (early diagnosis); and those diagnosed after becoming symptomatic and arousing clinical suspicion (late diagnosis). Models considered the costs of screening and of care including hematopoietic cell transplantation for affected individuals. Key decision variables were derived from the literature and from a survey of families with children affected by SCID, which was used to describe the clinical history and healthcare utilization for affected subjects. Sensitivity analyses were conducted to explore the influence of these decision variables. Results: Over a 70-year time horizon, the average cost per infant was $8.89 without screening and $14.33 with universal screening. The model predicted that universal screening in the U.S. would cost approximately $22.4 million/year with a gain of 880 life years and 802 QALYs. Sensitivity analyses showed that screening test specificity and disease incidence were critical driving forces affecting the incremental cost-effectiveness ratio (ICER). Assuming a SCID incidence of 1/75,000 births and test specificity and sensitivity each at 0.99, screening remained cost-effective up to a maximum cost of $15 per infant screened. Conclusion: At our current estimated screening cost of $4.22/infant, universal screening for SCID would be a cost effective means to improve quality and duration of life for children with SCID. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chan, Kee] Boston Univ, Coll Hlth & Rehabil Sci, Sargent Coll, Dept Hlth Sci, Boston, MA 02215 USA. [Chan, Kee] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Davis, Joie] NIAID, NIH, Bethesda, MD 20892 USA. [Pai, Sung-Yun; Bonilla, Francisco A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Pai, Sung-Yun] Childrens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Pai, Sung-Yun] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bonilla, Francisco A.] Childerns Hosp, Div Immunol, Dept Med, Boston, MA USA. [Puck, Jennifer M.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Puck, Jennifer M.] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Apkon, Michael] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Apkon, Michael] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Chan, Kee; Davis, Joie; Puck, Jennifer M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Chan, Kee] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Apkon, Michael] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Apkon, Michael] Yale Univ, Sch Management, New Haven, CT 06510 USA. RP Chan, K (reprint author), Boston Univ, Coll Hlth & Rehabil Sci, Sargent Coll, Dept Hlth Sci, 635 Commonwealth Ave, Boston, MA 02215 USA. EM keechan@bu.edu FU NHGRI; NIH; Division of Intramural Research; USIDNET [NO1-AI-30070]; Jeffrey Modell Foundation FX Funds for this work came from the NHGRI, NIH, Division of Intramural Research, USIDNET grant NO1-AI-30070 to JMP and the Jeffrey Modell Foundation. We are grateful to the Immune Deficiency Foundation SCID Initiative and SCID.net for posting our survey online and to the parents of SCID children who recounted and re-lived their experiences for us in the hope that future SCID children would benefit. NR 38 TC 41 Z9 43 U1 3 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2011 VL 104 IS 3 BP 383 EP 389 DI 10.1016/j.ymgme.2011.07.007 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800027 PM 21810544 ER PT J AU Markello, TC Gahl, WA AF Markello, Thomas C. Gahl, William A. TI Response to editor for ABCC6 does not transport adenosine - Relevance to pathomechanism of pseudoxanthoma elasticum SO MOLECULAR GENETICS AND METABOLISM LA English DT Letter C1 [Markello, Thomas C.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Markello, TC (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10-10C103, Bethesda, MD 20892 USA. EM bgahl@helix.nih.gov NR 3 TC 0 Z9 0 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2011 VL 104 IS 3 BP 422 EP 422 DI 10.1016/j.ymgme.2011.08.028 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800036 ER PT J AU Fyfe, JC Kurzhals, RL Hawkins, MG Wang, P Yuhki, N Giger, U Van Winkle, TJ Haskins, ME Patterson, DF Henthorn, PS AF Fyfe, John C. Kurzhals, Rebeccah L. Hawkins, Michelle G. Wang, Ping Yuhki, Naoya Giger, Urs Van Winkle, Thomas J. Haskins, Mark E. Patterson, Donald F. Henthorn, Paula S. TI A complex rearrangement in GBE1 causes both perinatal hypoglycemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats (vol 90, pg 383, 2007) SO MOLECULAR GENETICS AND METABOLISM LA English DT Correction C1 [Fyfe, John C.; Kurzhals, Rebeccah L.] Michigan State Univ, Coll Vet Med, Lab Comparat Med Genet, E Lansing, MI 48824 USA. [Hawkins, Michelle G.; Wang, Ping; Giger, Urs; Haskins, Mark E.; Patterson, Donald F.; Henthorn, Paula S.] Univ Penn, Sch Vet Med, Med Genet Sect, Philadelphia, PA 19104 USA. [Yuhki, Naoya] NCI, Lab Genom Div, Frederick, MD 21702 USA. [Van Winkle, Thomas J.; Haskins, Mark E.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Fyfe, JC (reprint author), Michigan State Univ, Coll Vet Med, Lab Comparat Med Genet, 2209 Biomed & Phys Sci, E Lansing, MI 48824 USA. EM fyfe@cvm.msu.edu NR 1 TC 0 Z9 0 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2011 VL 104 IS 3 BP 423 EP 423 DI 10.1016/j.ymgme.2011.08.014 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800037 ER PT J AU Rosenberg, SA Kochenderfer, JN AF Rosenberg, Steven A. Kochenderfer, James N. TI Personalized Cell Transfer Immunotherapy for B-Cell Malignancies and Solid Cancers SO MOLECULAR THERAPY LA English DT Editorial Material ID CHIMERIC ANTIGEN RECEPTOR; MODIFIED T-CELLS; ANTITUMOR-ACTIVITY; ADOPTIVE IMMUNOTHERAPY; IN-VIVO; GENETIC-MODIFICATION; ADVERSE EVENT; PHASE-I; LYMPHOCYTES; PERSISTENCE C1 [Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Kochenderfer, James N.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, CRC-10,10 Ctr Dr,Room 3-3940, Bethesda, MD 20892 USA. EM sar@nih.gov NR 42 TC 5 Z9 5 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD NOV PY 2011 VL 19 IS 11 BP 1928 EP 1930 DI 10.1038/mt.2011.223 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 843VL UT WOS:000296703000002 PM 22051601 ER PT J AU Quinn, K Quirion, MR Lo, CY Misplon, JA Epstein, SL Chiorini, JA AF Quinn, Kathrina Quirion, Mary R. Lo, Chia-Yun Misplon, Julia A. Epstein, Suzanne L. Chiorini, John A. TI Intranasal Administration of Adeno-associated Virus Type 12 (AAV12) Leads to Transduction of the Nasal Epithelia and Can Initiate Transgene-specific Immune Response SO MOLECULAR THERAPY LA English DT Article ID CILIATED AIRWAY EPITHELIUM; T-CELL EPITOPES; INFLUENZA-VIRUS; NEUTRALIZING ANTIBODIES; EFFICIENT TRANSDUCTION; GERMLINE TRANSMISSION; GENE DELIVERY; IN-VIVO; VECTORS; VACCINATION AB A critical aspect in defining the utility of a vector for gene therapy applications is the cell tropism and biodistribution of the vector. Adeno-associated virus type 12 (AAV12) has several unique biological and immunological properties that could be exploited for gene therapy purposes, including a unique cell surface receptor, transduction of epithelial cells, and limited neutralization by pooled human antibodies. However, little is known about its cell tropism and biodistribution in vivo. In vivo biodistribution studies with AAV12 vectors encoding a cytomegalovirus promoted luciferase transgene indicated preferential transduction of the nasal epithelia which was not observed with AAV2-based vectors. Expression peaked 2 weeks postadministration, before decreasing to a persistent level. The level of neutralizing antibodies (Nab) induced was sevenfold lower for AAV12 than for AAV2, an advantage for use in repeat administration. Furthermore, vectors encoding influenza A nucleoprotein (NP), an antigen which has previously been shown to induce immune protection against challenge, resulted in generation of both anti-A/NP antibodies and lung anti-A/NP T cells. Our findings suggest further evaluation of AAV12 as a vector for gene therapy and as a potential nasal vaccine. C1 [Quinn, Kathrina; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Quirion, Mary R.; Lo, Chia-Yun; Misplon, Julia A.; Epstein, Suzanne L.] US FDA, Gene Therapy & Immunogen Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Room 1A21, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov FU NIH FX We thank Sandra Wainer and Beverly Handelman (MPTB, NIDCR, NIH) for their expertise in AAV vector production, Giovanni DiPasquale (MPTB, NIDCR, NIH) for assistance with Xenogen Imaging, William Swaim (MPTB, NIDCR, NIH) for help with immunofluorescence and confocal microscopy, and Milton Papa (VRC, NIDCR, NIH) for assistance with retro-orbital bleeding. This work was funded by an NIH intramural grant, to J.A.C. NR 39 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD NOV PY 2011 VL 19 IS 11 BP 1990 EP 1998 DI 10.1038/mt.2011.146 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 843VL UT WOS:000296703000010 PM 21829176 ER PT J AU Li, H Lasaro, MO Jia, B Lin, SW Haut, LH High, KA Ertl, HCJ AF Li, Hua Lasaro, Marcio O. Jia, Bei Lin, Shih Wen Haut, Larissa H. High, Katherine A. Ertl, Hildegund C. J. TI Capsid-specific T-cell Responses to Natural Infections With Adeno-associated Viruses in Humans Differ From Those of Nonhuman Primates SO MOLECULAR THERAPY LA English DT Article ID RECOMBINANT AAV VECTORS; HUMAN-FACTOR-IX; SKELETAL-MUSCLE; GENE-TRANSFER; IMMUNE-RESPONSES; HEMOPHILIA-B; INTRAMUSCULAR INJECTION; EFFICIENT TRANSDUCTION; ADENOVIRUS INFECTIONS; CLINICAL-TRIAL AB Hepatic adeno-associated virus serotype 2 (AAV2)-mediated gene transfer failed to achieve sustained transgene product expression in human subjects. We formulated the hypothesis that rejection of AAV-transduced hepatocytes is caused by AAV capsid-specific CD8(+) T cells that become reactivated upon gene transfer. Although this hypothesis was compatible with clinical data, which showed a rise in circulating AAV capsid-specific T cells following injection of AAV vectors, it did not explain that AAV vectors achieved long-term transgene expression in rhesus macaques, which are naturally infected with AAV serotypes closely related to those of humans. To address this apparent contradiction, we tested human and rhesus macaque samples for AAV capsid-specific T cells by intracellular cytokine staining combined with staining for T-cell subset and differentiation markers. This highly sensitive method, which could provide a tool to monitor adverse T-cell responses in gene transfer trials, showed that AAV capsid-specific CD8(+) and CD4(+) T cells can be detected in blood of naturally infected humans and rhesus macaques. They are present at higher frequencies in rhesus macaques. Furthermore, T cells from humans and rhesus macaques exhibit striking differences in their differentiation status and in their functions, which may explain the disparate duration of AAV-mediated gene transfer in these two species. C1 [Li, Hua; Lasaro, Marcio O.; Jia, Bei; Lin, Shih Wen; Haut, Larissa H.; Ertl, Hildegund C. J.] Wistar Inst Anat & Biol, Program Immunol, Philadelphia, PA 19104 USA. [Jia, Bei] Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing, Peoples R China. [Lin, Shih Wen] NCI, NIH, Div Canc Epidemiol & Genet, Rockville, MD USA. [High, Katherine A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [High, Katherine A.] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. RP Ertl, HCJ (reprint author), Wistar Inst Anat & Biol, Program Immunol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM ertl@wistar.upenn.edu FU National Institutes of Health [P01HL078810]; NCI [CA10815]; Howard Hughes Medical Institute FX This work is supported by a grant from the National Institutes of Health (P01HL078810) and by institutional grants to the Wistar Institute including an NCI Cancer Core Grant (CA10815). K. A. H. is supported by the Howard Hughes Medical Institute. We would like to acknowledge Debbie Davis in Wistar Phlebotomy department for collecting blood samples for healthy human volunteers for our study. NR 33 TC 21 Z9 21 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD NOV PY 2011 VL 19 IS 11 BP 2021 EP 2030 DI 10.1038/mt.2011.81 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 843VL UT WOS:000296703000013 PM 21587208 ER PT J AU Deichmann, A Brugman, MH Bartholomae, CC Schwarzwaelder, K Verstegen, MMA Howe, SJ Arens, A Ott, MG Hoelzer, D Seger, R Grez, M Hacein-Bey-Abina, S Cavazzana-Calvo, M Fischer, A Paruzynski, A Gabriel, R Glimm, H Abel, U Cattoglio, C Mavilio, F Cassani, B Aiuti, A Dunbar, CE Baum, C Gaspar, HB Thrasher, AJ von Kalle, C Schmidt, M Wagemaker, G AF Deichmann, Annette Brugman, Martijn H. Bartholomae, Cynthia C. Schwarzwaelder, Kerstin Verstegen, Monique M. A. Howe, Steven J. Arens, Anne Ott, Marion G. Hoelzer, Dieter Seger, Reinhard Grez, Manuel Hacein-Bey-Abina, Salima Cavazzana-Calvo, Marina Fischer, Alain Paruzynski, Anna Gabriel, Richard Glimm, Hanno Abel, Ulrich Cattoglio, Claudia Mavilio, Fulvio Cassani, Barbara Aiuti, Alessandro Dunbar, Cynthia E. Baum, Christopher Gaspar, H. Bobby Thrasher, Adrian J. von Kalle, Christof Schmidt, Manfred Wagemaker, Gerard TI Insertion Sites in Engrafted Cells Cluster Within a Limited Repertoire of Genomic Areas After Gammaretroviral Vector Gene Therapy SO MOLECULAR THERAPY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC STEM-CELLS; CHRONIC GRANULOMATOUS-DISEASE; RETROVIRAL INTEGRATION; CLONAL DOMINANCE; PROGENITOR CELLS; MUTAGENESIS; SCID-X1; MARKING; TRANSCRIPTION AB Vector-associated side effects in clinical gene therapy have provided insights into the molecular mechanisms of hematopoietic regulation in vivo. Surprisingly, many retrovirus insertion sites (RIS) present in engrafted cells have been found to cluster nonrandomly in close association with specific genes. Our data demonstrate that these genes directly influence the in vivo fate of hematopoietic cell clones. Analysis of insertions thus far has been limited to individual clinical studies. Here, we studied >7,000 insertions retrieved from various studies. More than 40% of all insertions found in engrafted gene-modified cells were clustered in the same genomic areas covering only 0.36% of the genome. Gene classification analyses displayed significant overrepresentation of genes associated with hematopoietic functions and relevance for cell growth and survival in vivo. The similarity of insertion distributions indicates that vector insertions in repopulating cells cluster in predictable patterns. Thus, insertion analyses of preclinical in vitro and murine in vivo studies as well as vector insertion repertoires in clinical trials yielded concerted results and mark a small number of interesting genomic loci and genes that warrants further investigation of the biological consequences of vector insertions. C1 [Deichmann, Annette] Natl Ctr Tumor Dis, NCT, Dept Translat Oncol, D-69120 Heidelberg, Germany. [Deichmann, Annette; Bartholomae, Cynthia C.; Schwarzwaelder, Kerstin; Arens, Anne; Paruzynski, Anna; Gabriel, Richard; Glimm, Hanno; Abel, Ulrich; von Kalle, Christof; Schmidt, Manfred] German Canc Res Ctr, Heidelberg, Germany. [Brugman, Martijn H.; Verstegen, Monique M. A.; Wagemaker, Gerard] Erasmus MC, Dept Hematol, Rotterdam, Netherlands. [Brugman, Martijn H.; Baum, Christopher] Hannover Med Sch, Dept Expt Hematol, D-3000 Hannover, Germany. [Howe, Steven J.; Gaspar, H. Bobby; Thrasher, Adrian J.] UCL, Inst Child Hlth, Mol Immunol Unit, London, England. [Arens, Anne] German Canc Res Ctr, Core Facil Prote & Genom, D-6900 Heidelberg, Germany. [Ott, Marion G.; Hoelzer, Dieter] Univ Hosp, Dept Hematol Oncol, Frankfurt, Germany. [Gabriel, Richard] Univ Childrens Hosp, Div Hematol Immunol, Zurich, Switzerland. [Grez, Manuel] Inst Biomed Res, Frankfurt, Germany. [Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina; Fischer, Alain] Hop Necker Enfants Malad, INSERM, Unit 768, Paris, France. [Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina; Fischer, Alain] Univ Paris 05, Fac Med, Paris, France. [Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina] Hop Necker Enfants Malad, Dept Biotherapies, Paris, France. [Fischer, Alain] Hop Necker Enfants Malad, Unit Immunol & Hematol Pediat, Paris, France. [Abel, Ulrich] Univ Heidelberg, Dept Med Biometry, Heidelberg, Germany. [Abel, Ulrich] Tumor Ctr Heidelberg Mannheim, Heidelberg, Germany. [Cattoglio, Claudia; Mavilio, Fulvio] Inst Sci H San Raffaele, IIT Unit Mol Neurosci, Milan, Italy. [Mavilio, Fulvio] Univ Modena & Reggio Emilia, Dept Biomed Sci, Modena, Italy. [Cassani, Barbara; Aiuti, Alessandro] San Raffaele Telethon Inst Gene Therapy HSR TIGET, Milan, Italy. [Aiuti, Alessandro] Univ Roma Tor Vergata, Rome, Italy. [Dunbar, Cynthia E.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Gaspar, H. Bobby; Thrasher, Adrian J.] Great Ormond St Hosp NHS Trust, Dept Clin Immunol, London, England. RP Schmidt, M (reprint author), Natl Ctr Tumor Dis, NCT, Dept Translat Oncol, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM manfred.schmidt@nct-heidelberg.de RI MAVILIO, Fulvio/J-6125-2013; Brugman, Martijn/F-3389-2011; Cassani, Barbara/K-3871-2016; AIUTI, ALESSANDRO/K-3918-2016; OI Brugman, Martijn/0000-0003-2675-2705; Cassani, Barbara/0000-0002-4115-8109; AIUTI, ALESSANDRO/0000-0002-5398-1717; Mavilio, Fulvio/0000-0003-0459-4320 FU NIH [R01 CA 112470-01]; Deutsche Forschungsgemeinschaft DFG [Ka976/5-3, SCHM 2134/1-1, SFB738-C3]; Bundesministerium fur Bildung und Forschung BMBF [01GU0601 (TreatID), 01GU0809 (iGene)]; Netherlands Health Research Organization ZonMw; Translational Gene Therapy Program [43100016]; European Commission [QLK3-CT-2001-00427-INHERINET, LSHB-CT-2004-005242-CONSERT, LSHB-CT-2006-018933, LSHB-CT-2006-19038]; Fondazione Telethon FX Funding was provided by NIH R01 CA 112470-01 (http://www.nih.gov), by the Deutsche Forschungsgemeinschaft DFG (http://www.dfg.de), grant Ka976/5-3, SCHM 2134/1-1 and SFB738-C3 by the Bundesministerium fur Bildung und Forschung BMBF (www.bmbf.de), grant 01GU0601 (TreatID) and 01GU0809 (iGene), the Netherlands Health Research Organization ZonMw (www.zonmw.nl), Translational Gene Therapy Program, project 43100016, and by the European Commission's 5th and 6th Framework Programs (http://ec.europa.eu/research), Contracts QLK3-CT-2001-00427-INHERINET, LSHB-CT-2004-005242-CONSERT, LSHB-CT-2006-018933 and LSHB-CT-2006-19038. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 26 Z9 26 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD NOV PY 2011 VL 19 IS 11 BP 2031 EP 2039 DI 10.1038/mt.2011.178 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 843VL UT WOS:000296703000014 PM 21862999 ER PT J AU Sung, MH Hager, GL AF Sung, Myong-Hee Hager, Gordon L. TI More to Hi-C than meets the eye SO NATURE GENETICS LA English DT Editorial Material ID GLUCOCORTICOID-RECEPTOR BINDING; CHROMATIN ACCESSIBILITY; DNA INTERACTIONS; CAPTURE AB Diversification and specialization of high-throughput technologies demand assay-specific treatment of data for reliable interpretation. A new study shows that data generated using the Hi-C approach contain hidden features of interchromosomal DNA interactions, which are revealed through analysis with an integrated probabilistic model that corrects for multiple sources of bias in the data. C1 [Sung, Myong-Hee; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Sung, MH (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov NR 11 TC 2 Z9 2 U1 2 U2 9 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 NOV PY 2011 VL 43 IS 11 BP 1047 EP 1048 DI 10.1038/ng.984 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000004 PM 22030604 ER PT J AU Lienert, F Wirbelauer, C Som, I Dean, A Mohn, F Schubeler, D AF Lienert, Florian Wirbelauer, Christiane Som, Indrani Dean, Ann Mohn, Fabio Schuebeler, Dirk TI Identification of genetic elements that autonomously determine DNA methylation states SO NATURE GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; HISTONE H3 METHYLTRANSFERASE; DE-NOVO METHYLATION; CPG ISLAND SHORES; CHROMATIN-STRUCTURE; ES CELLS; TRANSCRIPTION; LINEAGE; NANOG; PLURIPOTENT AB Cytosine methylation is a repressive, epigenetically propagated DNA modification. Although patterns of DNA methylation seem tightly regulated in mammals, it is unclear how these are specified and to what extent this process entails genetic or epigenetic regulation. To dissect the role of the underlying DNA sequence, we sequentially inserted over 50 different DNA elements into the same genomic locus in mouse stem cells. Promoter sequences of approximately 1,000 bp autonomously recapitulated correct DNA methylation in pluripotent cells. Moreover, they supported proper de novo methylation during differentiation. Truncation analysis revealed that this regulatory potential is contained within small methylation-determining regions (MDRs). MDRs can mediate both hypomethylation and de novo methylation in cis, and their activity depends on developmental state, motifs for DNA-binding factors and a critical CpG density. These results demonstrate that proximal sequence elements are both necessary and sufficient for regulating DNA methylation and reveal basic constraints of this regulation. C1 [Lienert, Florian; Wirbelauer, Christiane; Mohn, Fabio; Schuebeler, Dirk] Friedrich Miescher Inst Biomed Res, Basel, Switzerland. [Lienert, Florian; Schuebeler, Dirk] Univ Basel, Fac Sci, Basel, Switzerland. [Som, Indrani; Dean, Ann] NIDDKD, Cellular & Dev Biol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Schubeler, D (reprint author), Friedrich Miescher Inst Biomed Res, Basel, Switzerland. EM dirk@fmi.ch FU Boehringer Ingelheim; National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health; Novartis Research Foundation; European Union [FP7-HEALTH-2010-257082, LSHG-CT-2006-037415]; European Research Council [ERC-204264]; Swiss initiative in Systems Biology FX We are grateful to M. Pietrzak for sequencing. We thank M. Lorincz of the University of British Columbia-Vancouver for providing plasmids for RMCE and S. Fiering for advice. We would also like to thank members of the Schubeler group and S. Gasser for critical comments on the manuscript. F.L. is supported by a PhD fellowship of the Boehringer Ingelheim Fonds. Research in the laboratory of A.D. is supported by the Intramural Program of National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health. Research in the laboratory of D.S. is supported by the Novartis Research Foundation, by the European Union (NoE "EpiGeneSys" FP7-HEALTH-2010-257082, LSHG-CT-2006-037415), the European Research Council (ERC-204264) and by the RTD "Cellplasticity" of the Swiss initiative in Systems Biology (SystemsX.ch). NR 51 TC 179 Z9 180 U1 0 U2 31 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 NOV PY 2011 VL 43 IS 11 BP 1091 EP U78 DI 10.1038/ng.946 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000012 PM 21964573 ER PT J AU Barrett, JH Iles, MM Harland, M Taylor, JC Aitken, JF Andresen, PA Akslen, LA Armstrong, BK Avril, MF Azizi, E Bakker, B Bergman, W Bianchi-Scarra, G Bressac-de Paillerets, B Calista, D Cannon-Albright, LA Corda, E Cust, AE Debniak, T Duffy, D Dunning, AM Easton, DF Friedman, E Galan, P Ghiorzo, P Giles, GG Hansson, J Hocevar, M Hoiom, V Hopper, JL Ingvar, C Janssen, B Jenkins, MA Jonsson, G Kefford, RF Landi, G Landi, MT Lang, J Lubinski, J Mackie, R Malvehy, J Martin, NG Molven, A Montgomery, GW van Nieuwpoort, FA Novakovic, S Olsson, H Pastorino, L Puig, S Puig-Butille, JA Randerson-Moor, J Snowden, H Tuominen, R VanBelle, P van der Stoep, N Whiteman, DC Zelenika, D Han, JL Fang, SY Lee, JE Wei, QY Lathrop, GM Gillanders, EM Brown, KM Goldstein, AM Kanetsky, PA Mann, GJ MacGregor, S Elder, DE Amos, CI Hayward, NK Gruis, NA Demenais, F Bishop, JAN Bishop, DT AF Barrett, Jennifer H. Iles, Mark M. Harland, Mark Taylor, John C. Aitken, Joanne F. Andresen, Per Arne Akslen, Lars A. Armstrong, Bruce K. Avril, Marie-Francoise Azizi, Esther Bakker, Bert Bergman, Wilma Bianchi-Scarra, Giovanna Bressac-de Paillerets, Brigitte Calista, Donato Cannon-Albright, Lisa A. Corda, Eve Cust, Anne E. Debniak, Tadeusz Duffy, David Dunning, Alison M. Easton, Douglas F. Friedman, Eitan Galan, Pilar Ghiorzo, Paola Giles, Graham G. Hansson, Johan Hocevar, Marko Hoeiom, Veronica Hopper, John L. Ingvar, Christian Janssen, Bart Jenkins, Mark A. Joensson, Goeran Kefford, Richard F. Landi, Giorgio Landi, Maria Teresa Lang, Julie Lubinski, Jan Mackie, Rona Malvehy, Josep Martin, Nicholas G. Molven, Anders Montgomery, Grant W. van Nieuwpoort, Frans A. Novakovic, Srdjan Olsson, Hakan Pastorino, Lorenza Puig, Susana Puig-Butille, Joan Anton Randerson-Moor, Juliette Snowden, Helen Tuominen, Rainer VanBelle, Patricia van der Stoep, Nienke Whiteman, David C. Zelenika, Diana Han, Jiali Fang, Shenying Lee, Jeffrey E. Wei, Qingyi Lathrop, G. Mark Gillanders, Elizabeth M. Brown, Kevin M. Goldstein, Alisa M. Kanetsky, Peter A. Mann, Graham J. MacGregor, Stuart Elder, David E. Amos, Christopher I. Hayward, Nicholas K. Gruis, Nelleke A. Demenais, Florence Bishop, Julia A. Newton Bishop, D. Timothy CA GenoMEL Consortium TI Genome-wide association study identifies three new melanoma susceptibility loci SO NATURE GENETICS LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; PHENOTYPIC CHARACTERISTICS; SEQUENCE VARIANTS; RISK; CANCER; METAANALYSIS; GENE; WOMEN; NEVI; POPULATION AB We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 x 10(-9)), an SNP in MX2 (rs45430, P = 2.9 x 10-9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 x 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 x 10(-7) under a fixed-effects model and P = 1.2 x 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series. C1 [Barrett, Jennifer H.; Iles, Mark M.; Harland, Mark; Taylor, John C.; Randerson-Moor, Juliette; Snowden, Helen; Bishop, Julia A. Newton; Bishop, D. Timothy] St James Univ Hosp, Leeds Canc Res UK Ctr, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds, W Yorkshire, England. [Aitken, Joanne F.] Canc Council, Viertel Ctr Res Canc Control, Brisbane, Qld, Australia. [Andresen, Per Arne] Oslo Univ Hosp, Rikshosp, Dept Pathol, Oslo, Norway. [Akslen, Lars A.; Molven, Anders] Univ Bergen, Gade Inst, Bergen, Norway. [Akslen, Lars A.; Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Armstrong, Bruce K.; Kefford, Richard F.; Mann, Graham J.] Westmead Millennium Inst, Westmead, NSW, Australia. [Avril, Marie-Francoise] Univ Descartes, Serv Dermatol, Hop Cochin, Assistance Publ Hop Paris, Paris, France. [Azizi, Esther; Friedman, Eitan] Sheba Med Ctr, Dept Dermatol, Tel Hashomer, Israel. [Azizi, Esther; Friedman, Eitan] Sheba Med Ctr, Oncogenet Unit, Tel Hashomer, Israel. [Azizi, Esther; Friedman, Eitan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Bakker, Bert; van der Stoep, Nienke] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Dept Clin Genet, Leiden, Netherlands. [Bergman, Wilma; van Nieuwpoort, Frans A.; Gruis, Nelleke A.] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Bianchi-Scarra, Giovanna; Ghiorzo, Paola; Pastorino, Lorenza] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Bressac-de Paillerets, Brigitte; Corda, Eve; Demenais, Florence] Fdn Jean Daussel CEPH, INSERM, U946, Paris, France. [Bressac-de Paillerets, Brigitte] Inst Canc Gustave Roussy, Serv Genet, Dept Biopathol, Villejuif, France. [Calista, Donato; Landi, Giorgio] Maurizio Bufalini Hosp, Dermatol Unit, Cesena, Italy. [Cannon-Albright, Lisa A.] Univ Utah, Sch Med, Dept Internal Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Cust, Anne E.; Giles, Graham G.; Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Cust, Anne E.] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Debniak, Tadeusz; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Szczecin, Poland. [Duffy, David; Martin, Nicholas G.; Montgomery, Grant W.; Whiteman, David C.; MacGregor, Stuart; Hayward, Nicholas K.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Cambridge, England. [Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Galan, Pilar] INSERM, UMR U557, Bobigny, France. [Galan, Pilar] Ctr Rech Nutr Humaine, Inst Natl Rech Agron, U1125, Bobigny, France. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Hansson, Johan; Hoeiom, Veronica; Tuominen, Rainer] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Hocevar, Marko; Novakovic, Srdjan] Inst Oncol Ljubljana, Ljubljana, Slovenia. [Ingvar, Christian] Univ Lund Hosp, Dept Surg, S-22185 Lund, Sweden. [Janssen, Bart] ServiceXS, Leiden, Netherlands. [Joensson, Goeran; Olsson, Hakan] Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. [Landi, Maria Teresa; Goldstein, Alisa M.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lang, Julie; Mackie, Rona] Univ Glasgow, Dept Med Genet, Glasgow, Lanark, Scotland. [Malvehy, Josep; Puig, Susana; Puig-Butille, Joan Anton] Univ Barcelona, Inst Invest Biomed August Pi Sune, Dept Dermatol, Melanoma Unit,Hosp Clin, Barcelona, Spain. [Puig, Susana; Puig-Butille, Joan Anton] Inst Salud Carlos III, Ctr Biomed Res Rare Dis CIBERER, Barcelona, Spain. [VanBelle, Patricia; Elder, David E.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Zelenika, Diana; Lathrop, G. Mark] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Han, Jiali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Han, Jiali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Han, Jiali] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Unit 1365, Houston, TX 77030 USA. [Lee, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Gillanders, Elizabeth M.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Brown, Kevin M.] NCI, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD USA. [Kanetsky, Peter A.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Demenais, Florence] Univ Paris 07, Inst Univ Hematol, Paris, France. RP Bishop, DT (reprint author), St James Univ Hosp, Leeds Canc Res UK Ctr, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds, W Yorkshire, England. EM d.t.bishop@leeds.ac.uk RI Whiteman, David/P-2728-2014; Bakker, Egbert/D-3525-2009; Macgregor, Stuart/C-6442-2009; Jonsson, Goran/D-1212-2014; Mann, Graham/G-4758-2014; Bianchi Scarra, Giovanna/G-8933-2014; Demenais, Florence/G-3298-2013; hayward, nicholas/C-1367-2015; Armstrong, Bruce/K-9464-2015; Montgomery, Grant/B-7148-2008; Martin, Ludovic/K-2674-2015; Duffy, David/B-7392-2013; Marti, Rosa/A-2256-2010; Bruno, William/N-7477-2013; Andreotti, Virginia/K-4506-2016; Hoiom, Veronica/F-4153-2012; Akslen, Lars /C-1202-2017; bertazzi, pietro alberto/D-5039-2017; Jenkins, Mark/P-7803-2015; OI Whiteman, David/0000-0003-2563-9559; Bakker, Egbert/0000-0002-2843-7357; Macgregor, Stuart/0000-0001-6731-8142; Mann, Graham/0000-0003-1301-405X; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; hayward, nicholas/0000-0003-4760-1033; Armstrong, Bruce/0000-0001-8940-7525; Montgomery, Grant/0000-0002-4140-8139; Duffy, David/0000-0001-7227-632X; Marti, Rosa/0000-0001-6866-6114; Gruis, Nelleke/0000-0002-5210-9150; Dunning, Alison Margaret/0000-0001-6651-7166; Bishop, Tim/0000-0002-8752-8785; albright, lisa/0000-0003-2602-3668; Newton Bishop, Julia/0000-0001-9147-6802; Puig, Susana/0000-0003-1337-9745; Giles, Graham/0000-0003-4946-9099; , Srdjan/0000-0002-8888-4810; Martin, Nicholas/0000-0003-4069-8020; Bruno, William/0000-0002-0337-0168; Andreotti, Virginia/0000-0002-2569-0832; Akslen, Lars /0000-0003-2710-9543; bertazzi, pietro alberto/0000-0003-3475-2449; Badenas, Celia/0000-0002-0621-0477; Jenkins, Mark/0000-0002-8964-6160; Barrett, Jenny/0000-0002-1720-7724 FU Wellcome Trust [076113]; European Commission [LSHC-CT-2006-018702]; Cancer Research UK [C588/A4994, C588/A10589, C8216/A6129]; US National Institutes of Health (NIH) [CA83115]; NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics FX This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from their website (see URLs). Funding for the project was provided by the Wellcome Trust under award 076113.; The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project grant (C8216/A6129) and by a grant from the US National Institutes of Health (NIH; CA83115). This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. Funding specific to particular locations is acknowledged below. NR 35 TC 114 Z9 115 U1 3 U2 22 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 NOV PY 2011 VL 43 IS 11 BP 1108 EP U98 DI 10.1038/ng.959 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000015 PM 21983787 ER PT J AU MacGregor, S Montgomery, GW Liu, JZ Zhao, ZZ Henders, AK Stark, M Schmid, H Holland, EA Duffy, DL Zhang, M Painter, JN Nyholt, DR Maskiell, JA Jetann, J Ferguson, M Cust, AE Jenkins, MA Whiteman, DC Olsson, H Puig, S Bianchi-Scarra, G Hansson, J Demenais, F Landi, MT Debniak, T Mackie, R Azizi, E Bressac-de Paillerets, B Goldstein, AM Kanetsky, PA Gruis, NA Elder, DE Newton-Bishop, JA Bishop, DT Iles, MM Helsing, P Amos, CI Wei, QY Wang, LE Lee, JE Qureshi, AA Kefford, RF Giles, GG Armstrong, BK Aitken, JF Han, JL Hopper, JL Trent, JM Brown, KM Martin, NG Mann, GJ Hayward, NK AF MacGregor, Stuart Montgomery, Grant W. Liu, Jimmy Z. Zhao, Zhen Zhen Henders, Anjali K. Stark, Mitchell Schmid, Helen Holland, Elizabeth A. Duffy, David L. Zhang, Mingfeng Painter, Jodie N. Nyholt, Dale R. Maskiell, Judith A. Jetann, Jodie Ferguson, Megan Cust, Anne E. Jenkins, Mark A. Whiteman, David C. Olsson, Hakan Puig, Susana Bianchi-Scarra, Giovanna Hansson, Johan Demenais, Florence Landi, Maria Teresa Debniak, Tadeusz Mackie, Rona Azizi, Esther Bressac-de Paillerets, Brigitte Goldstein, Alisa M. Kanetsky, Peter A. Gruis, Nelleke A. Elder, David E. Newton-Bishop, Julia A. Bishop, D. Timothy Iles, Mark M. Helsing, Per Amos, Christopher I. Wei, Qingyi Wang, Li-E Lee, Jeffrey E. Qureshi, Abrar A. Kefford, Richard F. Giles, Graham G. Armstrong, Bruce K. Aitken, Joanne F. Han, Jiali Hopper, John L. Trent, Jeffrey M. Brown, Kevin M. Martin, Nicholas G. Mann, Graham J. Hayward, Nicholas K. CA Lund Melanoma Grp TI Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3 SO NATURE GENETICS LA English DT Article ID CUTANEOUS MELANOMA; VARIANTS; RISK; COMPONENTS; DESIGN; ONSET; GENES AB We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 x 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 x 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density. C1 [MacGregor, Stuart; Montgomery, Grant W.; Liu, Jimmy Z.; Zhao, Zhen Zhen; Henders, Anjali K.; Stark, Mitchell; Duffy, David L.; Painter, Jodie N.; Nyholt, Dale R.; Whiteman, David C.; Martin, Nicholas G.; Hayward, Nicholas K.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Schmid, Helen; Holland, Elizabeth A.; Kefford, Richard F.; Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Westmead, NSW 2145, Australia. [Schmid, Helen; Holland, Elizabeth A.; Kefford, Richard F.; Mann, Graham J.] Melanoma Inst Australia, Westmead, NSW, Australia. [Zhang, Mingfeng; Qureshi, Abrar A.; Han, Jiali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Maskiell, Judith A.; Cust, Anne E.; Jenkins, Mark A.; Hopper, John L.] Univ Melbourne, Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Jetann, Jodie; Ferguson, Megan; Aitken, Joanne F.] Canc Council Queensland, Viertel Ctr Res Canc Control, Brisbane, Qld, Australia. [Cust, Anne E.; Armstrong, Bruce K.] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Olsson, Hakan] Univ Lund Hosp, Dept Oncol, Lund Canc Ctr, S-22185 Lund, Sweden. [Puig, Susana] Univ Barcelona, Inst Invest Biomed August Pi Sune, Hosp Clin, Dept Dermatol,Melanoma Unit, Barcelona, Spain. [Puig, Susana] Inst Salud Carlos III, Ctr Biomed Res Rare Dis CIBERER, Barcelona, Spain. [Bianchi-Scarra, Giovanna] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Hansson, Johan] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Hansson, Johan] Karolinska Univ Hosp, Stockholm, Sweden. [Demenais, Florence; Bressac-de Paillerets, Brigitte] Fdn Jean Dausset CEPH, INSERM, U946, Paris, France. [Demenais, Florence] Univ Paris Diderot, Inst Univ Hematol Paris, Paris, France. [Landi, Maria Teresa; Goldstein, Alisa M.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Debniak, Tadeusz] Int Hereditary Canc Ctr, Szczecin, Poland. [Mackie, Rona] Univ Glasgow, Dept Publ Hlth, Glasgow, Lanark, Scotland. [Azizi, Esther] Sheba Med Ctr, Dermatooncol Unit, Dept Dermatol, Tel Hashomer, Israel. [Bressac-de Paillerets, Brigitte] Inst Canc Gustave Roussy, Serv Genet, Villejuif, France. [Kanetsky, Peter A.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gruis, Nelleke A.] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Elder, David E.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Newton-Bishop, Julia A.; Bishop, D. Timothy; Iles, Mark M.] St James Univ Hosp, Canc Res UK Clin Ctr Leeds, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds, W Yorkshire, England. [Helsing, Per] Oslo Univ Hosp, Dept Dermatol, Oslo, Norway. [Amos, Christopher I.; Wei, Qingyi; Wang, Li-E] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lee, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Qureshi, Abrar A.; Han, Jiali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Han, Jiali] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trent, Jeffrey M.] Translat Genom Res Inst, Genet Basis Human Dis Div, Phoenix, AZ USA. [Trent, Jeffrey M.] Van Andel Res Inst, Ctr Canc Genom & Computat Biol, Grand Rapids, MI USA. [Brown, Kevin M.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP MacGregor, S (reprint author), Queensland Inst Med Res, Brisbane, Qld 4006, Australia. EM stuart.macgregor@qimr.edu.au RI Macgregor, Stuart/C-6442-2009; Nyholt, Dale/C-8384-2013; Stark, Mitchell/E-3542-2010; Mann, Graham/G-4758-2014; Bianchi Scarra, Giovanna/G-8933-2014; Demenais, Florence/G-3298-2013; hayward, nicholas/C-1367-2015; Armstrong, Bruce/K-9464-2015; Montgomery, Grant/B-7148-2008; Duffy, David/B-7392-2013; Whiteman, David/P-2728-2014; Jenkins, Mark/P-7803-2015 OI Gruis, Nelleke/0000-0002-5210-9150; Bishop, Tim/0000-0002-8752-8785; Newton Bishop, Julia/0000-0001-9147-6802; Puig, Susana/0000-0003-1337-9745; Giles, Graham/0000-0003-4946-9099; Martin, Nicholas/0000-0003-4069-8020; Macgregor, Stuart/0000-0001-6731-8142; Stark, Mitchell/0000-0002-4510-2161; Mann, Graham/0000-0003-1301-405X; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; hayward, nicholas/0000-0003-4760-1033; Armstrong, Bruce/0000-0001-8940-7525; Montgomery, Grant/0000-0002-4140-8139; Duffy, David/0000-0001-7227-632X; Whiteman, David/0000-0003-2563-9559; Jenkins, Mark/0000-0002-8964-6160 FU Melanoma Research Alliance; National Cancer Institute (NCI) of the US National Institutes of Health (NIH) [CA88363, CA83115, CA122838, CA87969, CA055075, CA100264, CA133996, CA49449]; National Health and Medical Research Council (NHMRC) of Australia [107359, 200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 402761, 443036, 442915, 442981, 496610, 496675, 496739, 552485, 552498]; Cancer Councils New South Wales, Victoria and Queensland; Cancer Institute New South Wales; Cooperative Research Centre (CRC) for Discovery of Genes for Common Human Diseases, Cerylid Biosciences (Melbourne); Australian Cancer Research Foundation; Wellcome Trust [WT084766/Z/08/Z]; Australian National Health and Medical Research Council (NHMRC) [2004-2009]; NHMRC [496674, 613705, 520018]; NCI of the NIH [CA109544]; University of Sydney Medical Foundation; Cancer Institute [10/ECF/2-06]; DCEG; European Commission [LSHC-CT-2006-018702]; Cancer Research UK [C588/A4994]; NIH [CA83115, CA100264, 2P50CA093459, P30CA016672, R01CA133996, HG004446]; Fondo de Investigaciones Sanitarias [09/1393]; [HHSN268200782096C] FX This work was supported by the Melanoma Research Alliance, the National Cancer Institute (NCI) of the US National Institutes of Health (NIH) (CA88363, CA83115, CA122838, CA87969, CA055075, CA100264, CA133996 and CA49449), the National Health and Medical Research Council (NHMRC) of Australia (107359, 200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 402761, 443036, 442915, 442981, 496610, 496675, 496739, 552485 and 552498), the Cancer Councils New South Wales, Victoria and Queensland, the Cancer Institute New South Wales, the Cooperative Research Centre (CRC) for Discovery of Genes for Common Human Diseases, Cerylid Biosciences (Melbourne), the Australian Cancer Research Foundation, The Wellcome Trust and donations from Neville and Shirley Hawkins. Endometriosis sample genotyping was funded by a grant from the Wellcome Trust (WT084766/Z/08/Z). The Australian Twin Registry is supported by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant (2004-2009). D.L.D., N.K.H. and G.W.M. are supported by the NHMRC Fellowships scheme and J.L.H. is an Australia Fellow of the NHMRC. S.M. is the recipient of a Career Development Award from the NHMRC (496674, 613705). D.C.W. is a Future Fellow of the Australian Research Council. K.M.B. is supported by the NCI of the NIH. J.M.T. is supported by the NCI of the NIH (CA109544). B.K.A. is supported by the University of Sydney Medical Foundation. A.E.C. is the recipient of a NHMRC public health postdoctoral fellowship (520018) and a Cancer Institute NSW Early Career Development Fellowship (10/ECF/2-06). A.M.G. and M.T.L. were supported by the Intramural Research Program of the NIH, NCI and DCEG. The GenoMEL replication sample was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Award (C588/A4994) and by the NIH (CA83115). Research at M.D. Anderson Cancer Center (MDACC) was partially supported by NIH grants (CA100264, 2P50CA093459, P30CA016672 and R01CA133996). The Center for Inherited Disease Research performed genotyping for MDACC and is supported by contract (HHSN268200782096C). GENEVA performed data cleaning and is supported by an NIH grant (HG004446). Research by the Barcelona team was supported by Fondo de Investigaciones Sanitarias (09/1393). NR 21 TC 71 Z9 73 U1 1 U2 12 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 NOV PY 2011 VL 43 IS 11 BP 1114 EP U104 DI 10.1038/ng.958 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000016 PM 21983785 ER PT J AU Prickett, TD Wei, XM Cardenas-Navia, I Teer, JK Lin, JC Walia, V Gartner, J Jiang, JJ Cherukuri, PF Molinolo, A Davies, MA Gershenwald, JE Stemke-Hale, K Rosenberg, SA Margulies, EH Samuels, Y AF Prickett, Todd D. Wei, Xiaomu Cardenas-Navia, Isabel Teer, Jamie K. Lin, Jimmy C. Walia, Vijay Gartner, Jared Jiang, Jiji Cherukuri, Praveen F. Molinolo, Alfredo Davies, Michael A. Gershenwald, Jeffrey E. Stemke-Hale, Katherine Rosenberg, Steven A. Margulies, Elliott H. Samuels, Yardena TI Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma SO NATURE GENETICS LA English DT Article ID PHASE-II; CANCER; GLUTAMATE; REVEALS; METALLOPROTEINASE; INHIBITION; CELLS; BRAF AB G protein-coupled receptors (GPCRs), the largest human gene family, are important regulators of signaling pathways. However, knowledge of their genetic alterations is limited. In this study, we used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 GPCRs in melanoma. This investigation revealed that one family member, GRM3, was frequently mutated and that one of its mutations clustered within one position. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MEK, leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after short hairpin RNA-mediated knockdown of GRM3 or treatment with a selective MEK inhibitor, AZD-6244, which is currently being used in phase 2 clinical trials. Our study yields the most comprehensive map of genetic alterations in the GPCR gene family. C1 [Prickett, Todd D.; Wei, Xiaomu; Cardenas-Navia, Isabel; Walia, Vijay; Gartner, Jared; Jiang, Jiji; Samuels, Yardena] NHGRI, Canc Genet Branch, US NIH, Bethesda, MD 20892 USA. [Teer, Jamie K.; Cherukuri, Praveen F.; Margulies, Elliott H.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Teer, Jamie K.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Lin, Jimmy C.] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD USA. [Lin, Jimmy C.] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD USA. [Molinolo, Alfredo] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Davies, Michael A.; Stemke-Hale, Katherine] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Samuels, Y (reprint author), NHGRI, Canc Genet Branch, US NIH, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov RI Walia, Vijay/F-1647-2013; Stemke-Hale, Katherine/K-9113-2013 OI Stemke-Hale, Katherine/0000-0002-1231-4192 FU National Human Genome Research Institute; National Cancer Institute; US National Institutes of Health, USA; University of Texas MD Anderson Cancer Center Melanoma Informatics, Tissue Resource and Pathology Core; Melanoma Specialized Programs of Research Excellence [P50 CA93459]; Melanoma Research Alliance; American Society of Clinical Oncology; MD Anderson Physician-Scientist Program; National Institute of Dental and Craniofacial Research, NIH FX We thank S. Gutkind, J. Cronin, H. Abaan, P. Cruz, J. Mullikin, N. Hansen and members of the US National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program for generating the sequence data analyzed here. We thank S. Hoogstraten-Miller and I. Ginty for assistance with the mouse experiments and S. Anderson for assistance with FACS analysis. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, US National Institutes of Health, USA. Grant support was also provided by the University of Texas MD Anderson Cancer Center Melanoma Informatics, Tissue Resource and Pathology Core and the Melanoma Specialized Programs of Research Excellence (P50 CA93459). M.A.D. is supported by funding from the Melanoma Research Alliance, the American Society of Clinical Oncology and the MD Anderson Physician-Scientist Program. A.M. is supported by the Intramural Research program of the National Institute of Dental and Craniofacial Research, NIH. NR 22 TC 78 Z9 79 U1 0 U2 13 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 NOV PY 2011 VL 43 IS 11 BP 1119 EP U114 DI 10.1038/ng.950 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000017 PM 21946352 ER PT J AU Chambers, JC Zhang, WH Sehmi, J Li, XZ Wass, MN Van der Harst, P Holm, H Sanna, S Kavousi, M Baumeister, SE Coin, LJ Deng, GH Gieger, C Heard-Costa, NL Hottenga, JJ Kuhnel, B Kumar, V Lagou, V Liang, LM Luan, JA Vidal, PM Leach, IM O'Reilly, PF Peden, JF Rahmioglu, N Soininen, P Speliotes, EK Yuan, X Thorleifsson, G Alizadeh, BZ Atwood, LD Borecki, IB Brown, MJ Charoen, P Cucca, F Das, D de Geus, EJC Dixon, AL Doering, A Ehret, G Eyjolfsson, GI Farrall, M Forouhi, NG Friedrich, N Goessling, W Gudbjartsson, DF Harris, TB Hartikainen, AL Heath, S Hirschfield, GM Hofman, A Homuth, G Hypponen, E Janssen, HLA Johnson, T Kangas, AJ Kema, IP Kuhn, JP Lai, S Lathrop, M Lerch, MM Li, Y Liang, TJ Lin, JP Loos, RJF Martin, NG Moffatt, MF Montgomery, GW Munroe, PB Musunuru, K Nakamura, Y O'Donnell, CJ Olafsson, I Penninx, BW Pouta, A Prins, BP Prokopenko, I Puls, R Ruokonen, A Savolainen, MJ Schlessinger, D Schouten, JNL Seedorf, U Sen-Chowdhry, S Siminovitch, KA Smit, JH Spector, TD Tan, WT Teslovich, TM Tukiainen, T Uitterlinden, AG Van der Klauw, MM Vasan, RS Wallace, C Wallaschofski, H Wichmann, HE Willemsen, G Wurtz, P Xu, C Yerges-Armstrong, LM Abecasis, GR Ahmadi, KR Boomsma, DI Caulfield, M Cookson, WO van Duijn, CM Froguel, P Matsuda, K McCarthy, MI Meisinger, C Mooser, V Pietilainen, KH Schumann, G Snieder, H Sternberg, MJE Stolk, RP Thomas, HC Thorsteinsdottir, U Uda, M Waeber, G Wareham, NJ Waterworth, DM Watkins, H Whitfield, JB Witteman, JCM Wolffenbuttel, BHR Fox, CS Ala-Korpela, M Stefansson, K Vollenweider, P Volzke, H Schadt, EE Scott, J Jarvelin, MR Elliott, P Kooner, JS AF Chambers, John C. Zhang, Weihua Sehmi, Joban Li, Xinzhong Wass, Mark N. Van der Harst, Pim Holm, Hilma Sanna, Serena Kavousi, Maryam Baumeister, Sebastian E. Coin, Lachlan J. Deng, Guohong Gieger, Christian Heard-Costa, Nancy L. Hottenga, Jouke-Jan Kuehnel, Brigitte Kumar, Vinod Lagou, Vasiliki Liang, Liming Luan, Jian'an Vidal, Pedro Marques Leach, Irene Mateo O'Reilly, Paul F. Peden, John F. Rahmioglu, Nilufer Soininen, Pasi Speliotes, Elizabeth K. Yuan, Xin Thorleifsson, Gudmar Alizadeh, Behrooz Z. Atwood, Larry D. Borecki, Ingrid B. Brown, Morris J. Charoen, Pimphen Cucca, Francesco Das, Debashish de Geus, Eco J. C. Dixon, Anna L. Doering, Angela Ehret, Georg Eyjolfsson, Gudmundur I. Farrall, Martin Forouhi, Nita G. Friedrich, Nele Goessling, Wolfram Gudbjartsson, Daniel F. Harris, Tamara B. Hartikainen, Anna-Liisa Heath, Simon Hirschfield, Gideon M. Hofman, Albert Homuth, Georg Hyppoenen, Elina Janssen, Harry L. A. Johnson, Toby Kangas, Antti J. Kema, Ido P. Kuehn, Jens P. Lai, Sandra Lathrop, Mark Lerch, Markus M. Li, Yun Liang, T. Jake Lin, Jing-Ping Loos, Ruth J. F. Martin, Nicholas G. Moffatt, Miriam F. Montgomery, Grant W. Munroe, Patricia B. Musunuru, Kiran Nakamura, Yusuke O'Donnell, Christopher J. Olafsson, Isleifur Penninx, Brenda W. Pouta, Anneli Prins, Bram P. Prokopenko, Inga Puls, Ralf Ruokonen, Aimo Savolainen, Markku J. Schlessinger, David Schouten, Jeoffrey N. L. Seedorf, Udo Sen-Chowdhry, Srijita Siminovitch, Katherine A. Smit, Johannes H. Spector, Timothy D. Tan, Wenting Teslovich, Tanya M. Tukiainen, Taru Uitterlinden, Andre G. Van der Klauw, Melanie M. Vasan, Ramachandran S. Wallace, Chris Wallaschofski, Henri Wichmann, H-Erich Willemsen, Gonneke Wuertz, Peter Xu, Chun Yerges-Armstrong, Laura M. Abecasis, Goncalo R. Ahmadi, Kourosh R. Boomsma, Dorret I. Caulfield, Mark Cookson, William O. van Duijn, Cornelia M. Froguel, Philippe Matsuda, Koichi McCarthy, Mark I. Meisinger, Christa Mooser, Vincent Pietilainen, Kirsi H. Schumann, Gunter Snieder, Harold Sternberg, Michael J. E. Stolk, Ronald P. Thomas, Howard C. Thorsteinsdottir, Unnur Uda, Manuela Waeber, Gerard Wareham, Nicholas J. Waterworth, Dawn M. Watkins, Hugh Whitfield, John B. Witteman, Jacqueline C. M. Wolffenbuttel, Bruce H. R. Fox, Caroline S. Ala-Korpela, Mika Stefansson, Kari Vollenweider, Peter Voelzke, Henry Schadt, Eric E. Scott, James Jarvelin, Marjo-Riitta Elliott, Paul Kooner, Jaspal S. CA Alcohol Genome-wide Assoc AlcGen Diabet Genetics Replication Genetic Invest Anthropometric Global Lipids Genetics Consortium Genetics Liver Dis GOLD Consortium Int Consortium Blood Pressure ICBP Meta-Anal Glucose Insulin-Related TI Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma SO NATURE GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; SALT EXPORT PUMP; METABOLIC SYNDROME; RISK-FACTORS; HEPATOCELLULAR-CARCINOMA; HEREDITARY CHOLESTASIS; SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; COMMON VARIANTS AB Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. C1 [Chambers, John C.; Zhang, Weihua; Coin, Lachlan J.; O'Reilly, Paul F.; Charoen, Pimphen; Sen-Chowdhry, Srijita; Tukiainen, Taru; Wuertz, Peter; Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, London, England. [Chambers, John C.; Thomas, Howard C.; Kooner, Jaspal S.] Imperial Coll Healthcare Natl Hlth Serv NHS Trust, London, England. [Chambers, John C.; Zhang, Weihua; Sehmi, Joban; Das, Debashish; Kooner, Jaspal S.] Ealing Hosp NHS Trust, Middlesex, England. [Sehmi, Joban; Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England. [Li, Xinzhong] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, Inst Clin Sci, London, England. [Wass, Mark N.; Sternberg, Michael J. E.] Univ London Imperial Coll Sci Technol & Med, Div Mol Biosci, Struct Bioinformat Grp, London, England. [Van der Harst, Pim; Leach, Irene Mateo] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 AB Groningen, Netherlands. [Holm, Hilma; Thorleifsson, Gudmar; Gudbjartsson, Daniel F.; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Sanna, Serena; Cucca, Francesco; Lai, Sandra; Uda, Manuela] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Kavousi, Maryam; Hofman, Albert; Janssen, Harry L. A.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Kavousi, Maryam; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Netherlands Genom Initiat, Rotterdam, Netherlands. [Baumeister, Sebastian E.; Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17487 Greifswald, Germany. [Deng, Guohong; Tan, Wenting] Third Mil Med Univ, Southwest Hosp, Inst Infect Dis, Chongqing, Peoples R China. [Gieger, Christian; Kuehnel, Brigitte] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Hottenga, Jouke-Jan; de Geus, Eco J. C.; Willemsen, Gonneke; Boomsma, Dorret I.] VU Univ Amsterdam VUA, Dept Biol Psychol, Amsterdam, Netherlands. [Kumar, Vinod; Nakamura, Yusuke; Matsuda, Koichi] Univ Tokyo, Inst Med Sci, Mol Med Lab, Tokyo, Japan. [Lagou, Vasiliki; Alizadeh, Behrooz Z.; Prins, Bram P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, Groningen, Netherlands. [Lagou, Vasiliki; Rahmioglu, Nilufer; Prokopenko, Inga; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Lagou, Vasiliki; Prokopenko, Inga; McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Luan, Jian'an; Forouhi, Nita G.; Loos, Ruth J. F.; Wareham, Nicholas J.] Addenbrookes Hosp, Med Res Council Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Vidal, Pedro Marques] Univ Lausanne Hosp, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland. [Vidal, Pedro Marques; Ehret, Georg] Univ Lausanne, Lausanne, Switzerland. [Peden, John F.; Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England. [Soininen, Pasi; Kangas, Antti J.; Savolainen, Markku J.; Tukiainen, Taru; Wuertz, Peter; Ala-Korpela, Mika] Univ Oulu, Inst Clin Med, Computat Med Res Grp, Oulu, Finland. [Soininen, Pasi; Kangas, Antti J.; Savolainen, Markku J.; Tukiainen, Taru; Wuertz, Peter; Ala-Korpela, Mika] Univ Oulu, Bioctr, Oulu, Finland. [Soininen, Pasi; Ala-Korpela, Mika] Univ Eastern Finland, Dept Biosci, Nucl Magnet Resonance NMR Metabon Lab, Kuopio, Finland. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Yuan, Xin; Mooser, Vincent; Waterworth, Dawn M.] GlaxoSmithKline Inc, Genet, King Of Prussia, PA USA. [Atwood, Larry D.; Musunuru, Kiran] Boston Univ, Sch Med, Boston, MA 02118 USA. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Brown, Morris J.; Wallace, Chris] Univ Cambridge, Cambridge Inst Med Res, Diabet Inflammat Lab, Cambridge, England. [Charoen, Pimphen] Mahidol Univ, Fac Trop Med, Dept Trop Hyg, Bangkok, Thailand. [de Geus, Eco J. C.] VUA, Amsterdam, Netherlands. [de Geus, Eco J. C.] VUA Med Ctr, Amsterdam, Netherlands. [Dixon, Anna L.; Moffatt, Miriam F.; Cookson, William O.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Doering, Angela; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Ehret, Georg] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Ehret, Georg] CHU Vaudois, IUMSP, CH-1011 Lausanne, Switzerland. [Ehret, Georg] Univ Hosp Geneva, Dept Med, Geneva, Switzerland. [Eyjolfsson, Gudmundur I.] Lab Mjodd, Reykjavik, Iceland. [Farrall, Martin; Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Friedrich, Nele; Wallaschofski, Henri] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, D-17487 Greifswald, Germany. [Goessling, Wolfram] Brigham & Womens Hosp, Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Div Genet, Boston, MA 02115 USA. [Goessling, Wolfram] Brigham & Womens Hosp, Div Gastroenterol, Gastrointestinal Canc Ctr, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hartikainen, Anna-Liisa; Pouta, Anneli] Univ Oulu, Inst Clin Med, Oulu, Finland. [Heath, Simon; Lathrop, Mark] CEA IG Ctr Natl Genotypage, Evry, France. [Hirschfield, Gideon M.; Siminovitch, Katherine A.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Hirschfield, Gideon M.] Toronto Western Hosp, Ctr Liver, Toronto, ON M5T 2S8, Canada. [Hirschfield, Gideon M.] Univ Birmingham, Liver Res Ctr, Birmingham, W Midlands, England. [Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Hyppoenen, Elina] Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Janssen, Harry L. A.; Schouten, Jeoffrey N. L.] Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands. [Johnson, Toby; Munroe, Patricia B.; Caulfield, Mark] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol & Genome Ctr, London, England. [Kema, Ido P.] Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands. [Kuehn, Jens P.; Puls, Ralf] Ernst Moritz Arndt Univ Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany. [Lathrop, Mark] Fdn Jean Dausset Ceph, Paris, France. [Lerch, Markus M.] Univ Med Greifswald, Dept Med A, Greifswald, Germany. [Li, Yun] Univ N Carolina, Dept Biostat, Dept Genet, Chapel Hill, NC USA. [Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Lin, Jing-Ping] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Martin, Nicholas G.; Montgomery, Grant W.; Whitfield, John B.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Musunuru, Kiran] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Musunuru, Kiran] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Musunuru, Kiran] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Olafsson, Isleifur] Landspitali Univ Hosp, Dept Clin Biochem, Reykjavik, Iceland. [Penninx, Brenda W.; Smit, Johannes H.] VUA Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Penninx, Brenda W.; Smit, Johannes H.] VUA Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Pouta, Anneli; Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Lifecourse & Serv, Oulu, Finland. [Ruokonen, Aimo] Univ Oulu, Inst Diagnost, Oulu, Finland. [Savolainen, Markku J.; Ala-Korpela, Mika] Univ Oulu, Clin Res Ctr, Dept Internal Med, Oulu, Finland. [Savolainen, Markku J.; Ala-Korpela, Mika] Univ Oulu, Clin Res Ctr, Bioctr Oulu, Oulu, Finland. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. [Siminovitch, Katherine A.] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [Siminovitch, Katherine A.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Siminovitch, Katherine A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Siminovitch, Katherine A.] Toronto Gen Res Inst, Toronto, ON, Canada. [Spector, Timothy D.; Ahmadi, Kourosh R.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Teslovich, Tanya M.; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Van der Klauw, Melanie M.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Van der Klauw, Melanie M.; Sternberg, Michael J. E.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, Groningen, Netherlands. [Van der Klauw, Melanie M.; Sternberg, Michael J. E.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Biobank, Groningen, Netherlands. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Willemsen, Gonneke; Boomsma, Dorret I.] VUA Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Xu, Chun] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Xu, Chun] Toronto Gen Res Inst, Toronto, ON, Canada. [Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Rotterdam, Netherlands. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, London, England. [McCarthy, Mark I.] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England. [Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Pietilainen, Kirsi H.] Helsinki Univ Hosp, Div Internal Med, Dept Med, Obes Res Unit, Helsinki, Finland. [Pietilainen, Kirsi H.] Inst Mol Med FIMM, Helsinki, Finland. [Pietilainen, Kirsi H.] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Schumann, Gunter] Kings Coll London, Inst Psychiat, MRC Social Genet Dev Psychiat SGDP Ctr, London WC2R 2LS, England. [Stolk, Ronald P.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Thomas, Howard C.] Univ London Imperial Coll Sci Technol & Med, Fac Med, London, England. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. [Schadt, Eric E.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC, HPA, Ctr Environm Hlth, London, England. RP Chambers, JC (reprint author), Univ London Imperial Coll Sci Technol & Med, Norfolk Pl, London, England. EM john.chambers@ic.ac.uk; p.elliott@ic.ac.uk; j.kooner@ic.ac.uk RI Marques-Vidal, Pedro/C-9449-2009; Smith, Albert Vernon/K-5150-2015; Grarup, Niels/K-2807-2015; Aben, Katja/G-9686-2016; Ejebe, Kenechi/I-9238-2016; Kyvik, Kirsten /K-5680-2016; Matullo, Giuseppe/K-6383-2016; Visvikis-Siest, Sophie/H-2324-2014; Bochud, Murielle/A-3981-2010; Coin, Lachlan/A-9001-2014; Erdmann, Jeanette/A-4417-2009; Naitza, Silvia/D-5620-2017; Feitosa, Mary/K-8044-2012; Palmer, Lyle/K-3196-2014; Boehm, Bernhard/F-8750-2015; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Mattace- Raso, Francesco/L-2541-2015; Hirschfield, Gideon/M-2143-2015; Polasek, Ozren/B-6002-2011; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Prokopenko, Inga/H-3241-2014; Lerch, Markus M./E-2206-2016; Knowles, Josh/C-9241-2013; Marusic, Ana/E-7683-2013; Kuznetsova, Tatiana/I-6882-2013; Colaus, PsyColaus/K-6607-2013; Lagou, Vasiliki/N-8451-2013; van der Klauw, Melanie/A-2138-2014; Hypponen, Elina/B-2596-2014; Hernaez, Ruben/C-4039-2014; Kiemeney, Lambertus/D-3357-2009; Meisinger, Christine/B-5358-2014; Grobbee, Diederick/C-7651-2014; Siminovitch, Katherine/K-1475-2013; Ridderstrale, Martin/F-7678-2012; Elliott, Amanda/G-5120-2012; Rudan, Igor/I-1467-2012; Heath, Simon/J-4138-2012; Soininen, Pasi/B-9716-2008; EHRET, Georg/A-9532-2009; Kronenberg, Florian/B-1736-2008; Lucas, Gavin/D-4346-2012; Laan, Maris/A-4100-2011; Singleton, Andrew/C-3010-2009; Stolk, Ronald/B-2341-2013; Wolffenbuttel, Bruce/A-8419-2011; Willems van Dijk, Ko/A-1798-2008; OI Matsuda, Koichi/0000-0001-7292-2686; Kumari, Meena/0000-0001-9716-1035; Melzer, David/0000-0002-0170-3838; Goessling, Wolfram/0000-0001-9972-1569; Forouhi, Nita/0000-0002-5041-248X; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Wallace, Chris/0000-0001-9755-1703; Vandenput, Liesbeth/0000-0002-1712-6131; Jorgensen, Torben/0000-0001-9453-2830; Zgaga, Lina/0000-0003-4089-9703; Zeggini, Eleftheria/0000-0003-4238-659X; Ramachandran, Vasan/0000-0001-7357-5970; Luben, Robert/0000-0002-5088-6343; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Adeyemo, Adebowale/0000-0002-3105-3231; Hide, Winston/0000-0002-8621-3271; Arora, Pankaj/0000-0003-2420-3550; Meisinger, Christa/0000-0002-9026-6544; sanna, serena/0000-0002-3768-1749; Marques-Vidal, Pedro/0000-0002-4548-8500; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Ikram, Mohammad Arfan/0000-0003-0372-8585; Abecasis, Goncalo/0000-0003-1509-1825; Smith, Albert Vernon/0000-0003-1942-5845; Gudbjartsson, Daniel/0000-0002-5222-9857; Marroni, Fabio/0000-0002-1556-5907; Seshadri, Sudha/0000-0001-6135-2622; Sternberg, Michael/0000-0002-1884-5445; Magi, Reedik/0000-0002-2964-6011; Wass, Mark/0000-0001-5428-6479; Org, Elin/0000-0003-1451-9375; Grarup, Niels/0000-0001-5526-1070; Aben, Katja/0000-0002-0214-2147; Ejebe, Kenechi/0000-0002-6090-8657; Kyvik, Kirsten /0000-0003-2981-0245; Visvikis-Siest, Sophie/0000-0001-8104-8425; Bochud, Murielle/0000-0002-5727-0218; Coin, Lachlan/0000-0002-4300-455X; Feitosa, Mary/0000-0002-0933-2410; Seedorf, Udo/0000-0003-4652-5358; Heard-Costa, Nancy/0000-0001-9730-0306; Palmer, Lyle/0000-0002-1628-3055; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Hirschfield, Gideon/0000-0002-6736-2255; Polasek, Ozren/0000-0002-5765-1862; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Prokopenko, Inga/0000-0003-1624-7457; Lerch, Markus M./0000-0002-9643-8263; Marusic, Ana/0000-0001-6272-0917; Kuznetsova, Tatiana/0000-0003-3564-7405; van der Klauw, Melanie/0000-0001-7178-009X; Hypponen, Elina/0000-0003-3670-9399; Hernaez, Ruben/0000-0002-1518-4020; Kiemeney, Lambertus/0000-0002-2368-1326; Grobbee, Diederick/0000-0003-4472-4468; Rudan, Igor/0000-0001-6993-6884; EHRET, Georg/0000-0002-5730-0675; Kronenberg, Florian/0000-0003-2229-1120; Laan, Maris/0000-0002-8519-243X; Stolk, Ronald/0000-0002-0518-1205; Wolffenbuttel, Bruce/0000-0001-9262-6921; Willems van Dijk, Ko/0000-0002-2172-7394; Martin, Nicholas/0000-0003-4069-8020; Wain, Louise/0000-0003-4951-1867; Wurtz, Peter/0000-0002-5832-0221; Watkins, Hugh/0000-0002-5287-9016; Visscher, Peter/0000-0002-2143-8760; Marmot, Michael/0000-0002-2431-6419; Prabhakaran, Dorairaj/0000-0002-3172-834X; Ouwehand, Willem/0000-0002-7744-1790; Kaprio, Jaakko/0000-0002-3716-2455; Lawlor, Debbie A/0000-0002-6793-2262; Rivolta, Carlo/0000-0002-0733-9950; Johansson, Asa/0000-0002-2915-4498 FU European Commission; European Science Foundation; European Science Council; US NIH; US National Institute of Mental Health; US NIDDK; Genetic Association Information Network; US National Institute on Aging; US National Human Genome Research Institute; US NHLBI; UK NIHR; NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; NIHR Comprehensive Biomedical Research Centre Guy's and St. Thomas' NHS Trust; UK Biotechnology and Biological Sciences Research Council; UK MRC; British Heart Foundation; Wellcome Trust; Swiss National Science Foundation; Academy of Finland; Finnish Cardiovascular Research Foundation; Swedish Research Council; Swedish Heart-Lung Foundation; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; German Federal Ministry of Education and Research; German National Genome Research Network; Netherlands Organization for Scientific Research; Dutch Ministries of Economic Affairs, of Education, Culture and Science, for Health, Welfare and Sports; Netherlands Organization for Health Research and Development; Dutch government; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Dutch Brain Foundation; Dutch Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Canadian Institutes for Health Research; Ontario Research Fund; Barts and the London Charity; University Medical Center Groningen; University of Groningen; University of Oulu, Biocenter Oulu; University Hospital Oulu; Biocentrum Helsinki; Erasmus Medical Center and Erasmus University, Rotterdam; Karolinska Institutet; Stockholm County Council; Municipality of Rotterdam; Federal State of Mecklenburg-West Pomerania; AstraZeneca; GlaxoSmithKline; Siemens Healthcare; Novo Nordisk Foundation; Yrjo Jahnsson Foundation; Biomedicum Helsinki Foundation; Gyllenberg Foundation; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Boston University School of Medicine; Instrumentarium Science Foundation; Jenny and Antti Wihuri Foundation; Canadian Primary Biliary Cirrhosis Society FX We thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of data. We also thank the research participants who took part in these studies. Major support for the work came from European Commission (FP5, FP6 and FP7); European Science Foundation; European Science Council; US NIH; US National Institute of Mental Health; US NIDDK; Genetic Association Information Network; US National Institute on Aging; US National Human Genome Research Institute; US NHLBI; UK NIHR; NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; NIHR Comprehensive Biomedical Research Centre Guy's and St. Thomas' NHS Trust; UK Biotechnology and Biological Sciences Research Council; UK MRC; British Heart Foundation; Wellcome Trust; Swiss National Science Foundation; Academy of Finland; Finnish Cardiovascular Research Foundation; Swedish Research Council; Swedish Heart-Lung Foundation; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; German Federal Ministry of Education and Research; German National Genome Research Network; Netherlands Organization for Scientific Research; Dutch Ministries of Economic Affairs, of Education, Culture and Science, for Health, Welfare and Sports; Netherlands Organization for Health Research and Development; Economic Structure Enhancing Fund of the Dutch government; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Dutch Brain Foundation; Dutch Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Canadian Institutes for Health Research; Ontario Research Fund; The Barts and the London Charity; University Medical Center Groningen; University of Groningen; University of Oulu, Biocenter Oulu; University Hospital Oulu; Biocentrum Helsinki; Erasmus Medical Center and Erasmus University, Rotterdam; Karolinska Institutet; Stockholm County Council; Municipality of Rotterdam; Federal State of Mecklenburg-West Pomerania; AstraZeneca; GlaxoSmithKline; Siemens Healthcare; Novo Nordisk Foundation; Yrjo Jahnsson Foundation; Biomedicum Helsinki Foundation; Gyllenberg Foundation; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Robert Dawson Evans Endowment, Boston University School of Medicine; Instrumentarium Science Foundation; Jenny and Antti Wihuri Foundation and the Canadian Primary Biliary Cirrhosis Society. A full list of acknowledgments is provided in the Supplementary Note. NR 72 TC 181 Z9 186 U1 9 U2 78 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 NOV PY 2011 VL 43 IS 11 BP 1131 EP U129 DI 10.1038/ng.970 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000019 PM 22001757 ER PT J AU de Cabo, R AF de Cabo, Rafael TI Rafael de Cabo SO NATURE MEDICINE LA English DT Editorial Material C1 NIA, Mech & Intervent Aging Sect, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Mech & Intervent Aging Sect, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. NR 0 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 1078-8956 J9 NAT MED JI Nat. Med. PD NOV PY 2011 VL 17 IS 11 BP 1350 EP 1351 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 844VV UT WOS:000296779300023 ER PT J AU Murray, PJ Wynn, TA AF Murray, Peter J. Wynn, Thomas A. TI Protective and pathogenic functions of macrophage subsets SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID TUMOR-ASSOCIATED MACROPHAGES; ALTERNATIVELY ACTIVATED MACROPHAGES; REGULATORY T-CELLS; SUBCAPSULAR SINUS MACROPHAGES; INFLAMMATORY-BOWEL-DISEASE; CYTOKINE GM-CSF; DENDRITIC CELLS; PULMONARY-FIBROSIS; BONE-MARROW; GENE-EXPRESSION AB Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals. They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals. In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis. We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing. Finally, we briefly discuss the characterization of macrophage heterogeneity in humans. C1 [Murray, Peter J.] St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Murray, Peter J.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Wynn, Thomas A.] NIAID, Program Barrier Immun & Repair, Bethesda, MD 20892 USA. [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Murray, PJ (reprint author), St Jude Childrens Hosp, Dept Infect Dis, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM peter.murray@stjude.org; twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Hartwell Foundation, US National Institutes of Health (NIH) [P30 CA21765]; American Lebanese Syrian Associated Charities; US National Institute of Allergy and Infectious Diseases, NIH FX Work in P.J.M.'s laboratory is supported by The Hartwell Foundation, US National Institutes of Health (NIH) CORE grant P30 CA21765 and the American Lebanese Syrian Associated Charities. T.A.W. is supported by the Intramural Program of the US National Institute of Allergy and Infectious Diseases, NIH. NR 176 TC 1238 Z9 1271 U1 55 U2 369 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD NOV PY 2011 VL 11 IS 11 BP 723 EP 737 DI 10.1038/nri3073 PG 15 WC Immunology SC Immunology GA 842GW UT WOS:000296584700011 PM 21997792 ER PT J AU Hoffer, BJ Harvey, BK AF Hoffer, Barry J. Harvey, Brandon K. TI PARKINSON DISEASE Is GDNF beneficial in Parkinson disease? SO NATURE REVIEWS NEUROLOGY LA English DT Editorial Material ID NEUROTROPHIC FACTOR; ALPHA-SYNUCLEIN; EXPRESSION; INFUSION; NEURONS C1 [Hoffer, Barry J.; Harvey, Brandon K.] Natl Inst Drug Abuse, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Hoffer, BJ (reprint author), Natl Inst Drug Abuse, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM bhoffer@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999, ZIA DA000443-11]; NINDS NIH HHS [R01 NS070825] NR 10 TC 10 Z9 10 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD NOV PY 2011 VL 7 IS 11 BP 600 EP 602 DI 10.1038/nrneurol.2011.149 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 844GL UT WOS:000296735600002 PM 21931353 ER PT J AU Goldstein, RZ Volkow, ND AF Goldstein, Rita Z. Volkow, Nora D. TI Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID ANTERIOR CINGULATE CORTEX; POSITRON-EMISSION-TOMOGRAPHY; MEDIAL ORBITOFRONTAL CORTEX; COCAINE-DEPENDENT PATIENTS; SELF-MEDICATION HYPOTHESIS; ADOLESCENT MARIJUANA USERS; OPPONENT-PROCESS THEORY; SALIENT COGNITIVE TASK; CEREBRAL-BLOOD-FLOW; GRAY-MATTER AB The loss of control over drug intake that occurs in addiction was initially believed to result from disruption of subcortical reward circuits. However, imaging studies in addictive behaviours have identified a key involvement of the prefrontal cortex (PFC) both through its regulation of limbic reward regions and its involvement in higher-order executive function (for example, self-control, salience attribution and awareness). This Review focuses on functional neuroimaging studies conducted in the past decade that have expanded our understanding of the involvement of the PFC in drug addiction. Disruption of the PFC in addiction underlies not only compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of free will. C1 [Goldstein, Rita Z.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM rgoldstein@bnl.gov FU US National Institute on Drug Abuse [R01DA023579]; NIAAA; Department of Energy, Office of Biological and Environmental Research FX This study was supported by grants from the US National Institute on Drug Abuse (R01DA023579 to R. Z. G.), the Intramural NIAAA program and the Department of Energy, Office of Biological and Environmental Research (for infrastructure support). We are grateful for A. B. Konova's contribution to the design of figure 2. We are indebted to our reviewers whose comments were greatly appreciated and guided our revision of the original manuscript. NR 222 TC 488 Z9 499 U1 26 U2 167 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD NOV PY 2011 VL 12 IS 11 BP 652 EP 669 DI 10.1038/nrn3119 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 842GU UT WOS:000296584400011 PM 22011681 ER PT J AU Heilig, M Goldman, D Berrettini, W O'Brien, CP AF Heilig, Markus Goldman, David Berrettini, Wade O'Brien, Charles P. TI Pharmacogenetic approaches to the treatment of alcohol addiction SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID OPIOID-RECEPTOR GENE; CORTICOTROPIN-RELEASING-FACTOR; STRESSFUL LIFE EVENTS; SINGLE-NUCLEOTIDE POLYMORPHISM; RANDOMIZED CONTROLLED-TRIAL; WITHDRAWAL-INDUCED ANXIETY; PLACEBO-CONTROLLED TRIAL; SUBSTANCE USE DISORDERS; CHILDHOOD SEXUAL-ABUSE; ETHANOL-DEPENDENT RATS AB Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments. C1 [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Berrettini, Wade; O'Brien, Charles P.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Heilig, Markus/0000-0003-2706-2482 FU US National Institute on Alcohol Abuse and Alcoholism; US National Institutes of Health (NIH) [P20-DA-025995, R01-DA-025201, P60-DA 05186]; NIH [P60-DA-005186-23, 5-P50-DA-012756-11, R01-DA-024553, R01-AA017164-2] FX The authors want to acknowledge many co-workers in their respective laboratories who over the years have contributed to work reviewed here; C.P.O. particularly wishes to acknowledge contributions by D. Oslin. The laboratories of M.H. and D.G. are supported by the intramural programme of the US National Institute on Alcohol Abuse and Alcoholism. W.H.B. is supported by US National Institutes of Health (NIH) grants P20-DA-025995, R01-DA-025201 and P60-DA 05186. C.P.O. is supported by NIH grants P60-DA-005186-23, 5-P50-DA-012756-11, R01-DA-024553 and R01-AA017164-2. NR 157 TC 105 Z9 106 U1 6 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD NOV PY 2011 VL 12 IS 11 BP 670 EP 684 DI 10.1038/nrn3110 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 842GU UT WOS:000296584400012 PM 22011682 ER PT J AU Badiani, A Belin, D Epstein, D Calu, D Shaham, Y AF Badiani, Aldo Belin, David Epstein, David Calu, Donna Shaham, Yavin TI Opiate versus psychostimulant addiction: the differences do matter SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID VENTRAL TEGMENTAL AREA; MESOLIMBIC DOPAMINE SYSTEM; CONDITIONED PLACE PREFERENCE; STRESS-INDUCED REINSTATEMENT; NUCLEUS-ACCUMBENS DOPAMINE; SELF-ADMINISTERED COCAINE; MEDIAL PREFRONTAL CORTEX; HEROIN-SEEKING BEHAVIOR; FREELY MOVING RATS; CONTEXT-INDUCED REINSTATEMENT AB The publication of the psychomotor stimulant theory of addiction in 1987 and the finding that addictive drugs increase dopamine concentrations in the rat mesolimbic system in 1988 have led to a predominance of psychobiological theories that consider addiction to opiates and addiction to psychostimulants as essentially identical phenomena. Indeed, current theories of addiction - hedonic allostasis, incentive sensitization, aberrant learning and frontostriatal dysfunction - all argue for a unitary account of drug addiction. This view is challenged by behavioural, cognitive and neurobiological findings in laboratory animals and humans. Here, we argue that opiate addiction and psychostimulant addiction are behaviourally and neurobiologically distinct and that the differences have important implications for addiction treatment, addiction theories and future research. C1 [Badiani, Aldo] Univ Roma La Sapienza, Dept Physiol & Pharmacol Vittorio Erspamer, I-00185 Rome, Italy. [Badiani, Aldo] Univ Roma La Sapienza, Drug Addict & Clin Pharmacol Unit, Univ Hosp Umberto I, I-00185 Rome, Italy. [Belin, David] Univ Poitiers, AVENIR Team Psychobiol Compuls Disorders, INSERM, Expt & Clin Neurosci Lab, F-86000 Poitiers, France. [Epstein, David; Calu, Donna; Shaham, Yavin] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Badiani, A (reprint author), Univ Roma La Sapienza, Dept Physiol & Pharmacol Vittorio Erspamer, Piazzale Aldo Moro 5, I-00185 Rome, Italy. EM aldo.badiani@uniroma1.it; yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI belin, david/0000-0002-7383-372X; Calu, Donna/0000-0003-2377-9494 FU Sapienza University of Rome, Italy; Institut National de la Sante et de la Recherche Medicale (INSERM); US National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) FX This Perspective was written with financial support from the Ricerche di Universita Program of the Sapienza University of Rome, Italy (A. B.), the Institut National de la Sante et de la Recherche Medicale (INSERM) (D. B.) and the Intramural Research Program of the US National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) (D. C., D. E. and Y.S.). We thank R. See for sharing with us unpublished data that are included in the summary diagram in FIG. 4, A. Ettenberg for sharing historical data with us, and M. Heilig and E. Koya for very helpful comments. NR 256 TC 143 Z9 148 U1 8 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD NOV PY 2011 VL 12 IS 11 BP 685 EP 700 DI 10.1038/nrn3104 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 842GU UT WOS:000296584400013 PM 21971065 ER PT J AU Chittuluru, JR Chaban, Y Monnet-Saksouk, J Carrozza, MJ Sapountzi, V Selleck, W Huang, JH Utley, RT Cramet, M Allard, S Cai, G Workman, JL Fried, MG Tan, S Cote, J Asturias, FJ AF Chittuluru, Johnathan R. Chaban, Yuriy Monnet-Saksouk, Julie Carrozza, Michael J. Sapountzi, Vasileia Selleck, William Huang, Jiehuan Utley, Rhea T. Cramet, Myriam Allard, Stephane Cai, Gang Workman, Jerry L. Fried, Michael G. Tan, Song Cote, Jacques Asturias, Francisco J. TI Structure and nucleosome interaction of the yeast NuA4 and Piccolo-NuA4 histone acetyltransferase complexes SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID CODING REGIONS; PROMOTER NUCLEOSOMES; ELECTRON-MICROSCOPY; EMBRYONIC STEM; H2A VARIANTS; CHROMATIN; TRANSCRIPTION; ACETYLATION; BINDING; ENHANCER AB We have used EM and biochemistry to characterize the structure of NuA4, an essential yeast histone acetyltransferase (HAT) complex conserved throughout eukaryotes, and we have determined the interaction of NuA4 with the nucleosome core particle (NCP). The ATM-related Tra1 subunit, which is shared with the SAGA coactivator complex, forms a large domain joined to a second region that accommodates the catalytic subcomplex Piccolo and other NuA4 subunits. EM analysis of a NuA4-NCP complex shows the NCP bound at the periphery of NuA4. EM characterization of Piccolo and Piccolo-NCP provided further information about subunit organization and confirmed that histone acetylation requires minimal contact with the NCP. A small conserved region at the N terminus of Piccolo subunit enhancer of Polycomb-like 1 (Epl1) is essential for NCP interaction, whereas the subunit yeast homolog of mammalian Ing1 2 (Yng2) apparently positions Piccolo for efficient acetylation of histone H4 or histone H2A tails. Taken together, these results provide an understanding of the NuA4 subunit organization and the NuA4-NCP interactions. C1 [Chittuluru, Johnathan R.; Chaban, Yuriy; Cai, Gang; Asturias, Francisco J.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Monnet-Saksouk, Julie; Sapountzi, Vasileia; Utley, Rhea T.; Cramet, Myriam; Allard, Stephane; Cote, Jacques] Univ Laval, Canc Res Ctr, Hotel Dieu Quebec CHUQ, Quebec City, PQ, Canada. [Carrozza, Michael J.] Natl Inst Environm Hlth Sci, Lab Struct Biol, Res Triangle Pk, NC USA. [Selleck, William; Huang, Jiehuan; Tan, Song] Penn State Univ, Ctr Eukaryot Gene Regulat, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Workman, Jerry L.] Stowers Inst Med Res, Kansas City, MO USA. [Fried, Michael G.] Univ Kentucky, Ctr Struct Biol, Dept Mol & Cellular Biochem, Lexington, KY USA. RP Asturias, FJ (reprint author), Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. EM jacques.cote@crhdq.ulaval.ca; asturias@scripps.edu RI Cai, Gang/B-1103-2012; Huang, Jiehuan/A-7077-2013; Cote, Jacques/I-8901-2014; OI Cai, Gang/0000-0001-8622-3907; Cote, Jacques/0000-0001-6751-555X; saksouk, julie/0000-0003-1885-1762 FU US National Institutes of Health [R01 GM67167, R01 GM060489, R01 GM070662, F31 GM086978]; Canadian Institutes of Health [MOP-14308]; Canada Research Chair FX This work was supported by US National Institutes of Health grants R01 GM67167 (F.J.A.), R01 GM060489 (S.T.) and R01 GM070662 (M.G.F.), and fellowship F31 GM086978 (J.R.C.), by a Canadian Institutes of Health Research grant MOP-14308 (J.C.) and fellowship (V.S.), and by a Canada Research Chair (J.C.). We also acknowledge the National Resource for Automated Macromolecular Microscopy. NR 50 TC 28 Z9 28 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD NOV PY 2011 VL 18 IS 11 BP 1196 EP U148 DI 10.1038/nsmb.2128 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 844FX UT WOS:000296734200005 PM 21984211 ER PT J AU Shin, BS Kim, JR Walker, SE Dong, JS Lorsch, JR Dever, TE AF Shin, Byung-Sik Kim, Joo-Ran Walker, Sarah E. Dong, Jinsheng Lorsch, Jon R. Dever, Thomas E. TI Initiation factor eIF2 gamma promotes eIF2-GTP-Met-tRNA(i)(Met) ternary complex binding to the 40S ribosome SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID ELONGATION-FACTOR TU; ACID BIOSYNTHETIC GENES; AMINOACYL-TRANSFER-RNA; START CODON SELECTION; TRANSLATION INITIATION; CRYSTAL-STRUCTURE; BETA-SUBUNIT; EF-TU; SACCHAROMYCES-CEREVISIAE; CONFORMATIONAL-CHANGE AB In contrast to prokaryotic elongation factor EF-Tu, which delivers aminoacyl-tRNAs to the ribosomal A-site, eukaryotic initiation factor eIF2 binds methionyl initiator transfer RNA (Met-tRNA(i)(Met)) to the P-site of the 40S ribosomal subunit. The results of directed hydroxyl radical probing experiments to map binding of Saccharomyces cerevisiae eIF2 on the ribosome and on Met-tRNA(i)(Met) revealed that eIF2 gamma primarily contacts the acceptor stem of Met-tRNA(i)(Met) and identified a key binding interface between domain III of eIF2 gamma and 18S rRNA helix h44 on the 40S subunit. Whereas the analogous domain III of EF-Tu contacts the T stem of tRNAs, biochemical analyses demonstrated that eIF2 gamma domain III is important for ribosome, not Met-tRNA(i)(Met). Thus, despite their structural similarity, eIF2 and EF-Tu bind tRNAs in substantially different manners, and we propose that the tRNA-binding domain III of EF-Tu has acquired a new ribosome-binding function in eIF2 gamma. C1 [Shin, Byung-Sik; Kim, Joo-Ran; Dong, Jinsheng; Dever, Thomas E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. [Walker, Sarah E.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. RP Dever, TE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. EM tdever@nih.gov OI Dever, Thomas/0000-0001-7120-9678 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; US National Institutes of Health; NIH [GM62128] FX We thank A. Hinnebusch, R. Green and our colleagues in the Dever, Lorsch and Hinnebusch laboratories for advice and helpful discussions. We thank J. Fringer (US National Institutes of Health), D. Eyler, S. He, H. Zaher (all Johns Hopkins University) and O. Uhlenbeck (Northwestern University) for protocols and reagents. This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health (T.E.D.) and by grant GM62128 from the NIH (J.R.L.). NR 49 TC 35 Z9 36 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD NOV PY 2011 VL 18 IS 11 BP 1227 EP U1 DI 10.1038/nsmb.2133 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 844FX UT WOS:000296734200009 PM 22002225 ER PT J AU Kim, M Sun, ZYJ Rand, KD Shi, XM Song, LK Cheng, YX Fahmy, AF Majumdar, S Ofek, G Yang, YP Kwong, PD Wang, JH Engen, JR Wagner, G Reinherz, EL AF Kim, Mikyung Sun, Zhen-Yu J. Rand, Kasper D. Shi, Xiaomeng Song, Likai Cheng, Yuxing Fahmy, Amr F. Majumdar, Shreoshi Ofek, Gilad Yang, Yongping Kwong, Peter D. Wang, Jia-Huai Engen, John R. Wagner, Gerhard Reinherz, Ellis L. TI Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; EXCHANGE-MASS-SPECTROMETRY; COMPLEMENTARITY-DETERMINING REGION; STRUCTURAL BASIS; GP41 ECTODOMAIN; COMBINING SITE; HEAVY-CHAIN; EPITOPE; 2F5; 4E10 AB Broadly neutralizing antibodies such as 2F5 are directed against the membrane-proximal external region (MPER) of HIV-1 GP41 and recognize well-defined linear core sequences. These epitopes can be engrafted onto protein scaffolds to serve as immunogens with high structural fidelity. Although antibodies that bind to this core GP41 epitope can be elicited, they lack neutralizing activity. To understand this paradox, we used biophysical methods to investigate the binding of human 2F5 to the MPER in a membrane environment, where it resides in vivo. Recognition is stepwise, through a paratope more extensive than core binding site contacts alone, and dynamic rearrangement through an apparent scoop-like movement of heavy chain complementarity-determining region 3 (CDRH3) is essential for MPER extraction from the viral membrane. Core-epitope recognition on the virus requires the induction of conformational changes in both the MPER and the paratope. Hence, target neutralization through this lipid-embedded viral segment places stringent requirements on the plasticity of the antibody combining site. C1 [Kim, Mikyung; Cheng, Yuxing; Majumdar, Shreoshi; Wang, Jia-Huai; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Kim, Mikyung; Song, Likai; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sun, Zhen-Yu J.; Fahmy, Amr F.; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Rand, Kasper D.; Shi, Xiaomeng; Engen, John R.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Rand, Kasper D.; Shi, Xiaomeng; Engen, John R.] Northeastern Univ, Barnett Inst Chem & Biol Anal, Boston, MA 02115 USA. [Song, Likai; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Song, Likai] Natl High Magnet Field Lab, Tallahassee, FL USA. [Cheng, Yuxing] Harvard Univ, Sch Publ Hlth, PhD Program Biol Sci Publ Hlth, Boston, MA 02115 USA. [Ofek, Gilad; Yang, Yongping; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Wang, Jia-Huai] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Immunobiol Lab, 44 Binney St, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu OI Rand, Kasper/0000-0002-6337-5489 FU US National Institutes of Health (NIH) [RO1AI84785, U19AI91693]; Gates Foundation; NIH [RO1-GM086507]; Waters Corporation; The Danish Council for Independent Research in Natural Sciences [09-063876]; US National High Magnetic Field Laboratory (NHMFL); US National Science Foundation [DMR-0654118]; State of Florida; US Department of Energy; The Collaboration for AIDS Vaccine Discovery (CAVD) Program FX This work was supported by US National Institutes of Health (NIH) grants RO1AI84785 and U19AI91693 to E.L.R. and G.W., and a grant from the Gates Foundation, The Collaboration for AIDS Vaccine Discovery (CAVD) Program to E.L.R., G.W. and J.R.E. J.R.E. was also supported by NIH grant RO1-GM086507 and funding through a cooperative research agreement with the Waters Corporation. K.D.R. was supported by The Danish Council for Independent Research in Natural Sciences (FNU grant 09-063876). J.R.E. would like to thank T.E. Wales for expert technical assistance. L.S. was also supported by an US National High Magnetic Field Laboratory (NHMFL) User Collaboration Grants Program award. The NHMFL is funded by the US National Science Foundation through the Cooperative Agreement No. DMR-0654118, the State of Florida, and the US Department of Energy. NR 58 TC 51 Z9 51 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD NOV PY 2011 VL 18 IS 11 BP 1235 EP U81 DI 10.1038/nsmb.2154 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 844FX UT WOS:000296734200010 PM 22002224 ER PT J AU Szyk, A Deaconescu, AM Piszczek, G Roll-Mecak, A AF Szyk, Agnieszka Deaconescu, Alexandra M. Piszczek, Grzegorz Roll-Mecak, Antonina TI Tubulin tyrosine ligase structure reveals adaptation of an ancient fold to bind and modify tubulin SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID D-ALANINE LIGASE; ALPHA-TUBULIN; BRAIN TUBULIN; POSTTRANSLATIONAL MODIFICATIONS; GLUTATHIONE SYNTHETASE; ESCHERICHIA-COLI; POOR-PROGNOSIS; BETA-TUBULIN; RAT-BRAIN; MICROTUBULES AB Tubulin tyrosine ligase (TTL) catalyzes the post-translational C-terminal tyrosination of alpha-tubulin. Tyrosination regulates recruitment of microtubule-interacting proteins. TTL is essential. Its loss causes morphogenic abnormalities and is associated with cancers of poor prognosis. We present the first crystal structure of TTL (from Xenopus tropicalis), defining the structural scaffold upon which the diverse TTL-like family of tubulin-modifying enzymes is built. TTL recognizes tubulin using a bipartite strategy. It engages the tubulin tail through low-affinity, high-specificity interactions, and co-opts what is otherwise a homo-oligomerization interface in structurally related ATP grasp-fold enzymes to form a tight hetero-oligomeric complex with the tubulin body. Small-angle X-ray scattering and functional analyses reveal that TTL forms an elongated complex with the tubulin dimer and prevents its incorporation into microtubules by capping the tubulin longitudinal interface, possibly modulating the partition of tubulin between monomeric and polymeric forms. C1 [Szyk, Agnieszka; Roll-Mecak, Antonina] Natl Inst Neurol Disorders & Stroke, Cell Biol & Biophys Unit, Bethesda, MD USA. [Deaconescu, Alexandra M.] Brandeis Univ, Dept Biochem, Waltham, MA 02254 USA. [Piszczek, Grzegorz; Roll-Mecak, Antonina] NHLBI, Bethesda, MD 20892 USA. RP Roll-Mecak, A (reprint author), Natl Inst Neurol Disorders & Stroke, Cell Biol & Biophys Unit, Bethesda, MD USA. EM antonina@mail.nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS)/NIH FX A.R.-M. is a Searle Scholar and is supported by the intramural program of the National Institute of Neurological Disorders and Stroke (NINDS)/NIH. NR 60 TC 32 Z9 34 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD NOV PY 2011 VL 18 IS 11 BP 1250 EP U98 DI 10.1038/nsmb.2148 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 844FX UT WOS:000296734200012 PM 22020298 ER PT J AU Kidwell, CS Burgess, R Menon, R Warach, S Latour, LL AF Kidwell, C. S. Burgess, R. Menon, R. Warach, S. Latour, L. L. TI Hyperacute injury marker (HARM) in primary hemorrhage A distinct form of CNS barrier disruption SO NEUROLOGY LA English DT Article ID INTRACEREBRAL HEMORRHAGE; BRAIN; STROKE; EXTRAVASATION; HEMATOMA; RAT AB Objective: The objective of the study was to characterize a previously unreported form of CNS barrier disruption in intracerebral hemorrhage (ICH): hyperacute injury marker (HARM). Methods: In this retrospective cohort analysis of patients presenting with primary ICH, precontrast and postcontrast MRI scans obtained within 5 days of symptom onset were analyzed. The presence of CNS barrier disruption was defined by 1) perihematomal or intrahematomal enhancement visualized on postcontrast T1-weighted MRI or 2) HARM: sulcal or ventricular hyperintensity visualized on postcontrast fluid-attenuated inversion recovery sequences (graded on a 5-point scale). Results: Forty-six patients were included in the analysis. Mean age was 65 years, median NIH Stroke Scale score was 7, and mean ICH volume was 12.2 mL (range 0.3-46.9 mL). HARM was visualized in 85% of patients, and this was moderate to severe in 50%. In all cases, the sulcal enhancement was noncontiguous with the hematoma. Of those patients with postcontrast T1-weighted imaging, perihematomal or intrahematomal contrast enhancement was visualized in 75% of patients. Conclusions: This study demonstrates that HARM occurs in intracerebral hemorrhage and that it likely represents a second type of CNS barrier disruption distinct from parenchymal postcontrast T1-weighted enhancement. Similar to T1 enhancement, this phenomenon may serve as a clinically useful biomarker to test therapies aimed at stabilizing acute ICH and CNS barrier disruption. Future studies are needed to further define the time course and prognostic implications of this finding. Neurology (R) 2011;77:1725-1728 C1 [Kidwell, C. S.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. [Kidwell, C. S.; Burgess, R.; Menon, R.] Georgetown Univ, Stroke Ctr, Washington, DC 20007 USA. [Warach, S.; Latour, L. L.] NINDS, NIH, Bethesda, MD 20892 USA. RP Kidwell, CS (reprint author), Georgetown Univ, Med Ctr, Dept Neurol, 4000 Reservoir Rd NW,Bldg D,Suite 150, Washington, DC 20007 USA. EM ck256@georgetown.edu FU Baxter International Inc.; NIH/NINDS; NIH (NINDS, NIMHD); NINDS, Division of Intramural Research FX Dr. Kidwell serves on the editorial boards of Neurocritical Care, the Journal of Neuroimaging, and Stroke Research and Treatment; serves/served as a consultant for Embrella Cardiovascular, Inc., Inc. and Simcere Pharmaceutical Group; and receives research support from Baxter International Inc. and the NIH/NINDS. Dr. Burgess receives research support from the NIH/NINDS. Dr. Menon receives research support from the NIH (NINDS, NIMHD). Dr. Warach serves on the editorial boards of the Journal of Cerebral Blood Flow and Metabolism, Stroke, The Lancet Neurology, International Journal of Stroke, and Cerebrovascular Diseases; and receives research support from NINDS, Division of Intramural Research. Dr. Latour reports no disclosures.; Supported in part by the Division of Intramural Research, National Institute of Neurological Disorders and Stroke (NINDS). NR 10 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD NOV PY 2011 VL 77 IS 19 BP 1725 EP 1728 DI 10.1212/WNL.0b013e318236ef46 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 844SO UT WOS:000296767800008 PM 22031531 ER PT J AU Unverzagt, FW McClure, LA Wadley, VG Jenny, NS Go, RC Cushman, M Kissela, BM Kelley, BJ Kennedy, R Moy, CS Howard, V Howard, G AF Unverzagt, F. W. McClure, L. A. Wadley, V. G. Jenny, N. S. Go, R. C. Cushman, M. Kissela, B. M. Kelley, B. J. Kennedy, R. Moy, C. S. Howard, V. Howard, G. TI Vascular risk factors and cognitive impairment in a stroke-free cohort SO NEUROLOGY LA English DT Article ID BLOOD-PRESSURE; CARDIOVASCULAR HEALTH; RACIAL-DIFFERENCES; ALZHEIMER-DISEASE; HEART-FAILURE; DECLINE; HYPERTENSION; PROFILE; DEMENTIA; AGE AB Objective: To examine vascular risk factors, as measured by the Framingham Stroke Risk Profile (FSRP), to predict incident cognitive impairment in a large, national sample of black and white adults age 45 years and older. Methods: Participants included subjects without stroke at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with at least 2 cognitive function assessments during the follow-up (n = 23,752). Incident cognitive impairment was defined as decline from a baseline score of 5 or 6 (of possible 6 points) to the most recent follow-up score of 4 or less on the Six-item Screener (SIS). Subjects with suspected stroke during follow-up were censored. Results: During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment. Baseline FSRP score was associated with incident cognitive impairment. An adjusted model revealed that male sex (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.43-1.77), black race (OR = 2.09, 95% CI 1.88-2.35), less education (less than high school graduate vs college graduate, OR = 2.21, 95% CI 1.88-2.60), older age (10-year increments, OR = 2.11, per 10-year increase in age, 95% CI 2.05-2.18), and presence of left ventricular hypertrophy (LVH, OR = 1.29, 95% CI 1.06-1.58) were related to development of cognitive impairment. When LVH was excluded from the model, elevated systolic blood pressure was related to incident cognitive impairment. Conclusions: Total FSRP score, elevated blood pressure, and LVH predict development of clinically significant cognitive dysfunction. Prevention and treatment of high blood pressure may be effective in preserving cognitive health. Neurology (R) 2011;77:1729-1736 C1 [Unverzagt, F. W.] Indiana Univ, Dept Psychiat, Sch Med, Indianapolis, IN 46202 USA. [McClure, L. A.; Wadley, V. G.; Go, R. C.; Kennedy, R.; Howard, V.; Howard, G.] Univ Alabama, Dept Biostat, Birmingham, AL USA. [McClure, L. A.; Wadley, V. G.; Go, R. C.; Kennedy, R.; Howard, V.; Howard, G.] Univ Alabama, Dept Med, Birmingham, AL USA. [McClure, L. A.; Wadley, V. G.; Go, R. C.; Kennedy, R.; Howard, V.; Howard, G.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Jenny, N. S.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Cushman, M.] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Kissela, B. M.; Kelley, B. J.] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. [Moy, C. S.] NINDS, Bethesda, MD 20892 USA. RP Unverzagt, FW (reprint author), Indiana Univ, Dept Psychiat, Sch Med, 1111 W 10th St,Suite PB 218A, Indianapolis, IN 46202 USA. EM funverza@iupui.edu RI McClure, Leslie/P-2929-2015; OI Kissela, Brett/0000-0002-9773-4013 FU NIH; Posit Science Inc; Eli Lilly and Company; Genzyme Corporation; NIH (NINDS, NICHD, NHLBI); NASA; Amgen; Jefferson County Office of Senior Citizens Services; GlaxoSmithKline; American Diabetic Association; NIH/NINDS; Allergan, Inc.; NexStim; Novartis; NIH (NINDS, NIA, NIDDK); NIH (NINDS, NIDDK, NIOSH); NIH (NINDS, NIAMS, NICHD, NHLBI); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services [U01 NS041588] FX Dr. Unverzagt has served as a consultant to Eli Lilly and Company; serves on the editorial boards of the Journal of the International Neuropsychological Association and Neuropsychology; receives research support from the NIH and Posit Science Inc; and holds stock in Eli Lilly and Company. Dr. McClure serves on a Data Monitoring Committee for the NIH/NINDS and receives research support from Genzyme Corporation, the NIH (NINDS, NICHD, NHLBI), and NASA. Dr. Wadley has received funding for travel from Amgen; serves on the editorial board of Current Gerontology and Geriatrics Research; and receives research support from Genzyme Corporation, the NIH, and the Jefferson County Office of Senior Citizens Services. Dr. Jenny serves on the editorial board of Arteriosclerosis, Thrombosis and Vascular Biology; serves as a consultant for Tethys Bioscience, Inc.; receives research support from GlaxoSmithKline, the NIH, and the American Diabetic Association; and holds stock in Haematologic Technologies, Inc. Dr. Go receives research support from the NIH/NINDS. Dr. Cushman serves on the editorial boards of the Journal of Thrombosis and Haemostasis, Circulation, Archives of Internal Medicine, and the Journal of Thrombosis and Thrombolysis; and receives/has received research support from Amgen, GlaxoSmithKline, and the NIH. Dr. Kissela serves on scientific advisory boards for Northstar Neuroscience and Allergan, Inc.; has received funding for travel and speaker honoraria from Allergan, Inc.; has received research support from NexStim and the NIH; and provides medico-legal reviews. Dr. Kelley receives/has received research support from Novartis and the NIH. Dr. Kennedy receives research support from the NIH (NINDS, NIA, NIDDK). Dr. Moy reports no disclosures. Dr. V. Howard serves/has served on scientific advisory boards for Amgen, Boehringer-Ingelheim, Mitsubishi, PhotoThera, and MediciNova; her spouse serves on a scientific advisory boards for Bayer Schering Pharma; has received funding for travel from Amgen; serves as a consultant for NIH review committees; her spouse has provided legal consulting for Merck Serono; and receives research support from the NIH (NINDS, NIDDK, NIOSH). Dr. G. Howard serves/has served on scientific advisory boards for Bayer Schering Pharma, Abbott, Boehringer Ingelheim, BrainsGate, Cerevast Therapeutics, Inc., CoAxia, Inc., MediciNova, Inc., Mitsubishi Tanabe Pharma Corporation, and PhotoThera; serves as Stroke Section Editor for the Journal of The American Society of Hypertension; and receives research support from Amgen and the NIH (NINDS, NIAMS, NICHD, NHLBI).; This research project is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis, or interpretation of the data. NR 40 TC 64 Z9 64 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD NOV PY 2011 VL 77 IS 19 BP 1729 EP 1736 DI 10.1212/WNL.0b013e318236ef23 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 844SO UT WOS:000296767800009 PM 22067959 ER PT J AU Lin, FR Ferrucci, L Metter, EJ An, Y Zonderman, AB Resnick, SM AF Lin, Frank R. Ferrucci, Luigi Metter, E. Jeffrey An, Yang Zonderman, Alan B. Resnick, Susan M. TI Hearing Loss and Cognition in the Baltimore Longitudinal Study of Aging SO NEUROPSYCHOLOGY LA English DT Article DE hearing loss; cognition; aging; dementia ID PRECLINICAL ALZHEIMERS-DISEASE; OLD-AGE; MEMORY IMPAIRMENT; STRONG CONNECTION; DEMENTIA; DECLINE; POPULATION; ACUITY; ADULTS; DYSFUNCTION AB Objective: To determine the relationship between hearing loss and cognitive function as assessed with a standardized neurocognitive battery. We hypothesized a priori that greater hearing loss is associated with lower cognitive test scores on tests of memory and executive function. Method: A cross-sectional cohort of 347 participants >= 55 years in the Baltimore Longitudinal Study of Aging without mild cognitive impairment or dementia had audiometric and cognitive testing performed in 1990-1994. Hearing loss was defined by an average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better-hearing ear. Cognitive testing consisted of a standardized neurocognitive battery incorporating tests of mental status, memory, executive function, processing speed, and verbal function. Regression models were used to examine the association between hearing loss and cognition while adjusting for confounders. Results: Greater hearing loss was significantly associated with lower scores on measures of mental status (Mini-Mental State Exam), memory (Free Recall), and executive function (Stroop Mixed, Trail Making B). These results were robust to analyses accounting for potential confounders, nonlinear effects of age, and exclusion of individuals with severe hearing loss. The reduction in cognitive performance associated with a 25 dB hearing loss was equivalent to the reduction associated with an age difference of 6.8 years. Conclusion: Hearing loss is independently associated with lower scores on tests of memory and executive function. Further research examining the longitudinal association of hearing loss with cognitive functioning is needed to confirm these cross-sectional findings. C1 [Ferrucci, Luigi; Metter, E. Jeffrey] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [An, Yang; Zonderman, Alan B.; Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Lin, Frank R.] Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Lin, FR (reprint author), Ctr Aging & Hlth, Suite 2-700,2024 E Monument St, Baltimore, MD 21205 USA. EM flin1@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Deafness and Other Communication Disorders [1K23DC001279] FX This work was supported by National Institute on Deafness and Other Communication Disorders Grant 1K23DC001279 to Dr. Lin and the intramural research program of the National Institute on Aging. NR 70 TC 108 Z9 118 U1 11 U2 50 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD NOV PY 2011 VL 25 IS 6 BP 763 EP 770 DI 10.1037/a0024238 PG 8 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 843IF UT WOS:000296664800009 PM 21728425 ER PT J AU White, DB Bursac, Z DiLillo, V West, DS AF White, Della B. Bursac, Zoran DiLillo, Vicki West, Delia S. TI Weight Loss Goals Among African-American Women With Type 2 Diabetes in a Behavioral Weight Control Program SO OBESITY LA English DT Article ID PATIENTS EXPECTATIONS; TREATMENT OUTCOMES; OBESITY; PREVALENCE; OVERWEIGHT; TRIAL; MEN; US AB African-American women with type 2 diabetes experience limited weight loss in behavioral weight control programs. Some research suggests that overly ambitious weight loss expectations may negatively affect weight losses achieved but it is unknown whether they affect weight loss among African-American women. The current study examined personal weight loss goals and expected satisfaction with a reasonable weight loss among African-American women with type 2 diabetes starting a behavioral obesity treatment. We also explored associations among these factors and weight loss treatment outcomes. Self-identified African-American women (N = 84) in a 24-session group program were assessed at baseline and 6-month follow-up. At baseline, women indicated weight loss goals of 14.1 +/- 6.6 kg (14% of initial weight). They also reported relatively high expected satisfaction with a reasonable weight loss (7-10%). On average, participants lost 3.0 +/- 3.9 kg (3% of initial weight) and attended 73 +/- 21% of group sessions. Neither weight loss goals nor expected satisfaction with a reasonable weight loss was correlated with either actual weight loss outcome or attendance. Having higher personal weight loss goals was associated with lower expectations of satisfaction with a reasonable weight loss. This suggests that African-American women with type 2 diabetes enter treatment hoping to lose far more weight than they are likely to achieve. It is important to understand the psychosocial sequelae of failing to reach these goals on subsequent weight maintenance and future weight loss attempts within this population. C1 [White, Della B.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Bursac, Zoran] Univ Arkansas Med Sci, Coll Publ Hlth, Dept Biostat, Little Rock, AR 72205 USA. [DiLillo, Vicki] Ohio Wesleyan Univ, Dept Psychol, Delaware, OH 43015 USA. [West, Delia S.] Univ Arkansas Med Sci, Coll Publ Hlth, Dept Hlth Behav, Little Rock, AR 72205 USA. RP West, DS (reprint author), NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. EM WestDelia@uams.edu FU National Human Genome Research Institute, National Institutes of Health; [DK RO1-54041] FX This study was supported by grant DK RO1-54041 and (in part) by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 15 TC 5 Z9 5 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD NOV PY 2011 VL 19 IS 11 BP 2283 EP 2285 DI 10.1038/oby.2010.350 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 843UF UT WOS:000296697900024 PM 21273996 ER PT J AU Chang, JR Koo, E Agron, E Hallak, J Clemons, T Azar, D Sperduto, RD Ferris, FL Chew, EY AF Chang, Jessica R. Koo, Euna Agron, Elvira Hallak, Joelle Clemons, Traci Azar, Dimitri Sperduto, Robert D. Ferris, Frederick L., III Chew, Emily Y. CA Age-Related Eye Dis Study Grp TI Risk Factors Associated with Incident Cataracts and Cataract Surgery in the Age-Related Eye Disease Study (AREDS) AREDS Report Number 32 SO OPHTHALMOLOGY LA English DT Article ID BEAVER DAM EYE; BLUE MOUNTAINS EYE; POSTERIOR SUBCAPSULAR CATARACTS; ULTRAVIOLET-LIGHT EXPOSURE; ASPIRIN-LIKE ANALGESICS; LONG-TERM INCIDENCE; BODY-MASS INDEX; LENS OPACITIES; BARBADOS EYE; EVALUATION PROJECT AB Objective: To investigate potential risk factors associated with incident nuclear, cortical, and posterior subcapsular (PSC) cataracts and cataract surgery in participants in the Age-Related Eye Disease Study (AREDS). Design: Clinic-based prospective cohort study. Participants: Persons (n = 4425) 55 to 80 years of age enrolled in a controlled clinical trial of antioxidant vitamins and minerals, AREDS, for age-related macular degeneration and cataract. Methods: Lens photographs were graded centrally for nuclear, cortical, and PSC opacities using the AREDS system for classifying cataracts. Type-specific incident cataracts were defined as an increase in cataract grade from none or mild at baseline to a grade of moderate at follow-up, also with a grade of at least moderate at the final visit, or cataract surgery. Cox regression analyses were used to assess baseline risk factors associated with type-specific opacities and cataract surgery. Main Outcome Measures: Moderate cataract was defined as a grade of 4.0 or more for nuclear opacity, 10% or more involvement within the full visible lens for cortical opacity, and 5% or more involvement of the central 5-mm circle of the lens for PSC opacity. These were graded on baseline and annual lens photographs. Results: A clinic-based cohort of 4425 persons 55 to 80 years of age at baseline was followed up for an average of 9.8 +/- 2.4 years. The following associations were found: increasing age with increased risk of all types of cataract and cataract surgery; males with increased risk of PSC and decreased risk of cortical cataracts; nonwhite persons with increased risk of cortical cataract; hyperopia with decreased risk of PSC, nuclear cataract, and cataract surgery; Centrum (Wyeth Consumer Healthcare, Madison, NJ) use with decreased risk of nuclear cataract; diabetes with increased risk of cortical, PSC cataract, and cataract surgery; higher educational level with decreased risk of cortical cataract; and smoking with increased risk of cortical cataract and cataract surgery. Estrogen replacement therapy in female participants increased the risk of cataract surgery. Conclusions: These findings largely are consistent with the results of previous studies, providing further evidence for possible modifiable risk factors for age-related cataract. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011;118:2113-2119 (C) 2011 by the American Academy of Ophthalmology. C1 [Koo, Euna; Agron, Elvira; Ferris, Frederick L., III; Chew, Emily Y.] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Chang, Jessica R.] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Hallak, Joelle; Azar, Dimitri] Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL USA. [Clemons, Traci; Sperduto, Robert D.] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bldg 10,CRC Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU National Eye Institute/National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; Howard Hughes Medical Institute-National Institutes of Health; National Institutes of Health; Pfizer FX Supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; the Howard Hughes Medical Institute-National Institutes of Health Scholars Program (JRC); and the Clinical Research Training Program at the National Institutes of Health, a public-private partnership supported jointly by the NIH and Pfizer (EK). NR 64 TC 45 Z9 45 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2011 VL 118 IS 11 BP 2113 EP 2119 DI 10.1016/j.ophtha.2011.03.032 PG 7 WC Ophthalmology SC Ophthalmology GA 842EG UT WOS:000296573500003 PM 21684602 ER PT J AU Phillips, D Aponte, AM Covian, R Neufeld, E Yu, ZX Balaban, RS AF Phillips, Darci Aponte, Angel M. Covian, Raul Neufeld, Edward Yu, Zu-Xi Balaban, Robert S. TI Homogenous protein programming in the mammalian left and right ventricle free walls SO PHYSIOLOGICAL GENOMICS LA English DT Article DE left ventricle; energy metabolism; proteomics; myocardial biochemistry and function ID CORONARY BLOOD-FLOW; ENERGY-METABOLISM; ENZYME-ACTIVITIES; EXERCISING DOGS; RAT-HEART; MASS; MORPHOMETRY; MYOCARDIUM; MECHANISMS; BALANCE AB Phillips D, Aponte AM, Covian R, Neufeld E, Yu ZX, Balaban RS. Homogenous protein programming in the mammalian left and right ventricle free walls. Physiol Genomics 43: 1198-1206, 2011. First published August 30, 2011; doi:10.1152/physiolgenomics.00121.2011.-Despite identical cardiac outputs, the right (RV) and left ventricle (LV) have very different embryological origins and resting workload. These differences suggest that the ventricles have different protein programming with regard to energy metabolism and contractile elements. The objective of this study was to determine the relative RV and LV protein expression levels, with an emphasis on energy metabolism. The RV and LV protein contents of the rabbit and porcine heart were determined with quantitative gel electrophoresis (2D-DIGE), mass spectrometry, and optical spectroscopy techniques. Surprisingly, the expression levels for more than 600 RV and LV proteins detected were similar. This included proteins many different compartments and metabolic pathways. In addition, no isoelectric shifts were detected in 2D-DIGE consistent with no differential posttranslational modifications in these proteins. Analysis of the RV and LV metabolic response to work revealed that the metabolic rate increases much faster with workload in the RV compared with LV. This implies that the generally lower metabolic stress of the RV actually approaches LV metabolic stress at maximum workloads. Thus, identical levels of energy conversion and mechanical elements in the RV and LV may be driven by the performance requirements at maximum workloads. In summary, the ventricles of the heart manage the differences in overall workload by modifying the amounts of cytosol, not its composition. The constant myocyte composition in the LV and RV implies that the ratio of energy metabolism and contractile elements may be optimal for the sustained cardiac contractile activity in the mammalian heart. C1 [Phillips, Darci; Covian, Raul; Neufeld, Edward; Balaban, Robert S.] NHLBI, Lab Cardiac Energet, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, NHLBI Prote Core, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, NHLBI Pathol Core, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, Lab Cardiac Energet, 10 Ctr Dr,Rm B1D-416, Bethesda, MD 20892 USA. EM rsb@nih.gov FU National Institutes of Health Division of Intramural Research FX These studies were funded by the National Institutes of Health Division of Intramural Research. NR 33 TC 9 Z9 9 U1 0 U2 27 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD NOV PY 2011 VL 43 IS 21 BP 1198 EP 1206 DI 10.1152/physiolgenomics.00121.2011 PG 9 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 844OW UT WOS:000296758000002 PM 21878611 ER PT J AU Grosche, B Lackland, DT Land, CE Simon, SL Apsalikov, KN Pivina, LM Bauer, S Gusev, BI AF Grosche, Bernd Lackland, Daniel T. Land, Charles E. Simon, Steven L. Apsalikov, Kazbek N. Pivina, Ludmilla M. Bauer, Susanne Gusev, Boris I. TI Mortality from Cardiovascular Diseases in the Semipalatinsk Historical Cohort, 1960-1999, and its Relationship to Radiation Exposure SO RADIATION RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; CORONARY-HEART-DISEASE; NUCLEAR TEST-SITE; IONIZING-RADIATION; STROKE BELT; EPIDEMIOLOGIC EVIDENCE; MINERS COHORT; LOCAL FALLOUT; SOLID CANCER; KAZAKSTAN AB Grosche, B., Lackland, D. T., Land, C. E., Simon, S. L., Apsalikov, K. N., Pivina, L. M., Bauer, S. and Gusev, B. I. Mortality from Cardiovascular Diseases in the Semipalatinsk Historical Cohort, 1960-1999, and its Relationship to Radiation Exposure. Radiat. Res. 176, 660-669 (2011). The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose-response analyses were conducted for both the entire cohort and the exposed group only. A dose-response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose-response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation-related mortality from cardiovascular disease. (C) 2011 by Radiation Research Society C1 [Grosche, Bernd] Fed Off Radiat Protect, Dept Radiat Protect & Hlth, D-85764 Oberschleissheim, Germany. [Lackland, Daniel T.] Med Univ S Carolina, Charleston, SC 29425 USA. [Land, Charles E.; Simon, Steven L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Apsalikov, Kazbek N.; Pivina, Ludmilla M.; Gusev, Boris I.] Sci Res Inst Radiat Med & Ecol, Semipalatinsk, Kazakhstan. [Bauer, Susanne] Univ Copenhagen, Inst Publ Hlth, Copenhagen, Denmark. RP Gusev, BI (reprint author), Fed Off Radiat Protect, Dept Radiat Protect & Hlth, Ingolstaedter Landstr 1, D-85764 Oberschleissheim, Germany. EM bgrosche@bfs.de RI Apsalikov, Kazbek/C-2974-2014; OI Grosche, Bernd/0000-0003-2024-3555 FU European Commission [IC15-CT98-0218]; U.S. National Institute of Allergy and Infectious Diseases; U.S. National Cancer Institute, NIAID [Y2-A1-5077]; NCI [Y3-CO-5117] FX Part of this work, namely the follow-up of the cohort, was funded by the European Commission under contract IC15-CT98-0218. Participation of C. E. Land and S. L. Simon was made possible by an Intra-Agency Agreement between the U.S. National Institute of Allergy and Infectious Diseases and the U.S. National Cancer Institute, NIAID agreement no. Y2-A1-5077 and NCI agreement no. Y3-CO-5117. NR 44 TC 12 Z9 14 U1 1 U2 10 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD NOV PY 2011 VL 176 IS 5 BP 660 EP 669 DI 10.1667/RR2211.1 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 841VZ UT WOS:000296544600011 PM 21787182 ER PT J AU Grant, EJ Neriishi, K Cologne, J Eguchi, H Hayashi, T Geyer, S Izumi, S Nishi, N Land, C Stevens, RG Sharp, GB Nakachi, K AF Grant, Eric J. Neriishi, Kazuo Cologne, John Eguchi, Hidetaka Hayashi, Tomonori Geyer, Susan Izumi, Shizue Nishi, Nobuo Land, Charles Stevens, Richard G. Sharp, Gerald B. Nakachi, Kei TI Associations of Ionizing Radiation and Breast Cancer-Related Serum Hormone and Growth Factor Levels in Cancer-Free Female A-Bomb Survivors SO RADIATION RESEARCH LA English DT Article ID POSTMENOPAUSAL WOMEN; RISK; PREMENOPAUSAL; PERSPECTIVES; ESTROGENS AB Grant, E. J., Neriishi, K., Cologne, J., Eguchi, H., Hayashi, T., Geyer, S., Izumi, S., Nishi, N., Land, C., Stevens, R. G., Sharp, G. B. and Nakachi, K. Associations of Ionizing Radiation and Breast Cancer-Related Serum Hormone and Growth Factor Levels in Cancer-Free Female A-Bomb Survivors. Radiat. Res. 176, 678-687 (2011). Levels of exposure to ionizing radiation are increasing for women worldwide due to the widespread use of CT and other radiologic diagnostic modalities. Exposure to ionizing radiation as well as increased levels of estradiol and other sex hormones are acknowledged breast cancer risk factors, but the effects of whole-body radiation on serum hormone levels in cancer-free women are unknown. This study examined whether ionizing radiation exposure is associated with levels of serum hormones and other markers that may mediate radiation-associated breast cancer risk. Serum samples were measured from cancer-free women who attended biennial health examinations with a wide range of past radiation exposure levels (N = 412, ages 26-79). The women were selected as controls for separate case-control studies from a cohort of A-bomb survivors. Outcome measures included serum levels of total estradiol, bioavailable estradiol, testosterone, progesterone, prolactin, insulin-like growth factor-1 (IGF1), insulin-like growth factor-binding protein 3 (IGFBP-3), and ferritin. Relationships were assessed using repeated-measures regression models fitted with generalized estimating equations. Geometric mean serum levels of total estradiol and bioavailable estradiol increased with 1 Gy of radiation dose among samples collected from postmenopausal women (17%(1Gy), 95% CI: 1%-36% and 21%(1Gy), 95% CI: 4%-40%, respectively), while they decreased in samples collected from premenopausal women (-11%(1Gy), 95% CI: -20%-1% and -12%(1Gy), 95% CI: -20%- -2%, respectively). Interactions by menopausal status were significant (P = 0.003 and P < 0.001, respectively). Testosterone levels increased with radiation dose in postmenopausal samples (30.0%(1Gy), 95% CI: 13%-49%) while they marginally decreased in premenopausal samples (-10%(1Gy), 95% CI: -19%-0%) and the interaction by menopausal status was significant (P < 0.001). Serum levels of IGF1 increased linearly with radiation dose (11%(1Gy), 95% CI: 2%-18%) and there was a significant interaction by menopausal status (P = 0.014). Radiation-associated changes in serum levels of estradiol, bioavailable estradiol, testosterone and IGF1 were modified by menopausal status at the time of collection. No associations with radiation were observed in serum levels of progesterone, prolactin, IGFBP-3 or ferritin. (C) 2011 by Radiation Research Society C1 [Grant, Eric J.] Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, Hiroshima 7320815, Japan. [Neriishi, Kazuo] Radiat Effects Res Fdn, Dept Clin Studies, Minami Ku, Hiroshima 7320815, Japan. [Cologne, John] Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 7320815, Japan. [Hayashi, Tomonori; Nakachi, Kei] Radiat Effects Res Fdn, Dept Radiobiol Mol Epidemiol, Minami Ku, Hiroshima 7320815, Japan. [Eguchi, Hidetaka] Saitama Med Univ, Int Med Ctr, Translat Res Ctr, Hidaka, Saitama 3501241, Japan. [Geyer, Susan] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Izumi, Shizue] Oita Univ, Dept Comp Sci & Intelligent Syst, Oita 8701192, Japan. [Nishi, Nobuo] Natl Inst Hlth & Nutr, Ctr Collaborat & Partnership, Shinjuku Ku, Tokyo 1628636, Japan. [Land, Charles] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Stevens, Richard G.] Univ Connecticut, Ctr Hlth, Dept Community Med, Farmington, CT 06030 USA. [Sharp, Gerald B.] NIAID, Epidemiol Branch, Basic Sci Program, Div Aids,NIH, Bethesda, MD 20892 USA. RP Grant, EJ (reprint author), Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, 5-2 Hijiyama Pk, Hiroshima 7320815, Japan. EM egrant@rerf.or.jp RI Geyer, Susan/E-3112-2011 FU Japanese Ministry of Health, Labor and Welfare (MHLW); U.S. Department of Energy (DOE); RERF [RP 06-02]; US National Cancer Institute [NO1-CP-31012]; Japanese Ministry of Education, Culture, Sports, Science and Technology [14031227, 15026220]; National Academy of Sciences FX We deeply thank the participating members of the AHS. The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a private, non-profit foundation funded by the Japanese Ministry of Health, Labor and Welfare (MHLW) and the U.S. Department of Energy (DOE), the latter in part through the National Academy of Sciences. This publication was supported by RERF Research Protocol RP 06-02 and by US National Cancer Institute contract NO1-CP-31012 and the Japanese Ministry of Education, Culture, Sports, Science and Technology grants 14031227 and 15026220. NR 39 TC 5 Z9 5 U1 0 U2 1 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD NOV PY 2011 VL 176 IS 5 BP 678 EP 687 DI 10.1667/RR2631.1 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 841VZ UT WOS:000296544600013 PM 21718103 ER PT J AU Ryan, JL Krishnan, S Movsas, B Coleman, CN Vikram, B Yoo, SS AF Ryan, Julie L. Krishnan, Sunil Movsas, Benjamin Coleman, C. Norman Vikram, Bhadrasain Yoo, Stephen S. TI Decreasing the Adverse Effects of Cancer Therapy: An NCI Workshop on the Preclinical Development of Radiation Injury Mitigators/Protectors SO RADIATION RESEARCH LA English DT Editorial Material ID MEDICAL COUNTERMEASURES; AGENTS C1 [Ryan, Julie L.] Univ Rochester, Med Ctr, Dept Dermatol, Rochester, NY 14642 USA. [Ryan, Julie L.] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Krishnan, Sunil] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Movsas, Benjamin] Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA. [Coleman, C. Norman; Vikram, Bhadrasain; Yoo, Stephen S.] NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH, Bethesda, MD USA. RP Ryan, JL (reprint author), Univ Rochester, Med Ctr, Dept Dermatol, 601 Elmwood Ave,Box 697, Rochester, NY 14642 USA. EM Julie_Ryan@urmc.rochester.edu; Yoosu@mail.nih.gov FU NCI NIH HHS [U10 CA037420, R25 CA102618-08, R25 CA102618]; NCRR NIH HHS [KL2 RR024136] NR 10 TC 12 Z9 12 U1 0 U2 2 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD NOV PY 2011 VL 176 IS 5 BP 688 EP 691 DI 10.1667/RR2704.1 PG 4 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 841VZ UT WOS:000296544600014 PM 21883022 ER PT J AU Venkatesan, AM Wood, BJ Gervais, DA AF Venkatesan, Aradhana M. Wood, Bradford J. Gervais, Debra A. TI Percutaneous Ablation in the Kidney SO RADIOLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA; RADIO-FREQUENCY ABLATION; GUIDED RADIOFREQUENCY ABLATION; INTENSITY FOCUSED ULTRASOUND; TERM-FOLLOW-UP; THERMAL ABLATION; TUMOR ABLATION; LAPAROSCOPIC CRYOABLATION; HEPATOCELLULAR-CARCINOMA; HEPATIC CRYOSURGERY C1 [Venkatesan, Aradhana M.; Wood, Bradford J.] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Gervais, Debra A.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal & Intervent Radiol, Boston, MA 02114 USA. RP Venkatesan, AM (reprint author), NIH, Ctr Clin, Dept Radiol & Imaging Sci, 10 Ctr Dr,Bldg 10,Room 1C369,MSC 1182, Bethesda, MD 20892 USA. EM VenkatesanA@cc.nih.gov NR 112 TC 32 Z9 33 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2011 VL 261 IS 2 BP 375 EP 391 DI 10.1148/radiol.11091207 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 841PL UT WOS:000296524600007 PM 22012904 ER PT J AU Rosenberg, RD Haneuse, SJPA Geller, BM Buist, DSM Miglioretti, DL Brenner, RJ Smith-Bindman, R Taplin, SH AF Rosenberg, Robert D. Haneuse, Sebastien J. P. A. Geller, Berta M. Buist, Diana S. M. Miglioretti, Diana L. Brenner, R. James Smith-Bindman, Rebecca Taplin, Stephen H. CA Breast Canc Surveillance Consortiu TI Timeliness of Follow-up after Abnormal Screening Mammogram: Variability of Facilities SO RADIOLOGY LA English DT Article ID URBAN MINORITY WOMEN; MANAGEMENT RECOMMENDATIONS; RACIAL-DIFFERENCES; DIAGNOSIS; TIME; QUALITY; CONCORDANCE; BIOPSIES; CARE AB Purpose: To describe the timeliness of follow-up care in community-based settings among women who receive a recommendation for immediate follow-up during the screening mammography process and how follow-up timeliness varies according to facility and facility-level characteristics. Materials and Methods: This was an institutional review board-approved and HIPAA-compliant study. Screening mammograms obtained from 1996 to 2007 in women 40-80 years old in the Breast Cancer Surveillance Consortium were examined. Inclusion criteria were a recommendation for immediate follow-up at screening, or subsequent imaging, and observed follow-up within 180 days of the recommendation. Recommendations for additional imaging (AI) and biopsy or surgical consultation (BSC) were analyzed separately. The distribution of time to follow-up care was estimated by using the Kaplan-Meier estimator. Results: Data were available on 214 897 AI recommendations from 118 facilities and 35 622 BSC recommendations from 101 facilities. The median time to subsequent follow-up care after recommendation was 14 days for AI and 16 days for BSC. Approximately 90% of AI follow-up and 81% of BSC follow-up occurred within 30 days. Facilities with higher recall rates tended to have longer AI follow-up times (P < .001). Over the study period, BSC follow-up rates at 15 and 30 days improved (P < .001). Follow-up times varied substantially across facilities. Timely follow-up was associated with larger volumes of the recommended procedures but not notably associated with facility type nor observed facility-level characteristics. Conclusion: Most patients with follow-up returned within 3 weeks of the recommendation. (C) RSNA, 2011 C1 [Rosenberg, Robert D.] Univ New Mexico HSC, Dept Radiol, Albuquerque, NM 87131 USA. [Haneuse, Sebastien J. P. A.; Buist, Diana S. M.; Miglioretti, Diana L.] Grp Hlth Res Inst, Seattle, WA USA. [Geller, Berta M.] Univ Vermont, Off Hlth Promot Res, Burlington, VT USA. [Miglioretti, Diana L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Brenner, R. James] Bay Imaging Consultants, Carol Ann Read Breast Hlth Ctr, Oakland, CA USA. [Brenner, R. James; Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Taplin, Stephen H.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Rosenberg, RD (reprint author), Univ New Mexico HSC, Dept Radiol, 1 Univ New Mexico,HSC 10 5530, Albuquerque, NM 87131 USA. EM rrosenb@unm.edu FU American Cancer Society [PA 8357]; National Cancer Institute; American Cancer Society FX Supported by the American Cancer Society (grant PA 8357).; R. D. R. Financial activities related to the present article: institution received grants, grant support for travel to meetings for the study or other purposes, and payment for writing or reviewing the manuscript from the National Cancer Institute and American Cancer Society. Financial activities not related to the present article: institution received grants from National Cancer Institute and American Cancer Society. Other relationships: none to disclose. S.J.P.A.H. Financial activities related to the present article: institution received a grant and support for travel to meetings for the study or other purposes from the National Cancer Institute. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. B. M. G. Financial activities related to the present article: institution received a grant and support for travel to meetings for the study or other purposes from National Cancer Institute. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. D. S. M. B. Financial activities related to the present article: institution received a grant and support for travel to meetings for the study or other purposes from the National Institutes of Health and American Cancer Society. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. D. L. M. Financial activities related to the present article: institution received grants from the National Cancer Institute-funded Breast Cancer Surveillance Consortium cooperative agreement. Financial activities not related to the present article: institution has grants pending from the National Institutes of Health. Other relationships: none to disclose. R.J.B. No potential conflicts of interest to disclose. R. S. No potential conflicts of interest to disclose. S. H. T. Financial activities related to the present article: is an employee of the U. S. federal government through the National Cancer Institute. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. NR 27 TC 11 Z9 13 U1 2 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2011 VL 261 IS 2 BP 404 EP 413 DI 10.1148/radiol.11102472 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 841PL UT WOS:000296524600009 PM 21900620 ER PT J AU Vanness, DJ Knudsen, AB Lansdorp-Vogelaar, I Rutter, CM Gareen, IF Herman, BA Kuntz, KM Zauber, AG van Ballegooijen, M Feuer, EJ Chen, MH Johnson, CD AF Vanness, David J. Knudsen, Amy B. Lansdorp-Vogelaar, Iris Rutter, Carolyn M. Gareen, Ilana F. Herman, Benjamin A. Kuntz, Karen M. Zauber, Ann G. van Ballegooijen, Marjolein Feuer, Eric J. Chen, Mei-Hsiu Johnson, C. Daniel TI Comparative Economic Evaluation of Data from the ACRIN National CT Colonography Trial with Three Cancer Intervention and Surveillance Modeling Network Microsimulations SO RADIOLOGY LA English DT Article ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; SERVICES TASK-FORCE; FECAL-OCCULT-BLOOD; COST-EFFECTIVENESS ANALYSIS; COLORECTAL-CANCER; VIRTUAL COLONOSCOPY; LARGE-INTESTINE; LARGE-BOWEL; CONVENTIONAL COLONOSCOPY; EXTRACOLONIC FINDINGS AB Purpose: To estimate the cost-effectiveness of computed tomographic (CT) colonography for colorectal cancer (CRC) screening in average-risk asymptomatic subjects in the United States aged 50 years. Materials and Methods: Enrollees in the American College of Radiology Imaging Network National CT Colonography Trial provided informed consent, and approval was obtained from the institutional review board at each site. CT colonography performance estimates from the trial were incorporated into three Cancer Intervention and Surveillance Modeling Network CRC microsimulations. Simulated survival and lifetime costs for screening 50-year-old subjects in the United States with CT colonography every 5 or 10 years were compared with those for guideline-concordant screening with colonoscopy, flexible sigmoidoscopy plus either sensitive unrehydrated fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT), and no screening. Perfect and reduced screening adherence scenarios were considered. Incremental cost-effectiveness and net health benefits were estimated from the U. S. health care sector perspective, assuming a 3% discount rate. Results: CT colonography at 5- and 10-year screening intervals was more costly and less effective than FOBT plus flexible sigmoidoscopy in all three models in both 100% and 50% adherence scenarios. Colonoscopy also was more costly and less effective than FOBT plus flexible sigmoidoscopy, except in the CRC-SPIN model assuming 100% adherence (incremental cost-effectiveness ratio: $26300 per life-year gained). CT colonography at 5- and 10-year screening intervals and colonoscopy were net beneficial compared with no screening in all model scenarios. The 5-year screening interval was net beneficial over the 10-year interval except in the MISCAN model when assuming 100% adherence and willingness to pay $50000 per life-year gained. Conclusion: All three models predict CT colonography to be more costly and less effective than non-CT colonographic screening but net beneficial compared with no screening given model assumptions. (C) RSNA, 2011 C1 [Vanness, David J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53726 USA. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Lansdorp-Vogelaar, Iris; van Ballegooijen, Marjolein] Erasmus MC Univ Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands. [Rutter, Carolyn M.] Grp Hlth Seattle, Ctr Hlth Studies, Seattle, WA USA. [Gareen, Ilana F.; Herman, Benjamin A.; Chen, Mei-Hsiu] Brown Univ, Ctr Stat Sci, Providence, RI 02912 USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Johnson, C. Daniel] Mayo Clin, Dept Radiol, Scottsdale, AZ USA. RP Vanness, DJ (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, 610 Walnut St, Madison, WI 53726 USA. EM dvanness@wisc.edu RI Gareen, Ilana/I-2816-2014; OI Gareen, Ilana/0000-0002-0457-5595; Herman, Benjamin/0000-0001-6649-0354 FU United BioSource FX D.J.V. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received money for a consultancy from United BioSource; was employed by United BioSource. Other relationships: none to disclose. A. B. K. No potential conflicts of interest to disclose. I. L. V. No potential conflicts of interest to disclose. C. M. R. No potential conflicts of interest to disclose. I. F. G. No potential conflicts of interest to disclose. B. A. H. No potential conflicts of interest to disclose. K. M. K. No potential conflicts of interest to disclose. A.G.Z. No potential conflicts of interest to disclose. M. v. B. No potential conflicts of interest to disclose. E.J.F. No potential conflicts of interest to disclose. M. H. C. No potential conflicts of interest to disclose. C.D.J. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received money for a software license/patent; receives royalties from GE Medical Systems; institution receives royalties from GE Medical Systems. Other relationships: none to disclose. NR 73 TC 11 Z9 11 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2011 VL 261 IS 2 BP 487 EP 498 DI 10.1148/radiol.11102411 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 841PL UT WOS:000296524600018 PM 21813740 ER PT J AU Charoenpanich, A Wall, ME Tucker, CJ Andrews, DMK Lalush, DS Loboa, EG AF Charoenpanich, Adisri Wall, Michelle E. Tucker, Charles J. Andrews, Danica M. K. Lalush, David S. Loboa, Elizabeth G. TI Microarray Analysis of Human Adipose-Derived Stem Cells in Three-Dimensional Collagen Culture: Osteogenesis Inhibits Bone Morphogenic Protein and Wnt Signaling Pathways, and Cyclic Tensile Strain Causes Upregulation of Proinflammatory Cytokine Regulators and Angiogenic Factors SO TISSUE ENGINEERING PART A LA English DT Article ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; STROMAL CELLS; DIFFERENTIATION POTENTIALS; OSTEOBLAST BIOLOGY; MECHANICAL STRAIN; MINERAL DENSITY; GENE-EXPRESSION; RETINOIC ACID; GROWTH-FACTOR; TGF-BETA AB Human adipose-derived stem cells (hASC) have shown great potential for bone tissue engineering. However, the molecular mechanisms underlying this potential are not yet known, in particular the separate and combined effects of three-dimensional (3D) culture and mechanical loading on hASC osteogenesis. Mechanical stimuli play a pivotal role in bone formation, remodeling, and fracture repair. To further understand hASC osteogenic differentiation and response to mechanical stimuli, gene expression profiles of proliferating or osteogenically induced hASC in 3D collagen I culture in the presence and absence of 10% uniaxial cyclic tensile strain were examined using microarray analysis. About 847 genes and 95 canonical pathways were affected during osteogenesis of hASC in 3D culture. Pathway analysis indicated the potential roles of Wnt/beta-catenin signaling, bone morphogenic protein (BMP) signaling, platelet-derived growth factor (PDGF) signaling, and insulin-like growth factor 1 (IGF-1) signaling in hASC during osteogenic differentiation. Application of 10% uniaxial cyclic tensile strain suggested synergistic effects of strain with osteogenic differentiation media on hASC osteogenesis as indicated by significantly increased calcium accretion of hASC. There was no significant further alteration in the four major pathways (Wnt/beta-catenin, BMP, PDGF, and IGF-1). However, 184 transcripts were affected by 10% cyclic tensile strain. Function and network analysis of these transcripts suggested that 10% cyclic tensile strain may play a role during hASC osteogenic differentiation by upregulating two crucial factors in bone regeneration: (1) proinflammatory cytokine regulators interleukin 1 receptor antagonist and suppressor of cytokine signaling 3; (2) known angiogenic inductors fibroblast growth factor 2, matrix metalloproteinase 2, and vascular endothelial growth factor A. This is the first study to investigate the effects of both 3D culture and mechanical load on hASC osteogenic differentiation. A complete microarray analysis investigating both the separate effect of soluble osteogenic inductive factors and the combined effects of chemical and mechanical stimulation was performed on hASC undergoing osteogenic differentiation. We have identified specific genes and pathways associated with mechanical response and osteogenic potential of hASC, thus providing significant information toward improved understanding of our use of hASC for functional bone tissue engineering applications. C1 [Loboa, Elizabeth G.] N Carolina State Univ, Univ N Carolina, Joint Dept Biomed Engn, Dept Mat Sci & Engn, Raleigh, NC 27695 USA. [Tucker, Charles J.; Andrews, Danica M. K.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. [Loboa, Elizabeth G.] N Carolina State Univ, Mat Sci & Engn Dept, Raleigh, NC 27695 USA. RP Loboa, EG (reprint author), N Carolina State Univ, Univ N Carolina, Joint Dept Biomed Engn, Dept Mat Sci & Engn, 4208 EB3,911 Oval Dr,Campus Box 7115, Raleigh, NC 27695 USA. EM egloboa@ncsu.edu FU NIH, National Institute of Environmental Health Sciences; National Center for Research Resources [10KR51023]; NIH/NIBIB [R03EB008790-01A2] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, by National Center for Research Resources grant 10KR51023 (EGL), and by NIH/NIBIB grant R03EB008790-01A2 (EGL). NR 57 TC 20 Z9 20 U1 2 U2 8 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 NOV PY 2011 VL 17 IS 21-22 BP 2615 EP 2627 DI 10.1089/ten.tea.2011.0107 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 842SD UT WOS:000296619500004 PM 21767168 ER PT J AU Booth, GS AF Booth, Garrett S. TI Apheresis granulocytes: light microscopic changes at time of outdate and beyond SO TRANSFUSION LA English DT Editorial Material C1 [Booth, Garrett S.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Booth, GS (reprint author), Vanderbilt Univ, Blood Bank, Sch Med, Pathol labs, TVC 4605, Nashville, TN 37232 USA. EM garrett.s.booth@vanderbilt.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD NOV PY 2011 VL 51 IS 11 BP 2267 EP 2268 DI 10.1111/j.1537-2995.2011.03361.x PG 2 WC Hematology SC Hematology GA 839MQ UT WOS:000296371300003 PM 22023183 ER PT J AU Roy, AL Sen, R Roeder, RG AF Roy, Ananda L. Sen, Ranjan Roeder, Robert G. TI Enhancer-promoter communication and transcriptional regulation of Igh SO TRENDS IN IMMUNOLOGY LA English DT Review ID CLASS SWITCH RECOMBINATION; LONG-RANGE INTERACTIONS; LOCUS-CONTROL REGION; B-CELL DEVELOPMENT; COACTIVATOR OCA-B; HEAVY-CHAIN LOCUS; TFII-I; CHROMATIN ARCHITECTURE; EPIGENETIC REGULATION; VARIABLE-REGION AB Transcriptional regulation of eukaryotic protein-coding genes requires the participation of site-specific transcription factors that bind distal regulatory elements, as well as factors that, together with RNA polymerase II, form the basal transcription machinery at the core promoter. Gene regulation requires proper communication between promoters and enhancers, often over great distances. Therefore, it is important to understand the potentially inter-related transcription factor interactions at both of these elements. How this is achieved on tissue-specific genes, such as the immunoglobulin heavy chain (IgH) in B cells remains unclear. Here, we review known interactions at the Igh variable region (V(H)) promoters and present our perspective on promoter-enhancer interactions that are likely important for Ig gene regulation in B cells. C1 [Roy, Ananda L.] Tufts Univ, Sch Med, Dept Pathol, Program Immunol, Boston, MA 02111 USA. [Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Roeder, Robert G.] Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10021 USA. RP Roy, AL (reprint author), Tufts Univ, Sch Med, Dept Pathol, Program Immunol, Boston, MA 02111 USA. EM ananda.roy@tufts.edu; Senranja@grc.nia.nih.goy; roeder@mail.rockefeller.edu FU National Institute on Aging (Baltimore); National Institutes of Health [CA113872, 1R56AI079206] FX R.S. is supported by the Intramural Research Program of the National Institute on Aging (Baltimore), R.G.R is supported by National Institutes of Health Grant CA113872, and A.L.R is supported by National Institutes of Health grant 1R56AI079206. NR 71 TC 14 Z9 14 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD NOV PY 2011 VL 32 IS 11 BP 532 EP 539 DI 10.1016/j.it.2011.06.012 PG 8 WC Immunology SC Immunology GA 845NB UT WOS:000296828400005 PM 21855411 ER PT J AU Yewdell, JW AF Yewdell, Jonathan W. TI DRiPs solidify: progress in understanding endogenous MHC class I antigen processing SO TRENDS IN IMMUNOLOGY LA English DT Review ID DEFECTIVE RIBOSOMAL PRODUCTS; CRYPTIC TRANSLATION PRODUCTS; ALTERNATIVE READING FRAMES; NEWLY SYNTHESIZED PROTEINS; MESSENGER-RNA TRANSLATION; CYTOTOXIC LYMPHOCYTES-T; ENDOPLASMIC-RETICULUM; OXIDATIVE-STRESS; MAMMALIAN-CELLS; PEPTIDE LIGANDS AB Defective ribosomal products (DRiPs) are a subset of rapidly degraded polypeptides that provide peptide ligands for major histocompatibility complex (MHC) class I molecules. Here, recent progress in understanding DRIP biogenesis is reviewed. These findings place DRiPs at the center of the MHC class I antigen processing pathway, linking immunosurveillance of viruses and tumors to mechanisms of specialized translation and cellular compartmentalization. DRiPs enable the immune system to rapidly detect alterations in cellular gene expression with great sensitivity. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS [ZIA AI000542-23] NR 124 TC 69 Z9 69 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD NOV PY 2011 VL 32 IS 11 BP 548 EP 558 DI 10.1016/j.it.2011.08.001 PG 11 WC Immunology SC Immunology GA 845NB UT WOS:000296828400007 PM 21962745 ER PT J AU Pan, XQ Zhang, CL Shi, ZM AF Pan, Xiaoqun Zhang, Cuilin Shi, Zumin TI Soft drink and sweet food consumption and suicidal behaviours among Chinese adolescents SO ACTA PAEDIATRICA LA English DT Article DE Adolescents; China; Soft drink; Suicidal behaviour ID PSYCHIATRIC-PATIENTS; MENTAL-HEALTH; RISK-FACTORS; SUGAR INTAKE; OVERWEIGHT; DEPRESSION; MANAGEMENT; DISORDERS; IDEATION; SUCROSE AB Aim: Greater soft drink consumption was associated with increased risk of mental health problems in Western countries. The objective of the study was to examine the association between soft drink and sweet food consumption and suicidal behaviours among adolescents in China. Methods: In 2005, a population-based cross-sectional study was conducted in 100 schools in Jiangsu Province, China. Participants were aged 12-19 years old (n = 23 976). Results: Among the participants, 20.5% reported daily soft drink consumption; 18.6% reported having suicidal ideation. Soft drink consumption was significantly and positively associated with risk of suicidal plan or suicide attempt. Prevalence of suicidal plan was 12.8% among those who consumed soft drink at least three times per day and 6.2% among those who did not consume any soft drinks. In multivariate analyses, compared with soft drink consumption less than once per day, consumption at least three times per day was associated with 80% increased risk for suicidal plan and more than 3.5-fold increased risk for suicide attempt. Of note, nonconsumption of soft drinks was also associated with about 32% elevated risk for suicidal plan and suicidal attempt. High frequency intake of sweet food was associated with increased risk of suicidal behaviours. Conclusions: There is a positive association between consumption of soft drinks and sweet food and risks for suicidal behaviours among adolescents in China. Prospective studies are warranted to confirm these findings. C1 [Pan, Xiaoqun; Shi, Zumin] Jiangsu Prov Ctr Dis Control & Prevent, Dept Nutr & Foodborne Dis Prevent, Nanjing 210009, Peoples R China. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Shi, Zumin] Univ Adelaide, Discipline Med, Adelaide, SA, Australia. RP Shi, ZM (reprint author), Jiangsu Prov Ctr Dis Control & Prevent, Dept Nutr & Foodborne Dis Prevent, 172 Jiangsu Rd, Nanjing 210009, Peoples R China. EM zumins@vip.sina.com RI Shi, Zumin/A-1093-2009 OI Shi, Zumin/0000-0002-3099-3299 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health FX The authors thank the participating Regional Centers for Disease Control and Prevention in Jiangsu province, including the Nanjing, Suzhou, Xuzhou, Yanchen, Yixin, Sheyang, Kunshan and Tongzhou Centers for their support for the data collection. Dr. Cuilin Zhang was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health. NR 32 TC 9 Z9 9 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD NOV PY 2011 VL 100 IS 11 BP E215 EP E222 DI 10.1111/j.1651-2227.2011.02369.x PG 8 WC Pediatrics SC Pediatrics GA 840EO UT WOS:000296421300005 PM 21627691 ER PT J AU Pinto, C Di Fabio, F Maiello, E Pini, S Latiano, T Aschele, C Garufi, C Bochicchio, A Rosati, G Aprile, G Giaquinta, S Torri, V Bardelli, A Gion, M Martoni, A AF Pinto, C. Di Fabio, F. Maiello, E. Pini, S. Latiano, T. Aschele, C. Garufi, C. Bochicchio, A. Rosati, G. Aprile, G. Giaquinta, S. Torri, V. Bardelli, A. Gion, M. Martoni, A. TI Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study) SO ANNALS OF ONCOLOGY LA English DT Article DE 5-fluorouracil; chemoradiotherapy; oxaliplatin; panitumumab; radiotherapy; rectal cancer ID EPIDERMAL-GROWTH-FACTOR; METASTATIC COLORECTAL-CANCER; SQUAMOUS-CELL CARCINOMA; FACTOR RECEPTOR; NEOADJUVANT TREATMENT; CETUXIMAB; CHEMORADIOTHERAPY; CAPECITABINE; TRIAL; CHEMORADIATION AB Background: The aim of this phase II study was to assess the activity of panitumumab in combination with oxaliplatin, 5-fluorouracil, and external radiotherapy (RT) as preoperative treatment in locally advanced rectal cancer patients. Patients and methods: Patients had rectal adenocarcinoma, cT3N+ or cT4N-/+ stage, located <12 cm from the anal margin. Panitumumab was administered before the start of chemo-RT, and every 2 weeks in combination with 5-luorouracil-oxaliplatin with concurrent RT. Rectal surgery was carried out 7-8 weeks after the end of neoadjuvant treatment. The primary end point was a pathological complete response rate of 25%. Results: Sixty patients were enrolled from February 2007 to October 2009. Fifty-five (91.7%) patients underwent surgery. Rate of pathological complete response was 21.1% (95% confidence interval 10.4% to 31.6%). Pathological downstaging occurred in 33 of 57 (57.9%) patients. Grade 3-4 toxicity during neoadjuvant treatment was diarrhea (38.9%), cutaneous reactions (18.6%), nausea (5.1%), asthenia (3.4%), anorexia (3.4%), and neutropenia (1.7%). One toxic death was observed for diarrhea. Conclusions: In our study, the primary end point is not reached and panitumumab combination treatment was associated with high incidence of grade 3-4 diarrhea. The higher pathological complete response rate in comparison with the results of previous neoadjuvant rectal cancer trials with anti-epidermal growth factor receptor monoclonal antibodies supports further studies necessary to understand the possibility of optimal regimens and sequences with chemo-RT. C1 [Pinto, C.; Di Fabio, F.; Pini, S.; Giaquinta, S.; Martoni, A.] St Orsola Marcello Malpighi Hosp, Med Oncol Unit, I-40138 Bologna, Italy. [Maiello, E.; Latiano, T.] IRCCS Casa Sollievo Sofferenza, Med Oncol Unit, San Giovanni Rotondo, Italy. [Aschele, C.] Natl Canc Inst, Dept Med Oncol, Genoa, Italy. [Garufi, C.] Regina Elena Inst Canc Res, Dept Med Oncol, Rome, Italy. [Bochicchio, A.] CROB, Med Oncol Unit, Rionero In Vulture, Italy. [Rosati, G.] San Carlo Hosp, Med Oncol Unit, Potenza, Italy. [Aprile, G.] Osped S Maria Misericordia, Med Oncol Unit, Udine, Italy. [Torri, V.] Mario Negri Inst Pharmacol Res, Dept Oncol, Milan, Italy. [Bardelli, A.] Univ Turin, Mol Genet Lab, Sch Med, Inst Canc Res & Treatment, Turin, Italy. [Gion, M.] Gen Reg Hosp, Ctr Study Biol Markers Malignancy, Venice, Italy. RP Pinto, C (reprint author), St Orsola Marcello Malpighi Hosp, Med Oncol Unit, Via Albertoni 15, I-40138 Bologna, Italy. EM carmine.pinto@aosp.bo.it FU Amgen-Dompe, Italy [20062089] FX Amgen-Dompe, Italy [drug (panitumumab, Vectibix) and educational grant (20062089)]. NR 40 TC 22 Z9 23 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2011 VL 22 IS 11 BP 2424 EP 2430 DI 10.1093/annonc/mdq782 PG 7 WC Oncology SC Oncology GA 838LL UT WOS:000296292700012 PM 21385884 ER PT J AU Kang-Sickel, JCC Butler, MA Frame, L Serdar, B Chao, YCE Egeghy, P Rappaport, SM Toennis, CA Li, W Borisova, T French, JE Nylander-French, LA AF Kang-Sickel, Juei-Chuan C. Butler, Mary Ann Frame, Lynn Serdar, Berrin Chao, Yi-Chun E. Egeghy, Peter Rappaport, Stephen M. Toennis, Christine A. Li, Wang Borisova, Tatyana French, John E. Nylander-French, Leena A. TI The utility of naphthyl-keratin adducts as biomarkers for jet-fuel exposure SO BIOMARKERS LA English DT Article DE Biomarkers; CYP2E1; dermal exposure; glutathione S-transferase mu 1 (GSTM1); glutathione S-transferase theta 1 (GSTT1); jet fuel (JP-8); keratin adduct; NAD(P) H:quinone oxidoreductase (NQO1); 1-naphthol; 2-naphthol; naphthalene; urine ID POLYCYCLIC AROMATIC-HYDROCARBONS; GENETIC POLYMORPHISMS; DERMAL EXPOSURE; IN-VITRO; NAPHTHALENE METABOLITES; MAINTENANCE WORKERS; URINARY BIOMARKERS; ALBUMIN ADDUCTS; FOUNDRY WORKERS; AIR-POLLUTION AB We investigated the association between biomarkers of dermal exposure, naphthyl-keratin adducts (NKA), and urine naphthalene biomarker levels in 105 workers routinely exposed to jet-fuel. A moderate correlation was observed between NKA and urine naphthalene levels (p = 0.061). The NKA, post-exposure breath naphthalene, and male gender were associated with an increase, while CYP2E1*6 DD and GSTT1-plus (++/+-) genotypes were associated with a decrease in urine naphthalene level (p < 0.0001). The NKA show great promise as biomarkers for dermal exposure to naphthalene. Further studies are warranted to characterize the relationship between NKA, other exposure biomarkers, and/or biomarkers of biological effects due to naphthalene and/or PAH exposure. C1 [Kang-Sickel, Juei-Chuan C.; Chao, Yi-Chun E.; Nylander-French, Leena A.] Univ N Carolina, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Butler, Mary Ann; Toennis, Christine A.] NIOSH, Div Appl Res & Technol, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Frame, Lynn; Borisova, Tatyana] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Lubbock, TX 79430 USA. [Serdar, Berrin] Univ Colorado Denver, Dept Environm & Occupat Hlth, Colorado Sch Publ Hlth, Aurora, CO USA. [Egeghy, Peter] US EPA, Natl Exposure Res Lab, Human Exposure & Atmospher Sci Div, Res Triangle Pk, NC 27711 USA. [Rappaport, Stephen M.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Li, Wang] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Lubbock, TX 79430 USA. [French, John E.] Natl Inst Environm Hlth Sci, Host Susceptibil Branch, Natl Toxicol Program, Res Triangle Pk, NC USA. RP Kang-Sickel, JCC (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, CB 7431,Rosenau Hall, Chapel Hill, NC 27599 USA. EM leena_french@unc.edu OI Egeghy, Peter/0000-0002-1727-0766 FU NIEHS [P42ES05948]; National Institute for Occupational Safety and Health (NIOSH) [T42/CCT422952, T42/008673] FX The authors report no conflicts of interest. Mention of company names and/or products does not constitute endorsement by the National Institute for Occupational Safety and Health. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health. This work was supported by NIEHS (P42ES05948), NIOSH (T42/CCT422952 and T42/008673), and the NIEHS Intramural Research Program. It has been subjected to United States Environmental Protection Agency review and approved for publication. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH, or the United States government. NR 55 TC 3 Z9 3 U1 2 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-750X J9 BIOMARKERS JI Biomarkers PD NOV PY 2011 VL 16 IS 7 BP 590 EP 599 DI 10.3109/1354750X.2011.611598 PG 10 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA 837VC UT WOS:000296232100006 PM 21961652 ER PT J AU Tavora, F Burke, A Oliveira, JB AF Tavora, Fabio Burke, Allen Oliveira, Joao Bosco TI Re: Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy SO CARDIOVASCULAR PATHOLOGY LA English DT Letter C1 [Tavora, Fabio; Burke, Allen] Univ Maryland, Med Ctr, Dept Pathol, Baltimore, MD 21201 USA. [Oliveira, Joao Bosco] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Tavora, F (reprint author), Univ Maryland, Med Ctr, Dept Pathol, Baltimore, MD 21201 USA. EM allen.burke@gmail.com RI Tavora, Fabio/A-7561-2009; OI Oliveira, Joao/0000-0001-9388-8173 NR 2 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-8807 J9 CARDIOVASC PATHOL JI Cardiovasc. Pathol. PD NOV-DEC PY 2011 VL 20 IS 6 BP 387 EP 388 DI 10.1016/j.carpath.2010.11.002 PG 2 WC Cardiac & Cardiovascular Systems; Pathology SC Cardiovascular System & Cardiology; Pathology GA 839YD UT WOS:000296404500012 PM 21185745 ER PT J AU Hofmann, JN Yu, K Bagni, RK Lan, Q Rothman, N Purdue, MP AF Hofmann, Jonathan N. Yu, Kai Bagni, Rachel K. Lan, Qing Rothman, Nathaniel Purdue, Mark P. TI Intra-individual variability over time in serum cytokine levels among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO CYTOKINE LA English DT Article DE Cytokines; Inflammation; Variability; Serum; Cancer ID NECROSIS-FACTOR-ALPHA; NON-HODGKIN-LYMPHOMA; BIOLOGICAL VARIATION; INFLAMMATION; RISK; INTERLEUKIN-6; BIOMARKERS; WOMEN AB Background: Serum measurements of cytokines, mediators of various B and T cell activities, are important markers of inflammation and immune dysregulation. We assessed the reproducibility of serum cytokine measurements over a five-year period among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Methods: Levels of 13 cytokines [interleukin (IL) 1 beta, IL-2, 1L-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon-gamma (IFN gamma), granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF alpha)] in stored sera from three collections (study baseline,+1 year, and + 5 years) among 28 randomly selected PLCO participants were measured using a high-sensitivity Luminex xMap-based multiplex panel. Within-and between-subject components of variance were estimated from random effects models and were used to calculate the coefficient of variation (CV) and intraclass correlation coefficient (ICC) for analytes with <30% of samples below the limit of detection (LOD). Spearman correlation coefficients between measurements of the same analyte over time and between analytes were also calculated. Results: Among the six cytokines with <30% of samples below the LOD, we observed excellent reproducibility for IL-6, IL-7, IL-13, and TNF alpha (ICC >= 0.73), and fair to good reproducibility for IL-8 (ICC = 0.55) and IL-10 (ICC = 0.60). Spearman correlation coefficients comparing paired measurements of each cytokine at baseline and at +5 years were high (p >= 0.74) with the exception of IL-10 (p = 0.44). Conclusions: These results suggest that measurements of most of the cytokines evaluated in this study were highly reproducible over five-year periods. Published by Elsevier Ltd. C1 [Hofmann, Jonathan N.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bagni, Rachel K.] SAIC Frederick Inc, Prot Express Lab, Frederick, MD USA. RP Hofmann, JN (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8109,MSC 7240, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention; National Cancer Institute, NIH, DHHS FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., Mr. Tim Sheehy and staff, DNA Extraction and Staging Laboratory, SAIC-Frederick, Inc, and Ms. Jackie King and staff, BioReliance, Inc. Most importantly, we acknowledge the study participants for their contributions to making this study possible. NR 20 TC 20 Z9 20 U1 1 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD NOV PY 2011 VL 56 IS 2 BP 145 EP 148 DI 10.1016/j.cyto.2011.06.012 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 837OX UT WOS:000296214200003 PM 21764327 ER PT J AU Greig, BW Stetler-Stevenson, M AF Greig, Bruce W. Stetler-Stevenson, Maryalice TI USING RPMI TRANSPORT MEDIA INCREASES RECOVERY OF PAUCICELLULAR SPECIMENS SUBMITTED FOR FLOW CYTOMETRY TESTING SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 26th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 14-18, 2011 CL Portland, OR SP Int Clin Cytometry Soc C1 [Greig, Bruce W.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Stetler-Stevenson, Maryalice] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2011 VL 80B IS 6 BP 380 EP 380 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 838FT UT WOS:000296273300020 ER PT J AU Santiago, M Tembhare, P Yuan, CM Stetler-Stevenson, M AF Santiago, Margo Tembhare, Prashant Yuan, Constance M. Stetler-Stevenson, Maryalice TI CD117 EXPRESSION IN ADULT T-CELL LEUKEMIA/LYMPHOMA SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 26th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 14-18, 2011 CL Portland, OR SP Int Clin Cytometry Soc C1 [Santiago, Margo; Tembhare, Prashant; Yuan, Constance M.; Stetler-Stevenson, Maryalice] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2011 VL 80B IS 6 BP 386 EP 386 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 838FT UT WOS:000296273300036 ER PT J AU Tembhare, P Yuan, C Filie, A Stetler-Stevenson, M AF Tembhare, Prashant Yuan, Constance Filie, Armando Stetler-Stevenson, Maryalice TI FLOW CYTOMETRIC IMMUNOPHENOTYPIC ASSESSMENT OF T-CELL CLONALITY IN CEREBROSPINAL FLUID AND FINE NEEDLE ASPIRATE SPECIMENS USING LIMITED V BETA REPERTOIRE ANALYSIS SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 26th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 14-18, 2011 CL Portland, OR SP Int Clin Cytometry Soc C1 [Tembhare, Prashant; Yuan, Constance; Filie, Armando; Stetler-Stevenson, Maryalice] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2011 VL 80B IS 6 BP 387 EP 387 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 838FT UT WOS:000296273300040 ER PT J AU Kvistborg, P Shu, CJ Heemskerk, B Thrue, CA Toebes, M Robbins, P Besser, M Dudley, ME Haanen, JBAG Hadrup, SR Schumacher, TNM AF Kvistborg, Pia Shu, Chengyi Jenny Heemskerk, Bianca Thrue, Charlotte Albaek Toebes, Mireille Robbins, Paul Besser, Michal Dudley, Mark E. Haanen, John B. A. G. Hadrup, Sine Reker Schumacher, Ton N. M. TI HIGH THROUGHPUT DISSECTION OF THERAPY-INDUCED ANTIGEN-SPECIFIC T CELL RESPONSES SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 26th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 14-18, 2011 CL Portland, OR SP Int Clin Cytometry Soc C1 [Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Toebes, Mireille; Haanen, John B. A. G.; Schumacher, Ton N. M.] Netherlands Canc Inst, Amsterdam, Netherlands. [Thrue, Charlotte Albaek; Hadrup, Sine Reker] Herlev Hosp, CCIT, Ctr Canc Immune Therapy, Copenhagen, Denmark. [Robbins, Paul; Dudley, Mark E.] NCI, Surg Branch, Ctr Canc Res, NIH, Washington, DC USA. [Besser, Michal] Sheba Canc Res Ctr, Ella Inst Melanoma Res & Treatment, Tel Hashomer, Israel. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2011 VL 80B IS 6 BP 396 EP 396 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 838FT UT WOS:000296273300065 ER PT J AU Gao, B Bataller, R AF Gao, Bin Bataller, Ramon TI Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets SO GASTROENTEROLOGY LA English DT Review DE Alcohol Liver Disease; Innate Immunity; Adaptive Immunity; Cytokines; Inflammation ID INDUCED FATTY LIVER; TUMOR-NECROSIS-FACTOR; RANDOMIZED CONTROLLED-TRIAL; ACTIVATED PROTEIN-KINASE; INDUCED HEPATIC-FIBROSIS; PLACEBO-CONTROLLED TRIAL; SHORT-TERM SURVIVAL; DOUBLE-BLIND; NONALCOHOLIC STEATOHEPATITIS; TRANSCRIPTION 3 AB Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the disease focused on ethanol metabolism-associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. We review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD, improving our understanding of its pathogenesis. Despite this progress, no targeted therapies are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets. C1 [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Bataller, Ramon] Ctr Invest Biomed Red Enfermedades Hepat & Digest, Inst Invest Biomed August Pi & Sunyer, Liver Unit, Hosp Clin, Barcelona, Catalonia, Spain. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov; bataller@clinic.ub.es FU Intramural NIH HHS [Z99 AA999999, ZIA AA000369-10] NR 160 TC 416 Z9 436 U1 14 U2 111 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2011 VL 141 IS 5 BP 1572 EP 1585 DI 10.1053/j.gastro.2011.09.002 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 841KW UT WOS:000296512200021 PM 21920463 ER PT J AU Davern, TJ Chalasani, N Fontana, RJ Hayashi, PH Protiva, P Kleiner, DE Engle, RE Nguyen, H Emerson, SU Purcell, RH Tillmann, HL Gu, JZ Serrano, J Hoofnagle, JH AF Davern, Timothy J. Chalasani, Naga Fontana, Robert J. Hayashi, Paul H. Protiva, Petr Kleiner, David E. Engle, Ronald E. Hanh Nguyen Emerson, Suzanne U. Purcell, Robert H. Tillmann, Hans L. Gu, Jiezhun Serrano, Jose Hoofnagle, Jay H. CA DILIN TI Acute Hepatitis E Infection Accounts for Some Cases of Suspected Drug-Induced Liver Injury SO GASTROENTEROLOGY LA English DT Article DE Liver Disease; Drug Toxicity; Treatment; Cirrhosis ID E VIRUS-INFECTION; UNITED-STATES; TRANSPLANT RECIPIENTS; CAUSALITY ASSESSMENT; ENZYME-IMMUNOASSAY; CLINICAL-FEATURES; IMMUNOGLOBULIN-M; BLOOD-DONORS; SWINE; EPIDEMIOLOGY AB BACKGROUND & AIMS: The diagnosis of drug-induced liver injury relies on exclusion of other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of HEV infection among patients with drug-induced liver injury in the United States. METHODS: The Drug-Induced Liver Injury Network (DILIN) is a prospective study of patients with suspected drug-induced liver injury; clinical information and biological samples are collected to investigate pathogenesis and disease progression. We analyzed serum samples, collected from patients enrolled in DILIN, for immunoglobulin (Ig) G and IgM against HEV; selected samples were tested for HEV RNA. RESULTS: Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive for antiHEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM (collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients who had anti-HEV IgM were mostly older men (89%; mean age, 67 years), and 2 were human immunodeficiency virus positive. Clinical reassessment of the 9 patients with antiHEV IgM indicated that acute hepatitis E was the most likely diagnosis for 7 and might be the primary diagnosis for 2. CONCLUSIONS: HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected to be drug induced. Serologic testing for HEV infection should be performed, particularly if clinical features are compatible with acute viral hepatitis. C1 [Davern, Timothy J.] Calif Pacific Med Ctr, Liver Transplant Program, Dept Transplantat, San Francisco, CA 94115 USA. [Chalasani, Naga] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. [Fontana, Robert J.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Hayashi, Paul H.] Univ N Carolina, Dept Internal Med, Chapel Hill, NC USA. [Protiva, Petr] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Engle, Ronald E.; Hanh Nguyen; Emerson, Suzanne U.; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Tillmann, Hans L.; Gu, Jiezhun] Duke Clin Res Inst, Durham, NC USA. [Serrano, Jose; Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. RP Davern, TJ (reprint author), Calif Pacific Med Ctr, Liver Transplant Program, Dept Transplantat, 2340 Clay St,Room 306, San Francisco, CA 94115 USA. EM davernt@sutterhealth.org OI Kleiner, David/0000-0003-3442-4453 FU Glaxo; Biolex; Mochida; Merck; BMS; J J; Salix; KaroBio; Vertex; Amylin; Lilly; Bristol-Myers Squibb; GlaxoSmithKline; Medtronic; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [1U01DK065021, 1U01DK065193, 1U01DK065201, 1U01DK065184, 1U01DK065211, 1U01DK065238, 1U01DK065176]; National Institute of Allergy and Infectious Diseases and the National Cancer Institute, National Institutes of Health FX The authors disclose the following: Dr. Chalasani has received fees for consulting or DSMB activities related to drug hepatotoxicity in last 12 months from Glaxo, Biolex, Mochida, Merck, BMS, J & J, Salix, KaroBio, and Vertex, and has received research grants from Amylin and Lilly. Dr Fontana is on the speaker's bureau of Genentech and Gilead Sciences and has received research support or consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, and Medtronic. The remaining authors disclose no conflicts.; The DILIN network is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, under the following cooperative agreements: 1U01DK065021, 1U01DK065193, 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, and 1U01DK065176. This study was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, National Institutes of Health. NR 38 TC 129 Z9 131 U1 1 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2011 VL 141 IS 5 BP 1665 EP U215 DI 10.1053/j.gastro.2011.07.051 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 841KW UT WOS:000296512200031 PM 21855518 ER PT J AU Scholes, D Yu, O Raebel, MA Trabert, B Holt, VL AF Scholes, D. Yu, O. Raebel, M. A. Trabert, B. Holt, V. L. TI Improving automated case finding for ectopic pregnancy using a classification algorithm SO HUMAN REPRODUCTION LA English DT Editorial Material DE ectopic pregnancy; algorithms; classification trees; information systems; sensitivity and specificity ID HMO-RESEARCH-NETWORK; CARE AB BACKGROUND: Research and surveillance work addressing ectopic pregnancy often rely on diagnosis and procedure codes available from automated data sources. However, the use of these codes may result in misclassification of cases. Our aims were to evaluate the accuracy of standard ectopic pregnancy codes; and, through the use of additional automated data, to develop and validate a classification algorithm that could potentially improve the accuracy of ectopic pregnancy case identification. METHODS: Using automated databases from two US managed-care plans, Group Health Cooperative (GH) and Kaiser Permanente Colorado (KPCO), we sampled women aged 15-44 with an ectopic pregnancy diagnosis or procedure code from 2001 to 2007 and verified their true case status through medical record review. We calculated positive predictive values (PPV) for code-selected cases compared with true cases at both sites. Using additional variables from the automated databases and classification and regression tree (CART) analysis, we developed a case-finding algorithm at GH (n = 280), which was validated at KPCO (n = 500). RESULTS: Compared with true cases, the PPV of code-selected cases was 68 and 81% at GH and KPCO, respectively. The case-finding algorithm identified three predictors: >= 2 visits with an ectopic pregnancy code within 180 days; International Classification of Diseases, 9th Revision, Clinical Modification codes for tubal pregnancy; and methotrexate treatment. Relative to true cases, performance measures for the development and validation sets, respectively, were: 93 and 95% sensitivity; 81 and 81% specificity; 91 and 96% PPV; 84 and 79% negative predictive value. Misclassification proportions were 32% in the development set and 19% in the validation set when using standard codes; they were 11 and 8%, respectively, when using the algorithm. CONCLUSIONS: The ectopic pregnancy algorithm improved case-finding accuracy over use of standard codes alone and generalized well to a second site. When using administrative data to select potential ectopic pregnancy cases, additional widely available automated health plan data offer the potential to improve case identification. C1 [Scholes, D.; Yu, O.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Scholes, D.; Holt, V. L.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Raebel, M. A.] Kaiser Permanente, Inst Hlth Res, Denver, CO 80237 USA. [Trabert, B.] NCI, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. [Holt, V. L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Scholes, D (reprint author), Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, 1730 Minor Ave,16th Floor, Seattle, WA 98101 USA. EM scholes.d@ghc.org RI Trabert, Britton/F-8051-2015 FU NICHD NIH HHS [T32 HD052462, R03 HD052687] NR 21 TC 4 Z9 4 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD NOV PY 2011 VL 26 IS 11 BP 3163 EP 3168 DI 10.1093/humrep/der299 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 836IZ UT WOS:000296106600033 PM 21911435 ER PT J AU Gillespie, JJ Wattam, AR Cammer, SA Gabbard, JL Shukla, MP Dalay, O Driscoll, T Hix, D Mane, SP Mao, CH Nordberg, EK Scott, M Schulman, JR Snyder, EE Sullivan, DE Wang, CX Warren, A Williams, KP Xue, T Yoo, HS Zhang, CD Zhang, Y Will, R Kenyon, RW Sobral, BW AF Gillespie, Joseph J. Wattam, Alice R. Cammer, Stephen A. Gabbard, Joseph L. Shukla, Maulik P. Dalay, Oral Driscoll, Timothy Hix, Deborah Mane, Shrinivasrao P. Mao, Chunhong Nordberg, Eric K. Scott, Mark Schulman, Julie R. Snyder, Eric E. Sullivan, Daniel E. Wang, Chunxia Warren, Andrew Williams, Kelly P. Xue, Tian Yoo, Hyun Seung Zhang, Chengdong Zhang, Yan Will, Rebecca Kenyon, Ronald W. Sobral, Bruno W. TI PATRIC: the Comprehensive Bacterial Bioinformatics Resource with a Focus on Human Pathogenic Species SO INFECTION AND IMMUNITY LA English DT Review ID IV SECRETION SYSTEM; MULTIPLE SEQUENCE ALIGNMENT; BRUCELLA-ABORTUS; ERYTHRITOL CATABOLISM; INTRACELLULAR LIFE; HIGH-THROUGHPUT; DATABASE; GENOME; GENES; INTEGRATION AB Funded by the National Institute of Allergy and Infectious Diseases, the Pathosystems Resource Integration Center (PATRIC) is a genomics-centric relational database and bioinformatics resource designed to assist scientists in infectious-disease research. Specifically, PATRIC provides scientists with (i) a comprehensive bacterial genomics database, (ii) a plethora of associated data relevant to genomic analysis, and (iii) an extensive suite of computational tools and platforms for bioinformatics analysis. While the primary aim of PATRIC is to advance the knowledge underlying the biology of human pathogens, all publicly available genome-scale data for bacteria are compiled and continually updated, thereby enabling comparative analyses to reveal the basis for differences between infectious free-living and commensal species. Herein we summarize the major features available at PATRIC, dividing the resources into two major categories: (i) organisms, genomes, and comparative genomics and (ii) recurrent integration of community-derived associated data. Additionally, we present two experimental designs typical of bacterial genomics research and report on the execution of both projects using only PATRIC data and tools. These applications encompass a broad range of the data and analysis tools available, illustrating practical uses of PATRIC for the biologist. Finally, a summary of PATRIC's outreach activities, collaborative endeavors, and future research directions is provided. C1 [Sobral, Bruno W.] Virginia Tech, Cyberinfrastruct Div, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. [Gillespie, Joseph J.] Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Nordberg, Eric K.] HHS NIH NCI SRA Int Inc, Rockville, MD 20852 USA. [Wang, Chunxia] Novozymes Biol Inc, Salem, VA 24153 USA. [Williams, Kelly P.] Sandia Natl Labs, Livermore, CA 94551 USA. RP Sobral, BW (reprint author), Virginia Tech, Cyberinfrastruct Div, Virginia Bioinformat Inst, Washington St,MC 0477, Blacksburg, VA 24061 USA. EM sobral@vbi.vt.edu OI Driscoll, Timothy/0000-0002-5119-0372; Gillespie, Joseph/0000-0002-5447-7264 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900040C] FX This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200900040C awarded to B. W. S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or the National Institutes of Health. NR 57 TC 127 Z9 127 U1 2 U2 32 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 NOV PY 2011 VL 79 IS 11 BP 4286 EP 4298 DI 10.1128/IAI.00207-11 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GB UT WOS:000296352400001 PM 21896772 ER PT J AU Arumugam, TU Takeo, S Yamasaki, T Thonkukiatkul, A Miura, K Otsuki, H Zhou, H Long, CA Sattabongkot, J Thompson, J Wilson, DW Beeson, JG Healer, J Crabb, BS Cowman, AF Torii, M Tsuboi, T AF Arumugam, Thangavelu U. Takeo, Satoru Yamasaki, Tsutomu Thonkukiatkul, Amporn Miura, Kazutoyo Otsuki, Hitoshi Zhou, Hong Long, Carole A. Sattabongkot, Jetsumon Thompson, Jennifer Wilson, Danny W. Beeson, James G. Healer, Julie Crabb, Brendan S. Cowman, Alan F. Torii, Motomi Tsuboi, Takafumi TI Discovery of GAMA, a Plasmodium falciparum Merozoite Micronemal Protein, as a Novel Blood-Stage Vaccine Candidate Antigen SO INFECTION AND IMMUNITY LA English DT Article ID GROWTH-INHIBITORY ANTIBODIES; ANCHORED MEMBRANE-PROTEINS; MALARIA PARASITE; HUMAN ERYTHROCYTES; INVASION PATHWAYS; HUMAN-POPULATIONS; RECEPTOR; BINDING; ERADICATION; RON2 AB One of the solutions for reducing the global mortality and morbidity due to malaria is multivalent vaccines comprising antigens of several life cycle stages of the malarial parasite. Hence, there is a need for supplementing the current set of malaria vaccine candidate antigens. Here, we aimed to characterize glycosylphosphatidylinositol (GPI)-anchored micronemal antigen (GAMA) encoded by the PF08_0008 gene in Plasmodium falciparum. Antibodies were raised against recombinant GAMA synthesized by using a wheat germ cell-free system. Immunoelectron microscopy demonstrated for the first time that GAMA is a microneme protein of the merozoite. Erythrocyte binding assays revealed that GAMA possesses an erythrocyte binding epitope in the C-terminal region and it binds a nonsialylated protein receptor on human erythrocytes. Growth inhibition assays revealed that anti-GAMA antibodies can inhibit P. falciparum invasion in a dose-dependent manner and GAMA plays a role in the sialic acid (SA)-independent invasion pathway. Anti-GAMA antibodies in combination with anti-erythrocyte binding antigen 175 exhibited a significantly higher level of invasion inhibition, supporting the rationale that targeting of both SA-dependent and SA-independent ligands/pathways is better than targeting either of them alone. Human sera collected from areas of malaria endemicity in Mali and Thailand recognized GAMA. Since GAMA in P. falciparum is refractory to gene knockout attempts, it is essential to parasite invasion. Overall, our study indicates that GAMA is a novel blood-stage vaccine candidate antigen. C1 [Arumugam, Thangavelu U.; Takeo, Satoru; Yamasaki, Tsutomu; Tsuboi, Takafumi] Ehime Univ, Cell Free Sci & Technol Res Ctr, Matsuyama, Ehime 7908577, Japan. [Tsuboi, Takafumi] Ehime Univ, Venture Business Lab, Matsuyama, Ehime 7908577, Japan. [Thonkukiatkul, Amporn] Burapha Univ, Dept Biol, Fac Sci, Chon Buri 20131, Thailand. [Miura, Kazutoyo; Zhou, Hong; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Otsuki, Hitoshi] Tottori Univ, Div Med Zool, Fac Med, Tottori 6838503, Japan. [Sattabongkot, Jetsumon] Armed Forces Res Inst Med Sci, Dept Entomol, Bangkok 10400, Thailand. [Thompson, Jennifer; Wilson, Danny W.; Healer, Julie; Cowman, Alan F.] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia. [Beeson, James G.; Crabb, Brendan S.] Burnet Inst, Melbourne, Vic 3004, Australia. [Torii, Motomi] Ehime Univ, Dept Mol Parasitol, Grad Sch Med, Toon, Ehime 7910295, Japan. [Torii, Motomi; Tsuboi, Takafumi] Ehime Univ, Ehime Proteomed Res Ctr, Toon, Ehime 7910295, Japan. RP Tsuboi, T (reprint author), Ehime Univ, Cell Free Sci & Technol Res Ctr, 3 Bunkyo Cho, Matsuyama, Ehime 7908577, Japan. EM tsuboi@ccr.ehime-u.ac.jp RI Cowman, Alan/C-7642-2013; Crabb, Brendan/F-5287-2013 OI Cowman, Alan/0000-0001-5145-9004; FU Bill and Melinda Gates Foundation; Ministry of Education, Culture, Sports, Science and Technology [21249028, 21022034, 23406007, 23117008]; Ministry of Health, Labor, and Welfare, Japan [H21-Chikyukibo-ippan-005]; National Institute of Allergy and Infectious Diseases/NIH; PATH/Malaria Vaccine Initiative FX This research was supported in part by grants from The Bill and Melinda Gates Foundation, from the Ministry of Education, Culture, Sports, Science and Technology (21249028, 21022034, 23406007, and 23117008), and from the Ministry of Health, Labor, and Welfare, Japan (H21-Chikyukibo-ippan-005). This study was supported in part by the intramural program of the National Institute of Allergy and Infectious Diseases/NIH, and the GIA Reference Center is supported by the PATH/Malaria Vaccine Initiative. NR 38 TC 28 Z9 28 U1 0 U2 5 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 NOV PY 2011 VL 79 IS 11 BP 4523 EP 4532 DI 10.1128/IAI.05412-11 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GB UT WOS:000296352400023 PM 21896773 ER PT J AU Mital, J Hackstadt, T AF Mital, Jeffrey Hackstadt, Ted TI Role for the Src Family Kinase Fyn in Sphingolipid Acquisition by Chlamydiae SO INFECTION AND IMMUNITY LA English DT Article ID ENDOGENOUSLY SYNTHESIZED SPHINGOMYELIN; GOLGI-APPARATUS; INCLUSION MEMBRANE; PLASMA-MEMBRANE; TRACHOMATIS INCLUSION; INTRACELLULAR GROWTH; AMPHIPHYSIN-IIM; EARLY ENDOSOMES; LIPID DROPLETS; INFECTED CELLS AB The bacterial obligate intracellular pathogen Chlamydia trachomatis replicates within a membrane-bound vacuole termed the inclusion. From within this protective environment, chlamydiae usurp numerous functions of the host cell to promote chlamydial survival and replication. Here we utilized a small interfering RNA (siRNA)-based screening protocol designed to identify host proteins involved in the trafficking of sphingomyelin to the chlamydial inclusion. Twenty-six host proteins whose deficiency significantly decreased sphingomyelin trafficking to the inclusion and 16 proteins whose deficiency significantly increased sphingomyelin trafficking to the inclusion were identified. The reduced sphingomyelin trafficking caused by downregulation of the Src family tyrosine kinase Fyn was confirmed in more-detailed analyses. Fyn silencing did not alter sphingomyelin synthesis or trafficking in the absence of chlamydial infection but reduced the amount of sphingomyelin trafficked to the inclusion in infected cells, as determined by two independent quantitative assays. Additionally, inhibition of Src family kinases resulted in increased cellular retention of sphingomyelin and significantly decreased incorporation into elementary bodies of both C. trachomatis and Chlamydophila caviae. C1 [Mital, Jeffrey; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM Ted_Hackstadt@NIH.gov FU NIAID/NIH FX This work was supported by the Intramural Research Program of the NIAID/NIH. NR 66 TC 5 Z9 5 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 NOV PY 2011 VL 79 IS 11 BP 4559 EP 4568 DI 10.1128/IAI.05692-11 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GB UT WOS:000296352400027 PM 21896774 ER PT J AU Babu, S Anuradha, R Kumar, NP George, PJ Kumaraswami, V Nutman, TB AF Babu, Subash Anuradha, R. Kumar, N. Pavan George, P. Jovvian Kumaraswami, V. Nutman, Thomas B. TI Filarial Lymphatic Pathology Reflects Augmented Toll-Like Receptor-Mediated, Mitogen-Activated Protein Kinase-Mediated Proinflammatory Cytokine Production SO INFECTION AND IMMUNITY LA English DT Article ID ENDOSYMBIOTIC WOLBACHIA-BACTERIA; IMMUNE-RESPONSES; BANCROFTIAN FILARIASIS; BRUGIA-MALAYI; PATHOGENESIS; DISEASE; EXPRESSION; PARASITES; INNATE; CELLS AB Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Toll-like receptors (TLRs) are thought to play a major role in the development of filarial pathology. To elucidate the role of TLRs in the development of lymphatic pathology, we examined cytokine responses to different Toll ligands in patients with chronic lymphatic pathology (CP), infected patients with subclinical pathology (INF), and uninfected, endemic-normal (EN) individuals. TLR2, -7, and -9 ligands induced significantly elevated production of Th1 and other proinflammatory cytokines in CP patients in comparison to both INF and EN patients. TLR adaptor expression was not significantly different among the groups; however, both TLR2 and TLR9 ligands induced significantly higher levels of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinases (MAPK) as well as increased activation of NF-kappa B in CP individuals. Pharmacologic inhibition of both ERK1/2 and p38 MAP kinase pathways resulted in significantly diminished production of proinflammatory cytokines in CP individuals. Our data, therefore, strongly suggest an important role for TLR2- and TLR9-mediated proinflammatory cytokine induction and activation of both the MAPK and NF-kappa B pathways in the development of pathology in human lymphatic filariasis. C1 [Babu, Subash; Anuradha, R.; Kumar, N. Pavan; George, P. Jovvian] Natl Inst Hlth, Int Ctr Excellence Res, Chennai, Tamil Nadu, India. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Babu, Subash] SAIC Frederick Inc, NCI Frederick, Frederick, MD USA. [Kumaraswami, V.] TB Res Ctr, Chennai, Tamil Nadu, India. RP Babu, S (reprint author), NIH ICER, Chennai, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 28 TC 9 Z9 11 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2011 VL 79 IS 11 BP 4600 EP 4608 DI 10.1128/IAI.05419-11 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GB UT WOS:000296352400031 PM 21875961 ER PT J AU Leysath, CE Chen, KH Moayeri, M Crown, D Fattah, R Chen, ZC Das, SR Purcell, RH Leppla, SH AF Leysath, Clinton E. Chen, Kuang-Hua Moayeri, Mahtab Crown, Devorah Fattah, Rasem Chen, Zhaochun Das, Suman R. Purcell, Robert H. Leppla, Stephen H. TI Mouse Monoclonal Antibodies to Anthrax Edema Factor Protect against Infection SO INFECTION AND IMMUNITY LA English DT Article ID BACILLUS-ANTHRACIS; ADENYLYL-CYCLASE; CALMODULIN-BINDING; EUKARYOTIC CELLS; LETHAL FACTOR; TOXIN; INTERNALIZATION; NEUTRALIZATION; INACTIVATION; CATALYSIS AB Bacillus anthracis is the causative agent of anthrax, and the tripartite anthrax toxin is an essential element of its pathogenesis. Edema factor (EF), a potent adenylyl cyclase, is one of the toxin components. In this work, anti-EF monoclonal antibodies (MAb) were produced following immunization of mice, and four of the antibodies were fully characterized. MAb 3F2 has an affinity of 388 pM, was most effective for EF detection, and appears to be the first antibody reported to neutralize EF by binding to the catalytic C(B) domain. MAb 7F10 shows potent neutralization of edema toxin activity in vitro and in vivo; it targets the N-terminal protective antigen binding domain. The four MAb react with three different domains of edema factor, and all were able to detect purified edema factor in Western blot analysis. None of the four MAb cross-reacted with the lethal factor toxin component. Three of the four MAb protected mice in both a systemic edema toxin challenge model and a subcutaneous spore-induced foreleg edema model. A combination of three of the MAb also significantly delayed the time to death in a third subcutaneous spore challenge model. This appears to be the first direct evidence that monoclonal antibody-mediated neutralization of EF alone is sufficient to delay anthrax disease progression. C1 [Leysath, Clinton E.; Chen, Kuang-Hua; Moayeri, Mahtab; Crown, Devorah; Fattah, Rasem; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Chen, Zhaochun; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Das, Suman R.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, Lab Bacterial Dis, NIH, 9000 Rockville Pike,Bldg 33,Room 1W20B-7, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov RI Das, Suman/C-8760-2009 FU National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD. NR 35 TC 12 Z9 12 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 NOV PY 2011 VL 79 IS 11 BP 4609 EP 4616 DI 10.1128/IAI.05314-11 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GB UT WOS:000296352400032 PM 21911463 ER PT J AU Butler, SL Valdez, H Westby, M Perros, M June, CH Jacobson, JM Levy, Y Cooper, DA Douek, D Lederman, MM Tebas, P AF Butler, Scott L. Valdez, Hernan Westby, Michael Perros, Manos June, Carl H. Jacobson, Jeffrey M. Levy, Yves Cooper, David A. Douek, Daniel Lederman, Michael M. Tebas, Pablo TI Disease-Modifying Therapeutic Concepts for HIV in the Era of Highly Active Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE clinical trials; disease-modifying therapy; genetic therapy; HIV infection; immune activation; microbial translocation; proof-of-concept ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL-ACTIVATION; LYMPHATIC TISSUE FIBROSIS; ZINC-FINGER NUCLEASES; C-REACTIVE PROTEIN; INFECTED PATIENTS; IMMUNE ACTIVATION; IN-VIVO; RALTEGRAVIR INTENSIFICATION; VIROLOGICAL SUPPRESSION AB Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes-both AIDS-defining and non-AIDS-defining clinical events-and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials. C1 [Butler, Scott L.] Pfizer Global Res & Dev, Infect Dis Grp, Sandwich CT13 9NJ, Kent, England. [Valdez, Hernan] Pfizer Inc, New York, NY USA. [Perros, Manos] AstraZeneca, Waltham, MA USA. [June, Carl H.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Levy, Yves] Univ Paris Est, INSERM, Fac Med,Creteil AP HP,Serv Immunol Clin, Unite U955,Grp Henri Mondor Albert Chenevier, Creteil, France. [Cooper, David A.] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Darlinghurst, NSW, Australia. [Cooper, David A.] St Vincents Hosp, Ctr Appl Med Res, Darlinghurst, NSW 2010, Australia. [Douek, Daniel] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Lederman, Michael M.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Tebas, Pablo] Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. RP Butler, SL (reprint author), Pfizer Global Res & Dev, Infect Dis Grp, Sandwich CT13 9NJ, Kent, England. EM scott.butler@pfizer.com FU Pfizer Global Research and Development; Pfizer, Inc. FX The study was sponsored by Pfizer Global Research and Development and was funded by Pfizer, Inc. Editorial assistance was provided by Jennifer Tobin of Health Interactions Ltd, with funding by Pfizer, Inc. C.J., Y.L., D. C., M. L., and P. T. were paid for their participation in the round-table discussions. NR 101 TC 13 Z9 14 U1 1 U2 2 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 NOV 1 PY 2011 VL 58 IS 3 BP 297 EP 303 DI 10.1097/QAI.0b013e31822ccfcc PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839QQ UT WOS:000296383900021 PM 21792065 ER PT J AU Dlamini, JN Hu, ZH Ledwaba, J Morris, L Maldarelli, FM Dewar, RL Highbarger, HC Somaroo, H Sangweni, P Follmann, DA Pau, AK AF Dlamini, J. Nomthandazo Hu, Zonghui Ledwaba, Johanna Morris, Lynn Maldarelli, Frank M. Dewar, Robin L. Highbarger, Helene C. Somaroo, Harsha Sangweni, Phumelele Follmann, Dean A. Pau, Alice K. CA Phidisa II Study Team TI Genotypic Resistance at Viral Rebound Among Patients Who Received Lopinavir/Ritonavir-Based or Efavirenz-Based First Antiretroviral Therapy in South Africa SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE antiretroviral naive; genotypic resistance; HIV; nonnucleoside reverse transcriptase inhibitors; protease inhibitors; South Africa ID DRUG-RESISTANCE; FAILURE AB Nonnucleoside reverse transcriptase inhibitor-drug resistance mutations (DRM) are increasingly reported in Africans failing their first antiretroviral regimen. The Phidisa II trial randomized treatment-naive participants to lopinavir/ritonavir or efavirenz with stavudine + lamivudine or zidovudine + didanosine. We report the prevalence of DRM in subjects who achieved HIV RNA <400 copies per milliliter at 6 months, but subsequently had 2 consecutive HIV RNA >1000 copies per milliliter. Sixty-eight participants fulfilled the inclusion criteria. nonnucleoside reverse transcriptase inhibitor-DRM were found in 17 of 36 (47.2%) efavirenz recipients, and M184V/I mutation in 14 of 40 (35.0%) lamivudine recipients. No protease inhibitor mutation was identified in 38 lopinavir/ritonavir recipients. This is one of the first studies in Africa confirming the paucity of protease inhibitor-associated DRM despite virologic failure. C1 [Hu, Zonghui; Follmann, Dean A.; Pau, Alice K.] NIAID, NIH, Div Clin Res, Bethesda, MD 20895 USA. [Dlamini, J. Nomthandazo] SAMHS, Off Clin Operat, Project Phidisa, Pretoria, South Africa. [Ledwaba, Johanna; Morris, Lynn] NICD, AIDS Virus Res Unit, Johannesburg, South Africa. [Maldarelli, Frank M.] NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. [Dewar, Robin L.; Highbarger, Helene C.] NCI, Virus Isolat & Serol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Somaroo, Harsha] SAMHS, Mil Hosp 2, Project Phidisa, Cape Town, South Africa. [Sangweni, Phumelele] SAMHS, Lab Sect, Project Phidisa, Pretoria, South Africa. RP Pau, AK (reprint author), NIAID, NIH, Div Clin Res, Bldg 10,Room 11C103,MSC 1880, Bethesda, MD 20895 USA. EM apau@niaid.nih.gov FU South African National Defence Force through SAMHS; United States National Institutes of Health-National Institute of Allergy and Infectious Diseases; United States Department of Defense (US DoD); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Supported by The South African National Defence Force through SAMHS, the United States National Institutes of Health-National Institute of Allergy and Infectious Diseases, and the United States Department of Defense (US DoD). This project has also been funded in in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 19 TC 8 Z9 8 U1 0 U2 2 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 NOV 1 PY 2011 VL 58 IS 3 BP 304 EP 308 DI 10.1097/QAI.0b013e3182278c29 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839QQ UT WOS:000296383900022 PM 21694608 ER PT J AU Khosla, S Bellido, TM Drezner, MK Gordon, CM Harris, TB Kiel, DP Kream, BE LeBoff, MS Lian, JB Peterson, CA Rosen, CJ Williams, JP Winer, KK Sherman, SS AF Khosla, Sundeep Bellido, Teresita M. Drezner, Marc K. Gordon, Catherine M. Harris, Tamara B. Kiel, Douglas P. Kream, Barbara E. LeBoff, Meryl S. Lian, Jane B. Peterson, Charlotte A. Rosen, Clifford J. Williams, John P. Winer, Karen K. Sherman, Sherry S. TI Forum on Aging and Skeletal Health: Summary of the Proceedings of an ASBMR Workshop SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Editorial Material DE AGING; GROWTH AND DEVELOPMENT; MENOPAUSE ID BONE-MINERAL DENSITY; HIP FRACTURE INCIDENCE; OXIDATIVE STRESS; VITAMIN-D; MENOPAUSAL TRANSITION; LEPTIN REGULATION; CROHNS-DISEASE; SEX STEROIDS; OLDER WOMEN; AGE AB With the aging of the population, the scope of the problem of age-related bone loss and osteoporosis will continue to increase. As such, it is critical to obtain a better understanding of the factors determining the acquisition and loss of bone mass from childhood to senescence. While there have been significant advances in recent years in our understanding of both the basic biology of aging and a clinical definition of age-related frailty, few of these concepts in aging research have been evaluated adequately for their relevance and application to skeletal aging or fracture prevention. The March 2011 Forum on Aging and Skeletal Health, sponsored by the NIH and ASBMR, sought to bring together leaders in aging and bone research to enhance communications among diverse fields of study so as to accelerate the pace of scientific advances needed to reduce the burden of osteoporotic fractures. This report summarizes the major concepts presented at that meeting and in each area identifies key questions to help set the agenda for future research in skeletal aging. (C) 2011 American Society for Bone and Mineral Research. C1 [Khosla, Sundeep] Mayo Clin, Endocrine Res Unit, Coll Med, Rochester, MN 55905 USA. [Williams, John P.; Sherman, Sherry S.] NIA, NIH, Bethesda, MD 20892 USA. [Bellido, Teresita M.] Indiana Univ Sch Med, Indianapolis, IN USA. [Drezner, Marc K.] Univ Wisconsin, Madison, WI 53706 USA. [Gordon, Catherine M.] Harvard Univ, Sch Med, Childrens Hosp Boston, Cambridge, MA 02138 USA. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Kiel, Douglas P.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Kream, Barbara E.] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [LeBoff, Meryl S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Lian, Jane B.] Univ Massachusetts, Sch Med, Dept Cell Biol, Amherst, MA 01003 USA. [Peterson, Charlotte A.] Univ Kentucky, Coll Hlth Sci, Lexington, KY 40506 USA. RP Khosla, S (reprint author), Mayo Clin, Endocrine Res Unit, Coll Med, 200 1st St SW,Guggenheim 7, Rochester, MN 55905 USA. EM khosla.sundeep@mayo.edu; shermans@nia.nih.gov OI Kiel, Douglas/0000-0001-8474-0310; Khosla, Sundeep/0000-0002-2936-4372 FU NCRR NIH HHS [UL1 RR025011]; NIA NIH HHS [U13AG037272, U13 AG037272]; NIAMS NIH HHS [R01 AR027032]; NIDCR NIH HHS [R37 DE012528] NR 79 TC 12 Z9 12 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2011 VL 26 IS 11 BP 2565 EP 2578 DI 10.1002/jbmr.488 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 839TH UT WOS:000296391600001 PM 21915901 ER PT J AU Shepherd, JA Wang, L Fan, B Gilsanz, V Kalkwarf, HJ Lappe, J Lu, Y Hangartner, T Zemel, BS Fredrick, M Oberfield, S Winer, KK AF Shepherd, John A. Wang, Li Fan, Bo Gilsanz, Vicente Kalkwarf, Heide J. Lappe, Joan Lu, Ying Hangartner, Thomas Zemel, Babette S. Fredrick, Margaret Oberfield, Sharon Winer, Karen K. TI Optimal Monitoring Time Interval Between DXA Measures in Children SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE CLINICAL/PEDIATRICS; GROWTH AND DEVELOPMENT; BONE DENSITOMETRY; QUANTITATION; STATISTICAL METHODS ID X-RAY ABSORPTIOMETRY; PEDIATRIC OFFICIAL POSITIONS; BONE-MINERAL DENSITY; LONG-TERM PRECISION; BODY-COMPOSITION; REPRODUCIBILITY; DENSITOMETERS; ADOLESCENTS; ACCURACY; WOMEN AB The monitoring time interval (MTI) is the expected time in years necessary to identify a change between two measures that exceeds the measurement error. Our purpose was to determine MTI values for dual-energy X-ray absorptiometry (DXA) scans in normal healthy children, according to age, sex, and skeletal site. 2014 children were enrolled in the Bone Mineral Density in Childhood Study and had DXA scans of the lumbar spine, total hip, nondominant forearm, and whole body. Measurements were obtained annually for seven visits from 2002 to 2010. Annualized rates of change were calculated by age and sex for all bone regions. A subgroup of 155 children ages 6 to 16 years (85 boys) had duplicate scans for calculation of scan precision. The bone mineral density (BMD) regions of interest included the spine, total body less head (TBLH), total hip, femoral neck, and one-third radius. Bone mineral content (BMC) was also evaluated for the spine and TBLH. The percent coefficient of variation (%CV) and MTI were calculated for each measure as a function of age and sex. The MTI values were substantially less than 1 year for the TBLH and spine BMD and BMC for boys <= 17 years and girls <= 15 years. The hip and one-third radius MTIs were generally 1 year in the same group. MTI values as low as 3 months were found during the peak growth years. However, the MTI values in late adolescence for all regions were substantially longer and became nonsensical as each region neared the age for peak bone density. All four DXA measurement sites had reasonable (< 1 year) MTI values for boys <= 17 years and girls <= 15 years. MTI was neither useful nor stable in late adolescence and young adulthood. Alternative criteria to determine scan intervals must be used in this age range. (C) 2011 American Society for Bone and Mineral Research. C1 [Shepherd, John A.; Wang, Li; Fan, Bo] Univ Calif San Francisco, Dept Radiol, Bone & Breast Dens Res Grp, San Francisco, CA 94143 USA. [Gilsanz, Vicente] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Kalkwarf, Heide J.] Cincinnati Childrens Hosp Med Ctr, Div Gen & Community Pediat, Cincinnati, OH USA. [Lappe, Joan] Creighton Univ, Osteoporosis Res Ctr, Omaha, NE 68178 USA. [Lu, Ying] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Hangartner, Thomas] Wright State Univ, BioMed Imaging Lab, Dayton, OH 45435 USA. [Zemel, Babette S.] Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA. [Fredrick, Margaret] Clin Trials & Surveys Corp, Baltimore, MD USA. [Oberfield, Sharon] St Lukes Roosevelt Hosp, New York, NY 10025 USA. [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Endocrinol Nutr & Growth Branch, Bethesda, MD USA. RP Shepherd, JA (reprint author), Univ Calif San Francisco, Dept Radiol & Bioimaging, Box 0628,MRSC AC122, San Francisco, CA 94143 USA. EM john.shepherd@radiology.ucsf.edu FU National Institute of Child Health and Human Development Bone Mineral Density in Childhood Study; NICHD [N01-HD-13328]; USPHS; National Center for Research Resources (NIH) [UL1-RR-026314]; CTSA [UL1-RR-024134] FX This study was funded by the National Institute of Child Health and Human Development Bone Mineral Density in Childhood Study, NICHD N01-HD-13328, USPHS Grant UL1-RR-026314 from the National Center for Research Resources (NIH), and CTSA grant UL1-RR-024134. The authors wish to thank the investigators and staff at Cincinnati Children's Hospital Medical Center, Creighton University, Children's Hospital of Philadelphia, St. Luke's-Roosevelt Hospital, and Children's Hospital of Los Angeles. We acknowledge the editorial support of Erin Reese. NR 20 TC 19 Z9 21 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2011 VL 26 IS 11 BP 2745 EP 2752 DI 10.1002/jbmr.473 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 839TH UT WOS:000296391600019 PM 21773995 ER PT J AU Beydoun, MA Beason-Held, LL Kitner-Triolo, MH Beydoun, HA Ferrucci, L Resnick, SM Zonderman, AB AF Beydoun, May A. Beason-Held, Lori L. Kitner-Triolo, Melissa H. Beydoun, Hind A. Ferrucci, Luigi Resnick, Susan M. Zonderman, Alan B. TI Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID ALZHEIMERS-DISEASE; REDUCED RISK; COHORT; LEVEL; OLDER; COMMUNITY; DECLINE; MIDLIFE; HEALTH; AD AB Background Statin use and serum cholesterol reduction have been proposed as preventions for dementia and mild cognitive impairment (MCI). Methods 1604 and 1345 eligible participants from the Baltimore Longitudinal Study of Aging (BLSA) were followed after age 50 for a median time of around 25 years, to examine the incidence of dementia (n = 259) and MCI (n = 138), respectively. Statin use (ever-use and time-dependent use), total cholesterol levels (TC; first visit and time-dependent), TC change trajectory from first visit and high-density lipoprotein (HDL-C): TC ratio (first visit and time-dependent) were the main exposures of interest. Cox proportional hazards models were used. Results Participants with incident dementia had a higher first-visit TC compared with participants who remained free of dementia and MCI, while first-visit TC was higher among statin ever-users compared with never-users (age-unadjusted associations). Statin users had a two- to threefold lower risk of developing dementia (HR = 0.41; 95% CI 0.18 to 0.92), but not MCI, when considering time-dependent 'statin use' with propensity score model adjustment. This association remained significant independently of serum cholesterol exposures. An elevated first-visit TC was associated with reduced MCI risk (upper quartile (Q(4)) vs Q(1): HR = 0.51; 95% CI 0.29 to 0.90). Compared with the lowest quartile (Q(1): 0.00-0.19), HDL-C: TC (time-dependent) in (Q(2): 0.19-0.24) was associated with reduced MCI risk (HR = 0.58; 95% CI 0.34 to 0.98). Among men only, TC decline from first visit was significantly associated with increased dementia risk (HR = 4.21; 95% CI 1.28 to 13.85). Conclusions Statins may have multifactorial effects on dementia but not MCI risk. Future interventions may be warranted, and research should focus on optimal serum TC, HDL-C: TC ratio and TC change trajectories. C1 [Beydoun, May A.; Beason-Held, Lori L.; Kitner-Triolo, Melissa H.; Ferrucci, Luigi; Resnick, Susan M.; Zonderman, Alan B.] NIA, NIH, Biomed Res Ctr, IRP, Baltimore, MD 21224 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 47 TC 39 Z9 40 U1 1 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD NOV PY 2011 VL 65 IS 11 BP 949 EP 957 DI 10.1136/jech.2009.100826 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 836VK UT WOS:000296143300002 PM 20841372 ER PT J AU Prasad, M Zhu, QL Sun, Y Wang, XF Kulkarni, A Boskey, A Feng, JQ Qin, CL AF Prasad, Monica Zhu, Qinglin Sun, Yao Wang, Xiaofang Kulkarni, Ashok Boskey, Adele Feng, Jian Q. Qin, Chunlin TI Expression of Dentin Sialophosphoprotein in Non-mineralized Tissues SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE gene expression; dentin sialophosphoprotein; biomineralization; non-mineralized tissues; DSPP knockout mice ID INTEGRIN-BINDING LIGAND; PULP STEM-CELLS; IN-VIVO; SIBLING PROTEINS; PERICYTE DIFFERENTIATION; BMP4 EXPRESSION; SIALOPROTEIN; BONE; GENE; MATRIX AB Dentin sialophosphoprotein (DSPP) and its cleaved products, dentin phosphoprotein (DPP) and dentin sialoprotein (DSP), play important roles in biomineralization. Believed to be tooth specific, the authors' group revealed its expression in bone, and more recently, they and other groups also showed its expression in a few types of soft tissues. In this study, the authors systematically examined the expression of DSPP in a variety of non-mineralized tissues using reverse-transcription polymerase chain reaction (RT-PCR), real-time PCR, Western immunoblotting, and immunohistochemistry analyses in wildtype mice as well as beta-galactosidase assays in the Dspp lacZ knock-in mice. These approaches showed the presence of DSPP in the salivary glands, cartilage, liver, kidney, and brain and its absence in the heart and spleen. Real-time PCR showed that the expression levels of DSPP mRNA in salivary glands, cartilage, liver, and kidney were higher than in the bone. Interestingly, DSPP was observed in the pericytes of blood vessels in the dental pulp, which are believed to be able to differentiate into odontoblasts. On the basis of these observations, the authors conclude that DSPP and/or its cleaved products may fulfill important functions in certain non-mineralized tissues in addition to its role in biomineralization. (J Histochem Cytochem 59: 1009-1021, 2011) C1 [Prasad, Monica; Zhu, Qinglin; Sun, Yao; Wang, Xiaofang; Feng, Jian Q.; Qin, Chunlin] Baylor Coll Dent, Dept Biomed Sci, Texas A&M Hlth Sci Ctr, Dallas, TX 75246 USA. [Zhu, Qinglin] Fourth Mil Med Univ, Sch Stomatol, Dept Operat Dent & Endodont, Xian 710032, Peoples R China. [Kulkarni, Ashok] NIDCR, Funct Genom Sect, NIH, Bethesda, MD USA. [Boskey, Adele] Hosp Special Surg, New York, NY 10021 USA. RP Qin, CL (reprint author), Baylor Coll Dent, Dept Biomed Sci, Texas A&M Hlth Sci Ctr, 3302 Gaston Ave,Room 400, Dallas, TX 75246 USA. EM cqin@bcd.tamhsc.edu OI Boskey, Adele/0000-0002-6181-2219 FU National Institutes of Health [DE005092] FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: This work was supported by grant DE005092 (to CQ) from the National Institutes of Health. NR 42 TC 18 Z9 20 U1 0 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD NOV PY 2011 VL 59 IS 11 BP 1009 EP 1021 DI 10.1369/0022155411423406 PG 13 WC Cell Biology SC Cell Biology GA 839JI UT WOS:000296361100005 PM 22043023 ER PT J AU Saikus, CE Ratnayaka, K Barbash, IM Colyer, JH Kocaturk, O Faranesh, AZ Lederman, RJ AF Saikus, Christina E. Ratnayaka, Kanishka Barbash, Israel M. Colyer, Jessica H. Kocaturk, Ozgur Faranesh, Anthony Z. Lederman, Robert J. TI MRI-Guided Vascular Access With an Active Visualization Needle SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE interventional MRI; vascular access; actively visualized devices ID MAGNETIC-RESONANCE; COMPATIBLE NEEDLES; DEVICES; TRACKING; BIOPSY; INTERVENTIONS; ARTIFACTS; BIPLANAR; IMAGES; NOISE AB Purpose: To develop an approach to vascular access under magnetic resonance imaging (MRI), as a component of comprehensive MRI-guided cardiovascular catheterization and intervention. Materials and Methods: We attempted jugular vein access in healthy pigs as a model of "difficult" vascular access. Procedures were performed under real-time MRI guidance using reduced field of view imaging. We developed an "active" MRI antenna-needle having an open-lumen, distinct tip appearance and indicators of depth and trajectory in order to enhance MRI visibility during the procedure. We compared performance of the active needle against an unmodified commercial passively visualized needle, measured by procedure success among operators with different levels of experience. Results: MRI-guided central vein access was feasible using both the active needle and the unmodified passive needle. The active needle required less time (88 vs. 244 sec, P = 0.022) and fewer needle passes (4.5 vs. 9.1, P = 0.028), irrespective of operator experience. Conclusion: MRI-guided access to central veins is feasible in our animal model. When image guidance is necessary for vascular access, performing this component under MRI will allow wholly MRI-guided catheterization procedures that do not require adjunctive imaging facilities such as x-ray or ultrasound. The active needle design showed enhanced visibility, as expected. These capabilities may permit more complex catheter-based cardiovascular interventional procedures enabled by enhanced image guidance. C1 [Saikus, Christina E.; Ratnayaka, Kanishka; Barbash, Israel M.; Colyer, Jessica H.; Kocaturk, Ozgur; Faranesh, Anthony Z.; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, 10 Ctr Dr,Bldg 10,2C713, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Kocaturk, Ozgur/A-1419-2016; OI lederman, robert/0000-0003-1202-6673 FU NHLBI Division of Intramural Research [Z01-HL005062-08, Z01-HL006041-01] FX Contract grant sponsor: NHLBI Division of Intramural Research; Contract grant numbers: Z01-HL005062-08, Z01-HL006041-01. NR 24 TC 9 Z9 9 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD NOV PY 2011 VL 34 IS 5 BP 1159 EP 1166 DI 10.1002/jmri.22715 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 837MC UT WOS:000296206900021 PM 22006552 ER PT J AU Schultz, JM Bhatti, R Madeo, AC Turriff, A Muskett, JA Zalewski, CK King, KA Ahmed, ZM Riazuddin, S Ahmad, N Hussain, Z Qasim, M Kahn, SN Meltzer, MR Liu, XZ Munisamy, M Ghosh, M Rehm, HL Tsilou, ET Griffith, AJ Zein, WM Brewer, CC Riazuddin, S Friedman, TB AF Schultz, Julie M. Bhatti, Rashid Madeo, Anne C. Turriff, Amy Muskett, Julie A. Zalewski, Christopher K. King, Kelly A. Ahmed, Zubair M. Riazuddin, Saima Ahmad, Nazir Hussain, Zawar Qasim, Muhammad Kahn, Shaheen N. Meltzer, Meira R. Liu, Xue Z. Munisamy, Murali Ghosh, Manju Rehm, Heidi L. Tsilou, Ekaterini T. Griffith, Andrew J. Zein, Wadih M. Brewer, Carmen C. Riazuddin, Sheikh Friedman, Thomas B. TI Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID NONSYNDROMIC HEARING-LOSS; MYOSIN-VIIA GENE; SYNDROME TYPE 1D; RECESSIVE DEAFNESS; RETINITIS-PIGMENTOSA; MISSENSE MUTATION; JAPANESE PATIENTS; SYNDROME TYPE-1; CADHERIN-23; IMPAIRMENT AB Background Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth. Methods and results To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele. Conclusions One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. Accession numbers The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively. C1 [Schultz, Julie M.; Friedman, Thomas B.] NIDCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Bhatti, Rashid; Ahmad, Nazir; Hussain, Zawar; Qasim, Muhammad; Kahn, Shaheen N.; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Madeo, Anne C.; Muskett, Julie A.; Zalewski, Christopher K.; King, Kelly A.; Griffith, Andrew J.; Brewer, Carmen C.] NIDCD, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. [Turriff, Amy; Meltzer, Meira R.; Tsilou, Ekaterini T.; Zein, Wadih M.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Ahmed, Zubair M.; Riazuddin, Saima] Childrens Hosp Res Fdn, Div Pediat Otolaryngol Head & Neck Surg, Cincinnati, OH 45229 USA. [Ahmed, Zubair M.; Riazuddin, Saima] Childrens Hosp Res Fdn, Div Ophthalmol, Cincinnati, OH 45229 USA. [Liu, Xue Z.] Miami Univ, Dept Otolaryngol, Miami, FL USA. [Munisamy, Murali; Ghosh, Manju] All India Inst Med Sci, Dept Pediat, Genet Unit, New Delhi, India. [Rehm, Heidi L.] Partners HealthCare Ctr Personalized Genet Med, Mol Med Lab, Cambridge, MA USA. [Rehm, Heidi L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Rehm, Heidi L.] Harvard Univ, Sch Med, Boston, MA USA. [Tsilou, Ekaterini T.] NICHHD, Ctr Res Mothers & Children, NIH, Bethesda, MD USA. [Riazuddin, Sheikh] Allama Iqbal Med Coll, Allama Iqbal Med Res Ctr, Lahore, Pakistan. RP Friedman, TB (reprint author), NIDCD, Mol Genet Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov RI Madeo, Anne/K-2880-2012 FU NIDCD [DC000039-14, DC000060-10, DC000064-10]; National Eye Institute; Higher Education Commission and Ministry of Science and Technology; International Center for Genetic Engineering and Biotechnology, Trieste, Italy [CRP/PAK08-01, 08/009] FX This study was supported by NIDCD intramural research funds DC000039-14, DC000060-10, and DC000064-10 to TBF, AJG and CCB, respectively, and the Intramural Research Program of the National Eye Institute, and support by the Higher Education Commission and Ministry of Science and Technology and the International Center for Genetic Engineering and Biotechnology, Trieste, Italy under project CRP/PAK08-01 Contract no. 08/009 to ShR. NR 50 TC 26 Z9 27 U1 0 U2 10 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD NOV PY 2011 VL 48 IS 11 BP 767 EP 775 DI 10.1136/jmedgenet-2011-100262 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 837KA UT WOS:000296198800008 PM 21940737 ER PT J AU Mondu, AM Rager, HC Kopp, W Virtamo, J Albanes, D AF Mondu, Alison M. Rager, Helen C. Kopp, William Virtamo, Jarmo Albanes, Demetrius TI Supplementation with alpha-Tocopherol or beta-Carotene Reduces Serum Concentrations of Vascular Endothelial Growth Factor-D, but Not -A or -C, in Male Smokers SO JOURNAL OF NUTRITION LA English DT Article ID LYMPH-NODE METASTASIS; NF-KAPPA-B; CELL LUNG-CANCER; PROSTATE-CANCER; VITAMIN-E; GENE-EXPRESSION; TUMOR-CELLS; VEGF-D; SIGNALING PATHWAY; GAMMA-TOCOTRIENOL AB Evidence from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study suggests that vitamin E and beta-carotene supplement use may influence the risk of several cancers. Vascular endothelial growth factors (VEGF) are proteins involved in angiogenesis, an important requirement for tumor growth and metastasis. Thus, vitamin E and beta-carotene may influence cancer risk through one or more VEGF. The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial in which participants were assigned to 1 of 4 supplementation groups based on a 2 x 2 factorial design: 1) alpha-tocopherol (vitamin E); 2) beta-carotene; 3) both; or 4) placebo. For the present study, 100 cancer-free participants with follow-up serum available were randomly selected from each intervention group. VEGF-A, -C, and -D concentrations were measured by ELISA in serum obtained at baseline and after at least 2 y of supplementation. Differences in change in VEGF levels from baseline to follow-up between intervention groups were assessed using the ANOVA test. Change in VEGF-A and VEGF-C concentrations between baseline and follow-up did not differ by intervention group (P = 0.45 and 0.29, respectively). The decrease in the serum VEGF-D concentration was greater in the men supplemented with alpha-tocopherol (-9.7 +/- 2.5%) or beta-carotene (-8.5 +/- 2.7%) and tended to be greater in those supplemented with both (-6.8 +/- 2.4%) compared to the placebo group, in which there was no change (-0.4 +/- 3.0%) (P = 0.03). In this population of male smokers, supplementation with alpha-tocopherol or beta-carotene was associated with a decrease in VEGF-D levels over time. Although the mechanism through which these supplements affect cancer etiolog remains unclear, our results support the hypothesis that vitamin E and beta-carotene may influence cancer progression through VEGF-mediated lymphangiogenesis. J. Nutr. 141: 2030-2034, 2011. C1 [Mondu, Alison M.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rager, Helen C.; Kopp, William] NCI, Appl Dev Res Directorate, SAIC Frederick Inc, Frederick, MD 21701 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welfare, Dept Chron Dis Prevent, Helsinki, Finland. RP Mondu, AM (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mondulam@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mondul, Alison/0000-0002-8843-1416 FU U.S. Public Health Service from the National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; National Cancer Institute; National Cancer Institute, NIH [HSN261200800001E] FX Supported by U.S. Public Health Service contracts from the National Cancer Institute, Department of Health and Human Services (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C, and by funding from the Intramural Research Program of the National Cancer Institute. The laboratory assays were funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HSN261200800001E. 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 37 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD NOV PY 2011 VL 141 IS 11 BP 2030 EP 2034 DI 10.3945/jn.111.143669 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 837PD UT WOS:000296214800017 PM 21956960 ER PT J AU Verkaik-Kloosterman, J Dodd, KW Dekkers, ALM van't Veer, P Ocke, MC AF Verkaik-Kloosterman, Janneke Dodd, Kevin W. Dekkers, Arnold L. M. van't Veer, Pieter Ocke, Marga C. TI A Three-Part, Mixed-Effects Model to Estimate the Habitual Total Vitamin D Intake Distribution from Food and Dietary Supplements in Dutch Young Children SO JOURNAL OF NUTRITION LA English DT Article ID MULTIVITAMIN-MULTIMINERAL SUPPLEMENTS; CONSUMPTION; NUTRIENTS; POPULATION; NUTRITION; FREQUENCY; EXPOSURE AB Statistical modeling of habitual micronutrient intake from food and dietary supplements using short-term measurements is hampered by heterogeneous variances and multirnodality. Summing short-term intakes from food and dietary supplements prior to simple correction for within-person variation (first add then shrink) may produce estimates of habitual total micronutrient intake so badly biased as to be smaller than estimates of habitual intake from food sources only. A 3-part model using a first shrink then add approach is proposed to estimate the habitual micronutrient intake from food among nonsupplement users, food among supplement users, and supplements. The population distribution of habitual total micronutrient intake is estimated by combining these 3 habitual intake distributions, accounting for possible interdependence between Eq. 2 and 3. The new model is an extension of a model developed by the USA National Cancer Institute. Habitual total vitamin D intake among young children was estimated using the proposed model and data from the Dutch food consumption survey (n = 1279). The model always produced habitual total intakes similar to or higher than habitual intakes from food sources only and also preserved the multimodal shape of the observed total vitamin D intake distribution. This proposed method incorporates several sources of covariate information that should provide more precise estimates of the habitual total intake distribution and the proportion of the population with intakes below/above cutpoint values. The proposed methodology could be useful for other complex situations, e.g. where high concentrations of micronutrients appear in episodically consumed foods. J. Nutr. 141: 2055-2063, 2011. C1 [Verkaik-Kloosterman, Janneke; Dekkers, Arnold L. M.; Ocke, Marga C.] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Dodd, Kevin W.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [van't Veer, Pieter] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. RP Verkaik-Kloosterman, J (reprint author), Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. EM Janneke.Verkaik@RIVM.nl NR 33 TC 6 Z9 7 U1 0 U2 6 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD NOV PY 2011 VL 141 IS 11 BP 2055 EP 2063 DI 10.3945/jn.111.142398 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 837PD UT WOS:000296214800021 PM 21956963 ER PT J AU Kang, JG Majerciak, V Uldrick, TS Wang, XH Kruhlak, M Yarchoan, R Zheng, ZM AF Kang, Jeong-Gu Majerciak, Vladimir Uldrick, Thomas S. Wang, Xiaohong Kruhlak, Michael Yarchoan, Robert Zheng, Zhi-Ming TI Kaposi's sarcoma-associated herpesviral IL-6 and human IL-6 open reading frames contain miRNA binding sites and are subject to cellular miRNA regulation SO JOURNAL OF PATHOLOGY LA English DT Article DE viral IL-6; IL-6; miRNA; Kaposi's sarcoma-associated herpesvirus; germinal centre; gene expression; post-transcriptional regulation ID PRIMARY EFFUSION LYMPHOMA; MULTICENTRIC CASTLEMANS-DISEASE; INDUCED CYTIDINE DEAMINASE; AU-RICH ELEMENT; VIRAL INTERLEUKIN-6; GENE-EXPRESSION; DNA-SEQUENCES; IN-VITRO; RNA; MICRORNAS AB Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral interleukin 6 (vIL-6) that mimics many activities of human IL-6 (hIL-6). Both vIL-6 and hIL-6 play important roles in stimulating the proliferation of tumours caused by KSHV. Here, we provide evidence that a miRNA pathway is involved in regulation of vIL-6 and hIL-6 expression through binding sites in their open reading frames (ORFs). We show a direct repression of vIL-6 by hsa-miR-1293 and hIL-6 by hsa-miR-608. The repression of vIL-6 by miR-1293 was reversed by disruption of the vIL-6 miR-1293 seed match through the introduction of point mutations. In addition, expression of vIL-6 or hIL-6 in KSHV-infected cells could be enhanced by transfection of the respective miRNA inhibitors. In situ hybridization of human lymph node sections revealed that miR-1293 is primarily expressed in the germinal centre but is deficient in the mantle zone of lymph nodes, where the expression of vIL-6 is often found in patients with KSHV-associated multicentric Castleman's disease, providing evidence of an anatomical correlation. Taking these factors together, our study indicates that IL-6 expression can be regulated by miRNA interactions in its ORF and provides evidence for the role of these interactions in the pathogenesis of KSHV-associated diseases. Copyright. (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Kang, Jeong-Gu; Majerciak, Vladimir; Uldrick, Thomas S.; Wang, Xiaohong; Yarchoan, Robert; Zheng, Zhi-Ming] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kruhlak, Michael] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Room 6N106, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov FU National Institutes of Health; National Cancer Institute; Centre for Cancer Research FX This study was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Centre for Cancer Research. We thank Natalia Pripuzova for construction of the vIL-6 expression vector pNP4, Giovanna Tosato and John Nicholas for providing anti-vIL-6 antibodies, Bert Vogelstein for providing RKO Dicer knockout cells, and other members of the Zheng laboratory for their assistance and critical comments. NR 63 TC 31 Z9 31 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD NOV PY 2011 VL 225 IS 3 BP 378 EP 389 DI 10.1002/path.2962 PG 12 WC Oncology; Pathology SC Oncology; Pathology GA 839ME UT WOS:000296369900008 PM 21984125 ER PT J AU Subramaniam, GA Warden, D Minhajuddin, A Fishman, MJ Stitzer, ML Adinoff, B Trivedi, M Weiss, R Potter, J Poole, SA Woody, GE AF Subramaniam, Geetha A. Warden, Diane Minhajuddin, Abu Fishman, Marc J. Stitzer, Maxine L. Adinoff, Bryon Trivedi, Madhukar Weiss, Roger Potter, Jennifer Poole, Sabrina A. Woody, George E. TI Predictors of Abstinence: National Institute of Drug Abuse Multisite Buprenorphine/Naloxone Treatment Trial in Opioid-Dependent Youth SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE treatment predictors; opioid dependent youth; buprenorphine treatment ID TREATMENT OUTCOMES; HIV TRANSMISSION; NALOXONE; ADOLESCENTS; RETENTION; METHADONE; NETWORK; RISK; DETOXIFICATION; PREVENTION AB Objective: To examine predictors of opioid abstinence in buprenorphine/naloxone (Bup/Nal)-assisted psychosocial treatment for opioid-dependent youth. Method: Secondary analyses were performed of data from 152 youth (15-21 years old) randomly assigned to 12 weeks of extended Bup/Nal therapy or up to 2 weeks of Bup/Nal detoxification with weekly individual and group drug counseling. Logistic regression models were constructed to identify baseline and during-treatment predictors of opioid-positive urine (OPU) at week 12. Predictors were selected based on significance or trend toward significance (i.e., p < .1), and backward stepwise selection was used, controlling for treatment group, to produce final independent predictors at p <= .05. Results: Youth presenting to treatment with previous 30-day injection drug use and more active medical/psychiatric problems were less likely to have a week-12 OPU. Those with early treatment opioid abstinence (i.e., weeks 1 and 2) and those who received additional nonstudy treatments during the study were less likely to have a week-12 OPU and those not completing 12 weeks of treatment were more likely to have an OPU. Conclusions: Youth with advanced illness (i.e., reporting injection drug use and additional health problems) and those receiving ancillary treatments to augment study treatment were more likely to have lower opioid use. Treatment success in the first 2 weeks and completion of 12 weeks of treatment were associated with lower rates of OPU. These findings suggest that youth with advanced illness respond well to Bup/Nal treatment and identify options for tailoring treatment for opioid-dependent youth presenting at community-based settings. Clinical trial registration information-Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents; http://www.clinicaltrials.gov; NCT00078130. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(11): 1120-1128. C1 [Subramaniam, Geetha A.] Natl Inst Drug Abuse, Div Clin Neurosci & Behav Res, Bethesda, MD 20892 USA. [Subramaniam, Geetha A.; Fishman, Marc J.; Stitzer, Maxine L.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Warden, Diane; Minhajuddin, Abu; Adinoff, Bryon; Trivedi, Madhukar] Univ Texas SW Med Ctr, Dallas, TX 75390 USA. [Weiss, Roger] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Weiss, Roger] McLean Hosp, Belmont, MA 02478 USA. [Potter, Jennifer] Univ Texas Hlth Sci Ctr, San Antonio, TX 78229 USA. [Poole, Sabrina A.; Woody, George E.] Univ Penn, Philadelphia, PA 19104 USA. [Poole, Sabrina A.; Woody, George E.] Treatment Res Inst, Philadelphia, PA USA. RP Subramaniam, GA (reprint author), Natl Inst Drug Abuse, Div Clin Neurosci & Behav Res, 6001 Execut Blvd,Room 3173,MSC 9593, Bethesda, MD 20892 USA. EM geetha.subramaniam@nih.gov RI Potter, Jennifer/C-6720-2008 OI Potter, Jennifer/0000-0002-7250-4422 FU National Institutes on Drug Abuse (NIDA) [U10-DA13043, KO5 DA-17009, U10.013034, K12-DA000357, U10-DA020024, U10-DA015831, K24-DA022288]; National Alliance for Research on Schizophrenia and Depression; National Institute of Alcohol Abuse and Alcoholism, NIDA; Department of Veterans Affairs; Agency for Healthcare Research and Quality; National Institute of Mental Health, NIDA; Naurex; Naurex, Torgacept; Naurex, Torgacept, and Valient FX This study was supported by the following grants from the National Institutes on Drug Abuse: U10-DA13043 and KO5 DA-17009 (G.E.W.) to the University of Pennsylvania, U10.013034 (MIS.) and K12-DA000357 (G.A.S., Paula Riggs, M.D.) to Johns Hopkins University, U10-DA020024 (B.A.) to University of Texas Southwestern Medical Center at Dallas, and U10-DA015831 (R.W.) and K24-DA022288 (R.W.) to McLean Hospital.; Dr. Warden holds stock in Pfizer and Bristol-Myers Squibb. He has received funding from the National Alliance for Research on Schizophrenia and Depression. Dr. Fishman is the medical director of Mountain Manor Treatment Center [MMTC], one of multiple research sites in this study. He is a beneficiary of the trust that owns MMTC and serves on the governing board of the trust and the board of directors of MMTC. The terms of Dr. Fishman's potential conflict of interest in research are managed by Johns Hopkins University in accordance with its conflict of interest policies. Dr. Weiss has received grants from the National Institute of Drug Abuse (NIDA) He has served as a consultant to Titan Pharmaceuticals. Dr. Adinoff has received grant support from the National Institute of Alcohol Abuse and Alcoholism, NIDA, and the Department of Veterans Affairs. He has served as a consultant to Shook, Hardy, and Bacon LIP and Paul J. Passante, P.C. He has received honoraria from the University of New Mexico, the Medical University of South Carolina, the American Institute of Biological Sciences, the American Academy of Addiction Psychiatry, the Methodist Medical Center, Vanderbilt University, the University of North Texas Health Care System, John Peter Smith Hospital, and Texas Tech University. Dr. Trivedi has served as a consultant for Abbott, Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb, Cepholon, CME Institute of Physicians, Eli Lilly and Co., Evotek, Forest, GlaxoSmithKline, Johnson and Johnson, Lundbeck, MedAvante, Neuronetics, Ostuka, Parnlab, Pfizer, PgxHealth, Rexahn, Shire, Takeda, Tat Medical/Puretech Venture, and Transcept. He has served on the speakers' bureau for Axon Advisors, Bristol-Myers Squibb, CME Institute of Physicians, Eli Lilly and Co., Forest, GlaxoSmithKline, Lundbeck, MedAvante, Otsuka, Pamlab, Pfizer, PgxHealth, Rexahn, and Takeda. He has received research support from the Agency for Healthcare Research and Quality, the National Institute of Mental Health, NIDA, Naurex, Torgacept, and Valient. Dr. Woody has served on the advisory board of the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System. Drs. Subramaniom, Minhajuddin, Stitzer, and Potter, and Ms. Poole report no biomedical financial interests or potential conflicts of interest. NR 34 TC 24 Z9 24 U1 3 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2011 VL 50 IS 11 BP 1120 EP 1128 DI 10.1016/j.jaac.2011.07.010 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 838PS UT WOS:000296305300007 PM 22024000 ER PT J AU Adleman, NE Kayser, R Dickstein, D Blair, RJR Pine, D Leibenluft, E AF Adleman, Nancy E. Kayser, Reilly Dickstein, Daniel Blair, R. James R. Pine, Daniel Leibenluft, Ellen TI Neural Correlates of Reversal Learning in Severe Mood Dysregulation and Pediatric Bipolar Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE functional magnetic resonance imaging; response reversal; bipolar disorder; severe mood dysregulation; pediatric ID VENTROMEDIAL PREFRONTAL CORTEX; FRONTAL-LOBE DAMAGE; EVENT-RELATED FMRI; DECISION-MAKING; DIFFERENTIAL CONTRIBUTIONS; ORBITOFRONTAL CORTEX; AMYGDALA ACTIVATION; REDUCED HIPPOCAMPAL; ANTERIOR CINGULATE; RESPONSE-REVERSAL AB Objective: Outcome and family history data differentiate children with severe mood dysregulation (SM.D), a syndrome characterized by chronic irritability, from children with "classic" episodic bipolar disorder (BD). Nevertheless, the presence of cognitive inflexibility in SMD and BD highlights the need to delineate neurophysiologic similarities and differences between the two patient groups. Functional magnetic resonance imaging was used to examine neural correlates of cognitive flexibility deficits in patients with SMD and BD versus healthy volunteers (HV). Method: During functional magnetic resonance imaging, subjects completed a response reversal task that assessed cognitive flexibility (n = 22 with SMD, 26 with BD, 34 HV). Task effects were examined in four regions of interest: caudate, cingulate gyrus, inferior frontal gyrus (IFG), and ventromedial prefrontal cortex. Results: Diagnosis-by-accuracy interactions emerged in the caudate and IFG. In these regions, the difference in activation was calculated between incorrect and correct trials. In the caudate, this value was smaller in subjects with SMD and with BD than in HV. In the IFG, however, this value was smaller in subjects with SMD than in those with BD and in HV. Post hoc analyses indicated that comorbid attention-deficit/hyperactivity disorder in patients may influence the caudate findings. Exploratory whole-brain analysis confirmed the caudate and IFG findings. In addition, other regions differentiating SMD from BD were identified (e.g., superior parietal lobule/precuneus and inferior temporal gyrus). Conclusions: in response to errors, similar perturbations occur in the caudate for youth with SMD and BD compared with HV youth. IFG deficits, in contrast, manifest in youth with SMD, but not with BD. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(11):1173-1185. C1 [Adleman, Nancy E.; Kayser, Reilly; Blair, R. James R.; Pine, Daniel; Leibenluft, Ellen] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dickstein, Daniel] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Adleman, NE (reprint author), 9000 Rockville Pike,Bldg 15K,Room 204, Bethesda, MD 20892 USA. EM adlemann@mail.nih.gov RI Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU NIMH, NIH FX This research was supported by the Intramural Research Program of the NIMH, NIH. NR 73 TC 26 Z9 26 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2011 VL 50 IS 11 BP 1173 EP 1185 DI 10.1016/j.jaac.2011.07.011 PG 13 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 838PS UT WOS:000296305300012 PM 22024005 ER PT J AU Vogt, MR Dowd, KA Engle, M Tesh, RB Johnson, S Pierson, TC Diamond, MS AF Vogt, Matthew R. Dowd, Kimberly A. Engle, Michael Tesh, Robert B. Johnson, Syd Pierson, Theodore C. Diamond, Michael S. TI Poorly Neutralizing Cross-Reactive Antibodies against the Fusion Loop of West Nile Virus Envelope Protein Protect In Vivo via Fc gamma Receptor and Complement-Dependent Effector Mechanisms SO JOURNAL OF VIROLOGY LA English DT Article ID HUMANIZED MONOCLONAL-ANTIBODY; DENGUE VIRUS; MEDIATED NEUTRALIZATION; INTRAVENOUS IMMUNOGLOBULIN; FLAVIVIRUS INFECTION; IMMUNE-RESPONSES; ENCEPHALITIS; MICE; IGG; RECOGNITION AB The human antibody response to flavivirus infection is dominantly directed against a cross-reactive epitope on the fusion loop of domain II (DII-FL) of the envelope (E) protein. Although antibodies against this epitope fail to recognize fully mature West Nile virus (WNV) virions and accordingly neutralize infection poorly in vitro, their functional properties in vivo remain less well understood. Here, we show that while passive transfer of poorly neutralizing monoclonal antibodies (MAb) and polyclonal antibodies against the DII-FL epitope protect against lethal WNV infection in wild-type mice, they fail to protect mice lacking activating Fc gamma receptors (Fc gamma R) and the complement opsonin C1q. Consistent with this, an aglycosyl chimeric mouse-human DII-FL MAb (E28) variant that lacks the ability to engage Fc gamma R and C1q also did not protect against WNV infection in wild-type mice. Using a series of immunodeficient mice and antibody depletions of individual immune cell populations, we demonstrate that the nonneutralizing DII-FL MAb E28 does not require T, B, or NK cells, inflammatory monocytes, or neutrophils for protection. Rather, E28 treatment decreased viral load in the serum early in the course of infection, which resulted in blunted dissemination to the brain, an effect that required phagocytic cells, C1q, and Fc gamma RIII (CD16). Overall, these studies enhance our understanding of the functional significance of immunodominant, poorly neutralizing antibodies in the polyclonal human antiflavivirus response and highlight the limitations of current in vitro surrogate markers of protection, such as cell-based neutralization assays, which cannot account for the beneficial effects conferred by these antibodies. C1 [Engle, Michael; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Vogt, Matthew R.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Tesh, Robert B.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Johnson, Syd] MacroGenics Inc, Rockville, MD 20850 USA. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, 660 S Euclid Ave,Box 8051, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu FU NIH [U01 AI061373, R01-AI077955]; Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research [U54 AI057160]; NIAID; [HHSN272201D000401/HHSN27200004/D04] FX This work was supported by grants and contracts from the NIH: grant U01 AI061373 and R01-AI077955 (M.S.D.), the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (U54 AI057160), HHSN272201D000401/HHSN27200004/D04 (R.B.T.), and the intramural program of NIAID. NR 84 TC 46 Z9 46 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 22 BP 11567 EP 11580 DI 10.1128/JVI.05859-11 PG 14 WC Virology SC Virology GA 840FB UT WOS:000296422700003 PM 21917960 ER PT J AU Callendret, B Bukh, J Eccleston, HB Heksch, R Hasselschwert, DL Purcell, RH Hughes, AL Walker, CM AF Callendret, Benoit Bukh, Jens Eccleston, Heather B. Heksch, Ryan Hasselschwert, Dana L. Purcell, Robert H. Hughes, Austin L. Walker, Christopher M. TI Transmission of Clonal Hepatitis C Virus Genomes Reveals the Dominant but Transitory Role of CD8(+) T Cells in Early Viral Evolution SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; 1 SEQUENCE STABILITY; ACUTE HCV INFECTION; ESCAPE MUTATIONS; NONSYNONYMOUS SUBSTITUTION; IMMUNE-RESPONSES; IN-VIVO; CHIMPANZEES; SELECTION; FITNESS AB The RNA genome of the hepatitis C virus (HCV) diversifies rapidly during the acute phase of infection, but the selective forces that drive this process remain poorly defined. Here we examined whether Darwinian selection pressure imposed by CD8(+) T cells is a dominant force driving early amino acid replacement in HCV viral populations. This question was addressed in two chimpanzees followed for 8 to 10 years after infection with a well-defined inoculum composed of a clonal genotype 1a (isolate H77C) HCV genome. Detailed characterization of CD8(+) T cell responses combined with sequencing of recovered virus at frequent intervals revealed that most acute-phase nonsynonymous mutations were clustered in class I epitopes and appeared much earlier than those in the remainder of the HCV genome. Moreover, the ratio of nonsynonymous to synonymous mutations, a measure of positive selection pressure, was increased 50-fold in class I epitopes compared with the rest of the HCV genome. Finally, some mutation of the clonal H77C genome toward a genotype 1a consensus sequence considered most fit for replication was observed during the acute phase of infection, but the majority of these amino acid substitutions occurred slowly over several years of chronic infection. Together these observations indicate that during acute hepatitis C, virus evolution was driven primarily by positive selection pressure exerted by CD8(+) T cells. This influence of immune pressure on viral evolution appears to subside as chronic infection is established and genetic drift becomes the dominant evolutionary force. C1 [Callendret, Benoit; Eccleston, Heather B.; Heksch, Ryan; Walker, Christopher M.] Nationwide Childrens Hosp, Res Inst, Ctr Vaccines & Immun, Columbus, OH 43205 USA. [Callendret, Benoit; Eccleston, Heather B.; Heksch, Ryan; Walker, Christopher M.] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Bukh, Jens; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Bukh, Jens] Copenhagen Univ Hosp Hvidovre, Copenhagen Hepatitis C Program CO HEP, Dept Infect Dis, Copenhagen, Denmark. [Bukh, Jens] Copenhagen Univ Hosp Hvidovre, Clin Res Ctr, Copenhagen, Denmark. [Bukh, Jens] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Fac Hlth Sci, Copenhagen, Denmark. [Hasselschwert, Dana L.] Univ Louisiana Lafayette, New Iberia Res Ctr, New Iberia, LA USA. [Hughes, Austin L.] Univ S Carolina, Div Biol Sci, Columbia, SC 29208 USA. RP Walker, CM (reprint author), Nationwide Childrens Hosp, Res Inst, Ctr Vaccines & Immun, Res 2 Bldg,Room WA4104,700 Childrens Dr, Columbus, OH 43205 USA. EM Christopher.Walker@nationwidechildrens.org FU Public Health Service [R37 AI47367, R01 GM43940]; American Liver Foundation; Lundbeck Foundation; NIAID, NIH; NCRR [5RR015087, RR016483, RR014491] FX This work was supported by Public Health Service grants R37 AI47367 to C. M. Walker and R01 GM43940 to A. L. Hughes. B. C. was the recipient of a Postdoctoral Research Fellowship from the American Liver Foundation. Jens Bukh was the recipient of a professorship at the University of Copenhagen, with external funding from the Lundbeck Foundation. This research was supported by the Intramural Research Program of the NIAID, NIH. Work at New Iberia Research Center was supported by grants 5RR015087, RR016483, and RR014491 from the NCRR. NR 55 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 22 BP 11833 EP 11845 DI 10.1128/JVI.02654-10 PG 13 WC Virology SC Virology GA 840FB UT WOS:000296422700027 PM 21900166 ER PT J AU Miyagi, E Andrew, A Kao, S Yoshida, T Strebel, K AF Miyagi, Eri Andrew, Amy Kao, Sandra Yoshida, Takeshi Strebel, Klaus TI Antibody-Mediated Enhancement of HIV-1 and HIV-2 Production from BST-2/Tetherin-Positive Cells SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 VPU PROTEIN; MULTIPLE-MYELOMA CELLS; PARTICLE RELEASE; ANTI-HM1.24 ANTIBODY; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; MOLECULAR-CLONING; ENVELOPE PROTEIN; XENOGRAFT MODELS AB BST-2/CD317/HM1.24/tetherin is a B-cell antigen overexpressed on the surface of myeloma cell lines and on neoplastic plasma cells of patients with multiple myeloma. Antibodies to BST-2 are in clinical trial for the treatment of multiple myeloma and are considered for the treatment of solid tumors with high BST-2 antigen levels. Functionally, BST-2 restricts the secretion of retroviruses, including human immunodeficiency virus type 1, as well as members of the herpesvirus, filovirus, and arenavirus families, presumably by tethering nascent virions to the cell surface. Here we report that BST-2 antibody treatment facilitates virus release from BST-2(+) cells by interfering with the tethering activity of BST-2. BST-2 antibodies were unable to release already tethered virions and were most effective when added early during virus production. BST-2 antibody treatment did not affect BST-2 dimerization and did not reduce the cell surface expression of BST-2. Interestingly, BST-2 antibody treatment reduced the nonspecific shedding of BST-2 and limited the encapsidation of BST-2 into virions. Finally, flotation analyses indicate that BST-2 antibodies affect the distribution of BST-2 within membrane rafts. Our data suggest that BST-2 antibody treatment may enhance virus release by inducing a redistribution of BST-2 at the cell surface, thus preventing it from accumulating at the sites of virus budding. C1 [Strebel, Klaus] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bldg 4,Room 310,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU NIH; NIAID, NIH FX This work was supported in part by a grant from the NIH Intramural AIDS Targeted Antiviral Program to K. S. and by the Intramural Research Program of the NIAID, NIH. NR 65 TC 8 Z9 9 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 22 BP 11981 EP 11994 DI 10.1128/JVI.05176-11 PG 14 WC Virology SC Virology GA 840FB UT WOS:000296422700041 PM 21917971 ER PT J AU Mukherjee, S Lin, TY Dowd, KA Manhart, CJ Pierson, TC AF Mukherjee, Swati Lin, Tsai-Yu Dowd, Kimberly A. Manhart, Carolyn J. Pierson, Theodore C. TI The Infectivity of prM-Containing Partially Mature West Nile Virus Does Not Require the Activity of Cellular Furin-Like Proteases SO JOURNAL OF VIROLOGY LA English DT Article ID BORNE ENCEPHALITIS-VIRUS; DENGUE VIRUS; ENVELOPE PROTEIN; STRUCTURAL BASIS; MEMBRANE-FUSION; ANTIBODY; NEUTRALIZATION; FLAVIVIRUSES; PARTICLES; CLEAVAGE AB Cleavage of the flavivirus prM protein by a cellular furin-like protease is a hallmark of virion maturation. While this cleavage is a required step in the viral life cycle, it can be inefficient. Virions that retain uncleaved prM may be infectious. We investigated whether cleavage by furin of prM on partially mature West Nile virus (WNV) during virus entry contributes to infectivity. Using quantitative assays of WNV infection, we found that virions incorporating considerable amounts of uncleaved prM protein were insensitive to treatment of cells with a potent inhibitor of furin activity. Thus, partially mature WNV does not require furin-like proteases for infectivity. C1 [Mukherjee, Swati; Lin, Tsai-Yu; Dowd, Kimberly A.; Manhart, Carolyn J.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 33 North Dr,Bldg 33,Room 2E19A-2, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov RI Lin, Tsai-Yu/B-8873-2016 OI Lin, Tsai-Yu/0000-0002-8076-1584 FU NIH, National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (NIAID). NR 31 TC 23 Z9 23 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 22 BP 12067 EP 12072 DI 10.1128/JVI.05559-11 PG 6 WC Virology SC Virology GA 840FB UT WOS:000296422700051 PM 21880759 ER PT J AU Chen, X Lee, G Maher, BS Fanous, AH Chen, J Zhao, Z Guo, A van den Oord, E Sullivan, PF Shi, J Levinson, DF Gejman, PV Sanders, A Duan, J Owen, MJ Craddock, NJ O'Donovan, MC Blackman, J Lewis, D Kirov, GK Qin, W Schwab, S Wildenauer, D Chowdari, K Nimgaonkar, V Straub, RE Weinberger, DR O'Neill, FA Walsh, D Bronstein, M Darvasi, A Lencz, T Malhotra, AK Rujescu, D Giegling, I Werge, T Hansen, T Ingason, A Noethen, MM Rietschel, M Cichon, S Djurovic, S Andreassen, OA Cantor, RM Ophoff, R Corvin, A Morris, DW Gill, M Pato, CN Pato, MT Macedo, A Gurling, HMD McQuillin, A Pimm, J Hultman, C Lichtenstein, P Sklar, P Purcell, SM Scolnick, E St Clair, D Blackwood, DHR Kendler, KS AF Chen, X. Lee, G. Maher, B. S. Fanous, A. H. Chen, J. Zhao, Z. Guo, A. van den Oord, E. Sullivan, P. F. Shi, J. Levinson, D. F. Gejman, P. V. Sanders, A. Duan, J. Owen, M. J. Craddock, N. J. O'Donovan, M. C. Blackman, J. Lewis, D. Kirov, G. K. Qin, W. Schwab, S. Wildenauer, D. Chowdari, K. Nimgaonkar, V. Straub, R. E. Weinberger, D. R. O'Neill, F. A. Walsh, D. Bronstein, M. Darvasi, A. Lencz, T. Malhotra, A. K. Rujescu, D. Giegling, I. Werge, T. Hansen, T. Ingason, A. Noeethen, M. M. Rietschel, M. Cichon, S. Djurovic, S. Andreassen, O. A. Cantor, R. M. Ophoff, R. Corvin, A. Morris, D. W. Gill, M. Pato, C. N. Pato, M. T. Macedo, A. Gurling, H. M. D. McQuillin, A. Pimm, J. Hultman, C. Lichtenstein, P. Sklar, P. Purcell, S. M. Scolnick, E. St Clair, D. Blackwood, D. H. R. Kendler, K. S. CA Int Schizophrenia Consortium TI GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE association study; cardiomyopathy; GWA data mining; meta-analysis; schizophrenia ID GENOME-WIDE ASSOCIATION; SIB-PAIR FAMILIES; COMMON VARIANTS; SUSCEPTIBILITY GENE; SAMPLES PROVIDES; PROTEIN MYOSPRYN; LINKAGE ANALYSES; BINDING PARTNER; DYSBINDIN GENE; LUNG-CANCER AB We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values <= 0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2) = 0.008; rs10043986-rs4704591, r(2) = 0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR) = 1.11, 95% confidence interval (CI) = 1.04-1.18, P = 8.2 x 10(-4) and rs4704591, OR = 1.07, 95% CI = 1.03-1.11, P = 3.0 x 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR = 1.11, 95% CI = 1.03-1.17, P = 0.0026 and rs4704591, OR = 1.07, 95% CI = 1.02-1.11, P = 0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted. Molecular Psychiatry (2011) 16, 1117-1129; doi:10.1038/mp.2010.96; published online 14 September 2010 C1 [Chen, X.; Lee, G.; Maher, B. S.; Fanous, A. H.; Chen, J.; van den Oord, E.; Kendler, K. S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. [Chen, X.; Kendler, K. S.] Virginia Commonwealth Univ, Dept Mol & Human Genet, Richmond, VA 23298 USA. [Fanous, A. H.] Washington VA Med Ctr, Washington, DC USA. [Fanous, A. H.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Zhao, Z.; Guo, A.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN USA. [van den Oord, E.] Virginia Commonwealth Univ, Dept Pharm, Richmond, VA 23298 USA. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Shi, J.; Levinson, D. F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Gejman, P. V.; Sanders, A.; Duan, J.] NorthShore Univ HealthSyst Res Inst, Ctr Psychiat Genet, Evanston, IL USA. [Owen, M. J.; Craddock, N. J.; O'Donovan, M. C.; Blackman, J.; Lewis, D.; Kirov, G. K.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Dept Psychol Med, Cardiff, S Glam, Wales. [Qin, W.; Schwab, S.; Wildenauer, D.] Univ Western Australia, Sch Psychiat, Perth, WA 6009, Australia. [Qin, W.; Schwab, S.; Wildenauer, D.] Western Australian Inst Med Res, Perth, WA, Australia. [Chowdari, K.; Nimgaonkar, V.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Chowdari, K.; Nimgaonkar, V.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Straub, R. E.; Weinberger, D. R.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [O'Neill, F. A.] Queens Univ Belfast, Dept Psychiat, Belfast, Antrim, North Ireland. [Walsh, D.] Hlth Res Board, Dublin, Ireland. [Bronstein, M.; Darvasi, A.] Hebrew Univ Jerusalem, Dept Genet, IL-91904 Jerusalem, Israel. [Lencz, T.; Malhotra, A. K.] N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Psychiat Res, Glen Oaks, NY USA. [Rujescu, D.; Giegling, I.] Univ Munich, Div Mol & Clin Neurobiol, Munich, Germany. [Werge, T.; Hansen, T.; Ingason, A.] Copenhagen Univ Hosp, Mental Hlth Ctr Sct Hans, Inst Psychiat, Roskilde, Denmark. [Noeethen, M. M.; Cichon, S.] Univ Bonn, Inst Human Genet, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Rietschel, M.] Univ Heidelberg, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth Mannheim, D-6800 Mannheim, Germany. [Rietschel, M.] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. [Cichon, S.] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Djurovic, S.; Andreassen, O. A.] Oslo Univ Hosp, Oslo, Norway. [Djurovic, S.; Andreassen, O. A.] Univ Oslo, Inst Psychiat, Oslo, Norway. [Cantor, R. M.; Ophoff, R.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Dept Human Genet, Los Angeles, CA USA. [Ophoff, R.] Univ Med Ctr Utrecht, Dept Med Genet, Cg Utrecht, Netherlands. [Corvin, A.; Morris, D. W.; Gill, M.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland. [Corvin, A.; Morris, D. W.; Gill, M.] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Pato, C. N.; Pato, M. T.] Univ So Calif, Ctr Genom Psychiat, Los Angeles, CA USA. [Macedo, A.] Univ Coimbra, Dept Psychiat, Coimbra, Portugal. [Gurling, H. M. D.; McQuillin, A.; Pimm, J.] UCL, Sch Med, Windeyer Inst Med Sci, Res Dept Mental Hlth Sci,Mol Psychiat Lab, London W1N 8AA, England. [Hultman, C.; Lichtenstein, P.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Sklar, P.; Purcell, S. M.; Scolnick, E.] Psychiat & Neurodev Genet Unit, Boston, MA USA. [Sklar, P.; Purcell, S. M.; Scolnick, E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [St Clair, D.] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Kendler, K. S.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. RP Chen, X (reprint author), Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, 800 E Leigh St,Suite 390, Richmond, VA 23298 USA. EM xchen@vcu.edu RI Ingason, Andres/G-6817-2012; Morley, Christopher P/K-1907-2014; Cahn , Wiepke /B-5743-2013; Gurling, Hugh/A-5029-2010; Maher, Brion/F-9185-2010; macedo santos, antonio/M-5737-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Myin-Germeys, Inez /L-5106-2014; Hansen, Thomas/O-5965-2014; Ruderfer, Douglas/M-5795-2016; Lencz, Todd/J-3418-2014 OI McQuillin, Andrew/0000-0003-1567-2240; Andreassen, Ole A./0000-0002-4461-3568; Visscher, Peter/0000-0002-2143-8760; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Morris, Derek/0000-0002-3413-570X; Myin-Germeys, Inez/0000-0002-3731-4930; Gill, Michael/0000-0003-0206-5337; lichtenstein, paul/0000-0003-3037-5287; Moran, Jennifer/0000-0002-5664-4716; Bruggeman, Richard/0000-0002-3238-8471; O'Neill, Francis Anthony/0000-0002-7531-7657; Morley, Christopher P/0000-0003-0185-7148; de Oliveira Barreto Coimbra Carvalho, Celia Maria/0000-0003-4453-8139; macedo santos, antonio/0000-0003-2180-2718; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Hansen, Thomas/0000-0001-6703-7762; Ruderfer, Douglas/0000-0002-2365-386X; Lencz, Todd/0000-0001-8586-338X FU Stanley Medical Research Institute [07R-1770]; NARSAD; CATIE; GAIN; international schizophrenia consortium; National Institutes of Health [MH41953, MH63480, MH56242, MH078075]; Donald & Barbara Zucker Foundation, USA; Medical Research Council; Wellcome Trust Foundation, UK; Research Council of Norway [163070/V50, 167153/V50]; South-Eastern Norway Health Authority [123/2004]; Science Foundation Ireland; Health Research Board, Ireland; Lundbeck Foundation; Danish National Advanced Technology Foundation, Denmark; National Institute of Mental Health [N01 MH900001, MH074027]; Eli Lilly and Company; National Alliance for Research on Schizophrenia and Depression; National Center for Research Resources FX We thank the volunteers, patients and their family members for participating in this study. This study was supported in part by a research grant (07R-1770) from the Stanley Medical Research Institute and an Independent Investigator Award from NARSAD to XC, and by grants to investigators involved in the collection and analyses of the samples from CATIE, GAIN, the international schizophrenia consortium and other independent samples (National Institutes of Health (MH41953, MH63480, MH56242, MH078075); NARSAD Young Investigator Award; Donald & Barbara Zucker Foundation, USA; the Medical Research Council and the Wellcome Trust Foundation, UK; the Research Council of Norway (Grant No. 163070/V50, 167153/V50); the South-Eastern Norway Health Authority (123/2004); Science Foundation Ireland and Health Research Board, Ireland; the Lundbeck Foundation and Danish National Advanced Technology Foundation, Denmark). The Ashkenazi samples are part of the Hebrew University Genetic Resource (HUGR). The principal investigators of the CATIE trial were Jeffrey A Lieberman, T Scott Stroup and Joseph P McEvoy. The CATIE trialwas funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. The principle investigators for the MGS were Pablo Gejman and Douglas Levinson. MGS study was supported by funding from the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression. Genotyping of part of the sample was supported by GAIN and the Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT with support from the National Center for Research Resources. NR 53 TC 28 Z9 28 U1 1 U2 13 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 NOV PY 2011 VL 16 IS 11 BP 1117 EP 1129 DI 10.1038/mp.2010.96 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 840HD UT WOS:000296429100011 PM 20838396 ER PT J AU Enoch, MA Gorodetsky, E Hodgkinson, C Roy, A Goldman, D AF Enoch, M-A Gorodetsky, E. Hodgkinson, C. Roy, A. Goldman, D. TI Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence SO MOLECULAR PSYCHIATRY LA English DT Article DE 5-HTTLPR; HTR3B; rs1176744; alcoholism; cocaine; heroin ID MAJOR DEPRESSION; HEROIN DEPENDENCE; N-ALCOHOLS; SUBUNIT; HTR3B; POLYMORPHISM; ASSOCIATION; SUSCEPTIBILITY; HIPPOCAMPUS; ONDANSETRON AB The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory serotonin (5-HT) transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging single-nucleotide polymorphisms (SNPs) across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain-of-function Ser129 allele predicted alcohol dependence (P = 0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (P = 0.01). Both the HTR3B Ser129 allele (P = 0.014, odds ratio (OR) = 1.7 (1.1-2.6)) and low 5-HTTLPR activity (P = 0.011, OR = 2.5 (1.3-4.6)) were more common in men with alcohol+drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol+drug dependence (OR = 6.0 (2.1-16.6)) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron. Molecular Psychiatry (2011) 16, 1139-1146; doi:10.1038/mp.2010.94; published online 14 September 2010 C1 [Enoch, M-A; Hodgkinson, C.; Goldman, D.] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Gorodetsky, E.] NIMH, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. [Roy, A.] New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv, E Orange, NJ USA. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism, NIH; National Institute of Drug Abuse, NIH [RO1 DA 10336-02] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and in part by grant RO1 DA 10336-02 to AR from the National Institute of Drug Abuse, NIH. NR 35 TC 35 Z9 36 U1 0 U2 10 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 NOV PY 2011 VL 16 IS 11 BP 1139 EP 1146 DI 10.1038/mp.2010.94 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 840HD UT WOS:000296429100013 PM 20838391 ER PT J AU Volkow, ND Wang, GJ Newcorn, JH Kollins, SH Wigal, TL Telang, F Fowler, JS Goldstein, RZ Klein, N Logan, J Wong, C Swanson, JM AF Volkow, N. D. Wang, G-J Newcorn, J. H. Kollins, S. H. Wigal, T. L. Telang, F. Fowler, J. S. Goldstein, R. Z. Klein, N. Logan, J. Wong, C. Swanson, J. M. TI Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway SO MOLECULAR PSYCHIATRY LA English DT Article DE attention; brain imaging; catecholamines; personality; psychiatric disorder; PET ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; HYPERACTIVITY DISORDER; INCENTIVE MOTIVATION; HUMAN BRAIN; ADULT ADHD; PERSONALITY; BINDING; PSYCHOPATHOLOGY; LEADERSHIP; BEHAVIOR AB Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [(11)C]raclopride and [(11)C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11 +/- 5 vs 14 +/- 3, P < 0.001) and was significantly correlated with D2/D3 receptors (accumbens: r = 0.39, P < 0.008; midbrain: r = 0.41, P < 0.005) and transporters (accumbens: r = 0.35, P < 0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor-and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD. Molecular Psychiatry (2011) 16, 1147-1154; doi:10.1038/mp.2010.97; published online 21 September 2010 C1 [Volkow, N. D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Volkow, N. D.; Telang, F.] NIAAA, Lab Neuroimaging, Bethesda, MD 90034 USA. [Wang, G-J; Fowler, J. S.; Goldstein, R. Z.; Klein, N.; Logan, J.; Wong, C.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Wang, G-J; Fowler, J. S.; Goldstein, R. Z.; Klein, N.; Logan, J.; Wong, C.] Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. [Wang, G-J; Newcorn, J. H.; Fowler, J. S.] Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA. [Kollins, S. H.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Wigal, T. L.; Swanson, J. M.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Executive Blvd,Room 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Kollins, Scott/G-2965-2012; OI Newcorn, Jeffrey /0000-0001-8993-9337 FU Eli Lilly; Ortho-McNeil Janssen; Addrenex Pharmaceuticals; Otsuka Pharmaceuticals; Shire Pharmaceuticals; McNeil; Novartis; Shire; Alza; Richwood; Celgene; Celltech; Gliatech; Cephalon; Watson; CIBA; Janssen; National Institutes of Health (NIH); National Institute of Mental Health [MH66961-02] FX Dr Newcorn reported being a recipient of research support from Eli Lilly and Ortho-McNeil Janssen, and serves as a consultant, advisor or both for Astra Zeneca, BioBehavioral Diagnostics, Eli Lilly, Novartis, Ortho-McNeil Janssen and Shire, and as a speaker for Ortho-McNeil Janssen. Dr Kollins reported receiving research support, consulting fees or both from Addrenex Pharmaceuticals, Otsuka Pharmaceuticals and Shire Pharmaceuticals. Dr Wigal reported receiving support from Eli Lilly, McNeil, Novartis and Shire. Dr Swanson reported receiving support from Alza, Richwood, Shire, Celgene, Novartis, Celltech, Gliatech, Cephalon, Watson, CIBA, Janssen and McNeil; has been on the advisory boards of Alza, Richwood, Shire, Celgene, Novartis, Celltech, UCB, Gliatech, Cephalon, McNeil and Eli Lilly; has been on the speaker's bureaus of Alza, Shire, Novartis, Cellthech, UCB, Cephalon, CIBA, Janssen and McNeil; and has consulted to Alza, Richwood, Shire, Clegene, Novarits, Celltech, UCB, Gliatech, Cephalon, Watson, CIBA, Jansen, McNeil and Eli Lilly. The other authors declare no conflict of interest.; This research was carried out at Brookhaven National Laboratory (BNL) and was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), the National Institute of Mental Health (MH66961-02) and infrastructure support from the Department of Energy. We thank the following BNL employees: Donald Warner for PET operations; David Schlyer and Michael Schueller for cyclotron operations; Pauline Carter, Millard Jayne and Barbara Hubbard for nursing care; Payton King for plasma analysis and Lisa Muench, Youwen Xu and Colleen Shea for radiotracer preparation; Karen Appelskog for protocol coordination; to the following Duke employees: Joseph English and Allan Chrisman, for subject recruitment and evaluation; to the following NIH employee: Linda Thomas for editorial assistance. We also thank the individuals who volunteered for these studies. NR 35 TC 90 Z9 91 U1 7 U2 57 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 NOV PY 2011 VL 16 IS 11 BP 1147 EP 1154 DI 10.1038/mp.2010.97 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 840HD UT WOS:000296429100014 PM 20856250 ER PT J AU Lagenaur, LA Sanders-Beer, BE Brichacek, B Pal, R Liu, X Liu, Y Yu, R Venzon, D Lee, PP Hamer, DH AF Lagenaur, L. A. Sanders-Beer, B. E. Brichacek, B. Pal, R. Liu, X. Liu, Y. Yu, R. Venzon, D. Lee, P. P. Hamer, D. H. TI Prevention of vaginal SHIV transmission in macaques by a live recombinant Lactobacillus SO MUCOSAL IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYANOVIRIN-N; RHESUS MACAQUES; MICROBICIDE TRIALS; SEXUAL TRANSMISSION; BACTERIAL VAGINOSIS; HIV-1 INFECTION; ANIMAL-MODEL; SOUTH-AFRICA; ACQUISITION AB Most human immunodeficiency virus (HIV) transmissions in women occur through the cervicovaginal mucosa, which is coated by a bacterial biofilm including Lactobacillus. This commensal bacterium has a role in maintaining a healthy mucosa and can be genetically engineered to produce antiviral peptides. Here, we report a 63% reduction in transmission of a chimeric simian/HIV (SHIV(SF162P3)) after repeated vaginal challenges of macaques treated with Lactobacillus jensenii expressing the HIV-1 entry inhibitor cyanovirin-N. Furthermore, peak viral loads in colonized macaques with breakthrough infection were reduced sixfold. Colonization and prolonged antiviral protein secretion by the genetically engineered lactobacilli did not cause any increase in proinflammatory markers. These findings lay the foundation for an accessible and durable approach to reduce heterosexual transmission of HIV in women, which is coitally independent, inexpensive, and enhances the natural protective effects of the vaginal microflora. C1 [Lagenaur, L. A.; Brichacek, B.; Hamer, D. H.] NCI, Gene Struct & Regulat Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Lagenaur, L. A.; Liu, X.; Liu, Y.; Lee, P. P.] Osel, Mountain View, CA USA. [Sanders-Beer, B. E.] BIOQUAL, Rockville, MD USA. [Pal, R.] Adv BioSci Labs, Rockville, MD USA. [Yu, R.] Cepheid, Sunnyvale, CA USA. [Venzon, D.] NCI, Biostat & Data Management Sect, NIH, Rockville, MD USA. RP Lagenaur, LA (reprint author), NCI, Gene Struct & Regulat Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM llagenaur@mail.nih.gov FU ABL under NIAID [HHSN272200800020C]; NIH [5R33AI071978-04]; BIOQUAL; ABL FX The SHIV virus stock was produced under NIAID contract HHSN272200800020C by ABL. NIH's Intramural AIDS Targeted Antiviral Program (IATAP) provided funding for the challenge study. This work was also supported by NIH grant 5R33AI071978-04. We thank Laurent Pessaint for preparation of Lactobacillus, placebo, and animal blood processing, Jack Greenhouse for quantitative SHIV RT-PCR, Matt Collins and Jermaine Hoes for animal sampling and care. We thank Jennifer Morgan and the Welkin E Johnson Laboratory (Harvard Medical School) for performing TRIM5 alpha sequencing. We thank Owen Schwartz and the Biological Imaging Facility for assistance with microscopy. We also thank Mario Roederer for critical reading of the manuscript.; LAL, XL, YL, and PPL work for Osel, Mountain View, CA, a company developing this approach as a topical microbicide. BIOQUAL (BES) and ABL (RP) are for-profit institutions and are subawardees to Osel. NR 49 TC 52 Z9 52 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD NOV PY 2011 VL 4 IS 6 BP 648 EP 657 DI 10.1038/mi.2011.30 PG 10 WC Immunology SC Immunology GA 840HE UT WOS:000296429200009 PM 21734653 ER PT J AU Conwit, RA Bhanushali, MJ Porter, JD Kaufmann, P Gutmann, L AF Conwit, Robin A. Bhanushali, Minal J. Porter, John D. Kaufmann, Petra Gutmann, Laurie TI ADDING MORE MUSCLE AND NERVE TO CLINICAL TRIALS SO MUSCLE & NERVE LA English DT Review DE amyotrophic lateral sclerosis; clinical research; muscular dystrophy; neuromuscular disorders; peripheral neuropathy ID FOLLOW-UP; ALS AB In this review we illustrate both the fundamentals and challenges of randomized clinical trials in neuromuscular disorders and suggest directions for prospective efforts to improve the design, conduct, rigor, and objectivity of these trials. Current research in clinical trials for neuromuscular disorders and key issues affecting these trials are reviewed. This perspective addresses the planning of clinical research, level of preclinical data needed to justify trials, patient recruitment and retention, and opportunities to access federal funding and infrastructure in support of clinical trials. The need for innovation in trial design and conduct, rigorous standards for the preclinical efficacy and safety data that support trial rationale, novel collaborative paradigms, objective interpretations of outcomes, and sharing of the lessons learned from trials in any one disorder among all neuromuscular trialists are imperative to improving the heretofore limited success in delivering novel, safe, and effective therapies to patients burdened by neuromuscular disorders. Muscle Nerve 44: 695-702, 2011 C1 [Conwit, Robin A.; Bhanushali, Minal J.; Kaufmann, Petra] Natl Inst Neurol Disorders & Stroke, Off Clin Res, NIH, Rockville, MD 20892 USA. [Porter, John D.] Natl Inst Neurol Disorders & Stroke, Neurogenet Cluster & Off Translat Res, Div Extramural Res, NIH, Rockville, MD 20892 USA. [Gutmann, Laurie] W Virginia Univ, Dept Neurol, Sch Med, Morgantown, WV 26506 USA. RP Bhanushali, MJ (reprint author), Natl Inst Neurol Disorders & Stroke, Off Clin Res, NIH, 6001 Execut Blvd,Suite 2-216, Rockville, MD 20892 USA. EM bhanushalimj@mail.nih.gov NR 14 TC 0 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD NOV PY 2011 VL 44 IS 5 BP 695 EP 702 DI 10.1002/mus.22130 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 839TU UT WOS:000296393100001 PM 22006684 ER PT J AU Moriyama, B Falade-Nwulia, O Leung, J Penzak, SR JJingo, C Huang, X Henning, SA Wilson, WH Walsh, TJ AF Moriyama, Brad Falade-Nwulia, Oluwaseun Leung, Janice Penzak, Scott R. JJingo, Caroline Huang, Xuan Henning, Stacey A. Wilson, Wyndham H. Walsh, Thomas J. TI Prolonged half-life of voriconazole in a CYP2C19 homozygous poor metabolizer receiving vincristine chemotherapy: avoiding a serious adverse drug interaction SO MYCOSES LA English DT Article C1 [Moriyama, Brad; Penzak, Scott R.; Henning, Stacey A.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Falade-Nwulia, Oluwaseun; Leung, Janice] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [JJingo, Caroline] NIAID, Bethesda, MD 20892 USA. [Huang, Xuan; Wilson, Wyndham H.] NCI, Bethesda, MD 20892 USA. [Walsh, Thomas J.] Cornell Univ, New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY 10065 USA. RP Walsh, TJ (reprint author), Cornell Univ, Weill Cornell Med Coll, Div Infect Dis, Transplantat Oncol Infect Dis Program, 1300 York Ave,A-421, New York, NY 10065 USA. EM thw2003@med.cornell.edu FU National Institutes of Health; Vestagen FX The authors thank Dr Barry Goldspiel for his thoughtful comments and review of the manuscript. This work was supported in part by the intramural research programme of the National Institutes of Health.; Dr Walsh is the recipient of a research grant from Vestagen and has served on advisory boards of Novartis, Ico and Trius. NR 0 TC 7 Z9 7 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0933-7407 J9 MYCOSES JI Mycoses PD NOV PY 2011 VL 54 IS 6 BP E877 EP E879 DI 10.1111/j.1439-0507.2011.02016.x PG 3 WC Dermatology; Mycology SC Dermatology; Mycology GA 837XJ UT WOS:000296243700034 PM 21615537 ER PT J AU Moulick, K Ahn, JH Zong, HL Rodina, A Cerchietti, L DaGama, EMG Caldas-Lopes, E Beebe, K Perna, F Hatzi, K Vu, LP Zhao, XY Zatorska, D Taldone, T Smith-Jones, P Alpaugh, M Gross, SS Pillarsetty, N Ku, T Lewis, JS Larson, SM Levine, R Erdjument-Bromage, H Guzman, ML Nimer, SD Melnick, A Neckers, L Chiosis, G AF Moulick, Kamalika Ahn, James H. Zong, Hongliang Rodina, Anna Cerchietti, Leandro DaGama, Erica M. Gomes Caldas-Lopes, Eloisi Beebe, Kristin Perna, Fabiana Hatzi, Katerina Vu, Ly P. Zhao, Xinyang Zatorska, Danuta Taldone, Tony Smith-Jones, Peter Alpaugh, Mary Gross, Steven S. Pillarsetty, Nagavarakishore Ku, Thomas Lewis, Jason S. Larson, Steven M. Levine, Ross Erdjument-Bromage, Hediye Guzman, Monica L. Nimer, Stephen D. Melnick, Ari Neckers, Len Chiosis, Gabriela TI Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90 SO NATURE CHEMICAL BIOLOGY LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL; MYELOID-LEUKEMIA; SIGNAL TRANSDUCER; STAT5 ACTIVATION; TYROSINE KINASE; B-CELLS; CHAPERONE; TRANSCRIPTION; INHIBITORS AB Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. We further show that the abundance of the PU-H71-enriched Hsp90 species, which is not dictated by Hsp90 expression alone, is predictive of the cell's sensitivity to Hsp90 inhibition. C1 [Moulick, Kamalika; Ahn, James H.; Rodina, Anna; DaGama, Erica M. Gomes; Caldas-Lopes, Eloisi; Perna, Fabiana; Vu, Ly P.; Zhao, Xinyang; Zatorska, Danuta; Taldone, Tony; Alpaugh, Mary; Nimer, Stephen D.; Chiosis, Gabriela] Sloan Kettering Inst, Mol Pharmacol & Chem Program, New York, NY USA. [Zong, Hongliang; Cerchietti, Leandro; Hatzi, Katerina; Guzman, Monica L.; Melnick, Ari] Weill Cornell Med Coll, Div Hematol & Oncol, New York, NY USA. [Beebe, Kristin; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Smith-Jones, Peter; Pillarsetty, Nagavarakishore; Ku, Thomas; Lewis, Jason S.; Larson, Steven M.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Gross, Steven S.] Cornell Univ, Dept Pharmacol, Weill Med Coll, New York, NY 10021 USA. [Levine, Ross] Mem Sloan Kettering Canc Ctr, Dept Med, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Levine, Ross] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Erdjument-Bromage, Hediye] Mem Sloan Kettering Canc Ctr, Microchem & Prote Core Mol Biol Program, New York, NY 10021 USA. RP Chiosis, G (reprint author), Sloan Kettering Inst, Mol Pharmacol & Chem Program, New York, NY USA. EM nimers@mskcc.org; amm2014@med.cornell.edu; neckers@nih.gov; chiosisg@mskcc.org RI Zong, Hongliang/F-9366-2013; OI Zong, Hongliang/0000-0002-5855-5733; Perna, Fabiana/0000-0002-3744-8672; Cerchietti, Leandro/0000-0003-0608-1350; Zhao, Xinyang/0000-0001-6677-7072 FU Geoffrey Beene Cancer Research Center of the Memorial Sloan-Kettering Cancer Center; Leukemia and Lymphoma Society; Breast Cancer Research Fund; SPORE Pilot Award and Research & Therapeutics Program in Prostate Cance; Hirshberg Foundation for Pancreatic Cancer; Byrne Fund [1U01 AG032969-01A1, 1R01 CA155226-01]; US National Cancer Institute (NCI) Cancer Center [P30 CA08748]; NCI [P50-CA86483]; Ludwig Center for Cancer Immunotherapy at MSKCC; US National Institutes of Health (NIH) through the NIH [1 DP2 OD007399-01]; V foundation; American Italian Cancer Foundation FX This work was supported in part by the Geoffrey Beene Cancer Research Center of the Memorial Sloan-Kettering Cancer Center (G.C.), Leukemia and Lymphoma Society (G.C., M.L.G., S.D.N., X.Z. and R.L.), Breast Cancer Research Fund (G.C.), the SPORE Pilot Award and Research & Therapeutics Program in Prostate Cancer (G.C.), the Hirshberg Foundation for Pancreatic Cancer (G.C.), the Byrne Fund (G.C.), 1U01 AG032969-01A1 (G.C.), 1R01 CA155226-01 (G.C. and A.M.) and US National Cancer Institute (NCI) Cancer Center Support Grant P30 CA08748 (H.E.B.). K.B. and L.N. were supported by funds from the Intramural Program of the NCI. S.M.L. and P.M.S.-J. are supported by the Ludwig Center for Cancer Immunotherapy at MSKCC and by NCI Grant P50-CA86483. M.L.G. is funded by the US National Institutes of Health (NIH) through the NIH Director's New Innovator Award Program, 1 DP2 OD007399-01 and the V foundation. F.P. is funded by the American Italian Cancer Foundation. We thank D. Toft (Mayo Clinic) and M. Cox (University of Texas) for the gifts of H9010 Hsp90-specific antibodies, L.A. Fabrizio, A.M. Morrishow, H. Deng and J. Fernandez for help with MS analysis, A. Perl, C.T. Jordan, M. Becker and J. Nicoll for providing the primary CML samples or suggestions on their use, and B. Clarkson, J. Bromberg and P. Gregor for suggestions with the manuscript. NR 46 TC 118 Z9 119 U1 2 U2 23 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 NOV PY 2011 VL 7 IS 11 BP 818 EP 826 DI 10.1038/nchembio.670 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 839PX UT WOS:000296381600012 PM 21946277 ER PT J AU Galli, SJ Borregaard, N Wynn, TA AF Galli, Stephen J. Borregaard, Niels Wynn, Thomas A. TI Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils SO NATURE IMMUNOLOGY LA English DT Review ID ALTERNATIVELY ACTIVATED MACROPHAGES; NF-KAPPA-B; COLONY-STIMULATING FACTOR; SUPPRESSOR-CELLS; DENDRITIC CELLS; HEMATOPOIETIC STEM; ADIPOSE-TISSUE; BONE-MARROW; IN-VIVO; EMERGENCY GRANULOPOIESIS AB Hematopoietic cells, including lymphoid and myeloid cells, can develop into phenotypically distinct 'subpopulations' with different functions. However, evidence indicates that some of these subpopulations can manifest substantial plasticity (that is, undergo changes in their phenotype and function). Here we focus on the occurrence of phenotypically distinct subpopulations in three lineages of myeloid cells with important roles in innate and acquired immunity: macrophages, mast cells and neutrophils. Cytokine signals, epigenetic modifications and other microenvironmental factors can substantially and, in some cases, rapidly and reversibly alter the phenotype of these cells and influence their function. This suggests that regulation of the phenotype and function of differentiated hematopoietic cells by microenvironmental factors, including those generated during immune responses, represents a common mechanism for modulating innate or adaptive immunity. C1 [Galli, Stephen J.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Galli, Stephen J.] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA. [Borregaard, Niels] Univ Copenhagen, Dept Hematol, Natl Univ Hosp, Copenhagen, Denmark. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, Program Barrier Immun & Repair, Bethesda, MD 20892 USA. RP Galli, SJ (reprint author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. EM sgalli@stanford.edu; borregaard@rh.dk; twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU US National Institutes of Health [AI70813, AI23990, CA72074]; Danish National Research Council; National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX We thank M. Tsai and J. Kalesnikoff for discussions; and J. Lilla for help with Figure 2. Supported by the US National Institutes of Health (AI70813, AI23990 and CA72074 to S.J.G.), the Danish National Research Council (N.B.) and the intramural research program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (T.A.W.). NR 140 TC 287 Z9 292 U1 9 U2 61 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2011 VL 12 IS 11 BP 1035 EP 1044 DI 10.1038/ni.2109 PG 10 WC Immunology SC Immunology GA 841GG UT WOS:000296500100008 PM 22012443 ER PT J AU Liu, ZH Lee, J Krummey, S Lu, W Cai, HB Lenardo, MJ AF Liu, Zhihua Lee, Jinwoo Krummey, Scott Lu, Wei Cai, Huaibin Lenardo, Michael J. TI The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease SO NATURE IMMUNOLOGY LA English DT Article ID PARKINSONS-DISEASE; ULCERATIVE-COLITIS; SUSCEPTIBILITY LOCI; DENDRITIC CELLS; ALPHA-SYNUCLEIN; CROHNS-DISEASE; ACTIVATION; CYCLOSPORINE; MUTATIONS; GENE AB Leucine-rich repeat kinase 2 (LRRK2) has been identified by genome-wide association studies as being encoded by a major susceptibility gene for Crohn's disease. Here we found that LRRK2 deficiency conferred enhanced susceptibility to experimental colitis in mice. Mechanistic studies showed that LRRK2 was a potent negative regulator of the transcription factor NFAT and was a component of a complex that included the large noncoding RNA NRON (an NFAT repressor). Furthermore, the risk-associated allele encoding LRRK2 Met2397 identified by a genome-wide association study for Crohn's disease resulted in less LRRK2 protein post-translationally. Severe colitis in LRRK2-deficient mice was associated with enhanced nuclear localization of NFAT1. Thus, our study defines a new step in the control of NFAT activation that involves an immunoregulatory function of LRRK2 and has important implications for inflammatory bowel disease. C1 [Liu, Zhihua; Lee, Jinwoo; Krummey, Scott; Lu, Wei; Lenardo, Michael J.] NIAID, Immunol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Cai, Huaibin] NIA, Unit Transgenesis, Neurogenet Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. EM lenardo@nih.gov RI Cai, Huaibin/H-3359-2013; OI Cai, Huaibin/0000-0002-8596-6108; Lee, Jinwoo/0000-0003-2991-4183 FU US National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Institute on Aging FX We thank M. Cookson (National Institute on Aging) for plasmid pCMV-2XMyc-LRRK2 expressing Myc-tagged wild-type or kinase-dead LRRK2; N. Bidere (Institut National de la Sante et de la Recherche Medicale) for luciferase constructs of NFAT and NF-kappa B and a renilla luciferase construct; N. Bidere, R. Germain, C. Kanellopoulou, B. Lo, A. Snow, J. Qin and H. Su for suggestions and comments; and colleagues at the Harvard Drosophila Screening Center for sharing screen results via the World Wide Web. Supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases and National Institute on Aging. NR 48 TC 136 Z9 139 U1 3 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2011 VL 12 IS 11 BP 1063 EP U65 DI 10.1038/ni.2113 PG 9 WC Immunology SC Immunology GA 841GG UT WOS:000296500100011 PM 21983832 ER PT J AU Chaturvedi, A Martz, R Dorward, D Waisberg, M Pierce, SK AF Chaturvedi, Akanksha Martz, Rebecca Dorward, David Waisberg, Michael Pierce, Susan K. TI Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments SO NATURE IMMUNOLOGY LA English DT Article ID CELL ANTIGEN-RECEPTOR; TRANSCRIPTION FACTORS; B-LYMPHOCYTES; LIPID RAFTS; C/EBP-BETA; T-CELLS; INTERNALIZATION; ACTIVATION; ENDOSOMES; CLATHRIN AB Binding of antigen to the B cell antigen receptor (BCR) triggers both BCR signaling and endocytosis. How endocytosis regulates BCR signaling remains unknown. Here we report that BCR signaling was not extinguished by endocytosis of BCRs; instead, BCR signaling initiated at the plasma membrane continued as the BCR trafficked intracellularly with the sequential phosphorylation of kinases. Blocking the endocytosis of BCRs resulted in the recruitment of both proximal and downstream kinases to the plasma membrane, where mitogen-activated protein kinases (MAPKs) were hyperphosphorylated and the kinase Akt and its downstream target Foxo were hypophosphorylated, which led to the dysregulation of gene transcription controlled by these pathways. Thus, the cellular location of the BCR serves to compartmentalize kinase activation to regulate the outcome of signaling. C1 [Chaturvedi, Akanksha; Martz, Rebecca; Waisberg, Michael; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Dorward, David] NIAID, Microscopy Unit, Rocky Mt Labs, Res Technol Sect,NIH, Hamilton, MT USA. RP Chaturvedi, A (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM achaturvedi@niaid.nih.gov; spierce@nih.gov FU US National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank T. Kirchhausen (Harvard Medical School) for dynasore. Supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 42 TC 41 Z9 41 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2011 VL 12 IS 11 BP 1119 EP U130 DI 10.1038/ni.2116 PG 9 WC Immunology SC Immunology GA 841GG UT WOS:000296500100018 PM 21964606 ER PT J AU Awua-Larbi, S Wong, TY Cotch, MF Durazo-Arvizu, R Jacobs, DR Klein, BEK Klein, R Lima, J Liu, K Kramer, H AF Awua-Larbi, Stella Wong, Tien Y. Cotch, Mary Frances Durazo-Arvizu, Ramon Jacobs, David R., Jr. Klein, Barbara E. K. Klein, Ronald Lima, Joao Liu, Kiang Kramer, Holly TI Retinal arteriolar caliber and urine albumin excretion: the Multi-Ethnic Study of Atherosclerosis SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE albuminuria; diabetic retinopathy; MESA (Multi-Ethnic Study of Atherosclerosis); retinal arteriolar; retinal venular ID CORONARY-HEART-DISEASE; HIGH BLOOD-PRESSURE; MICROVASCULAR ABNORMALITIES; HYPERTENSIVE RETINOPATHY; DIABETIC-RETINOPATHY; VESSEL DIAMETERS; INCIDENT STROKE; KIDNEY-DISEASE; RISK; MICROALBUMINURIA AB Background. Changes in retinal microvascular caliber, which occur prior to onset of retinopathy, may indicate presence of kidney damage. Methods. This study examined the association between retinal arteriolar [central retinal artery equivalent (CRAE)] and venular caliber [central retinal venule equivalent (CRVE)] and presence of albuminuria (micro- or macroalbuminuria) among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of adults aged 45-84 years without baseline clinical cardiovascular disease. During the second MESA exam, digital fundus photography was completed in 5897 participants who provided spot urine specimens. Albuminuria was defined by spot urine albumin/creatinine ratios >= 30 mg/g. Multivariable adjusted odds of albuminuria by quintiles of CRAE and CRVE were determined using logistic regression. Analyses were repeated after stratifying by presence of type 2 diabetes. Results. Albuminuria was noted in 11.5% (n = 675) and included 584 subjects with microalbuminuria and 91 with macroalbuminuria. A significant U-shaped pattern was seen with higher prevalence of albuminuria across quintile extremes in CRAE (15.7, 8.8 and 10.6% in CRAE Quintiles 1, 3 and 5, respectively; P < 0.0001). After adjustment for covariates, both narrower CRAE [odds ratios (OR) 1.55; 95% confidence interval (CI) 1.17-2.04, Quintile 1 versus 3) and wider CRAE (OR 1.44; 95% CI 1.07-1.93, Quintile 5 versus 3) were significantly associated with albuminuria. Associations appeared substantially stronger in adults with than without type 2 diabetes but the interaction term for diabetes and CRAE on presence of albuminuria did not meet statistical significance (P = 0.3). No association was noted between CRVE quintiles and albuminuria. Conclusions. Albuminuria is associated with narrower and wider arteriolar caliber. Future studies should determine whether variation in arteriolar caliber predicts incident albuminuria and whether associations are mediated by hypertension and diabetes. Such information could further clarify early microvascular processes in the pathogenesis of kidney disease. C1 [Durazo-Arvizu, Ramon; Kramer, Holly] Loyola Univ, Med Ctr, Dept Prevent Med, Maywood, IL 60153 USA. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Australia. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH Intramural Program, NIH, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. [Jacobs, David R., Jr.] Univ Oslo, Dept Nutr, Oslo, Norway. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Lima, Joao] Johns Hopkins Univ, Div Cardiol, Dept Cardiol, Baltimore, MD USA. [Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. RP Kramer, H (reprint author), Loyola Univ, Med Ctr, Dept Prevent Med, 2160 S 1st Ave, Maywood, IL 60153 USA. EM hkramer@lumc.edu OI Cotch, Mary Frances/0000-0002-2046-4350; Kramer, Holly/0000-0002-6374-837X; Klein, Ronald/0000-0002-4428-6237 FU National Heart, Lung and Blood Institute [N01-HC-95159, N01-HC-95169] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung and Blood Institute. The authors thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. This study was reported in poster at the American Society of Nephrology Meeting 2008 (S.A.-L.). NR 43 TC 9 Z9 9 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD NOV PY 2011 VL 26 IS 11 BP 3523 EP 3528 DI 10.1093/ndt/gfr095 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 839FH UT WOS:000296350400016 PM 21398363 ER PT J AU Chiu, CT Liu, GP Leeds, P Chuang, DM AF Chiu, Chi-Tso Liu, Guangping Leeds, Peter Chuang, De-Maw TI Combined Treatment with the Mood Stabilizers Lithium and Valproate Produces Multiple Beneficial Effects in Transgenic Mouse Models of Huntington's Disease SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Huntington's disease; lithium; valproate; GSK-3; HDACs; transgenic mouse model ID GLYCOGEN-SYNTHASE KINASE-3; TAIL SUSPENSION TEST; HISTONE DEACETYLASE INHIBITORS; STRIATAL NEURONAL LOSS; REDUCES BRAIN-DAMAGE; FORCED-SWIM TEST; NEUROTROPHIC FACTOR; INTRANUCLEAR INCLUSIONS; MOLECULAR-MECHANISMS; CORTICAL-NEURONS AB Emerging evidence suggests that the mood stabilizers lithium and valproate (VPA) have broad neuroprotective and neurotrophic properties, and that these occur via inhibition of glycogen synthase kinase 3 (GSK-3) and histone deacetylases (HDACs), respectively. Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by impaired movement, cognitive and psychiatric disturbances, and premature death. We treated N171-82Q and YAC128 mice, two mouse models of HD varying in genetic backgrounds and pathological progressions, with a diet containing therapeutic doses of lithium, VPA, or both. Untreated, these transgenic mice displayed a decrease in levels of GSK-3 beta serine 9 phosphorylation and histone H3 acetylation in the striatum and cerebral cortex around the onset of behavioral deficits, indicating a hyperactivity of GSK-3 beta and HDACs. Using multiple well-validated behavioral tests, we found that co-treatment with lithium and VPA more effectively alleviated spontaneous locomotor deficits and depressive-like behaviors in both models of HD mice. Furthermore, compared with monotherapy with either drug alone, co-treatment more successfully improved motor skill learning and coordination in N171-82Q mice, and suppressed anxiety-like behaviors in YAC128 mice. This combined treatment consistently inhibited GSK-3 beta and HDACs, and caused a sustained elevation in striatal as well as cortical brain-derived neurotrophic factor and heat shock protein 70. Importantly, co-treatment markedly prolonged median survival of N171-82Q mice from 31.6 to 41.6 weeks. Given that there is presently no proven treatment for HD, our results suggest that combined treatment with lithium and VPA, two mood stabilizers with a long history of safe use in humans, may have important therapeutic potential for HD patients. Neuropsychopharmacology (2011) 36, 2406-2421; doi:10.1038/npp.2011.128; published online 27 July 2011 C1 [Chiu, Chi-Tso; Liu, Guangping; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bldg 10,Room 3D38,10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services (IRP-NIMH-NIH-DHHS); HSU FX We thank Dr Michael Hayden and his colleagues of the Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada, for consultation and assistance in resolving issues surrounding the YAC128 mice in the early stage of our studies. We greatly appreciate the efforts of Dr Michael Rowe and Charlotte Wiest in initiating and expanding the colonies of the two mouse models of HD in our laboratory. We also thank Emily Fessler and Ioline Henter of the NIMH, NIH, for critical review and editorial assistance with this paper. This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services (IRP-NIMH-NIH-DHHS), and by the HSU family gift fund. NR 94 TC 62 Z9 63 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2011 VL 36 IS 12 BP 2406 EP 2421 DI 10.1038/npp.2011.128 PG 16 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 835XS UT WOS:000296070900005 PM 21796107 ER PT J AU Ayers, LW Missig, G Schulkins, J Rosen, JB AF Ayers, Luke W. Missig, Galen Schulkins, Jay Rosen, Jeffrey B. TI Oxytocin Reduces Background Anxiety in a Fear-Potentiated Startle Paradigm: Peripheral vs Central Administration SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE oxytocin; anxiety; fear; startle; PTSD ID POSTTRAUMATIC-STRESS-DISORDER; AUTISM SPECTRUM DISORDER; BLOOD-BRAIN-BARRIER; GROOMING BEHAVIOR; SOCIAL COGNITION; VIETNAM VETERANS; RESTING RATS; VASOPRESSIN; MODULATION; RESPONSES AB Oxytocin is known to have anti-anxiety and anti-stress effects. Using a fear-potentiated startle paradigm in rats, we previously demonstrated that subcutaneously administered oxytocin suppressed acoustic startle following fear conditioning compared with startle before fear conditioning (termed background anxiety), but did not have an effect on cue-specific fear-potentiated startle. The findings suggest oxytocin reduces background anxiety, an anxious state not directly related to cue-specific fear, but sustained beyond the immediate threat. The goal of the present study was to compare the effects of centrally and peripherally administered oxytocin on background anxiety and cue-specific fear. Male rats were given oxytocin either subcutaneously (SC) or intracerebroventricularly (ICV) into the lateral ventricles before fear-potentiated startle testing. Oxytocin doses of 0.01 and 0.1 mu g/kg SC reduced background anxiety. ICV administration of oxytocin at doses from 0,002 to 20 mu g oxytocin had no effect on background anxiety or cue-specific fear-potentiated startle. The 20 mu g ICV dose of oxytocin did reduce acoustic startle in non-fear conditioned rats. These studies indicate that oxytocin is potent and effective in reducing background anxiety when delivered peripherally, but not when delivered into the cerebroventricular system. Oxytocin given systemically may have anti-anxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in many anxiety and mental health disorder patients. Neuropsychopharmacology (2011) 36, 2488-2497; doi:10.1038/npp.2011.138; published online 27 July 2011 C1 [Ayers, Luke W.; Rosen, Jeffrey B.] Univ Delaware, Dept Psychol, Behav Neurosci Program, Newark, DE 19716 USA. [Missig, Galen] Univ Vermont, Grad Program Neurosci, Burlington, VT USA. [Schulkins, Jay] Georgetown Univ, Dept Neurosci, Washington, DC USA. [Schulkins, Jay] NIMH, Behav Endocrinol Sect, Washington, DC USA. [Schulkins, Jay] Amer Coll Obstetricians & Gynecologists, Res Dept, Washington, DC 20024 USA. RP Rosen, JB (reprint author), Univ Delaware, Dept Psychol, Behav Neurosci Program, 220 Wolf Hall, Newark, DE 19716 USA. EM jrosen@udel.edu FU U.S. Army Medical Research & Materiel Command [W81XWH-08-1-0182] FX This work was supported by Grant W81XWH-08-1-0182 from the Congressionally Directed Medical Research Programs, U.S. Army Medical Research & Materiel Command. NR 77 TC 21 Z9 22 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2011 VL 36 IS 12 BP 2488 EP 2497 DI 10.1038/npp.2011.138 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 835XS UT WOS:000296070900013 PM 21796104 ER PT J AU Zuo, YT Lu, HB Vaupel, DB Zhang, Y Chefer, SI Rea, WR Moore, AV Yang, YH Stein, EA AF Zuo, Yantao Lu, Hanbing Vaupel, D. Bruce Zhang, Yi Chefer, Svetlana I. Rea, William R. Moore, Anna V. Yang, Yihong Stein, Elliot A. TI Acute Nicotine-Induced Tachyphylaxis Is Differentially Manifest in the Limbic System SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE phMRI; nicotine; tolerance; relative cerebral blood volume ID CEREBRAL-BLOOD-FLOW; ACETYLCHOLINE-RECEPTORS; RAT-BRAIN; ALPHA-BUNGAROTOXIN; PHARMACOLOGICAL MRI; FUNCTIONAL MRI; CHOLINERGIC MECHANISMS; DOPAMINE ANTAGONISTS; CIGARETTE-SMOKING; NEURONAL-ACTIVITY AB Rapid tolerance develops to many of nicotine's behavioral and autonomic effects, A better understanding of the spatiotemporal patterns in neuronal activity as a consequence of acute nicotine tolerance (tachyphylaxis) may help explain its commonly found inverted 'U'-shaped biphasic dose-effect relationship on various behaviors. To this end, we employed high-resolution functional magnetic resonance imaging and relative cerebral blood volume (rCBV) as a marker of neuronal activity, to characterize the regional development of acute tolerance as a function of nicotine dose in naive, anesthetized rats. A single intravenous nicotine injection at 0.1 and 0.3, but not 0.03 mg/kg, significantly increased neuronal activity in many neocortical areas. In contrast, dose-dependent increases in rCBV were most pronounced in limbic regions, such that responses seen at 0.1 mg/kg nicotine in accumbens, hippocampus, amygdala, and several other limbic areas were not seen following 0.3 mg/kg nicotine. Finally, whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, subcortical limbic structures showed only a weak trend for tolerance. Lack of rCBV changes in animals receiving nicotine methiodide, a quaternary nicotine analog that does not cross the blood-brain barrier, supports a direct neuronal effect of nicotine rather than an action on the vasculature. These data provide pharmacodynamic insight into the regional heterogeneity of nicotine tachyphylaxis development, which may be relevant to behavioral and neurobiological mechanisms associated with repeated tobacco consumption. Neuropsychopharmacology (2011) 36, 2498-2512; doi:10.1038/npp.2011.139; published online 27 July 2011 C1 [Zuo, Yantao; Lu, Hanbing; Vaupel, D. Bruce; Chefer, Svetlana I.; Rea, William R.; Yang, Yihong; Stein, Elliot A.] NIDA, Intramural Res Program, Neuroimaging Res Branch, Baltimore, MD 21224 USA. [Zhang, Yi] NIMH, Bethesda, MD 20892 USA. [Moore, Anna V.] Massachusetts Gen Hosp, Dept Radiol, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. RP Stein, EA (reprint author), NIDA, Intramural Res Program, Neuroimaging Res Branch, 251 Bayview Blvd,Suite 200,Room 7A71 1A, Baltimore, MD 21224 USA. EM estein@mail.nih.gov FU US National Institutes of Health; National Institute on Drug Abuse; Intramural Research Program FX This research was funded by the US National Institutes of Health, National Institute on Drug Abuse, and Intramural Research Program. We thank Pradeep Kurup, MS and Tom Ross, PhD for their statistical assistance. NR 91 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2011 VL 36 IS 12 BP 2498 EP 2512 DI 10.1038/npp.2011.139 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 835XS UT WOS:000296070900014 PM 21796109 ER PT J AU Carlson, VCC Seabold, GK Helms, CM Garg, N Odagiri, M Rau, AR Daunais, J Alvarez, VA Lovinger, DM Grant, KA AF Carlson, Verginia C. Cuzon Seabold, Gail K. Helms, Christa M. Garg, Natasha Odagiri, Misa Rau, Andrew R. Daunais, James Alvarez, Veronica A. Lovinger, David M. Grant, Kathleen A. TI Synaptic and Morphological Neuroadaptations in the Putamen Associated with Long-Term, Relapsing Alcohol Drinking in Primates SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE self-administration monkeys; alcohol; caudate/putamen; synaptic morphology; glutamatergic transmission; GABAergic transmission ID PITUITARY-ADRENAL AXIS; CYNOMOLGUS MONKEYS; MACACA-FASCICULARIS; NONHUMAN-PRIMATES; DECISION-MAKING; INDIVIDUAL-DIFFERENCES; DORSOLATERAL STRIATUM; DORSOMEDIAL STRIATUM; MULTIPLE SCHEDULE; DENDRITIC SPINES AB Alcoholism and alcohol use disorders are characterized by several months to decades of heavy and problematic drinking, interspersed with periods of abstinence and relapse to heavy drinking. This alcohol-drinking phenotype was modeled using macaque monkeys to explore neuronal adaptations in the striatum, a brain region controlling habitual behaviors. Prolonged drinking with repeated abstinence narrowed the variability in daily intake, increased the amount of ethanol consumed in bouts, and led to higher blood ethanol concentrations more than twice the legal intoxication limit. After :the final abstinence period of this extensive drinking protocol, we found a selective increase in dendritic spine density and enhanced glutamatergic transmission in the putamen, but not in the caudate nucleus. Intrinsic excitability of medium-sized spiny neurons was also enhanced in the putamen of alcohol-drinking monkeys in comparison with non-drinkers, and GABAeric transmission was selectively suppressed in the putamen of heavy drinkers. These morphological and physiological changes indicate a shift in the balance of inhibitory/excitatory transmission that biases the circuit toward an enduring increase in synaptic activation of putamen output as a consequence of prolonged heavy drinking/relapse. The resultant potential for increased putamen activation may underlie an alcohol-drinking phenotype of regulated drinking and sustained intoxication. Neuropsychopharmacology (2011) 36, 2513-2528; doi:10.1038/npp.2011.140; published online 27 July 2011 C1 [Grant, Kathleen A.] Oregon Hlth & Sci Univ, Div Neurosci, Dept Behav Neurosci, Oregon Natl Primate Res Ctr, Portland, OR 97201 USA. [Daunais, James] Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27103 USA. [Carlson, Verginia C. Cuzon; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, NIH, Rockville, MD 20852 USA. [Seabold, Gail K.; Garg, Natasha; Alvarez, Veronica A.] NIAAA, Lab Integrat Neurosci, Sect Neuronal Struct, NIH, Rockville, MD 20852 USA. RP Grant, KA (reprint author), Oregon Hlth & Sci Univ, Div Neurosci, Dept Behav Neurosci, Oregon Natl Primate Res Ctr, Portland, OR 97201 USA. EM lovindav@mail.nih.gov; grantka@ohsu.edu RI Alvarez, Veronica /E-9745-2015 OI Alvarez, Veronica /0000-0003-2611-8675 FU NIAAA Division of Intramural Clinical and Biomedical Research [AA013510, AA017040, AA013641, RR000163] FX We thank Dr David Rossi for assistance with brain slicing techniques in monkeys, Steven Gonzales for data acquisition soft ware development, Dr Anne Lewis of ONPRC for overseeing the pathology, Dr Ted Hobbs of ONPRC for overseeing the craniotomy, and Dr Larry Sherman of ONPRC for overseeing the electrophysiology core. This study was supported by NIAAA Division of Intramural Clinical and Biomedical Research, AA013510, AA017040, AA013641, and RR000163. NR 66 TC 31 Z9 31 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2011 VL 36 IS 12 BP 2513 EP 2528 DI 10.1038/npp.2011.140 PG 16 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 835XS UT WOS:000296070900015 ER PT J AU Xiang, Y Shen, J AF Xiang, Yun Shen, Jun TI In vivo detection of intermediate metabolic products of [1-C-13]ethanol in the brain using C-13 MRS SO NMR IN BIOMEDICINE LA English DT Article DE in vivo C-13 MRS; ethanol; acetate; cerebral metabolism ID MAGNETIC-RESONANCE-SPECTROSCOPY; TRANSFER PULSE SEQUENCE; RAT-BRAIN; ETHANOL-METABOLISM; H-1-NMR SPECTROSCOPY; CEREBRAL METABOLISM; GLUTAMINE CYCLE; FREE ACETATE; 11.7 TESLA; ACETALDEHYDE AB In this study, in vivo C-13 MRS was used to investigate the labeling of brain metabolites after intravenous administration of [1-C-13]ethanol. After [1-C-13]ethanol had been administered systemically to rats, C-13 labels were detected in glutamate, glutamine and aspartate in the carboxylic and amide carbon spectral region. C-13-labeled bicarbonate HCO3- (161.0 ppm) was also detected. Saturating acetaldehyde C1 at 207.0 ppm was found to have no effect on the ethanol C1 (57.7 ppm) signal intensity after extensive signal averaging, providing direct in vivo evidence that direct metabolism of alcohol by brain tissue is minimal. To compare the labeling of brain metabolites by ethanol with labeling by glucose, in vivo time course data were acquired during intravenous co-infusion of [1-C-13]ethanol and [C-13(6)]-D-glucose. In contrast with labeling by [C-13(6)]-D-glucose, which produced doublets of carboxylic/amide carbons with a J coupling constant of 51 Hz, the simultaneously detected glutamate and glutamine singlets were labeled by [1-C-13]ethanol. As C-13 labels originating from ethanol enter the brain after being converted into [1-C-13]acetate in the liver, and the direct metabolism of ethanol by brain tissue is negligible, it is suggested that orally or intragastrically administered C-13-labeled ethanol may be used to study brain metabolism and glutamatergic neurotransmission in investigations involving alcohol administration. In vivo C-13 MRS of rat brain following intragastric administration of C-13-labeled ethanol is demonstrated. Published in 2011 by John Wiley & Sons, Ltd. C1 [Xiang, Yun; Shen, Jun] NIMH, Mol Imaging Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Intramural Res Program, NIH, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services (IRP-NIMH-NIH-DHHS), Bethesda, MD, USA FX The authors are grateful to Dr Su Xu, Mr Christopher Johnson and Dr Steve Li for their valuable help. Ms Ioline Henter provided editorial assistance. This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services (IRP-NIMH-NIH-DHHS), Bethesda, MD, USA. NR 53 TC 9 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD NOV PY 2011 VL 24 IS 9 BP 1054 EP 1062 DI 10.1002/nbm.1653 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 840DT UT WOS:000296419200004 PM 21312308 ER PT J AU Geramita, M van der Veen, JW Barnett, AS Savostyanova, AA Shen, J Weinberger, DR Marenco, S AF Geramita, Matthew van der Veen, Jan Willem Barnett, Alan S. Savostyanova, Antonina A. Shen, Jun Weinberger, Daniel R. Marenco, Stefano TI Reproducibility of prefrontal gamma-aminobutyric acid measurements with J-edited spectroscopy SO NMR IN BIOMEDICINE LA English DT Article DE N-acetylaspartic acid; glutamate plus glutamine (Glx); creatine; anterior cingulate cortex; white matter; gray matter; MRS; 3 T ID MAGNETIC-RESONANCE-SPECTROSCOPY; BRAIN IN-VIVO; GABA CONCENTRATION; ABSOLUTE QUANTITATION; T-2 RELAXATION; PANIC DISORDER; QUANTUM FILTER; VISUAL-CORTEX; WATER; METABOLITES AB gamma-Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the human brain, and GABA-ergic dysfunction has been implicated in a variety of neuropsychiatric disorders. Recent MRS techniques have allowed the quantification of GABA concentrations in vivo, and could therefore provide biologically relevant information. Few reports have formally characterized the reproducibility of these techniques, and differences in field strength, acquisition and processing parameters may result in large differences in measured GABA values. Here, we used a J-edited, single-voxel spectroscopy method of measurement of GABA + macromolecules (GABA +) in the anterior cingulate cortex (ACC) and right frontal white matter (rFWM) at 3 T. We measured the coefficient of variation within subjects (CVw) and intra-class correlation coefficients on two repeated scans obtained from 10 healthy volunteers with processing procedures developed in-house for the quantification of GABA + and other major metabolites. In addition, by segmenting the spectroscopic voxel into cerebrospinal fluid, gray matter and white matter, and employing a linear regression technique to extrapolate metabolite values to pure gray and white matter, we determined metabolite differences between gray and white matter in ACC and rFWM. CVw values for GABAR/creatine, GABA +/H2O, GABA +, creatine, partially co-edited glutamate + glutamine (Glx)/creatine, partially co-edited Glx and N-acetylaspartic acid (NAA)/creatine were all below 12% in both ACC and rFWM. After extrapolation to pure gray and pure white matter, CVw values for all metabolites were below 16%. We found metabolite ratios between gray and white matter for GABA +/creatine, GABA +, creatine, partially co-edited Glx and NAA/creatine to be 0.88 +/- 0.21 (standard deviation), 1.52 +/- 0.32, 1.77 +/- 0.4, 2.69 +/- 0.74 and 0.70 +/- 0.05, respectively. This study validates a reproducible method for the quantification of brain metabolites, and provides information on gray/white matter differences that may be important in the interpretation of results in clinical populations. Published in 2011 by John Wiley & Sons, Ltd. C1 [Marenco, Stefano] NIMH, Unit Multimodal Imaging Genet, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program GCAP,IRP, Bethesda, MD 20892 USA. [van der Veen, Jan Willem; Shen, Jun] NIMH, Magnet Resonance Spect Unit, Bethesda, MD 20892 USA. RP Marenco, S (reprint author), NIMH, Unit Multimodal Imaging Genet, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program GCAP,IRP, 10 Ctr Dr,Bldg 10,Room 3C103, Bethesda, MD 20892 USA. EM marencos@mail.nih.gov RI Marenco, Stefano/A-2409-2008; Farmer, Antonina/M-8914-2013 OI Marenco, Stefano/0000-0002-2488-2365; Farmer, Antonina/0000-0002-3305-8300 FU National Institute of Mental Health FX We thank Dharshan Chandramohan for help with the figures. This work was funded entirely by the National Institute of Mental Health Intramural Research Program. NR 49 TC 37 Z9 37 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD NOV PY 2011 VL 24 IS 9 BP 1089 EP 1098 DI 10.1002/nbm.1662 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 840DT UT WOS:000296419200009 PM 21290458 ER PT J AU Weston, EJ Pondo, T Lewis, MM Martell-Cleary, P Morin, C Jewell, B Daily, P Apostol, M Petit, S Farley, M Lynfield, R Reingold, A Hansen, NI Stoll, BJ Shane, AL Zell, E Schrag, SJ AF Weston, Emily J. Pondo, Tracy Lewis, Melissa M. Martell-Cleary, Pat Morin, Craig Jewell, Brenda Daily, Pam Apostol, Mirasol Petit, Sue Farley, Monica Lynfield, Ruth Reingold, Art Hansen, Nellie I. Stoll, Barbara J. Shane, Andi L. Zell, Elizabeth Schrag, Stephanie J. TI The Burden of Invasive Early-onset Neonatal Sepsis in the United States, 2005-2008 SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE early-onset; neonatal sepsis; group B Streptococcus; disease burden ID B-STREPTOCOCCAL DISEASE; BIRTH-WEIGHT INFANTS; NATIONAL-INSTITUTE; RESEARCH NETWORK; CHILD-HEALTH; RISK-FACTORS; INFECTIONS; PREVENTION; CONTINUES AB Background: Sepsis in the first 3 days of life is a leading cause of morbidity and mortality among infants. Group B Streptococcus (GBS), historically the primary cause of early-onset sepsis (EOS), has declined through widespread use of intrapartum chemoprophylaxis. We estimated the national burden of invasive EOS cases and deaths in the era of GBS prevention. Methods: Population-based surveillance for invasive EOS was conducted in 4 of the Centers for Disease Control and Prevention's Active Bacterial Core surveillance sites from 2005 to 2008. We calculated incidence using state and national live birth files. Estimates of the national number of cases and deaths were calculated, standardizing by race and gestational age. Results: Active Bacterial Core surveillance identified 658 cases of EOS; 72 (10.9%) were fatal. Overall incidence remained stable during the 3 years (2005: 0.77 cases/1000 live births; 2008: 0.76 cases/1000 live births). GBS (similar to 38%) was the most commonly reported pathogen followed by Escherichia coli (similar to 24%). Black preterm infants had the highest incidence (5.14 cases/1000 live births) and case fatality (24.4%). Nonblack term infants had the lowest incidence (0.40 cases/1000 live births) and case fatality (1.6%). The estimated national annual burden of EOS was approximately 3320 cases (95% confidence interval [CI] : 3060-3580), including 390 deaths (95% CI: 300-490). Among preterm infants, 1570 cases (95% CI: 1400-1770; 47.3% of the overall) and 360 deaths (95% CI: 280-460; 92.3% of the overall) occurred annually. Conclusions: The burden of invasive EOS remains substantial in the era of GBS prevention and disproportionately affects preterm and black infants. Identification of strategies to prevent preterm births is needed to reduce the neonatal sepsis burden. C1 [Weston, Emily J.] Ctr Dis Control & Prevent, Resp Dis Branch, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Stoll, Barbara J.; Shane, Andi L.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Martell-Cleary, Pat; Farley, Monica; Stoll, Barbara J.] VAMC, Atlanta, GA USA. [Morin, Craig; Jewell, Brenda; Lynfield, Ruth] Minnesota Dept Hlth, St Paul, MN USA. [Daily, Pam; Apostol, Mirasol; Reingold, Art] Univ Calif Berkeley, Berkeley, CA USA. [Petit, Sue] Connecticut Dept Hlth, Hartford, CT USA. [Hansen, Nellie I.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Stoll, Barbara J.; Shane, Andi L.] Childrens Healthcare Atlanta, Atlanta, GA USA. NICHHD, Neonatal Res Network, Bethesda, MD 20892 USA. RP Weston, EJ (reprint author), Ctr Dis Control & Prevent, Resp Dis Branch, Natl Ctr Immunizat & Resp Dis, 1600 Clifton Rd NE,MS C-23, Atlanta, GA 30333 USA. EM csi7@cdc.gov FU Centers for Disease Control and Prevention; National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX Supported by the Emerging Infections Program of the Centers for Disease Control and Prevention (to ABC). The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network's Early-Onset Sepsis Study. NR 24 TC 119 Z9 123 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD NOV PY 2011 VL 30 IS 11 BP 937 EP 941 DI 10.1097/INF.0b013e318223bad2 PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 839IP UT WOS:000296359200007 PM 21654548 ER PT J AU Esposito, DH Holman, RC Haberling, DL Tate, JE Podewils, LJ Glass, RI Parashar, U AF Esposito, Douglas H. Holman, Robert C. Haberling, Dana L. Tate, Jacqueline E. Podewils, Laura Jean Glass, Roger I. Parashar, Umesh TI Baseline Estimates of Diarrhea-associated Mortality Among United States Children Before Rotavirus Vaccine Introduction SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE diarrhea; mortality; US children; pre-rotavirus vaccine ID ACUTE GASTROENTERITIS HOSPITALIZATIONS; US CHILDREN; REDUCTION; MORBIDITY; INFANTS; DISEASE; DEATHS; TRENDS; AGE AB Objectives: Deaths due to diarrhea among US children declined substantially from the 1960s through the 1980s, but have not been recently assessed. We examined diarrhea-associated mortality among young US children from 1992 to 2006 to establish baseline estimates through which the effect of rotavirus vaccines, introduced in 2006, can be assessed. Methods: National Center for Health Statistics multiple cause-of-death mortality data were used to examine diarrhea-associated deaths and death rates among US children 1 to 59 months of age during 1992-2006. The winter residual method was used to indirectly estimate the annual number of diarrhea-associated deaths attributable to rotavirus. Results: An average of 369 diarrhea-associated deaths/year (3320 total deaths) occurred among US children 1 to 59 months of age during 1992-1998 and 2005-2006. The diarrhea-associated death rate increased 40% between the first 3 and last 2 years of the study period, from an average of 1.6 deaths per 100,000 to 2.3 deaths per 100,000. Black children died at almost 4 times the rate of white children. Diarrhea-associated deaths showed a winter seasonal pattern similar to that of rotavirus, particularly among children 4 to 23 months of age. Using indirect methods, we estimated 25 yearly rotavirus-associated deaths during the study period. Rotavirus vaccination could potentially prevent 21 of these deaths annually. Conclusions: Diarrhea-associated mortality among US children stabilized but appears to be increasing in recent years. Rotavirus was associated with a small but significant number of preventable deaths. The national multiple cause-of-death data should prove useful for assessing mortality impact of rotavirus vaccination in the United States. C1 [Esposito, Douglas H.; Tate, Jacqueline E.; Parashar, Umesh] Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Esposito, Douglas H.] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Off Workforce & Career Dev, Atlanta, GA 30333 USA. [Holman, Robert C.; Haberling, Dana L.] Ctr Dis Control & Prevent, Natl Ctr Emerging Zoonot & Infect Dis, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Podewils, Laura Jean] Ctr Dis Control & Prevent, Int Res & Programs Branch, Div TB Eliminat, Atlanta, GA USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Esposito, DH (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, 1600 Clinton Rd NE,MS E-03, Atlanta, GA 30333 USA. EM hgj4@cdc.gov FU Centers for Disease Control and Prevention FX Supported by the Centers for Disease Control and Prevention. NR 35 TC 9 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD NOV PY 2011 VL 30 IS 11 BP 942 EP 947 DI 10.1097/INF.0b013e3182254d19 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 839IP UT WOS:000296359200008 PM 21691244 ER PT J AU Setse, RW Siberry, GK Gravitt, PE Moss, WJ Agwu, AL Wheeling, JT Bohannon, BA Dominguez, KL AF Setse, Rosanna W. Siberry, George K. Gravitt, Patti E. Moss, William J. Agwu, Allison L. Wheeling, John T. Bohannon, Beverly A. Dominguez, Kenneth L. CA LEGACY Consortium TI Correlates of Sexual Activity and Sexually Transmitted Infections Among Human Immunodeficiency Virus-infected Youth in the LEGACY Cohort, United States, 2006 SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV-infected adolescents; Perinatally infected; Behaviorally infected; Sexual activity; Sexually transmitted infections ID ACQUIRED HIV-INFECTION; OLDER CHILDREN; RISK BEHAVIORS; DRUG-USERS; ADOLESCENTS; DISCLOSURE; HEALTH; TRANSMISSION; PREVALENCE; DIAGNOSIS AB Background: To determine the prevalence and correlates of sexual activity and sexually transmitted infections (STIs) among human immunodeficiency virus (HIV)-infected youth. Methods: The Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY) is an observational medical record study of perinatally and behaviorally HIV-infected (PHIV and BHIV) youth followed at 22 US HIV clinics. PHIV youth were HIV infected at birth or by breast-feeding. BHIV youth were HIV infected sexually or by injection drug use. We determined the prevalence of sexual activity during 2006 and examined correlates of sexual activity among 13- to 24-year-old PHIV youth using multivariable generalized linear models. Among sexually active persons, we determined the association between mode of HIV acquisition and non-HIV STI diagnosis using multivariable generalized linear models. Results: In all, 34% (195/571) of PHIV and 89% (162/181) of BHIV youth were sexually active. Eighty percent (155/195) of sexually active PHIV youth reported ever using condoms. Ninety-three percent discussed sex with a health care provider. Increasing age (adjusted prevalence ratio [APR]: 1.17 per year of age, 95% confidence interval [CI] = 1.12-1.23), having a boyfriend/girlfriend (APR: 2.74, 95% CI = 1.75-4.29), and injection drug use (APR: 1.38, 95% CI = 1.06-1.79) correlated with sexual activity after adjusting for socio-demographic and HIV-related clinical variables. Among sexually active youth, after adjusting for relevant confounders, PHIV youth were less likely than BHIV youth to have been diagnosed with an STI in 2006 (APR: 0.25, 95% [CI] = 0.13-0.46). Conclusions: Sexual activity among HIV-infected adolescents is common. Factors associated with sexual activity in this study should be taken into account in developing behavioral risk reduction interventions targeting PHIV youth. C1 [Setse, Rosanna W.; Gravitt, Patti E.; Moss, William J.] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent Maternal AIDS Branch, NIH, Bethesda, MD USA. [Agwu, Allison L.] Johns Hopkins Med Inst, Dept Pediat Infect Dis, Baltimore, MD 21205 USA. [Wheeling, John T.] Northrop Grummon Inc, Atlanta, GA USA. [Bohannon, Beverly A.; Dominguez, Kenneth L.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Setse, RW (reprint author), Johns Hopkins Sch Publ Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. EM rsetse@hotmail.com FU Centers for Disease Control and Prevention, Atlanta, GA [200-2004-09976] FX The LEGACY project was funded by the Centers for Disease Control and Prevention, Atlanta, GA, contract number 200-2004-09976.; In addition, we thank Kathy Joyce, Julie Davidson, Sharon Swanigan, Patrick Tschumper, Amanda Fournier and Kathleen Paul at Westat Inc. (Rockville, MD) for contractual support, site monitoring, and data management support. We also thank Vicki Peters (New York City Department of Health and Mental Hygiene) who has served as a consultant to the LEGACY project. We are also grateful to the patients and caregivers who consented to participate in LEGACY, as well as the administrative personnel at each study site, Westat and CDC. NR 40 TC 10 Z9 10 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD NOV PY 2011 VL 30 IS 11 BP 967 EP 973 DI 10.1097/INF.0b013e3182326779 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 839IP UT WOS:000296359200013 PM 22001904 ER PT J AU Long, JM Lee, GD Kelley-Bell, B Spangler, EL Perez, EJ Longo, DL de Cabo, R Zou, S Rapp, PR AF Long, Jeffrey M. Lee, Garrick D. Kelley-Bell, Bennett Spangler, Edward L. Perez, Evelyn J. Longo, Dan L. de Cabo, Rafael Zou, Sige Rapp, Peter R. TI Preserved learning and memory following 5-fluorouracil and cyclophosphamide treatment in rats SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Chemofog; Chemobrain; Spatial memory; Fear conditioning; Cognition ID HIPPOCAMPAL CELL-PROLIFERATION; ANTERIOR CINGULATE CORTEX; CONTEXTUAL FEAR MEMORY; BREAST-CANCER PATIENTS; COGNITIVE FUNCTION; ADJUVANT CHEMOTHERAPY; IMPAIRMENT; METHOTREXATE; WOMEN; MICE AB Some patients experience enduring cognitive impairment after cancer treatment, a condition termed "chemofog". Animal models allow assessment of chemotherapy effects on learning and memory per se, independent of changes due to cancer itself or associated health consequences such as depression. The present study examined the long-term learning and memory effects of a chemotherapy cocktail used widely in the treatment of breast cancer, consisting of 5-fluorouracil (5FU) and cyclophosphamide (CYP). Eighty 5-month old male F344 rats received contextual and cued fear conditioning before treatment with saline, or a low or high dose drug cocktail (50 mg/kg CYP and 75 mg/kg 5RJ, or 75 mg/kg CYP and 120 mg/kg 5W, i.p., respectively) every 30 days for 2 months. After a 2-month, no-drug recovery, both long-term retention and new task acquisition in the water maze and 14-unit T-maze were assessed. Neither dose of the CYP/5FU cocktail impaired retrograde fear memory despite marked toxicity documented by enduring weight loss and 50% mortality at the higher dose. Acquisition in the water maze and Stone maze was also normal relative to controls in rats treated with CYP/5FU. The results contribute to a growing literature suggesting that learning and memory mediated by the hippocampus can be relatively resistant to chemotherapy. Future investigation may need to focus on assessments of processing speed, executive function and attention, and the possible interactive contribution of cancer itself and aging to the post-treatment development of cognitive impairment. (C) 2011 Elsevier Inc. All rights reserved. C1 [Long, Jeffrey M.; Lee, Garrick D.; Kelley-Bell, Bennett; Spangler, Edward L.; Perez, Evelyn J.; de Cabo, Rafael; Zou, Sige; Rapp, Peter R.] NIA, Lab Expt Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. [Longo, Dan L.] NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Long, JM (reprint author), NIA, Lab Expt Gerontol, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM longjm@mail.nih.gov OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 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 42 TC 9 Z9 9 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD NOV PY 2011 VL 100 IS 1 BP 205 EP 211 DI 10.1016/j.pbb.2011.08.012 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 838OP UT WOS:000296302400029 PM 21875615 ER PT J AU Ehrenshaft, M Zhao, BZ Andley, UP Mason, RP Roberts, JE AF Ehrenshaft, Marilyn Zhao, Baozhong Andley, Usha P. Mason, Ronald P. Roberts, Joan E. TI Immunological Detection of N-formylkynurenine in Porphyrin-Mediated Photooxided Lens alpha-crystallin SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID ZN-SUPEROXIDE-DISMUTASE; CHAPERONE-LIKE ACTIVITY; SINGLET OXYGEN; PHOTOSENSITIZED OXIDATION; EXCITED-STATES; HUMAN CU; PROTEINS; TRYPTOPHAN; DAMAGE; CELLS AB Crystallin proteins are responsible for maintaining lens transparency and allowing the lens to focus light undistorted onto the retina. The alpha-crystallins are the major lens crystallins, and function as both structural proteins and chaperones to protect all lens proteins from damage leading to lens deterioration. Because lens crystallin proteins do not turn over, the damage they accumulate can lead to cataracts, the world's leading cause of blindness. Photosensitizing porphyrins can accumulate in the eye through either endogenous metabolism or through therapeutic or diagnostic procedures. Porphyrin buildup exacerbates lens aging through increased levels of singlet oxygen, resulting in protein polymerization and amino acid residue alteration. Tryptophans oxidize to kynurenine and N-formylkynurenine (NFK) causing irreversible changes in the refractive index of the normally transparent lens, leading to development of cataracts. Additionally, NFK is itself a photosensitizer, and its presence exacerbates lens deterioration. This work uses anti-NFK antiserum to study porphyrin-facilitated photooxidation of alpha-crystallin tryptophan residues. In vitro experiments show that four biologically interesting porphyrins mediate alpha-crystallin polymerization and accumulation of both protein radicals and NFK. Confocal microscopy of cultured human lens epithelial cells indicates that while all four porphyrins photosensitize cellular proteins, not all oxidize the tryptophans of cellular alpha-crystallin to NFK. C1 [Ehrenshaft, Marilyn; Zhao, Baozhong; Mason, Ronald P.] NIEHS, Lab Pharmacol & Toxicol, Res Triangle Pk, NC 27709 USA. [Andley, Usha P.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. RP Ehrenshaft, M (reprint author), NIEHS, Lab Pharmacol & Toxicol, POB 12233, Res Triangle Pk, NC 27709 USA. EM ehrensh1@niehs.nih.gov RI Zhao, Baozhong/B-5865-2011 FU National Institutes of Health; National Institute of Environmental Health Sciences [52 (Z01 ES050139-13)] FX The authors sincerely thank B. Jean Corbett and Mary Mason for their valuable help in the preparation of this manuscript. We are grateful to Jeff Tucker, Holly Rutledge and Agnes Janoshazi for their expert help with confocal microscopy. This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences 52 (Z01 ES050139-13). NR 42 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD NOV-DEC PY 2011 VL 87 IS 6 BP 1321 EP 1329 DI 10.1111/j.1751-1097.2011.00979.x PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 839EO UT WOS:000296348400010 PM 21770952 ER PT J AU Williams, MT Warnock, BJ Betz, JM Beck, JJ Gardner, DR Lee, ST Molyneux, RJ Colegate, SM AF Williams, Maria T. Warnock, Bonnie J. Betz, Joseph M. Beck, John J. Gardner, Dale R. Lee, Stephen T. Molyneux, Russell J. Colegate, Steven M. TI Detection of High Levels of Pyrrolizidine-N-oxides in the Endangered Plant Cryptantha crassipes (Terlingua Creek Cat's-eye) Using HPLC-ESI-MS SO PHYTOCHEMICAL ANALYSIS LA English DT Article DE Cryptantha crassipes; pyrrolizidine; N-oxides; lycopsamine; HPLC-ESI-MS; SPE ID ALKALOIDS; SENECIO; POLLEN AB Introduction - A previous investigation of pyrrolizidine alkaloids produced by nine species of Cryptantha identified at least two chemotypes within the genus. Other research has postulated that pyrrolizidine-N-oxide concentrations increase as the growing conditions become harsher, particularly with respect to water availability. Cryptantha crassipes is an endangered plant with a very limited distribution range within a dry, harsh Texan ecosystem. Objective - To determine the pyrrolizidine alkaloid (and their N-oxides) profile and concentrations in Cryptantha crassipes. Methodology - Methanolic extracts of Cryptantha crassipes were partitioned into dilute sulphuric acid and the alkaloids concentrated using strong cation exchange, solid-phase extraction columns. Extracts were analysed using reversed-phase high-pressure liquid chromatography coupled to electrospray ionisation ion trap mass spectrometry. Results - The N-oxides of lycopsamine and intermedine were the major pyrrolizidine alkaloids detected in Cryptantha crassipes. Smaller to trace amounts of other pyrrolizidine alkaloids observed were: the 7- and 3'-acetylated derivatives and the 1,2-dihydro analogs of lycopsamine-N-oxide and/or intermedine-N-oxide; a pair of unidentified N-oxides, isobaric with lycopsamine-N-oxide; and the N-oxides of leptanthine, echimiplatine, amabiline, echiumine and dihydroechiumine. Only trace amounts, if any, of the parent free base pyrrolizidine alkaloids were detected. The concentration of pyrrolizidine alkaloids was estimated to be 3-5% of the dry weight of milled leaves, or 10-50 times the levels previously reported for similar chemotypes. Conclusions - The high levels of the N-oxides of lycopsamine and intermedine establish the genus chemotype of the endangered Cryptantha crassipes and support earlier data linking high levels of N-oxides to dry, harsh growing conditions. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Gardner, Dale R.; Lee, Stephen T.; Colegate, Steven M.] ARS, Poisonous Plant Res Lab, USDA, Logan, UT USA. [Molyneux, Russell J.] Univ Hawaii, Coll Pharm, Hilo, HI 96720 USA. [Beck, John J.] ARS, Western Reg Res Ctr, USDA, Albany, CA USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Williams, Maria T.; Warnock, Bonnie J.] Sul Ross State Univ, Dept Nat Resource Management, Alpine, TX USA. RP Colegate, SM (reprint author), ARS, Poisonous Plant Res Lab, USDA, Logan, UT USA. EM steven.colegate@ars.usda.gov NR 18 TC 11 Z9 11 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0958-0344 J9 PHYTOCHEM ANALYSIS JI Phytochem. Anal. PD NOV-DEC PY 2011 VL 22 IS 6 BP 532 EP 540 DI 10.1002/pca.1314 PG 9 WC Biochemical Research Methods; Plant Sciences; Chemistry, Analytical SC Biochemistry & Molecular Biology; Plant Sciences; Chemistry GA 840EM UT WOS:000296421100008 PM 21433162 ER PT J AU Robbins, JB Schneerson, R Xie, GL Ake-Hanson, L Miller, MA AF Robbins, John B. Schneerson, Rachel Xie, Guilin Ake-Hanson, Lars Miller, Mark A. TI Capsular polysaccharide vaccine for Group B Neisseria meningitidis, Escherichia coli K1, and Pasteurella haemolytica A2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE polysialic acid; bacterial meningitis ID CELL-ADHESION MOLECULE; SEROGROUP-B; POLYSIALIC ACID; MENINGOCOCCAL POLYSACCHARIDE; MONOCLONAL-ANTIBODY; IMMUNE-RESPONSES; COMBINING SITES; HOST DEFENSE; N-CAM; INFECTIONS AB We reviewed the literature that is the basis for our proposal that (2 -> 8)-alpha-Neu5Ac conjugates will be safe and effective vaccines for Group B meningococci (GBMs), Escherichia coli K1, and Pasteurella haemolytica A2. Although (2 -> 8)-alpha-Neu5Ac is a virulence factor and a protective antigen of these three pathogens, it is also a component of normal tissues (neural cell adhesion molecule). Natural, anti-(2 -> 8)-alpha-Neu5Ac present in most adults, vaccine-induced antibodies, and even high levels of spontaneously appearing monoclonal anti-(2 -> 8)-alpha-Neu5Ac did not cause autoimmunity. Although it is not possible to prove a null hypothesis, there are no epidemiologic, serologic, immunologic, or clinical data to indicate that (2 -> 8)-alpha-Neu5Ac antibodies will induce pathology or an autoimmune disease. No increased pathology caused by these antibodies was found, even in neonates and infants of mothers recovered from GBM meningitis. The lack of pathology mediated by anti-(2 -> 8)-alpha-Neu5Ac may be explained by different presentations of (2 -> 8)-alpha-Neu5Ac on bacterial and mammalian cells and by the unusual physicochemical properties of anti-(2 -> 8)-alpha-Neu5Ac. Based on clinical and experimental data collected over 30 y and because (2 -> 8)-alpha-Neu5Ac is an essential virulence factor and a protective antigen for GBM, E. coli K1, and P. haemolytica A2, protein conjugates of it are easy to prepare using inexpensive and plentiful ingredients, and they would be compatible with routinely administered infant vaccines, clinical studies of these conjugates should proceed. C1 [Robbins, John B.; Schneerson, Rachel] NICHHD, Bethesda, MD 20892 USA. [Xie, Guilin] Lanzhou Inst Biol Prod, Lanzhou 730046, Gansu, Peoples R China. [Ake-Hanson, Lars] Univ Gothenburg, Dept Clin Immunol, S-41685 Gothenburg, Sweden. [Miller, Mark A.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Robbins, JB (reprint author), NICHHD, Bethesda, MD 20892 USA. EM robbinsjo@nichd.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We are grateful for helpful comments and suggestions from Willie Vann, Vince Pozsgay, Joanna Kubler-Kielb, and Irwin Arias. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 65 TC 16 Z9 17 U1 1 U2 9 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 NOV 1 PY 2011 VL 108 IS 44 BP 17871 EP 17875 DI 10.1073/pnas.1114489108 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839NH UT WOS:000296373400009 PM 22025709 ER PT J AU Park, JH Gail, MH Weinberg, CR Carroll, RJ Chung, CC Wang, ZM Chanock, SJ Fraumeni, JF Chatterjee, N AF Park, Ju-Hyun Gail, Mitchell H. Weinberg, Clarice R. Carroll, Raymond J. Chung, Charles C. Wang, Zhaoming Chanock, Stephen J. Fraumeni, Joseph F., Jr. Chatterjee, Nilanjan TI Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetic prediction; missing heritability; population genetics ID GENOME-WIDE ASSOCIATION; BREAST-CANCER; IDENTIFIES 5; HUMAN HEIGHT; LOCI; METAANALYSIS; ADAPTATION; DISEASE; GLIOMA; RISK AB Recent discoveries of hundreds of common susceptibility SNPs from genome-wide association studies provide a unique opportunity to examine population genetic models for complex traits. In this report, we investigate distributions of various population genetic parameters and their interrelationships using estimates of allele frequencies and effect-size parameters for about 400 susceptibility SNPs across a spectrum of qualitative and quantitative traits. We calibrate our analysis by statistical power for detection of SNPs to account for overrepresentation of variants with larger effect sizes in currently known SNPs that are expected due to statistical power for discovery. Across all qualitative disease traits, minor alleles conferred "risk" more often than "protection." Across all traits, an inverse relationship existed between "regression effects" and allele frequencies. Both of these trends were remarkably strong for type I diabetes, a trait that is most likely to be influenced by selection, but were modest for other traits such as human height or late-onset diseases such as type II diabetes and cancers. Across all traits, the estimated effect-size distribution suggested the existence of increasingly large numbers of susceptibility SNPs with decreasingly small effects. For most traits, the set of SNPs with intermediate minor allele frequencies (5-20%) contained an unusually small number of susceptibility loci and explained a relatively small fraction of heritability compared with what would be expected from the distribution of SNPs in the general population. These trends could have several implications for future studies of common and uncommon variants. C1 [Park, Ju-Hyun; Gail, Mitchell H.; Chanock, Stephen J.; Fraumeni, Joseph F., Jr.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Weinberg, Clarice R.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Chung, Charles C.; Wang, Zhaoming; Chanock, Stephen J.] NCI, Core Genotyping Facil, NIH, Dept Hlth & Human Serv, Gaithersburg, MD 20877 USA. RP Fraumeni, JF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. EM fraumeni@nih.gov; chattern@mail.nih.gov FU National Cancer Institute [R27-CA057030]; National Institute of Environmental Health Sciences FX This research was supported by the intramural programs of the National Cancer Institute and National Institute of Environmental Health Sciences. The research of R.J.C. was supported by a grant from the National Cancer Institute (R27-CA057030). NR 29 TC 70 Z9 71 U1 1 U2 17 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 NOV 1 PY 2011 VL 108 IS 44 BP 18026 EP 18031 DI 10.1073/pnas.1114759108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839NH UT WOS:000296373400036 PM 22003128 ER PT J AU DeLeo, FR Kennedy, AD Chen, L Wardenburg, JB Kobayashi, SD Mathema, B Braughton, KR Whitney, AR Villaruz, AE Martens, CA Porcella, SF McGavin, MJ Otto, M Musser, JM Kreiswirth, BN AF DeLeo, Frank R. Kennedy, Adam D. Chen, Liang Wardenburg, Juliane Bubeck Kobayashi, Scott D. Mathema, Barun Braughton, Kevin R. Whitney, Adeline R. Villaruz, Amer E. Martens, Craig A. Porcella, Stephen F. McGavin, Martin J. Otto, Michael Musser, James M. Kreiswirth, Barry N. TI Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; METHICILLIN-RESISTANT; UNITED-STATES; INFECTIONS; VIRULENCE; BACTEREMIA; SYSTEM; HEME; MRSA AB Staphylococcus aureus is a bacterial pathogen known to cause infections in epidemic waves. One such epidemic was caused by a clone known as phage-type 80/81, a penicillin-resistant strain that rose to world prominence in the late 1950s. The molecular underpinnings of the phage-type 80/81 outbreak have remained unknown for decades, nor is it understood why related S. aureus clones became epidemic in hospitals in the early 1990s. To better understand the molecular basis of these epidemics, we sequenced the genomes of eight S. aureus clinical isolates representative of the phage-type 80/81 clone, the Southwest Pacific clone [a community-associated methicillin-resistant S. aureus (MRSA) clone], and contemporary S. aureus clones, all of which are genetically related and belong to the same clonal complex (CC30). Genome sequence analysis revealed that there was coincident divergence of these clones from a recent common ancestor, a finding that resolves controversy about the evolutionary history of the lineage. Notably, we identified nonsynonymous SNPs in genes encoding accessory gene regulator C (agrC) and alpha-hemolysin (hla)-molecules important for S. aureus virulence-that were present in virtually all contemporary CC30 hospital isolates tested. Compared with the phage-type 80/81 and Southwest Pacific clones, contemporary CC30 hospital isolates had reduced virulence in mouse infection models, the result of SNPs in agrC and hla. We conclude that agr and hla (along with penicillin resistance) were essential for world dominance of phage-type 80/81 S. aureus, whereas key SNPs in contemporary CC30 clones restrict these pathogens to hospital settings in which the host is typically compromised. C1 [DeLeo, Frank R.; Kennedy, Adam D.; Kobayashi, Scott D.; Braughton, Kevin R.; Whitney, Adeline R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Chen, Liang; Mathema, Barun; Kreiswirth, Barry N.] Univ Med & Dent New Jersey, Publ Hlth Res Inst, TB Ctr, Newark, NJ 07103 USA. [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Villaruz, Amer E.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Bethesda, MD 20892 USA. [Martens, Craig A.; Porcella, Stephen F.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [McGavin, Martin J.] Univ Western Ontario, Dept Microbiol & Immunol, London, ON N6A 5C1, Canada. [McGavin, Martin J.] Univ Western Ontario, Schulich Sch Med & Dent, London, ON N6A 5C1, Canada. [Musser, James M.] Methodist Hosp, Res Inst, Dept Pathol & Genom Med, Methodist Hosp Syst, Houston, TX 77204 USA. [Musser, James M.] Methodist Hosp, Res Inst, Ctr Human Mol & Translat Infect Dis, Houston, TX 77204 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); Region V "Great Lakes" Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium (NIH) [1-U54-AI-057153]; Canadian Institutes for Health Research (CIHR) [MOP-12669] FX We thank Anita Mora (Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases) for assistance with graphics. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). J.B.W. acknowledges membership within and support from the Region V "Great Lakes" Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium (NIH Award 1-U54-AI-057153). M.J.M. acknowledges support from the Canadian Institutes for Health Research (CIHR Award MOP-12669). NR 25 TC 69 Z9 71 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 1 PY 2011 VL 108 IS 44 BP 18091 EP 18096 DI 10.1073/pnas.1111084108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839NH UT WOS:000296373400047 PM 22025717 ER PT J AU Tziotzios, C Walters, M Biesecker, LG AF Tziotzios, C. Walters, M. Biesecker, L. G. TI More than just a big thumb SO QJM-AN INTERNATIONAL JOURNAL OF MEDICINE LA English DT Editorial Material ID PROTEUS-SYNDROME C1 [Tziotzios, C.] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge CB2 0QQ, England. [Walters, M.] Univ Glasgow, Western Infirm, Gardiner Inst Med, Glasgow G11 6NT, Lanark, Scotland. [Biesecker, L. G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Tziotzios, C (reprint author), Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Hills Rd, Cambridge CB2 0QQ, England. EM ct287@cantab.net NR 3 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1460-2725 J9 QJM-INT J MED JI QJM-An Int. J. Med. PD NOV PY 2011 VL 104 IS 11 BP 989 EP 991 DI 10.1093/qjmed/hcq226 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 839GX UT WOS:000296354600012 PM 21106503 ER PT J AU Lambertini, L Lee, TL Chan, WY Lee, MJ Diplas, A Wetmur, J Chen, J AF Lambertini, Luca Lee, Tin-Lap Chan, Wai-Yee Lee, Men-Jean Diplas, Andreas Wetmur, James Chen, Jia TI Differential Methylation of Imprinted Genes in Growth-Restricted Placentas SO REPRODUCTIVE SCIENCES LA English DT Article DE genomic imprinting; intrauterine growth restriction (IUGR); placenta; DNA methylation; tiling array ID DNA METHYLATION; MICROARRAY EXPERIMENTS; SINGLE-CELL; EXPRESSION; NOISE; DISORDERS; REVEALS; WIDE; EVOLUTION; CANCER AB A complex network of epigenetic factors participates in regulating the monoallelic expression of a small subset of genes (similar to 1%) in the human genome. This phenomenon goes under the definition of genomic imprinting, a parent-of-origin effect that, when altered during early embryogenesis, may influence fetal development into adulthood. Pertubations in genomic imprinting have been associated with placental and fetal growth restrictions. We analyzed the differential DNA methylation of all known imprinted genes on 10 appropriate-for-gestational-age, clinically normal, placentas and 7 severe intrauterine growth-restricted placentas. Samples were pooled according to the diagnosis and analyzed by methylated DNA immunoprecipitation (MeDIP) on a tiling microarray platform. The distribution of the differentially methylated regions (DMRs) identified in growth-restricted placentas showed a slight tendency toward hypermethylation. Imprinted genes not expressed in placenta showed a unique DMR profile with the fewest hyper- and hypomethylated DMRs. Promoter and CpG island DMRs were sporadic and randomly distributed. The vast majority of DMR identified (similar to 99%) were mapped in introns, showing no common sequence features. Also, by using the more advanced array data mining softwares, no significant patterns emerged. In contrast, differential methylation showed a highly significant correlation with gene length. Overall these data suggest that differential methylation changes in growth-restricted placentas occur throughout the genomic regions, encompassing genes actively expressed in the placenta. These findings warrant caution in interpreting the significance of genes carrying clustered DMRs because the distribution of DMRs in a gene may be attributed as a function of its length rather than as a specific biological role. C1 [Lambertini, Luca; Diplas, Andreas; Chen, Jia] Mt Sinai Sch Med, Dept Prevent Med, New York, NY 10029 USA. [Lambertini, Luca; Lee, Men-Jean] Mt Sinai Sch Med, Dept Obstet Gynecol & Reprod Sci, New York, NY 10029 USA. [Lee, Tin-Lap; Chan, Wai-Yee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Clin Genom, Bethesda, MD USA. [Chan, Wai-Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Wetmur, James] Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA. [Wetmur, James] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Chen, Jia] Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. [Chen, Jia] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. RP Lambertini, L (reprint author), Mt Sinai Sch Med, Dept Prevent Med, 1 Gustave L Levi Pl,Box 1057, New York, NY 10029 USA. EM luca.lambertini@mssm.edu RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Mount Sinai Children's Environmental Health Center; Mount Sinai Child Health and Development Institute FX This work was supported by the Venture Capital Research Funding Program of the Mount Sinai Children's Environmental Health Center and Mount Sinai Child Health and Development Institute. NR 33 TC 13 Z9 14 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD NOV PY 2011 VL 18 IS 11 BP 1111 EP 1117 DI 10.1177/1933719111404611 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 837LX UT WOS:000296206300008 PM 21693779 ER PT J AU Jang, JH Green, CE Assassi, S Reveille, JD Ward, MM Weisman, MH Nicassio, PM AF Jang, Jennifer H. Green, Charles E. Assassi, Shervin Reveille, John D. Ward, Michael M. Weisman, Michael H. Nicassio, Perry M. TI The contribution of disease activity on functional limitations over time through psychological mediators: a 12-month longitudinal study in patients with ankylosing spondylitis SO RHEUMATOLOGY LA English DT Article DE Ankylosing spondylitis; Disease activity; Functional limitations; Depression; Internality; Helplessness ID ARTHRITIS HELPLESSNESS INDEX; RHEUMATOID-ARTHRITIS; DEPRESSION; DISABILITY; SEVERITY; PHQ-9 AB Objectives. To explore whether helplessness, internality and depression would mediate the relationship between disease activity and functional limitations in patients with AS in a 12-month longitudinal study. Methods. A total of 294 participants with AS meeting modified New York criteria completed clinical and psychological assessments at 6-month intervals. Psychological measures evaluated helplessness, depression and internality. Path analysis evaluated the direct and indirect effects of baseline disease activity on 12-month functional limitations via the psychological measures of helplessness, internality and depression at 6 months. Results. Baseline disease activity demonstrated direct and indirect effects on 12-month functional limitations. Helplessness and depression, but not internality, served as mediators of the relationship between disease activity and functional limitations. Conclusion. Higher baseline disease activity predicted greater functional limitations at 12 months through helplessness and depression. Our findings suggest that helplessness and depression may constitute future treatment targets in reducing functional limitations in patients with AS. C1 [Jang, Jennifer H.; Weisman, Michael H.] Cedars Sinai Med Ctr, Dept Med, Div Rheumatol, Los Angeles, CA 90048 USA. [Green, Charles E.] Univ Texas Hlth Sci Ctr Houston, Dept Pediat, Houston, TX USA. [Assassi, Shervin; Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Dept Med, Div Rheumatol, Houston, TX USA. [Ward, Michael M.] NIAMS, NIH, Bethesda, MD USA. [Nicassio, Perry M.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. RP Weisman, MH (reprint author), Cedars Sinai Med Ctr, Dept Med, Div Rheumatol, 8700 Beverly Blvd,Becker B-131, Los Angeles, CA 90048 USA. EM michael.weisman@cshs.org FU Australo-Anglo-American Spondylitis Consortium (TASC); US Department of Health and Human Services; NIH; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [P01-AR-052915-01]; National Center for Research Resources (NCRR) General Clinical Research Centers (GCRC) [M01-RR00425]; NIAMS/NIH FX This work was supported by grants from the Australo-Anglo-American Spondylitis Consortium (TASC), US Department of Health and Human Services, NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (P01-AR-052915-01) and the National Center for Research Resources (NCRR) General Clinical Research Centers (GCRC) (M01-RR00425) and the Intramural Research Program, NIAMS/NIH. NR 32 TC 5 Z9 5 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD NOV PY 2011 VL 50 IS 11 BP 2087 EP 2092 DI 10.1093/rheumatology/ker274 PG 6 WC Rheumatology SC Rheumatology GA 838MH UT WOS:000296295800023 PM 21875876 ER PT J AU Bateman, A Agrawal, S Birney, E Bruford, EA Bujnicki, JM Cochrane, G Cole, JR Dinger, ME Enright, AJ Gardner, PP Gautheret, D Griffiths-Jones, S Harrow, J Herrero, J Holmes, IH Huang, HD Kelly, KA Kersey, P Kozomara, A Lowe, TM Marz, M Moxon, S Pruitt, KD Samuelsson, T Stadler, PF Vilella, AJ Vogel, JH Williams, KP Wright, MW Zwieb, C AF Bateman, Alex Agrawal, Shipra Birney, Ewan Bruford, Elspeth A. Bujnicki, Janusz M. Cochrane, Guy Cole, James R. Dinger, Marcel E. Enright, Anton J. Gardner, Paul P. Gautheret, Daniel Griffiths-Jones, Sam Harrow, Jen Herrero, Javier Holmes, Ian H. Huang, Hsien-Da Kelly, Krystyna A. Kersey, Paul Kozomara, Ana Lowe, Todd M. Marz, Manja Moxon, Simon Pruitt, Kim D. Samuelsson, Tore Stadler, Peter F. Vilella, Albert J. Vogel, Jan-Hinnerk Williams, Kelly P. Wright, Mathew W. Zwieb, Christian TI RNAcentral: A vision for an international database of RNA sequences SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE sequence database; federation; noncoding RNA ID TRANS-ACTING SIRNAS; NONCODING RNAS; CAENORHABDITIS-ELEGANS; MICRORNA; GENES; ARABIDOPSIS; EXPRESSION; COMPLEX; ANNOTATION; RESOURCES AB During the last decade there has been a great increase in the number of noncoding RNA genes identified, including new classes such as microRNAs and piRNAs. There is also a large growth in the amount of experimental characterization of these RNA components. Despite this growth in information, it is still difficult for researchers to access RNA data, because key data resources for noncoding RNAs have not yet been created. The most pressing omission is the lack of a comprehensive RNA sequence database, much like UniProt, which provides a comprehensive set of protein knowledge. In this article we propose the creation of a new open public resource that we term RNAcentral, which will contain a comprehensive collection of RNA sequences and fill an important gap in the provision of biomedical databases. We envision RNA researchers from all over the world joining a federated RNAcentral network, contributing specialized knowledge and databases. RNAcentral would centralize key data that are currently held across a variety of databases, allowing researchers instant access to a single, unified resource. This resource would facilitate the next generation of RNA research and help drive further discoveries, including those that improve food production and human and animal health. We encourage additional RNA database resources and research groups to join this effort. We aim to obtain international network funding to further this endeavor. C1 [Bateman, Alex; Gardner, Paul P.; Harrow, Jen; Vogel, Jan-Hinnerk] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Agrawal, Shipra] IBAB, Bangalore 560100, Karnataka, India. [Agrawal, Shipra] BioCOS Life Sci Private Ltd, Bangalore 560100, Karnataka, India. [Birney, Ewan; Bruford, Elspeth A.; Cochrane, Guy; Enright, Anton J.; Herrero, Javier; Kersey, Paul; Vilella, Albert J.; Wright, Mathew W.] European Bioinformat Inst, Hinxton CB10 1SD, England. [Bujnicki, Janusz M.] Int Inst Mol & Cell Biol Warsaw, Lab Bioinformat & Prot Engn, PL-02109 Warsaw, Poland. [Bujnicki, Janusz M.] Fac Biol, Inst Mol Biol & Biotechnol, Lab Bioinformat, PL-61614 Poznan, Poland. [Cole, James R.] Michigan State Univ, Ctr Microbial Ecol, E Lansing, MI 48824 USA. [Dinger, Marcel E.] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. [Gautheret, Daniel] Univ Paris 11, UMR CNRS 8621, Inst Genet & Microbiol, F-91405 Orsay, France. [Griffiths-Jones, Sam; Kozomara, Ana] Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England. [Holmes, Ian H.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Huang, Hsien-Da] Natl Chiao Tung Univ, Inst Bioinformat & Syst Biol, Hsinchu 30050, Taiwan. [Kelly, Krystyna A.] Univ Cambridge, Dept Plant Sci, Cambridge CB2 3EA, England. [Lowe, Todd M.] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Marz, Manja] Inst Pharmaceut Chem, RNA Bioinformat Grp, D-35037 Marburg, Germany. [Moxon, Simon] Univ E Anglia, Norwich NR4 7TJ, Norfolk, England. [Pruitt, Kim D.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Samuelsson, Tore] Univ Goteborg, Dept Med Biochem, S-40530 Gothenburg, Sweden. [Stadler, Peter F.] Univ Leipzig, Bioinformat Grp, Dept Comp Sci, D-04009 Leipzig, Germany. [Williams, Kelly P.] Sandia Natl Labs, Livermore, CA 94551 USA. [Zwieb, Christian] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Bateman, A (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SA, England. EM agb@sanger.ac.uk RI Dinger, Marcel/D-4209-2009; Moxon, Simon/A-5385-2010; Wright, Mathew/H-5394-2012; Enright, Anton/F-3094-2011; Vogel, Jan-Hinnerk/C-4582-2013; Griffiths-Jones, Sam/H-2998-2014; Stadler, Peter F./L-7857-2015; OI Herrero, Javier/0000-0001-7313-717X; Bruford, Elspeth/0000-0002-8380-5247; Enright, Anton/0000-0002-6090-3100; Kersey, Paul/0000-0002-7054-800X; Birney, Ewan/0000-0001-8314-8497; Holmes, Ian/0000-0001-7639-5369; Dinger, Marcel/0000-0003-4423-934X; Vilella, Albert/0000-0002-2005-2516; Bateman, Alex/0000-0002-6982-4660; Wright, Mathew/0000-0002-2650-2426; Griffiths-Jones, Sam/0000-0001-6043-807X; Stadler, Peter F./0000-0002-5016-5191; Gardner, Paul/0000-0002-7808-1213; Cochrane, Guy/0000-0001-7954-7057 FU NHGRI NIH HHS [P41 HG003345] NR 50 TC 35 Z9 35 U1 1 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD NOV PY 2011 VL 17 IS 11 BP 1941 EP 1946 DI 10.1261/rna.2750811 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841DJ UT WOS:000296492400001 PM 21940779 ER PT J AU Dickinson, D Goldberg, TE Gold, JM Elvevag, B Weinberger, DR AF Dickinson, Dwight Goldberg, Terry E. Gold, James M. Elvevag, Brita Weinberger, Daniel R. TI Cognitive Factor Structure and Invariance in People With Schizophrenia, Their Unaffected Siblings, and Controls SO SCHIZOPHRENIA BULLETIN LA English DT Article DE cognition; general cognitive ability; factor analysis; structure invariance; data reduction ID NEUROCOGNITIVE DEFICITS; HEALTHY CONTROLS; VALIDITY; BATTERY; TRIAL AB Introduction: Separable, but positively correlated, factors emerge from analyses of cognitive test data in schizophrenia and control samples (eg, verbal memory and processing speed) and these factors guide data reduction. Additionally, data support a hierarchical model of cognitive performance, in which these correlations reflect the influence of a higher-order factor, referred to as "g." We tested these findings in large, carefully screened samples of people with schizophrenia (n = 496), their unaffected siblings (n = 504), and controls (n = 823). Furthermore, we tested the hypothesis that cognitive performance in schizophrenia is more generalized across domains than among siblings and controls. Method: A combination of exploratory and confirmatory factor analyses (EFA and CFA) and multiple groups CFA (MCFA) was used. Results: EFA yielded factors for verbal memory, visual memory, processing speed, working memory span, nback performance, and card sorting. The solution was consistent across groups, in terms of the factor assignments of individual cognitive variables and the magnitude of loadings. Method variance may have contributed to the card sorting, visual memory, and nback factors. CFA indicated that the hierarchical model, incorporating a "g" factor, was a good fit for data from all groups. MCFA suggested that this hierarchical structure was fully invariant for controls and siblings. While the variable/factor loadings for the schizophrenia group also were invariant with comparison groups, factor/"g" loadings were higher in schizophrenia, as were correlations among factor-based composite scores. Conclusions: Cognitive variables sort into domains consistently in schizophrenia, unaffected siblings, and controls. However, performance in schizophrenia is more generalized and less domain specific. C1 [Dickinson, Dwight; Elvevag, Brita; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Gold, James M.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Dickinson, Dwight] VISN 5 Mental Illness Res Educ & Clin Ctr, Baltimore, MD USA. [Goldberg, Terry E.] Zucker Hillside Hosp, Long Isl City, NY USA. RP Dickinson, D (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 3C104,MSC 1379, Bethesda, MD 20892 USA. EM Dwight.Dickinson@nih.gov FU Brief Assessment of Cognition in Schizophrenia test battery; National Institutes of Health, National Institute of Mental Health FX Brief Assessment of Cognition in Schizophrenia test battery (to T. E. G.).; This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. T. E. G. has consulted for Merck, Organon, Pfizer, and Wyeth; and has served as a consultant for Pfizer, Solvay, and AstraZeneca. D. D., B. E., and D. R. W. report no biomedical financial interests or potential conflicts of interest. NR 29 TC 27 Z9 27 U1 5 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD NOV PY 2011 VL 37 IS 6 BP 1157 EP 1167 DI 10.1093/schbul/sbq018 PG 11 WC Psychiatry SC Psychiatry GA 836ZD UT WOS:000296158100012 PM 20351040 ER PT J AU van den Borst, B Koster, A Yu, BB Gosker, HR Meibohm, B Bauer, DC Kritchevsky, SB Liu, YM Newman, AB Harris, TB Schols, AMWJ AF van den Borst, Bram Koster, Annemarie Yu, Binbing Gosker, Harry R. Meibohm, Bernd Bauer, Douglas C. Kritchevsky, Stephen B. Liu, Yongmei Newman, Anne B. Harris, Tamara B. Schols, Annemie M. W. J. CA Hlth ABC Study TI Is age-related decline in lean mass and physical function accelerated by obstructive lung disease or smoking? SO THORAX LA English DT Article ID LOWER-EXTREMITY FUNCTION; PULMONARY-DISEASE; OLDER-ADULTS; SYSTEMIC INFLAMMATION; BODY-COMPOSITION; ELDERLY SUBJECTS; COPD; LIMITATION; MORTALITY; ASSOCIATION AB Background and aims Cross-sectional studies suggest that obstructive lung disease (OLD) and smoking affect lean mass and mobility. A study was undertaken to investigate whether OLD and smoking accelerate the ageing-related decline in lean mass and physical functioning. Methods 260 patients with OLD (mean +/- SD forced expiratory volume in 1 s (FEV(1)) 63 +/- 18% predicted), 157 smoking controls (FEV(1) 95 +/- 16% predicted), 866 former-smoking controls (FEV(1) 100 +/- 16% predicted) and 891 never-smoking controls (FEV(1) 104 +/- 17% predicted) participating in the Health, Aging and Body Composition (ABC) Study were studied. At baseline the mean age was 74 +/- 3 years and participants reported no functional limitations. Baseline and 7-year longitudinal data of body composition (by dual-energy x-ray absorptiometry), muscle strength (by hand and leg dynamometry) and Short Physical Performance Battery (SPPB) were investigated. Results Compared with never-smoking controls, patients with OLD and smoking controls had a significantly lower weight, fat mass, lean mass and bone mineral content (BMC) at baseline (p<0.05). While the loss of weight, fat mass, lean mass and strength was comparable between patients with OLD and never-smoking controls, the SPPB declined 0.12 points/year faster in men with OLD (p=0.01) and BMC declined 4 g/year faster in women with OLD (p=0.02). In smoking controls only lean mass declined 0.1 kg/year faster in women (p=0.03) and BMC 8 g/year faster in men (p=0.02) compared with never-smoking controls. Conclusions Initially well-functioning older adults with mild-to-moderate OLD and smokers without OLD have a comparable compromised baseline profile of body composition and physical functioning, while 7-year longitudinal trajectories are to a large extent comparable to those observed in never-smokers without OLD. This suggests a common insult earlier in life related to smoking. C1 [van den Borst, Bram; Gosker, Harry R.; Schols, Annemie M. W. J.] Maastricht Univ Med Ctr, Dept Resp Med, NUTRIM Sch Nutr Toxicol & Metab, NL-6200 MD Maastricht, Netherlands. [van den Borst, Bram; Koster, Annemarie; Yu, Binbing; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Meibohm, Bernd] Univ Tennessee, Ctr Hlth Sci, Dept Pharmaceut Sci, Memphis, TN 38163 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. RP van den Borst, B (reprint author), Maastricht Univ Med Ctr, Dept Resp Med, NUTRIM Sch Nutr Toxicol & Metab, POB 616, NL-6200 MD Maastricht, Netherlands. EM b.vdborst@maastrichtuniversity.nl RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781; Gosker, Harry/0000-0002-7659-0225 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Heart Lung and Blood Institute [R01-HL-74104]; NIH, National Institute on Aging; Dutch Top Institute Pharma, The Netherlands [T1-201] FX This study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103 and N01-AG-6-2106 and National Heart Lung and Blood Institute grant R01-HL-74104. This research was supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging. This study was performed within the framework of the Dutch Top Institute Pharma project T1-201, The Netherlands. NR 37 TC 40 Z9 41 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD NOV PY 2011 VL 66 IS 11 BP 961 EP 969 DI 10.1136/thoraxjnl-2011-200010 PG 9 WC Respiratory System SC Respiratory System GA 837KG UT WOS:000296199700009 PM 21724748 ER PT J AU Cui, YX Huang, QH Auman, JT Knight, B Jin, XD Blanchard, KT Chou, J Jayadev, S Paules, RS AF Cui, Yuxia Huang, Qihong Auman, James Todd Knight, Brian Jin, Xidong Blanchard, Kerry T. Chou, Jeff Jayadev, Supriya Paules, Richard S. TI Genomic-Derived Markers for Early Detection of Calcineurin Inhibitor Immunosuppressant-Mediated Nephrotoxicity SO TOXICOLOGICAL SCIENCES LA English DT Article DE nephrotoxicity; cyclosporine; FK506 (tacrolimus); rapamycin; gene expression; biomarker; renin-angiotensin system ID CHRONIC CYCLOSPORINE NEPHROTOXICITY; RENIN-ANGIOTENSIN SYSTEM; TRIAL COMPARING TACROLIMUS; EPIDERMAL-GROWTH-FACTOR; BETA-INDUCIBLE GENE-H3; NA+-CL-COTRANSPORTER; MACULA DENSA; SODIUM TRANSPORTERS; DOWN-REGULATION; KIDNEY-DISEASE AB Calcineurin inhibitor (CI) therapy has been associated with chronic nephrotoxicity, which limits its long-term utility for suppression of allograft rejection. In order to understand the mechanisms of the toxicity, we analyzed gene expression changes that underlie the development of CI immunosuppressant-mediated nephrotoxicity in male Sprague-Dawley rats dosed daily with cyclosporine (CsA; 2.5 or 25 mg/kg/day), FK506 (0.6 or 6 mg/kg/day), or rapamycin (1 or 10 mg/kg/day) for 1, 7, 14, or 28 days. A significant increase in blood urea nitrogen was observed in animals treated with CsA (high) or FK506 (high) for 14 and 28 days. Histopathological examination revealed tubular basophilia and mineralization in animals given CsA (high) or FK506 (low and high). We identified a group of genes whose expression in rat kidney is correlated with CI-induced kidney injury. Among these genes are two genes, Slc12a3 and kidney-specific Wnk1 (KS-Wnk1), that are known to be involved in sodium transport in the distal nephrons and could potentially be involved in the mechanism of CI-induced nephrotoxicity. The downregulation of NCC (the Na-Cl cotransporter coded by Slc12a3) in rat kidney following CI treatment was confirmed by immunohistochemical staining, and the downregulation of KS-Wnk1 was confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR). We hypothesize that decreased expression of Slc12a3 and KS-Wnk1 could alter the sodium chloride reabsorption in the distal tubules and contribute to the prolonged activation of the renin-angiotensin system, a demonstrated contributor to the development of CI-induced nephrotoxicity in both animal models and clinical settings. Therefore, if validated as biomarkers in humans, SLC12A3 and KS-WNK1 could potentially be useful in the early detection and reduction of CI-related nephrotoxicity in immunosuppressed transplant patients when monitoring the health of kidney xenographs in clinical practice. C1 [Cui, Yuxia; Auman, James Todd; Paules, Richard S.] NIEHS, Environm Stress & Canc Grp, NIH, Res Triangle Pk, NC 27709 USA. [Huang, Qihong; Knight, Brian; Jin, Xidong; Blanchard, Kerry T.; Jayadev, Supriya] Boehringer Ingelheim Pharma Inc, Ridgefield, CT 06877 USA. [Chou, Jeff] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Paules, RS (reprint author), NIEHS, Environm Stress & Canc Grp, NIH, Mail Drop D2-03,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov FU National Institutes of Health; National Institute of Environmental Health Sciences; Boehringer Ingelheim Pharma., Inc. [CRADA Z01ES023026] FX Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences; Cooperative Research and Development Agreement between National Institute of Environmental Health Sciences and Boehringer Ingelheim Pharma., Inc. (CRADA Z01ES023026). NR 60 TC 5 Z9 6 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2011 VL 124 IS 1 BP 23 EP 34 DI 10.1093/toxsci/kfr217 PG 12 WC Toxicology SC Toxicology GA 836ZZ UT WOS:000296161100002 PM 21865292 ER PT J AU Fielden, MR Adai, A Dunn, RT Olaharski, A Searfoss, G Sina, J Aubrecht, J Boitier, E Nioi, P Auerbach, S Jacobson-Kram, D Raghavan, N Yang, Y Kincaid, A Sherlock, J Chen, SJ Car, B AF Fielden, Mark R. Adai, Alex Dunn, Robert T., II Olaharski, Andrew Searfoss, George Sina, Joe Aubrecht, Jiri Boitier, Eric Nioi, Paul Auerbach, Scott Jacobson-Kram, David Raghavan, Nandini Yang, Yi Kincaid, Andrew Sherlock, Jon Chen, Shen-Jue Car, Bruce CA Predictive Safety Testing Consorti Carcinogenicity Working Grp TI Development and Evaluation of a Genomic Signature for the Prediction and Mechanistic Assessment of Nongenotoxic Hepatocarcinogens in the Rat SO TOXICOLOGICAL SCIENCES LA English DT Article DE nongenotoxic; carcinogenesis; biomarkers; safety evaluation; liver; systems toxicology; toxicogenomics; methods; predictive toxicology; in vitro and alternatives ID CARCINOGENIC RISK-EVALUATION; ENHANCED CELL-PROLIFERATION; RODENT CARCINOGENICITY; IN-VIVO; TUMOR PROMOTION; CHEMICALS; TOXICOGENOMICS; LIVER; PHARMACEUTICALS; GENOTOXICITY AB Evaluating the risk of chemical carcinogenesis has long been a challenge owing to the protracted nature of the pathology and the limited translatability of animal models. Although numerous short-term in vitro and in vivo assays have been developed, they have failed to reliably predict the carcinogenicity of nongenotoxic compounds. Extending upon previous microarray work (Fielden, M. R., Nie, A., McMillian, M., Elangbam, C. S., Trela, B. A., Yang, Y., Dunn, R. T., II, Dragan, Y., Fransson-Stehen, R., Bogdanffy, M., et al. (2008). Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat. Toxicol. Sci. 103, 28-34), we have developed and extensively evaluated a quantitative PCR-based signature to predict the potential for nongenotoxic compounds to induce liver tumors in the rat as a first step in the safety assessment of potential nongenotoxic carcinogens. The training set was derived from liver RNA from rats treated with 72 compounds and used to develop a 22-gene signature on the TaqMan array platform, providing an economical and standardized assay protocol. Independent testing on over 900 diverse samples (66 compounds) confirmed the interlaboratory precision of the assay and its ability to predict known nongenotoxic hepatocarcinogens (NGHCs). When tested under different experimental designs, strains, time points, dose setting criteria, and other preanalytical processes, the signature sensitivity and specificity was estimated to be 67% (95% confidence interval [CI] = 38-88%) and 59% (95% CI = 44-72%), respectively, with an area under the receiver operating characteristic curve of 0.65 (95% CI = 0.46-0.83%). Compounds were best classified using expression data from short-term repeat dose studies; however, the prognostic expression changes appeared to be preserved after longer term treatment. Exploratory evaluations also revealed that different modes of action for nongenotoxic and genotoxic compounds can be discriminated based on the expression of specific genes. These results support a potential early preclinical testing paradigm to catalyze broader understanding of putative NGHCs. C1 [Fielden, Mark R.] Amgen Inc, Comparat Biol & Safety Sci, San Francisco, CA 94080 USA. [Adai, Alex; Kincaid, Andrew] Asuragen, Austin, TX 78744 USA. [Dunn, Robert T., II] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA 91320 USA. [Olaharski, Andrew] Roche, Non Clin Safety, Nutley, NJ 07110 USA. [Searfoss, George] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Sina, Joe] Merck Res Labs, West Point, PA 19486 USA. [Aubrecht, Jiri] Pfizer Inc, Groton, CT 06340 USA. [Boitier, Eric] Sanofi Aventis R&D, Vitry Sur Seine, France. [Nioi, Paul] Schering Plough Res Inst, Summit, NJ 08854 USA. [Auerbach, Scott] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27703 USA. [Jacobson-Kram, David] Food & Drug Adm, Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD 20993 USA. [Yang, Yi] Abbott Labs, Abbott Pk, IL 60064 USA. [Raghavan, Nandini] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ 08869 USA. [Sherlock, Jon] Life Technol, Foster City, CA 94404 USA. [Chen, Shen-Jue; Car, Bruce] Bristol Myers Squibb, Pharmaceut Candidate Optimizat, Princeton, NJ 08540 USA. RP Fielden, MR (reprint author), Amgen Inc, Comparat Biol & Safety Sci, 1120 Vet Blvd, San Francisco, CA 94080 USA. EM mfielden@amgen.com NR 45 TC 31 Z9 32 U1 3 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2011 VL 124 IS 1 BP 54 EP 74 DI 10.1093/toxsci/kfr202 PG 21 WC Toxicology SC Toxicology GA 836ZZ UT WOS:000296161100005 PM 21813463 ER PT J AU Park, TS Rosenberg, SA Morgan, RA AF Park, Tristen S. Rosenberg, Steven A. Morgan, Richard A. TI Treating cancer with genetically engineered T cells SO TRENDS IN BIOTECHNOLOGY LA English DT Review ID TUMOR-INFILTRATING LYMPHOCYTES; ENHANCED ANTITUMOR-ACTIVITY; CHIMERIC ANTIGEN RECEPTOR; VERSUS-HOST-DISEASE; TCR-ALPHA-BETA; GENE-THERAPY; METASTATIC MELANOMA; ADOPTIVE IMMUNOTHERAPY; RETROVIRAL VECTOR; ADVERSE EVENT AB Administration of ex vivo cultured, naturally occurring tumor-infiltrating lymphocytes (TILs) has been shown to mediate durable regression of melanoma tumors. However, the generation of TILs is not possible in all patients and there has been limited success in generating TIL in other cancers. Advances in genetic engineering have overcome these limitations by introducing tumor-antigen-targeting receptors into human T lymphocytes. Physicians can now genetically engineer lymphocytes to express highly active T-cell receptors (TCRs) or chimeric antigen receptors (CARs) targeting a variety of tumor antigens expressed in cancer patients. In this review, we discuss the development of TCR and CAR gene transfer technology and the expansion of these therapies into different cancers with the recent demonstration of the clinical efficacy of these treatments. C1 [Park, Tristen S.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 62 TC 109 Z9 127 U1 4 U2 38 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD NOV PY 2011 VL 29 IS 11 BP 550 EP 557 DI 10.1016/j.tibtech.2011.04.009 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 841AZ UT WOS:000296485700003 PM 21663987 ER PT J AU Kim, JH Adelstein, RS AF Kim, Jong Hyun Adelstein, Robert S. TI LPA(1)-Induced Migration Requires Nonmuscle Myosin II Light Chain Phosphorylation in Breast Cancer Cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID LYSOPHOSPHATIDIC ACID RECEPTOR; PROTEIN-COUPLED RECEPTOR; HEAVY-CHAIN; MOLECULAR-CLONING; BONE METASTASES; DISTINCT ROLES; INVASION; RHO; EXPRESSION; MOTILITY AB The enhanced migration found in tumor cells is often caused by external stimuli and the sequential participation of cytoskeleton-related signaling molecules. However, until now, the molecular connection between the lysophosphatidic acid (LPA) receptor and nonmuscle myosin II (NM II) has not been analyzed in detail for LPA-induced migration. Here, we demonstrate that LPA induces migration by activating the LPA(1) receptor which promotes phosphorylation of the 20 kDa NM II light chain through activation of Rho kinase (ROCK). We show that LPA-induced migration is insensitive to pertussis toxin (PTX) but does require the LPA1 receptor as determined by siRNA and receptor antagonists. LPA activates ROCK and also increases GTP-bound RhoA activity, concomitant with the enhanced membrane recruitment of RhoA. LPA-induced migration and invasion are attenuated by specific inhibitors including C3 cell-permeable transferase and Y-27632. We demonstrate that NM II plays an important role in LPA-induced migration and invasion by inhibiting its cellular function with blebbistatin and shRNA lentivirus directed againstNMII-A or II-B. Inhibition or loss of either NM II-A orNMII-B in 4T1 cells results in a decrease in migration and invasion. Restoration of the expression of NM II-A or NM II-B also rescued LPA-induced migration. Taken together, these results suggest defined pathways for signaling through the LPA 1 receptor to promote LPA-mediated NM II activation and subsequent cell migration in 4T1 breast cancer cells. J. Cell. Physiol. 226: 2881-2893, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Kim, Jong Hyun; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Adelstein, RS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bldg 10,Rm 6C-103B,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. EM adelster@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL004216-17, Z01 HL004218-17, Z01 HL004218-18, ZIA HL004230-14] NR 57 TC 23 Z9 26 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD NOV PY 2011 VL 226 IS 11 BP 2881 EP 2893 DI 10.1002/jcp.22631 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 824XF UT WOS:000295234800017 PM 21302283 ER PT J AU Chang, LW Kagaayi, J Arem, H Nakigozi, G Ssempijja, V Serwadda, D Quinn, TC Gray, RH Bollinger, RC Reynolds, SJ AF Chang, Larry W. Kagaayi, Joseph Arem, Hannah Nakigozi, Gertrude Ssempijja, Victor Serwadda, David Quinn, Thomas C. Gray, Ronald H. Bollinger, Robert C. Reynolds, Steven J. TI Impact of a mHealth Intervention for Peer Health Workers on AIDS Care in Rural Uganda: A Mixed Methods Evaluation of a Cluster-Randomized Trial SO AIDS AND BEHAVIOR LA English DT Article DE mHealth; Community health workers; HIV; Cluster-randomized trial; Mixed methods research ID MOBILE PHONES; ADHERENCE; COUNTRIES; CRISIS AB Mobile phone access in low and middle-income countries is rapidly expanding and offers an opportunity to leverage limited human resources for health. We conducted a mixed methods evaluation of a cluster-randomized trial exploratory substudy on the impact of a mHealth (mobile phone) support intervention used by community-based peer health workers (PHW) on AIDS care in rural Uganda. 29 PHWs at 10 clinics were randomized by clinic to receive the intervention or not. PHWs used phones to call and text higher level providers with patient-specific clinical information. 970 patients cared for by the PHWs were followed over a 26 month period. No significant differences were found in patients' risk of virologic failure. Qualitative analyses found improvements in patient care and logistics and broad support for the mHealth intervention among patients, clinic staff, and PHWs. Key challenges identified included variable patient phone access, privacy concerns, and phone maintenance. C1 [Chang, Larry W.; Quinn, Thomas C.; Bollinger, Robert C.; Reynolds, Steven J.] Johns Hopkins Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21287 USA. [Kagaayi, Joseph; Nakigozi, Gertrude; Ssempijja, Victor; Serwadda, David] Rakai Hlth Sci Program, Rakai, Uganda. [Arem, Hannah; Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Chang, LW (reprint author), Johns Hopkins Sch Med, Dept Med, Div Infect Dis, 1503 E Jefferson St,Room 116, Baltimore, MD 21287 USA. EM larrywillchang@gmail.com RI Emchi, Karma/Q-1952-2016 FU Intramural NIH HHS [ZIA AI000361-29]; NIAID NIH HHS [2T32-AI07291, T32 AI007291]; NICHD NIH HHS [R24 HD042854]; NIMH NIH HHS [1K23MH086338-01A2, K23 MH086338] NR 30 TC 51 Z9 51 U1 2 U2 29 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2011 VL 15 IS 8 BP 1776 EP 1784 DI 10.1007/s10461-011-9995-x PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 831MN UT WOS:000295735200019 PM 21739286 ER PT J AU Breslow, RA Chen, CM Graubard, BI Mukamal, KJ AF Breslow, Rosalind A. Chen, Chiung M. Graubard, Barry I. Mukamal, Kenneth J. TI Prospective Study of Alcohol Consumption Quantity and Frequency and Cancer-Specific Mortality in the US Population SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; cohort studies; diet; food habits; mortality; neoplasms; risk factors ID BREAST-CANCER; PROSPECTIVE COHORT; DRINKING PATTERNS; LUNG-CANCER; RISK; CARCINOGENICITY; BEVERAGES AB Prospective associations between quantity and frequency of alcohol consumption and cancer-specific mortality were studied using a nationally representative sample with pooled data from the 1988, 1990, 1991, and 1997-2004 administrations of the National Health Interview Survey (n = 323,354). By 2006, 8,362 participants had died of cancer. Cox proportional hazards regression was used to estimate relative risks. Among current alcohol drinkers, for all-site cancer mortality, higher-quantity drinking (>= 3 drinks on drinking days vs. 1 drink on drinking days) was associated with increased risk among men (relative risk (RR) = 1.24, 95% confidence interval (CI): 1.09, 1.41; P for linear trend = 0.001); higher-frequency drinking (>= 3 days/week vs. < 1 day/week) was associated with increased risk among women (RR = 1.32, 95% CI: 1.13, 1.55; P-trend < 0.001). Lung cancer mortality results were similar, but among never smokers, results were null. For colorectal cancer mortality, higher-quantity drinking was associated with increased risk among women (RR = 1.93, 95% CI: 1.17, 3.18; P-trend = 0.03). Higher-frequency drinking was associated with increased risk of prostate cancer (RR = 1.55, 95% CI: 1.01, 2.38; P for quadratic effect = 0.03) and tended to be associated with increased risk of breast cancer (RR = 1.44, 95% CI: 0.96, 2.17; P-trend = 0.06). Epidemiologic studies of alcohol and cancer mortality should consider the independent effects of quantity and frequency. C1 [Breslow, Rosalind A.] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. [Chen, Chiung M.] CSR Inc, Arlington, VA USA. [Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. RP Breslow, RA (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2071, Bethesda, MD 20892 USA. EM rbreslow@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism [HHSN267200800023C] FX Computer programming and statistical support were provided through the Alcohol Epidemiologic Data System, which is funded by contract HHSN267200800023C from the National Institute on Alcohol Abuse and Alcoholism. NR 22 TC 22 Z9 22 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 1 PY 2011 VL 174 IS 9 BP 1044 EP 1053 DI 10.1093/aje/kwr210 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 836EW UT WOS:000296093800007 PM 21965184 ER PT J AU Wilcox, AJ Weinberg, CR Basso, O AF Wilcox, Allen J. Weinberg, Clarice R. Basso, Olga TI On the Pitfalls of Adjusting for Gestational Age at Birth SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adjustment; collider; directed acyclic graph; gestational age; infant mortality; mediating variable; premature birth; stratification ID PRETERM BIRTH; CEREBRAL-PALSY; PERINATAL EPIDEMIOLOGY; MORTALITY CURVES; INFANT-MORTALITY; LUNG MATURATION; CAUSAL DIAGRAMS; WEIGHT; RISK; PREGNANCY AB Preterm delivery is a powerful predictor of newborn morbidity and mortality. Such problems are due to not only immaturity but also the pathologic factors (such as infection) that cause early delivery. The understanding of these underlying pathologic factors is incomplete at best. To the extent that unmeasured pathologies triggering preterm delivery also directly harm the fetus, they will confound the association of early delivery with neonatal outcomes. This, in turn, complicates studies of newborn outcomes more generally. When investigators analyze the association of risk factors with neonatal outcomes, adjustment for gestational age as a mediating variable will lead to bias. In the language of directed acyclic graphs, gestational age is a collider. The theoretical basis for colliders has been well described, and gestational age has recently been acknowledged as a possible collider. However, the impact of this problem, as well as its implications for perinatal research, has not been fully appreciated. The authors discuss the evidence for confounding and present simulations to explore how much bias is produced by adjustments for gestational age when estimating direct effects. Under plausible conditions, frank reversal of exposure-outcome associations can occur. When the purpose is causal inference, there are few settings in which adjustment for gestational age can be justified. C1 [Wilcox, Allen J.] NIEHS, Epidemiol Branch, Durham, NC 27709 USA. [Weinberg, Clarice R.] NIEHS, Biostat Branch, Durham, NC 27709 USA. [Basso, Olga] McGill Univ, Dept Obstet & Gynecol, Montreal, PQ H3A 2T5, Canada. [Basso, Olga] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3A 2T5, Canada. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch MD A3 05, POB 12233, Durham, NC 27709 USA. EM wilcox@niehs.nih.gov RI Basso, Olga/E-5384-2010; OI Basso, Olga/0000-0001-9298-4921; Wilcox, Allen/0000-0002-3376-1311 FU National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 43 TC 95 Z9 95 U1 2 U2 18 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 NOV 1 PY 2011 VL 174 IS 9 BP 1062 EP 1068 DI 10.1093/aje/kwr230 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 836EW UT WOS:000296093800009 PM 21946386 ER PT J AU Jones, NL AF Jones, Nancy L. TI Raising Scientific Experts SO AMERICAN SCIENTIST LA English DT Article ID ETHICS C1 NIAID, Bethesda, MD 20892 USA. RP Jones, NL (reprint author), NIAID, Bldg 31,Room 7A46, Bethesda, MD 20892 USA. EM jonesna@niaid.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 5 PU SIGMA XI-SCI RES SOC PI RES TRIANGLE PK PA PO BOX 13975, RES TRIANGLE PK, NC 27709 USA SN 0003-0996 J9 AM SCI JI Am. Scientist PD NOV-DEC PY 2011 VL 99 IS 6 BP 458 EP 461 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834WB UT WOS:000295994100016 ER PT J AU Jiang, HH Kim, TH Lee, S Chen, XY Youn, YS Lee, KC AF Jiang, Hai Hua Kim, Tae Hyung Lee, Seulki Chen, Xiaoyuan Youn, Yu Seok Lee, Kang Choon TI PEGylated TNF-related apoptosis-inducing ligand (TRAIL) for effective tumor combination therapy SO BIOMATERIALS LA English DT Article DE PEG-TRAIL; Doxorubicin; Sequential delivery; Microspheres; Combination therapy ID CANCER-CELLS; IN-VIVO; ANTITUMOR-ACTIVITY; ANTICANCER DRUG; DOXORUBICIN; DEATH; RECEPTORS; PRETREATMENT; MICROSPHERES; RESISTANCE AB Although PEGylated TNF-related apoptosis-inducing ligand (PEG-TRAIL) has good tumor cell specificity and stability, its therapeutic potential is restricted by the development of tumor cell resistance. The purpose of this study was to develop an effective combination therapy with sustained biological activity based on microspheres. Doxorubicin (DOX), PEG-TRAIL, and DOX plus PEG-TRAIL (dual agent) were microencapsulated into poly (lactic-co-glycolic acid) (PLGA) microspheres using a double-emulsion solvent extraction method. Prepared dual agent microspheres showed the encapsulation efficiency 69.4 +/- 2.3 for DOX and 87.7 +/- 2.9% for PEG-TRAIL Potential anti-tumor efficacy of this system was investigated in vitro and in vivo in a human colon cancer (HCT116) and in a human prostate cancer (PC-3). DOX and PEG-TRAIL release from dual agent microspheres were biologically active and significantly inhibited the TRAIL-sensitive HCT116 and resistant PC-3 cells in vitro. Dual agent microspheres simultaneous delivery of DOX and PEG-TRAIL was superior to all other DOX or PEG-TRAIL microspheres in vivo. A single local injection of PLGA microspheres loaded with low amounts of DOX, PEG-TRAIL or dual agent resulted in 14.8, 30.2, and 63.6% reductions in HCT116 tumor volume and 20.4, 14.2, and 67.7% reductions in PC-3 tumor volume at 35 days. Our findings show that dual agent microspheres offer a promising means of delivering DOX and PEG-TRAIL to tumor sites. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Jiang, Hai Hua; Kim, Tae Hyung; Youn, Yu Seok; Lee, Kang Choon] Sungkyunkwan Univ, Coll Pharm, Drug Targeting Lab, Suwon 440746, South Korea. [Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Lee, KC (reprint author), Sungkyunkwan Univ, Coll Pharm, Drug Targeting Lab, 300 Chonchon Dong, Suwon 440746, South Korea. EM kclee@skku.edu FU Korean Ministry of Education, Science, and Technology [2010K001256] FX This work was supported by a grant from the Korean Ministry of Education, Science, and Technology (Grant No. 2010K001256). NR 38 TC 27 Z9 27 U1 3 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD NOV PY 2011 VL 32 IS 33 BP 8529 EP 8537 DI 10.1016/j.biomaterials.2011.07.051 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 833CF UT WOS:000295858700019 PM 21855130 ER PT J AU Walsh, MJ Brimacombe, KR Veith, H Bougie, JM Daniel, T Leister, W Cantley, LC Israelsen, WJ Vander Heiden, MG Shen, M Auld, DS Thomas, CJ Boxer, MB AF Walsh, Martin J. Brimacombe, Kyle R. Veith, Henrike Bougie, James M. Daniel, Thomas Leister, William Cantley, Lewis C. Israelsen, William J. Vander Heiden, Matthew G. Shen, Min Auld, Douglas S. Thomas, Craig J. Boxer, Matthew B. TI 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE PKM2; Pyruvate kinase; Cellular metabolism; Anti-cancer strategies; Small molecule activators ID GENE; RAT; ISOZYMES; GROWTH; SYSTEM AB Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. Published by Elsevier Ltd. C1 [Walsh, Martin J.; Brimacombe, Kyle R.; Veith, Henrike; Bougie, James M.; Daniel, Thomas; Leister, William; Shen, Min; Auld, Douglas S.; Thomas, Craig J.; Boxer, Matthew B.] NHGRI, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, NIH, Rockville, MD 20850 USA. [Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. [Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Israelsen, William J.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Boxer, MB (reprint author), NHGRI, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, NIH, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM boxerm@mail.nih.gov RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research; National Human Genome Research Institute, National Institutes of Health FX We thank Paul Shinn, Danielle VanLeer and Christopher LeClair for assistance with compound management. This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 17 TC 29 Z9 30 U1 0 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 1 PY 2011 VL 21 IS 21 BP 6322 EP 6327 DI 10.1016/j.bmcl.2011.08.114 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 835HA UT WOS:000296025900021 PM 21958545 ER PT J AU Gan, L Miller, FW AF Gan, Lu Miller, Frederick W. TI State of the art: what we know about infectious agents and myositis SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE idiopathic inflammatory myopathy; infection; infectious myopathy; pathogenesis ID INCLUSION-BODY MYOSITIS; IDIOPATHIC INFLAMMATORY MYOPATHIES; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; BARR-VIRUS INFECTION; JUVENILE DERMATOMYOSITIS; PARVOVIRUS B19; PRESENTING MANIFESTATION; ENVIRONMENTAL-FACTORS; RHEUMATOID-ARTHRITIS; EXPERIMENTAL-MODEL AB Purpose of review Increasing evidence suggests that the idiopathic inflammatory myopathies (IIMs) result from certain environmental exposures in genetically susceptible individuals. Investigations have demonstrated that a variety of infections not only cause infectious myopathies but also could be possible triggers for IIM. This review summarizes published studies on the possible roles of infections in inflammatory muscle disease. Recent findings Many infectious agents have been linked to the development of IIMs via case reports, epidemiologic investigations, and animal models. Additional agents possibly involved in triggering the development of IMMs have been recently described, including Torque teno virus (TTV) and Borrelia burgdorferi. Novel animal models of myositis have been recently developed using Leishmania infantum or Chikungunya virus (CHIKV). New technologies to assess infectious agents include high-throughput methods for pathogen identification and novel approaches to identify gene expression of pathogens in tissues. Summary Understanding the causes of IIMs remains limited in part due to the rarity and heterogeneity of these disorders. Although no definitive studies have yet linked infectious agents with IIMs, additional evidence is accumulating and novel technologies may allow improved understanding of the roles of infections in IIMs and for possible future therapeutic and preventive measures. C1 [Miller, Frederick W.] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Program Clin Res, Natl Inst Hlth Clin Res Ctr,NIH, Bethesda, MD 20892 USA. RP Miller, FW (reprint author), Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Program Clin Res, Natl Inst Hlth Clin Res Ctr,NIH, 10,Room 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov RI Gan, Lu/L-5395-2014; OI Miller, Frederick/0000-0003-2831-9593 FU National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported by the intramural program of the National Institute of Environmental Health Sciences, National Institutes of Health. We thank Drs Lisa Rider, Terrance O'Hanlon, and Irene Whitt for helpful discussions and Drs Kathleen Coyle and Ejaz Shamim for their useful comments on the manuscript. NR 91 TC 8 Z9 9 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD NOV PY 2011 VL 23 IS 6 BP 585 EP 594 DI 10.1097/BOR.0b013e32834b5457 PG 10 WC Rheumatology SC Rheumatology GA 835IQ UT WOS:000296030400012 PM 21885972 ER PT J AU Dalal, M Sun, K Cappola, AR Ferrucci, L Crasto, C Fried, LP Semba, RD AF Dalal, Mansi Sun, Kai Cappola, Anne R. Ferrucci, Luigi Crasto, Candace Fried, Linda P. Semba, Richard D. TI Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; PARATHYROID-HORMONE; MINERAL METABOLISM; MAINTENANCE HEMODIALYSIS; ARTERY CALCIUM; FGF RECEPTOR; PLASMA; PHOSPHORUS AB Objective: Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of this study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women. Design and methods: A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70-79 years, who participated in the Women's Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, and peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication. Results: Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/ml. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6, 24.9, and 36.7% respectively (P=0.002). Serum log FGF23 was associated with cardiovascular disease (odds ratio per 1 S. D. increase=1.23, 95% confidence interval 1.17, 1.30; P<0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, high-density lipoprotein cholesterol, and renal function. Conclusion: Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease. C1 [Dalal, Mansi; Sun, Kai; Crasto, Candace; Semba, Richard D.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21225 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, M015,Smith Bldg,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu FU National Institute on Aging [R01 AG027012, R01 HL094507, R37 AG019905]; OPD-GCRC grant [RR00722]; NIA [N01-AG12112]; Johns Hopkins Older Americans' Independence Center; National Institute on Aging, NIH FX This work was supported by National Institute on Aging Grants R01 AG027012 and R01 HL094507, R37 AG019905, OPD-GCRC grant RR00722 and NIA Contract N01-AG12112, the Johns Hopkins Older Americans' Independence Center, and the Intramural Research Program, National Institute on Aging, NIH. NR 35 TC 27 Z9 27 U1 0 U2 4 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD NOV PY 2011 VL 165 IS 5 BP 797 EP 803 DI 10.1530/EJE-11-0577 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 836BN UT WOS:000296082100014 PM 21873490 ER PT J AU Li, S Tomic, M Stojilkovic, SS AF Li, Shuo Tomic, Melanija Stojilkovic, Stanko S. TI Characterization of novel Pannexin 1 isoforms from rat pituitary cells and their association with ATP-gated P2X channels SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE Pannexins; Purinergic P2X receptors; ATP release; Anterior pituitary; AtT-20 cells ID GAP-JUNCTION PROTEINS; PERMEATION PORE INHIBITION; INTERLEUKIN-1-BETA RELEASE; CONNEXIN FAMILY; RECEPTOR; HEMICHANNELS; ACTIVATION; COMMUNICATION; EXPRESSION; NEURONS AB Our previous studies have showed that Pannexin 1 (Panx1), a member of a recently discovered family of gap junction proteins, is expressed in the pituitary gland. Here we investigated the presence and expression pattern of Panx1 isoforms in pituitary cells, their roles in ATP release, and their association with purinergic P2X receptor subtypes that are native to pituitary cells. In addition to the full-size Panx1, termed Panx1a, pituitary cells also express two novel shorter isoforms, termed Panx1c and Panx1d, which formation reflects the existence of alternative splicing sites in exons 2 and 4, respectively. Panx1c is lacking the Phe108-Gln180 sequence and P2X1d is missing the Val307-Cys426 C-terminal end sequence. Confocal microscopy and biotin labeling revealed that Panx1 a is expressed in the plasma membrane, whereas Panx1c and Panx1d show the cytoplasmic localization when expressed as homomeric proteins. The three Panx1 isoforms and Panx2 form homomeric and heteromeric complexes in any combination. These splice forms can also physically associate with ATP-gated P2X2, P2X3, P2X4, and P2X7 receptor channels. The Panx1a-mediated ATP release in AtT-20 immortalized pituitary cells is attenuated when co-expressed with Panx1 c or Panx1 d. These results suggest that Panx1c and Panx1d may serve as dominant-negative effectors to modulate the functions of Panx1a through formation of heteromeric channels. The complex patterns of Panx1 expression and association could also define the P2X-dependent roles of these channels in cell types co-expressing both proteins. Published by Elsevier Inc. C1 [Li, Shuo; Tomic, Melanija; Stojilkovic, Stanko S.] NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Li, S (reprint author), NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM lishuo@mail.nih.gov RI Tomic, Melanija/C-3371-2016 FU NICHD, NIH FX This work was supported by the Intramural Research Program of the NICHD, NIH. Confocal microscopy was performed at the Microscopy and Imaging Core Facility (NICHD, NIH) with the assistance of Dr. Vincent Schram. NR 33 TC 27 Z9 28 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0016-6480 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD NOV 1 PY 2011 VL 174 IS 2 BP 202 EP 210 DI 10.1016/j.ygcen.2011.08.019 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 837QJ UT WOS:000296218000016 PM 21907716 ER PT J AU Beverley, SM Guo, HJ Novozhilova, N Hickerson, S Elnaiem, DE Sacks, D Turco, SJ AF Beverley, Stephen M. Guo, Hongjie Novozhilova, Natalia Hickerson, Suzanne Elnaiem, Dia-Eldin Sacks, David Turco, Salvatore J. TI The Synthesis and Role of Modified Glycoconjugates Comprising the Surface Glycocalyx in the Infectivity of the Protozoan Parasite Leishmania major SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Beverley, Stephen M.; Guo, Hongjie; Hickerson, Suzanne] Washington Univ Sch Med, St Louis, MO USA. [Novozhilova, Natalia; Turco, Salvatore J.] Univ Kentucky Med Ctr, Lexington, KY USA. [Elnaiem, Dia-Eldin; Sacks, David] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 31 BP 1462 EP 1462 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300034 ER PT J AU Ghirlanda, G Woodrum, B Ruben, M O'Keefe, B AF Ghirlanda, Giovanna Woodrum, Brian Ruben, Melissa O'Keefe, Barry TI Exploiting Multivalency: A Designed Dimer of CV-N Shows Improved anti-HIV Activity SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 09-12, 2011 CL Seattle, WA SP Soc Glycobiol C1 [Ghirlanda, Giovanna; Woodrum, Brian; Ruben, Melissa] Arizona State Univ, Tempe, AZ USA. [O'Keefe, Barry] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2011 VL 21 IS 11 MA 96 BP 1481 EP 1482 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 835OI UT WOS:000296045300095 ER EF